Virtual Library

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Background
Crizotinib is approved multinationally to treat advanced ALK-positive non-small-cell lung cancer (NSCLC). Most patients with crizotinib-treated ALK-positive NSCLC ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition beyond PD is clinically beneficial and the clinicopathologic characteristics associated with patients who experience clinical benefit.

Methods
Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials (the molecularly enriched expansion cohort of the phase I trial PROFILE 1001 and the phase II trial PROFILE 1005) who developed RECIST-defined PD were allowed to continue crizotinib if, in the investigator's opinion, they were deriving ongoing clinical benefit. In the present retrospective analyses, continuation of crizotinib beyond PD (CBPD) was defined as >3 weeks of crizotinib treatment after PD documentation. Baseline and post-progression characteristics, sites of PD, progression-free survival (PFS), and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed.

Results
Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A higher proportion of patients who continued CBPD responded to initial crizotinib treatment (74% vs. 55%), had an ECOG performance status of 0/1 at PD (96% vs. 82%), and had brain (56% vs. 28%) and/or bone (20% vs. 9%) as sites of PD compared with patients who did not continue CBPD. CBPD patients also had numerically longer median PFS from initial crizotinib treatment (7.3 months vs. 5.7 months) and significantly longer OS from the time of PD (median 16.4 months vs. 3.9 months; HR, 0.27; 95% CI: 0.17−0.42; P<0.0001; Figure 1). Multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS post-PD after adjusting for relevant factors. Figure 1. OS of patients who continued CBPD versus those who did not, from the time of PD. Shaded areas are 95% Hall-Wellner confidence bands. Figure 1

Conclusion
Continuing ALK inhibition after PD may provide survival benefit to a majority of patients with advanced ALK-positive NSCLC. Prolonged PFS on initial crizotinib, good performance status at PD, and progression in brain and/or bone are characteristics that were commonly found in patients who benefited from continued ALK inhibition.

Background
Crizotinib is an oral tyrosine kinase inhibitor targeting ALK and is approved multinationally for the treatment of advanced ALK-rearranged non-small cell lung cancer (NSCLC) due to its efficacy in controlling systemic tumor burden. The clinical effects of crizotinib in patients with brain metastases have not been previously studied in detail. To evaluate the clinical outcomes of patients with brain metastases on crizotinib, we conducted a retrospective analysis of pooled data from PROFILE 1005 (NCT00932451; a large ongoing global open-label, single-arm phase II study of crizotinib in patients with ALK-rearranged NSCLC who have received one or more treatment regimen for advanced/metastatic disease) and PROFILE 1007 (NCT00932893; an ongoing global randomized phase III study that compared crizotinib with standard second-line chemotherapy [docetaxel or pemetrexed] for advanced ALK-rearranged NSCLC; Shaw et al, N Engl J Med 2013). Subgroup analysis in PROFILE1007 showed that progression-free survival was longer with crizotinib than with chemotherapy for both patients with brain metastases (HR 0.67) and patients without brain metastases (HR 0.43) at baseline.

Methods
Patients with previously treated (but ALK-inhibitor-naïve) advanced ALK-rearranged NSCLC enrolled in either PROFILE 1005 or PROFILE 1007 (and randomized to crizotinib) were included in this analysis. Patients with asymptomatic brain metastases were eligible for both studies. The starting dose of crizotinib was 250 mg twice daily. Tumor assessments were evaluated by investigators based on RECIST. Baseline brain imaging (with either computed tomography or magnetic resonance imaging) was required in both studies, and if brain metastases were detected, subsequent brain imaging was required at 6-week intervals. Otherwise, imaging to assess brain metastases on treatment was performed as clinically indicated. Brain metastases were monitored as non-target or target lesions.

Results
A total of 275 patients, 31% of 888 patients included in this retrospective analysis, had asymptomatic brain metastases at baseline. Of the 888 patients included, 109 patients (12%) had no prior radiotherapy and 166 patients (19%) had prior radiotherapy for their brain metastases. Among the 109 patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR; % complete responses + partial responses + stable disease) at 12 weeks was 63%, with a systemic objective response rate (ORR) of 53%, and the intracranial DCR at 12 weeks was 56%, with an intracranial ORR of 7%. Among the 166 patients with previously treated brain metastases, the systemic DCR at 12 weeks was 65%, with a systemic ORR of 46%, and the intracranial DCR at 12 weeks was 62% weeks, with an intracranial ORR of 7%. Additional data, including outcomes for patients without brain metastases at baseline, will be presented.

Conclusion
In this large retrospective analysis, crizotinib was associated with an initial intracranial DCR of approximately 60% at 12 weeks in patients who were ALK-inhibitor-naïve and had untreated or previously treated brain metastases identified prior to initiation of therapy. Prospective studies may help to determine if crizotinib can delay the natural occurrence or progression of brain metastases in advanced ALK-positive NSCLC.

Background
Rearrangements of the ROS1 receptor tyrosine kinase gene identify a subset of NSCLC sensitive to the small-molecule ALK and MET inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Here we present updated efficacy and safety data for crizotinib in an expanded cohort of patients with advanced ROS1-rearranged NSCLC.

Methods
ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase I crizotinib study (PROFILE 1001; NCT00585195, Pfizer). Where available, samples were also tested for concurrent ALK rearrangement and MET amplification. Patients received crizotinib 250 mg BID, and responses were assessed using RECIST v1.0.

Results
At the data cut-off, 35 of 40 patients with ROS1-positive NSCLC were evaluable for response. Median age was 51 years (range 31–77), 80% of patients were never-smokers, and 98% had adenocarcinoma histology; 40% had received one prior regimen, and 45% had received 2–6 regimens for advanced/metastatic disease. 25 samples tested for concurrent ALK rearrangement (24 by FISH and 1 by PCR) and 12 samples tested for concurrent MET amplification (11 by FISH and 1 method not recorded) were all negative. The objective response rate (ORR) was 60% (95% CI: 42–76), with 2 complete responses, 19 partial responses, and 10 cases of stable disease. Median progression-free survival (PFS) had not been reached, with 25 patients (63%) still in follow-up for PFS; six patients (15%) experienced disease progression, and two (5%) died before progression occurred; 6-month PFS probability was 76% (95% CI: 55–88). The disease-control rate was 80% at 8 weeks and 66% at 16 weeks. The most common treatment-related adverse events (AEs) were visual impairment (80%), diarrhea (35%), and nausea (30%), with most patients (68%) reporting only AEs of grade 1 or 2 severity. Peripheral edema (28%) and elevated transaminases (18% AST, 15% ALT) were also reported, similar to previous experience with crizotinib. There were no treatment-related serious AEs and one patient discontinued treatment due to treatment-related nausea. Accrual of patients with ROS1-positive NSCLC is ongoing.

Conclusion
Similar to results obtained in ALK-positive NSCLC, crizotinib had marked antitumor activity with a high ORR (60%) in patients with ROS1-positive NSCLC, with a generally tolerable and manageable AE profile. These data suggest that crizotinib is an effective therapy for patients with advanced ROS1-positive NSCLC.

Background
XALKORI[Ò] (crizotinib) is a selective small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) and its oncogenic variants (ie, ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the hepatocyte growth factor receptor (HGFR, c-Met), c-ros oncogene 1 (ROS1), and Recepteur d’Origine Nantais (RON) RTKs. Clinical studies were conducted globally to determine the maximum tolerated dose, pharmacokinetics, antitumor efficacy and safety of crizotinib in patients with ALK-positive NSCLC and other tumors sensitive to crizotinib. The major objectives of this analysis were (1) to develop a population PK model that describes crizotinib plasma PK using pooled PK data across studies in cancer patients;.and (2) to identify potential covariates which may account for the inter-individual variability in crizotinib PK.

Methods
Population pharmacokinetic models were developed from a dataset comprised of 8,973 pharmacokinetic samples from 1,214 cancer patients receiving crizotinib at a starting dose of 250 mg BID in Phase I, II, and III trials. The effects of pre-defined covariates pertaining to demographic characteristics, baseline renal (creatinine clearance) and hepatic function (AST, albumin, and total bilirubin) on the pharmacokinetics of crizotinib were tested in the models.

Results
The study population consisted of 533 males (44%) and 681 females (56%). The patients were characterized by a wide range of body weights (33 to 160 kg) and ages (19 to 83 years). There were 189 (15.6%) elderly patients (over 65 years). The majority of patients in the analysis were White (52.8%) and Asian (43.1%), followed by Black (1.8%), Hispanic (1.2%), and Other (1%). Crizotinib PK was characterized by a two-compartment model with first-order absorption and a time-dependent decrease in apparent (oral) clearance (CL/F) from baseline following multiple 250 mg BID dosing. The interindividual variability was moderate, with 40% for CL/F and 52% for the apparent central volume of distribution (V2/F), respectively. The typical PK parameters for a 65 kg non-Asian male cancer patient with baseline creatinine clearance 91.6 mL/min and total bilirubin 0.41 mg/dL were 136 L/hr, 76 L/hr, 3,520 L, and 0.73 hr-1 for the CL/F after the first dose, CL/F at steady state, V2/F, and absorption rate constant (Ka), respectively. Age, AST, albumin, smoking, or ECOG performance status were not significant covariates for crizotinib CL/F (P>0.001). Asian race, gender, body weight, creatinine clearance, and total bilirubin described a portion of the variability in CL/F, and Asian race and gender also explained some of variability in V2/F. Asian race had the greatest effect on crizotinib exposure, with a 97% probability that a typical area under the plasma drug concentration-time curve at steady state (AUCss) in an Asian patient would be >25% higher than a typical AUCss value in a Non-Asian patient. None of the other covariates investigated were found to markedly affect the systemic exposure of crizotinib.

Conclusion
There was moderate inter-patient variability in crizotinib disposition. No starting dose adjustments of crizotinib 250 mg BID are recommended based on age, gender, body weight, or race.

Abstract not provided

Background
AP26113 is a novel tyrosine kinase inhibitor (TKI) that exhibits pan-ALK inhibitory activity against all 9 clinically-identified crizotinib-resistant mutants, including the L1196M gatekeeper, in preclinical experiments. AP26113 also inhibits ROS1 and selectively inhibits mutant EGFR (EGFRm) in preclinical experiments, including the T790M resistance mutation, without affecting the native receptor.

Methods
We report data from the dose finding component (3+3 design) of a phase 1/2 open-label, multicenter study in patients with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Dosing was once daily (QD) or twice daily.

Results
As of 17 April 2013, 55 patients were enrolled: 30mg (daily dose) n=3, 60mg n=3, 90mg n=8, 120 mg n=15, 180mg n=15, 240mg n=9, 300mg n=2; 62% female, median age 58 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=47), other (n=8). 33 patients discontinued: 22 disease progression, 6 adverse event (AE), 4 deaths (2 possibly related: sudden death, hypoxia), 1 withdrawal by subject. The most common AEs included fatigue (40%), nausea (36%), and diarrhea (33%), which were generally grade 1/2 in severity. The most common grade 3/4 AE was pneumonia (5%). Two patients experienced dose limiting toxicities: grade 3 ALT increase in 1 patient (240mg QD); grade 4 dyspnea and grade 3 hypoxia in 1 patient (300mg QD). Twenty-eight patients had ALK+ history (24 NSCLC, 4 other). Among 24 evaluable ALK+ patients, 15 responded. Responses were observed in 2/4 (50%) ALK+ TKI-naïve patients and 13/17 (76%) ALK+ patients with prior crizotinib therapy and no other ALK inhibitor exposure. Among ALK+ NSCLC patients with prior crizotinib only, 12/16 (75%) responded. The longest response is 40+ weeks (ongoing). 4 of 5 ALK+ patients with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 patient resistant to crizotinib and LDK378 (overall response = stable disease). CNS lesion improvements in all 4 patients are ongoing, with durations ranging from 15+ to 28+ weeks. Twenty patients had EGFRm history (19 NSCLC, 1 SCLC); 18 had ≥1 prior EGFR TKI. Of 18 evaluable EGFRm patients, 1 patient (prior erlotinib) responded at 120mg QD (duration 26+ weeks, ongoing), 7 patients had stable disease, including 4 with T790M by history (1 ongoing at 240mg QD, duration 16+ weeks). The maximum tolerated dose has not been defined; however, based on safety, efficacy, and pharmacokinetics, the recommended phase 2 dose (RP2D) is 180mg QD. Updated data will be presented.

Conclusion
AP26113 has promising anti-tumor activity in patients with ALK+ NSCLC and other ALK+ tumors, with initial evidence of activity in EGFRm patients, and is generally well tolerated. Five phase 2 cohorts are enrolling at the RP2D (180mg QD): 1) ALK inhibitor-naïve ALK+ NSCLC, 2) crizotinib-resistant ALK+ NSCLC, 3) single EGFR TKI-resistant NSCLC with documented T790M, 4) other tumors with AP26113 targets, 5) crizotinib-naïve or –resistant ALK+ NSCLC with active CNS metastases. Further phase 1 testing at 240mg QD will occur in EGFRm patients with documented T790M. NCT01449461

Background
EGFR T790M mutation and MET amplification have been implicated as mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in advanced NSCLC. We evaluated the feasibility of combining dacomitinib and crizotinib to overcome acquired resistance in patients with NSCLC whose last prior treatment was either single-agent erlotinib or gefitinib. Dacomitinib is an orally bioavailable, irreversible, small-molecule inhibitor of all kinase-active HER-family tyrosine kinases (EGFR/HER1, HER2, and HER4) with in vitro activity against T790M-mutated EGFR. Crizotinib is an ALK, ROS1, and MET TKI with demonstrated efficacy in the treatment of advanced ALK-positive and ROS1-positive NSCLC and several MET-amplified tumor types. Here we update previous data reported for PROFILE 1006 (Jänne et al, ESMO 2012; Pfizer, NCT01121575).

Methods
The study comprised a 3+3 design dose-escalation phase followed by an expansion phase of two concurrent cohorts: A) combined dacomitinib plus crizotinib and B) single-agent dacomitinib until progression, followed by combined dacomitinib plus crizotinib. The study enrolled patients with advanced NSCLC who had progressed after ≥1 line of chemotherapy/targeted therapy. The expansion phase was restricted to patients with acquired resistance to single-agent erlotinib or gefitinib, which was defined as PD following either a response or SD for 6 months. Patients in the expansion phase had a mandatory tumor biopsy for biomarker analysis at study entry. Endpoints included safety, best overall objective response rate (ORR), progression-free survival, and biomarkers in tumor and blood that are potentially predictive of antitumor activity.

Results
33 patients were enrolled in the dose-escalation phase of the study. Dose-limiting toxicities (DLTs) were the following grade 3 events: diarrhea (n=1), elevated ALT (n=1), and mucositis (n=1). The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination showed no DLTs in 10 evaluable patients and was taken forward into the expansion phase. At the time of data cut-off on 31 December 2012, 27 patients had enrolled in the expansion phase (23 in cohort A and 4 in cohort B). Patient characteristics were as follows: M/F, 11/16; median age, 60 years (range 42–82); ECOG PS 0/1/2, 4/19/4; Caucasian/Asian, 22/5; never-smokers/ex-smokers/smokers, 18/7/2; number of prior systemic therapies 1/2/3/>3, 9/8/3/6. Nine patients (33%) in the expansion phase had started ≥4 cycles (approximately 12 weeks) of the combination. There were 20 evaluable patients in expansion cohort A, with an ORR of 5%. A further 8 patients (40%) experienced SD, and 1 of these patients had an unconfirmed PR. Tumor samples were available for biomarker analyses from 18 patients in expansion cohort A. Analyses to date revealed 1/17 patient samples had MET amplification (MET:CEP7 ratio >2); 1/5 had EGFR amplification; 7/12 harbored the EGFR T790M mutation; 1/11 displayed a KRAS mutation; 18/18 were negative for ALK rearrangement by FISH.

Conclusion
The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination was administered with a manageable tolerability profile and was associated with clinical activity in patients with EGFR TKI-resistant advanced NSCLC. Analysis of predictive tumor biomarkers is underway in all patients in the expansion phase.

Background
To determine the frequency and predictive impact of ROS1-rearrangements on treatment outcomes in never-smoker patients with lung adenocarcinoma.

Methods
We concurrently analyzed ROS1- and ALK- rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never-smokers with lung adenocarcinoma. ROS1- and ALK- rearrangements were identified by fluorescent in situ hybridization.

Results
Of 208 tumors screened, seven (3.4%) were ROS1-rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase polymerase chain reaction. The frequency of ROS1-rearrangement was 5.7% (6/105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1-rearrangement had a higher objective response rate (ORR; 60.0 vs. 8.5%; P=0.01) and a longer median progression-free survival (PFS; not reached vs. 3.3 months; P=0.008) to pemetrexed than those without ROS1/ALK-rearrangement. The PFS to EGFR-TKIs in patients harboring ROS1-rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 vs. 7.8 months; P=0.01).

Conclusion
The frequency of ROS1-rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1-rearrangement is a druggable target in East-Asian never-smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1-rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.

Background
In case of progression under initial treatment, repeat biopsy is a new option procedure in advanced non-small cell lung cancer (NSCLC). Its justification is based on the assessment of biological markers (comparison to the initial status, emergence of resistance to chemotherapy or new biomarkers). The aim of this pragmatic prospective multicenter study was to assess feasibility and clinical utility of re-biopsy in real world setting in advanced NSCLC.

Methods
Patient’s main inclusion criteria was advanced NSCLC with an indication of repeat biopsy by the referent clinician. The primary outcome was the percentage of successful procedures; secondary outcomes were localization of the new biopsy, type of procedure, new biological status (comparison to initial status, new biomarkers, resistance biomarkers) and tolerance of the procedure.

Results
From May 2012 to May 2013, 18 centers included 102 patients. The characteristics of the 67 first patients were: male: 40%; age: 64.8 ± 10.9 years; PS 0/1: 87%; adenocarcinoma: 85%; EGFR mutated: 46.2%; no biological available assessment: 16.4%; controlled disease as best response to first line: 70%. Repeat biopsy was possible in 80.6%. The main failure reasons were: inaccessible lesion: 4.5%, medical contraindications: 14.9%. Main procedures were: bronchial endoscopy: 48.1%, trans thoracic needle biopsy: 24.1%. The procedure permits to find, in EGFR wild type population, 3 patients with a driver oncogene (1 HER2, 1 Ros1, 1 EML4 ALK); in EGFR mutated patients, 2 T790M mutations and to obtain in 3 patients with no biological data’s at the diagnosis, a biological profile. Complications were very low: 2 cases of moderate bleeding and 1 case of pneumothorax.

Conclusion
Repeat biopsy is a feasible procedure with acceptable adverse events. Recommendations should be realized on the indications of re-biopsy, the timing and the recommended site (primary versus metastasis, progressive target versus no progressive). Analysis of the complete population (n=102) will be presented at the meeting. Supported by an academic grant from Boehringer Ingelheim Company and Hoffmann-La Roche Company.

Abstract not provided

Background
Median survival of non-small cell lung cancer (NSCLC) patients with brain metastases is poor. We examined concurrent erlotinib and whole brain radiotherapy (WBRT) followed by maintenance erlotinib in patients with untreated brain metastases, given the potential radiosensitising properties of erlotinib and its direct effect on brain metastases and systemic activity.

Methods
Eighty NSCLC patients with KPS≥70 and multiple brain metastasis were randomised to placebo (n=40) or erlotinib (100mg, n=40) given concurrently with WBRT (20 Gy in 5 fractions). Following WBRT, patients continued with placebo or erlotinib (150mg) until disease progression. The primary end-point was neurological progression-free survival (nPFS).

Results
Fifteen patients (37.5%) from each arm were alive and without neurological progression 2 months after WBRT. Median nPFS was 1.6 months in both arms; nPFS HR 0.95 (95% CI, 0.59-1.54; p=0.84). Median overall survival (OS) was 2.9 and 3.4 months in the placebo and erlotinib arms; HR 0.95 (95% CI, 0.58-1.55; p =0.83). The frequency of EGFR mutations was low with only 1 out of 35 (3%) patients with available samples had activating EGFR-mutations. Grade 3/4 adverse event rates were similar between the two groups (70% in each arm), except for rash 20% (erlotinib) vs. 5% (placebo), and fatigue 17% vs. 35%. No significant QoL differences were found.

Conclusion
Our study showed no advantage in nPFS or OS for concurrent erlotinib and WBRT followed by maintenance erlotinib in patients with predominantly EGFR wild-type NSCLC and multiple brain metastases. Future studies should focus on the role of erlotinib with or without WBRT in patients with EGFR mutations.

Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have shown efficacy in advanced NSCLC with brain metastases (BM). Icotinib is a new EGFR-TKI. A randomized, double blind phase III trial proved that icotinib was non-inferior to gefitinib in terms of median progression free survival (PFS) in advanced NSCLC. We have conducted a phase II study to evaluate the efficacy and safety of icotinib in combination with WBRT in Chinese NSCLC patients with BM, and investigated the cerebrospinal fluid (CSF) concentrations of icotinib. .

Methods
From January 2012 to January 2013, 20 patients aged 18-75 years with Eastern Cooperative Oncology Group performance status 0-2 and BM from NSCLC,were recruited regardless of EGFR status. The treatment comprised icotinib 125mg, TID concurrently with WBRT (30Gy/10f/2w). CSF and plasma samples were collected at the same time from 10 patients at least 5 days after icotinib treatment. The concentrations of icotinib in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry. The primary end point was progression-free survival (PFS) determined by RECIST. Additional end points were response rate, safety and CSF concentrations of icotinib. EGFR mutation status was tested by Amplification Refractory Mutation System( ARMS)

Results
The median PFS was 7.3 months [95% confidence interval (CI) 4. 2-9.8]. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [NR versus 4.2 months (95% CI 2.9-5.1); P = 0.000]. The most prevalent site of first failure was extracranial in seven patients (70.0%）. The CNS response rates were 25% complete response (n=5), 55% partial response (n= 11), 15% stable disease (n=3), and 5% progressive disease (n =1). The overall response rate was 80% (n = 16). The most common adverse events were rash (40.0%), diarrhea (15.0%),nausea(45.0%), vomiting(20.0%), headache(35.0%), fatigue (45.0%). And no patient experienced grade ≥ 3 toxicity. The mean plasma and CSF concentrations of icotinib were 936.47 ± 503.80 and 8.93 ± 8.01ng/ml, respectively, and the mean ratio of CSF-plasma concentration was 1.04% ± 0.95.

Conclusion
Icotinib was well tolerated and showed promising activity in combination with WBRT in patients with BM from NSCLC. The concentrations of icotinib in CSF were much lower than that of plasma. Further randomized trials are warranted.

Background
Afatinib, an irreversible ErbB Family Blocker, was superior to pemetrexed/cisplatin in previously untreated patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in a global Phase III trial, LUX-Lung 3. In patients with the two most common EGFR mutations (Del19, L858R) median progression-free survival (PFS) was 13.6 vs. 6.9 months (HR=0.47, 95% CI: 0.34–0.65; p<0.0001). Here we present the results for subgroups of patients with or without brain metastases (BM) with NSCLC harbouring common EGFR mutations.

Methods
In LUX-Lung 3 EGFR mutation-positive patients were randomized 2:1 to afatinib 40 mg daily or up to 6 cycles of pemetrexed/cisplatin at standard doses. Patients with stable BM (asymptomatic, stable >4 weeks with no treatment required) were allowed. Presence of BM was documented by the investigator during screening. Tumour assessments were performed every 6 weeks until 48 weeks and every 12 weeks thereafter until progression, and reviewed independently and by the investigator.

Results
308 patients with common EGFR mutations were randomized (afatinib: 204, pemetrexed/cisplatin: 104), including 35 with baseline BM (afatinib: 20, pemetrexed/cisplatin: 15). Of these, Del19 mutation was detected in 11 (afatinib) and 8 (pemetrexed/cisplatin) patients and L858R in 9 (afatinib) and 7 (pemetrexed/cisplatin) patients. The baseline characteristics of patients with or without BM were comparable (females: 74% vs. 66%, median age: 61 vs. 62 years, ECOG 0: 31% vs. 41%, median time since diagnosis: 1.2 vs. 1.1 months, respectively). Within the BM group, baseline characteristics were balanced between treatment arms with the exception of ECOG 1; 80% of afatinib-treated patients had ECOG 1 compared with 53% of those treated with pemetrexed/cisplatin. Median PFS by independent review was 13.7 (afatinib) vs. 8.1 (pemetrexed/cisplatin) months in patients without BM (HR=0.47, 95% CI: 0.33–0.68; p<0.0001), and 11.1 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in patients with BM (HR=0.52, 95% CI: 0.22–1.23; p=0.13). Objective response in patients without BM was 59% (afatinib) vs. 23% (pemetrexed/cisplatin), odds ratio=4.8, p<0.0001, and 70% (afatinib) vs. 20% (pemetrexed/cisplatin), odds ratio=11.0, p=0.007, in patients with BM. Investigator review showed a median PFS of 13.6 (afatinib) vs. 6.9 (pemetrexed/cisplatin) months in patients without BM (HR=0.38, 95% CI: 0.27–0.53; p<0.0001), and 6.7 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in those with BM (HR=0.67, 95% CI: 0.29–1.57; p=0.36). By investigator review, progressive disease in the brain was observed for 4.2% (7/167) and 3.7% (3/82) of patients without BM at baseline for afatinib and pemetrexed/cisplatin, respectively. All but one of these patients (on afatinib) had intracranial progression only. The median (range) time to progression in the brain in this small group was 11.6 (1.3, 20.2) months (afatinib) and 5.5 (2.6, 8.2) months (pemetrexed/cisplatin).

Conclusion
In patients with previously untreated NSCLC harbouring common EGFR mutations afatinib remains efficacious regardless of the presence or absence of BM. Control of synchronous asymptomatic BM with afatinib compares favourably with existing data for cranial radiation therapy.

Abstract not provided

Background
NSCLC may utilize PD-L1 overexpression to escape immune surveillance. This mechanism has been suggested by recent clinical studies showing that NSCLC can respond to PD-L1/PD-1 blockade. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 from binding to its receptors, PD-1 and B7.1.

Methods
Patients received MPDL3280A IV q3w for up to 1 year in a Phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tissue was analyzed centrally for PD-L1 expression by IHC.

Results
As of Feb 1, 2013, 52 NSCLC patients were evaluable for safety and treated at doses of 0.03-20 mg/kg. The median age of patients was 61 years (range, 24-83). 17 (33%) of patients were ECOG PS 0 and 35 (67%) of patients were ECOG PS 1. Prior treatments included surgery (89%), radiotherapy (54%) and systemic therapy (98%). 15% of patients received 1 prior regimen, 21% received 2 and 62% received ≥3. Additionally, 14%, 62% and 25% of patients were EGFR-mutation positive, EGFR WT and EGFR status unknown/undetermined, respectively, and 12%, 40% and 48% of patients were KRAS-mutation positive, KRAS WT and KRAS status unknown/undetermined, respectively. Patients received treatment with MPDL3280A for a median duration of 106 days (range 1-450). Treatment-related Gr3/4 AEs occurred in 12% of patients, including fatigue (4%) and hypoxia (4%). 1 patient experienced a Gr3/4 immune-related AE (Gr3 hyperglycemia). No Gr3-5 pneumonitis or diarrhea was reported. 41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy. An ORR of 22% (9/41) was observed in patients (squamous [n=9]/nonsquamous [n=31]) with a duration of response range of 1+ to 214+ days. Additional patients had nonconventional responses after apparent radiographic progression but were considered to have progressive disease in this analysis. All responses were ongoing or improving at data cutoff. The 24-week PFS was 46%. ORR by patient characteristics was also examined. The ORR for patients with ≤2 prior therapies was 23% (4/17) and 23% (5/22) for patients with >2 prior therapies. Additionally, the response for former/current smokers was 23% (8/35) versus 17% (1/6) for never smokers. Between EGFR-mutation positive and EGFR WT patients, the ORRs also did not differ (25% [1/4] and 19% [5/26], respectively). In contrast, PD-L1 status was associated with ORR response as patients with PD-L1–positive tumors had an ORR of 80% (4/5) and patients with PD-L1–negative tumors had an ORR of 14% (4/28). Updated data, including responses by KRAS status, will be presented.

Conclusion
Treatment with MPDL3280A was generally well tolerated, with no cases of Gr3-5 pneumonitis. Rapid and durable responses were observed, including in an EGFR-mutation positive patient. Responses to MPDL3280A did not appear influenced by the number of prior treatment regimens but did appear to be associated with PD-L1 tumor status. Additional studies have been initiated in NSCLC.

Background
Currently approved cytotoxic chemotherapies for previously treated patients with NSCLC demonstrate few objective responses, which are generally of short duration, with limited impact on progression-free survival and overall survival. Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor whose activation by interaction with its ligands, PD-L1 or PD-L2, can lead to suppression of antitumor immunity. Preclinical and clinical data indicate that this pathway is important in NSCLC.MK-3475 is a humanized monoclonal IgG4 antibody against PD-1.

Methods
MK-3475 was administered at 10 mg/kg every three weeks to patients with NSCLC previously treated with two systemic regimens. At least one measurable tumor lesion, ECOG performance status of zero or one, and adequate laboratory function were required for eligibility. A new tumor biopsy no earlier than 60 days before the first dose of MK-3475 was required for study entry. Imaging assessments per investigators were performed every nine weeks until confirmed disease progression utilizing the immune-related response criteria (irRC). Independent central review of images was assessed with RECIST v1.1. PD-L1 expression on the pretreatment tumor sample was determined by immunohistochemistry. A cut-point associated with the Youden Index of the receiver-operating characteristic curve for PD-L1 staining was identified.

Results
Between April 2012 and September 2012, thirty-eight patients were enrolled. Median age was 63 years (range, 34-85 years), with 42% men and 42% with an ECOG performance status of zero. Previously treated, stable brain metastases were allowed and were present in 10%. Seven patients had an EGFR mutation, eight patients had a KRAS mutation, and one patient had an ALK gene rearrangement in their tumor. Fifty percent of patients experienced drug-related adverse events; the most common were fatigue, rash, and pruritus (16% each). The incidence of diarrhea was 13% (only grade 1 or 2 reported). One case of a drug-related grade 3-4 adverse event (grade 3 pulmonary edema: 3%) was seen. There were no drug-related fatalities. Using investigator-assessed irRC, the objective response rate (ORR; confirmed and unconfirmed) was 24%, including squamous and nonsquamous subtypes. Similar results were obtained using RECIST v1.1, yielding an ORR (confirmed and unconfirmed) of 21%. Most responses by irRC were observed by the time of first planned assessment at Week 9. The median duration of response by irRC has not been reached, with a median duration of follow-up of 9 months (minimum, 6 months). As of June 2013, seven of the nine responding patients by irRC continue on therapy. Pretreatment tumor PD-L1 expression was a statistically significant predictor of response. In patients with evaluable tumor PD-L1 expression, all confirmed responses by RECIST v1.1 (and irRC) occurred in patients with tumors strongly positive for PD-L1.

Conclusion
MK-3475 is generally well tolerated in previously treated patients with advanced NSCLC and provides durable objective responses. An additional cohort of patients whose tumors express PD-L1 is enrolling; preliminary safety and efficacy data, including PFS and OS, will be reported further at the World Conference on Lung Cancer 2013.

Background
Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian S, et al. New Engl J Med. 2012;366:2443-54). We present long-term safety and efficacy outcomes from a phase 1 study of nivolumab, a fully human IgG4 PD-1 receptor blocking monoclonal antibody, in patients with advanced NSCLC.

Methods
NSCLC patients enrolled between 2008–2012 received nivolumab 1, 3, and 10 mg/kg IV Q2W on either dose escalation or subsequent expansion cohorts. Tumors were assessed (RECIST 1.0) after each 4-dose cycle. Protocol was amended (Jan. 23, 2012) to explore nivolumab’s potential to deliver prolonged overall survival (OS) for the initial and expansion cohorts and the overall population.

Results
129 pretreated NSCLC patients (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) were treated as of March 2013. Responses (CR/PR) occurred in 22 patients (17%) and were durable (estimated median response duration, 74.0 weeks [6.1+, 133.9+]), and ongoing in 55% (12/22) of patients. The highest objective response rate (ORR) was at 3 mg/kg (24%) across NSCLC histologies. Responses were rapid; 50% of patients (11/22) demonstrated response at first tumor assessment (8 weeks). Among 12 responders who discontinued therapy for reasons other than disease progression, 3 responded for ≥24 weeks post therapy discontinuation, and all 3 had not progressed at the time of this analysis. An additional 6 of the 122 patients (5%) demonstrated unconventional “immune-related” responses (based on target lesions), but were not included among responders. Survival benefit was demonstrated by 1-year and 2-year landmark OS rates (42% and 14%; Table). Median OS was 9.6 months across doses and 14.9 months at 3 mg/kg across histologies. Median OS across doses was similar for squamous/non-squamous patients. Any grade drug-related select adverse events (AEs) occurred in 41% (53/129) of patients (grade 3/4 select AEs, 5% [6/129]); most common being skin (16%), gastrointestinal (12%), and pulmonary (7%). Any grade drug-related pneumonitis occurred in 6% (8/129) of patients (grade 3/4 pneumonitis, 2% [3/129]), resulting in 2 deaths early in the trial, leading to increased emphasis on management algorithms. Characteristics and management of nivolumab-related pneumonitis will be summarized.

Conclusion
In advanced NSCLC patients, nivolumab produced durable responses and survival benefit (1-year OS rate, 42%), with a long-term safety profile acceptable for the outpatient setting, supporting ongoing development in phase 3 trials with survival endpoints. Additional follow-up on patient survival will be presented at the time of the meeting.

Background
MUC1, a tumor antigen, has been considered to be a promising target antigen for cancer immunotherapy because it possesses a potent immunogenicity. It is processed and presented by antigen-presenting cells in a MHC-unrestricted pattern. Dendritic cell-based vaccine immunotherapy can elicit antigen-specific cytotoxic T lymphocytes in tumor-bearing hosts, and activated cytotoxic T lymphocytes are expected to attack cancer cells. In this study, we evaluated the efficacy of MUC1-targeted dendritic cell-based vaccine immunotherapy in patients with standard treatments-refractory advanced non-small-cell lung cancer (NSCLC).

Methods
The eligibility criteria of this immunotherapy were as follows: histologic or cytologic evidence of NSCLC that express MUC1 protein abundantly; an Eastern Cooperative Oncology Group performance status of 0-2; advanced stage of diseases refractory to any standard cancer treatments. The dendritic cells were prepared from peripheral blood mononuclear cells with cytokines interleukin-4 and granulocyte macrophage colony stimulating factor, pulsed with MUC1 peptides, and subsequently administered to patients by subcutaneous injection. The vaccinations were repeated bi-weekly, and assessable patients were received at least 6 vaccinations. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria.

Results
From June 2005 to December 2012, 36 patients were treated with dendritic cell-based vaccines, and 25 patients (69.4%) with median age of 61 years (range, 49-84 years) were assessable for tumor responses. The cohort consisted of 14 males and 11 females, and 22 patients had adenocarcinomas; 2 patients with squamous cell carcinomas and 1 patient with pleomorphic carcinoma. Among these patients, neither complete response nor partial response was obtained. Fourteen patients had progressive disease as the best response, and 10 patients had stable disease, yielding overall disease control rate of 40.0% (95%CI=20.8-59.2). Median survival time after the vaccines was 10.0 months, and 1-year survival rate was 32.3%. Adverse events related to the vaccines were less frequent. Immunological responses could be monitored in five patients, showing that MUC1-specific cytotoxic responses of effector immune cells were achieved in all of those patients, and the population of regulatory T lymphocytes in peripheral blood cells was decreased after the vaccines.

Conclusion
MUC1-targeted dendritic cell-based vaccine immunotherapy is feasible, and has a potential to control the diseases in patients with refractory NSCLC.

Abstract not provided

Background
Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need, while a personalized medicine approach is increasingly adopted in NSCLC guided by tumor molecular profiling. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies (ClinicalTrials.gov NCT01248247).

Methods
This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in NSCLC pts that failed at least 1 prior line of therapy. Patients are adaptively randomized to 4 arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS mutation status while predictive biomarkers are being developed by means of gene expression profiling, targeted next generation sequencing and protein expression. EGFR sensitizing mutations and EML4/ALK translocation in pts that are erlotinib and crizotinib naïve are exclusion criteria, while erlotinib resistant patients are excluded from erlotinib monotherapy. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers follows a rigorous, internally and externally reviewed statistical analysis that follows a training, testing methodology with validation in stage 2 of the trial. All Stage 1 and 2 randomization biomarker assays are CLIA-certified.

Results
286 pts have been enrolled, 236 biopsies performed,172 pts randomized, and 167 pts treated. 144 pts are evaluable for the 8-week DCR endpoint. Within the randomized pts group KRAS mutation rate is 22.8%, and EGFR mutation rate 14.8%, while 36.3% patients have been previously treated with erlotinib. Treatment is well tolerated with no unanticipated toxicity.

Conclusion
Accrual updates, demographics, and further details will be presented at the meeting. (Supported by NCI R01CA155196-01A1)

Background
The potential of personalized medicine for improvement of lung cancer patient outcome has been paradigmatically shown by the treatment of advanced EGFR mutation- and ALK translocation positive NSCLC patients with the respective tyrosine kinase inhibitors. Furthermore numerous targeted drugs for molecular defined subgroups of NSCLC (e.g. ROS1- rearrangements) are in clinical development with the potential to improve outcome. Therefore one of the major challenges today is the implementation of comprehensive high-quality real time molecular diagnostics and personalized therapy for all NSCLC patients regardless of where they are treated.

Methods
To increase the availability of molecular testing and subsequently personalized treatment options for NSCLC patients in the catchment area of our cancer center, we established the Network Genomic Medicine (NGM) in January 2010. NGM is a collaborative network currently encompassing more than 40 different health care providers representing the full spectrum of lung cancer care in Germany including university hospitals, large non-university lung clinics and office based oncologists. NGM is based at the Center for Integrated Oncology (CIO), i.e. the joint comprehensive cancer center of the University Hospitals of Cologne and Bonn. At the NGM - headquarter genetic and clinical data are analysed and patients without approved targeted treatment options are screened for recruitment into NGM-linked personalized trials offered by the Lung Cancer Group Cologne (LCGC). Before the introduction of routine Next Generation Sequencing (NGS) within NGM in 06/2013 we screened lung adenocarcinomas (AD) via single gene assays for mutations in EGFR, KRAS, BRAF and PIK3CA, for amplifications in HER2 and translocations in ALK, ROS1 and RET. Squamous cell lung cancer (SCC) patients were screened for amplifications in FGFR1 and mutations in DDR2.

Results
We screened 5,145 lung cancer patients from January 2010 till April 2013. Genomic testing was feasible in 3,863 tumor samples (75%). 63% of the patients were male and 65% of samples were AD. In AD the following frequencies of genetic lesions were detected: EGFR 13.8% (288/2078); ALK 3.3% (54/1618); KRAS 33.8% (831/2457); BRAF 3.5% (76/2123); PIK3CA 3.1% (70/2190); HER2 amplified 3.6% (62/1717); RET 4.7% (4/85) and ROS1 5.1% (7/135). In SCC we found a frequency of 21% (279/1333) for FGFR1 amplification and 2.1% (11/505) for DDR2 mutations. Further we saw 18 KRAS/PIK3CA, 5 EGFR/PIK3CA, 5 BRAF/PIK3CA double mutant samples and 3 samples where a FGFR amplification was co-occurring with a DDR2 mutation. Overall 40% of NSCLC patients harboured a potentially targetable molecular alteration. In addition we could allocate more than 40 patients to early personalized clinical trials via the close collaboration of the partners within NGM and LCGC. *The frequencies of RET and ROS1 are biased, because of a preselection of pan negative patients.

Conclusion
NGM is one of the largest prospective molecular screening efforts for NSCLC worldwide, with currently more than 3000 samples analysed per year. Our experiences so far underline that central comprehensive high-quality real time molecular diagnostics is feasible in a large health care provider network and allows implementation of personalized medicine in routine clinical care of lung cancer patients.

Background
There are few new effective therapeutic options for patients with advanced, lung SCCA; overall survival for metastatic disease being less than one year. The Cancer Genome Atlas (TCGA) project and similar studies have detected a significant number of somatic gene mutations/amplifications in patients with this disease, some of which are targetable by investigational agents. However, the frequency of these changes is low (5-20%) in these patients, making recruitment and treatment very challenging in the traditional single-agent trial setting. Our approach is to use a common platform (Next Generation DNA Sequencing) to enable a single “umbrella screening protocol” to efficiently find patients with varied, uncommon molecular changes.

Methods
Figure 1 This is a prospective, multi-substudy randomized Phase II/III Master Registration Protocol in which patients with advanced stage Lung SCCA (2[nd] line therapy)are randomized to biomarker-driven targeted therapy (TT) or standard of care (SOC) as shown in the schema after undergoing genomic screening. Genomic screening of a large patient resource provided by sites participating in the NCI North American Intergroup will identify molecular targets/biomarkers with an analytically validated diagnostic assay and a new drug match, leading to appropriate drug treatment-arm assignment. Archival FFPE tumor and/or core needle biopsies will be screened by a broad analytically validated next generation sequencing (NGS) platform centrally to establish eligibility within 10-14 days. This platform will be supplemented by individual immune-histochemical (IHC) protein assays performed in a CLIA setting as necessitated by the specific experimental agent used. Patients will be screened with homogeneous eligibility criteria. The overall trial objective is to establish a mechanism to genomically screen large but homogeneous cancer populations and subsequently assign and accrue simultaneously to multiple substudies comparing new TT to SOC therapy based on the identified therapeutic biomarker-drug combination. Each sub-study will function autonomously and will open and close independently of the other sub-studies. Drug combinations in the experimental arm will be allowed in appropriate settings and where appropriate the control arm may consist of FDA approved targeted therapy such as erlotinib. Each sub-study is independently powered for OS with an interim analysis for PFS to determine the “go-no go” decision to proceed from Phase II into Phase III. Each agent, along with the paired biomarker, that is successful at the interim analysis based on PFS will advance to a Phase III randomized registration trial (on behalf of the Master Protocol Steering Committee).

Results
NA

Conclusion
NA

Abstract not provided

Background
KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib plus pemetrexed enhances growth inhibition and apoptosis of NSCLC cell lines with and without RAS/RAF mutations in vitro when compared with either agent alone.

Methods
This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (1.5 mg daily) and pemetrexed (500 mg/m[2] every 3 weeks) in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 21 patients (50%). Plasma from 38 patients (90%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

Results
A total of 42 patients with NSCLC (19 KRAS WT [79% ≥ 2 prior therapies; 74% prior pemetrexed; 16% squamous] and 23 KRAS-mutant [57% ≥ 2 prior therapies; 43% prior pemetrexed; 4% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Response rate was 17% and disease control rate was 69% for the whole population of NSCLC. Of note, we observed disease control in 75% of patients previously treated with pemetrexed (including 4 partial responses [PRs]) and in 2 patients out of 4 with squamous histology (including one PR). Progression-free survival (PFS) was 5.1 months for all patients with NSCLC. Detailed efficacy results according to mutation status are shown in Table 1. Among KRAS WT, activity was seen in cancers with EGFR mutations or ALK rearrangement. Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

Conclusion
MEK inhibition with trametinib + pemetrexed demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. There was no significant difference in activity or efficacy across KRAS mutation subtypes. Interestingly, activity with this combination was broad and was seen in patients with squamous histology, patients with prior pemetrexed treatment, and those with EGFR mutation or ALK translocation.

Background
KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib enhances docetaxel-induced growth inhibition and apoptosis of NSCLC cell lines. Cell lines with the KRAS G12C point mutation, the most common KRAS mutation subtype (≈50% of KRAS-mutant NSCLC or ≈10% of all NSCLC), are more responsive to apoptosis induced by this combination.

Methods
This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (2.0 mg daily) and docetaxel (75 mg/m[2] every 3 weeks) in the presence of growth factors in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 17 patients (36%). Plasma from 42 patients (89%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

Results
A total of 47 patients with NSCLC (22 KRAS WT [64% ≥2 prior therapies; 27% squamous] and 25 KRAS-mutant [40% ≥2 prior therapies; 0% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Progression-free survival (PFS) was 4.2 months for all patients; efficacy results according to mutation status are shown in Table 1. Among KRAS-mutant patients, activity and efficacy were better in G12C compared with non-G12C subtypes. Among KRAS WT, activity was seen in cancers with EGFR mutations; clinical benefit was noted in 2 patients with ALK translocation (disease control 25 weeks and 60+ weeks). Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

Conclusion
MEK inhibition with trametinib + docetaxel (+ growth factors) demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. Cancers carrying the KRAS G12C point mutation may have improved activity and efficacy compared with non-G12C subtypes, consistent with preclinical observations. Additionally, clinical benefit with this combination was broad and was seen in patients with squamous histology and those with EGFR mutation or ALK translocation.

Background
Phase II data from patients with KRAS mutation-positive NSCLC, selumetinib (AZD6244, ARRY-142886) plus docetaxel showed promising efficacy versus placebo plus docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47). Median OS was 9.4 months (95% CI 6.8–13.6) in the selumetinib group and 5.2 months (95% CI 3.8–non-calculable) in the placebo group (HR for death 0∙80, 80% CI 0.56–1.14; one-sided p=0.21). Median PFS was 5.3 months (95% CI 4.6–6.4) and 2.1 months (95% CI 1.4–3.7), respectively (HR for progression 0∙58, 80% CI 0.42–0.79; one-sided p=0.014). 37% of patients in the selumetinib group and 0% in the placebo group had an objective response (two-sided p<0.0001). The KRAS mutation codon subtype might impact on prognosis and/or response to therapy. The BATTLE trial suggested that G12V or C KRAS mutations confer relatively poorer outcome within the KRAS mutant NSCLC sub-type (Ihle et al. J Natl Cancer Inst 2012;104:228–39). In cell lines carrying these codons, Akt phosphorylation but not ERK phosphorylation was low compared with other codons, suggesting these codons might confer greater dependence upon MEK/ERK signaling. We sought to understand if any codons or combinations of codons selected for striking treatment effects either between or within treatment groups in the Phase II study.

Methods
Post-hoc analysis explored the hypotheses that patients whose tumours carried G12C or G12V KRAS mutations would have a worse prognosis and that these patients would have a better outcome with the addition of selumetinib. Clinical benefit was measured by PFS, OS and ORR.

Results
G12V or G12C mutations were present in 57% of patients and whilst not reaching statistical significance, trends for PFS, OS and ORR support the hypothesis (see table, PFS). Patients with G12V mutations responded better to selumetinib plus docetaxel than other patients as measured by change in tumour size at week 6 (G12V=-62%, G12C=-8%, G12D=+3%, reduction across all codons=-18%; two sided p=0.007). It is therefore possible that trends supporting the primary hypothesis were driven by effects in the small number of G12V codons (n=9). Table. Summary of analysis of progression-free survival (PFS): MITT by mutation subgroup

Conclusion
Any impacts of codon sub-type on the treatment effect in this trial were not sufficiently significant to be detected in this small Phase II trial of 87 patients, but the trends observed in this retrospective subgroup analysis warrant monitoring of the impact of specific codons or groups of codons in future clinical trials.

Abstract not provided

Abstract

Abstract
Background Over fifty percent of all newly diagnosed lung cancer patients are aged over 65 years at the time of lung cancer diagnosis, and about 30% are aged over 70. Since lung cancer is a disease that mainly occurs in elderly, and smoking is the most important risk factor [1], many patients have (smoking-related) comorbidity at the time of lung cancer diagnosis. This may complicate the management of lung cancer and may also serve as a competing cause of death. Methods An overview of literature concerning the prevalence and prognostic influence of comorbidity in lung cancer patients as well as competing causes of death. ResultsPrevalence of comorbidity Previous studies have shown that over 70% of patients suffered from at least one serious comorbid condition at the time of lung cancer diagnosis [2, 3]. The prevalence of (especially tobacco-related) comorbidity was higher among lung cancer patients as compared to patients with other major tumour types or the general population [2, 4]. The most frequent concomitant diseases among lung cancer patients were tobacco-related, such as cardiovascular diseases (25-30%), chronic obstructive pulmonary diseases (COPD, 25-30%) and previous malignancies (about 20%) [2, 3]. Prognostic influence of comorbidity Since in most cancer trials significant comorbidity is an exclusion criteria, limited information is available on the prognostic influence of comorbidity (which is important information for everyday clinical practice). Previous studies have shown that comorbidity only had a significant influence on survival in case of a localized lung tumour or in case of severe comorbidity [2, 3, 5-7]. A poorer overall survival in patients with comorbidity might be explained by death due to complications of treatment, death from cancer due to less aggressive treatment, or an increased risk of mortality due to comorbid conditions (competing causes of death). Comorbidity may increase the risk of peroperative and postoperative complications, especially those of the cardiorespiratory system [8]. A previous population-based publication has also shown that up to 75% of elderly SCLC patients receiving chemotherapy developed grade 3-5 toxicity, and two thirds of these patients receiving chemotherapy were unable to complete the treatment [9]. Elderly patients with localized non-small cell lung cancer (NSCLC) underwent less surgery than younger patients, older patients with non-localized NSCLC received less chemotherapy or chemoradiation, and elderly with small cell lung cancer (SCLC) received less chemotherapy and chemoradiation [5, 9, 10]. Competing causes of death Increased mortality due to comorbidity is probably of less importance in case of a lethal disease as non-localized NSCLC or SCLC [2, 10, 11]. Most patients probably die of lung cancer before they become at risk of dying of the comorbid condition. Previous studies have shown that 80-90% of all lung cancer patients died of lung cancer. The most common other causes of death were other tobacco-related conditions as cancers and cardiovascular causes [12-14]. Respiratory failure is the most common immediate cause of death for patients with lung cancer, probably because most of them have lung disease besides cancer and therapy for lung cancer may also add to impairment of lung function [15]. The finding that over 90% of lung cancer patients have contributing causes of death, suggests the possibility that saving a patient from one cause may only allow another disease process to become the immediate cause of death [15]. Conclusions The majority of patients with lung cancer also have serious comorbidity, especially other smoking-related diseases as cardiovascular diseases and COPD. Besides making treatment complex, comorbid conditions may also serve as competing causes of death. References 1. Doll R, Peto R, Wheatley K et al. Mortality in relation to smoking: 40 years' observations on male British doctors. Bmj 1994; 309: 901-911. 2. Piccirillo JF, Tierney RM, Costas I et al. Prognostic importance of comorbidity in a hospital-based cancer registry. Jama 2004; 291: 2441-2447. 3. Janssen-Heijnen ML, Schipper RM, Razenberg PP et al. Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: a population-based study. Lung Cancer 1998; 21: 105-113. 4. Janssen-Heijnen ML, Houterman S, Lemmens VE et al. Prognostic impact of increasing age and co-morbidity in cancer patients: a population-based approach. Crit Rev Oncol Hematol 2005; 55: 231-240. 5. Luchtenborg M, Jakobsen E, Krasnik M et al. The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients. Eur J Cancer 2012; 48: 3386-3395. 6. Jorgensen TL, Hallas J, Friis S, Herrstedt J. Comorbidity in elderly cancer patients in relation to overall and cancer-specific mortality. Br J Cancer 2012; 106: 1353-1360. 7. Birim O, Kappetein AP, Bogers AJ. Charlson comorbidity index as a predictor of long-term outcome after surgery for nonsmall cell lung cancer. Eur J Cardiothorac Surg 2005; 28: 759-762. 8. Wang S, Wong ML, Hamilton N et al. Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans. J Clin Oncol 2012; 30: 1447-1455. 9. Janssen-Heijnen ML, Maas HA, van de Schans SA et al. Chemotherapy in elderly small-cell lung cancer patients: yes we can, but should we do it? Ann Oncol 2011; 22: 821-826. 10. Janssen-Heijnen ML, Smulders S, Lemmens VE et al. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax 2004; 59: 602-607. 11. Phernambucq EC, Spoelstra FO, Verbakel WF et al. Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity. Ann Oncol 2011; 22: 132-138. 12. Janssen-Heijnen ML, Maas HA, Siesling S et al. Treatment and survival of patients with small-cell lung cancer: small steps forward, but not for patients >80. Ann Oncol 2012; 23: 954–960. 13. Pirie K, Peto R, Reeves GK et al. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 2013; 381: 133-141. 14. Thun MJ, Carter BD, Feskanich D et al. 50-year trends in smoking-related mortality in the United States. N Engl J Med 2013; 368: 351-364. 15. Nichols L, Saunders R, Knollmann FD. Causes of death of patients with lung cancer. Arch Pathol Lab Med 2012; 136: 1552-1557.

Abstract not provided

Abstract
Results from the National Lung Screening Trial (NLST) showing a 20% reduction in lung cancer mortality in the screened arm have heightened awareness of the need for reliable risk prediction tools for estimating the probability of lung cancer. A key issue of uncertainty is which smokers should be targeted for low-dose computed tomography (LDCT) screening. The NLST used 55 - 74 years, ≥30 pack-years of smoking and up to 15 years since quitting as selection criteria. 7 million U.S. adults meet these entry criteria, and an estimated 94 million U.S. adults are current or former smokers. Validated risk prediction models could improve the outcomes of screening efforts. Such models have substantial public health implications and value in clinical decision making as well. Further, risk prediction tools could be incorporated into the design of smaller, more powerful, and “smarter” prevention trials. The first lung cancer risk prediction model was developed by Bach et al. using data from the Carotene and Retinol Efficacy Trial (CARET) of 14,000 heavy smokers and over 4,000 asbestos-exposed men. Variables included in the final model were age, gender, asbestos exposure, smoking history, cigarettes per day, duration of smoking and duration of cessation. Cronin et al. externally validated the Bach model in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study control arm (c statistic of 0.69). Spitz et al. expanded on this model adding epidemiologic and clinical data derived from an ongoing lung cancer case-control study. Their model included environmental tobacco smoke (for never and former smokers), family cancer history, asbestos and dust exposures, prior respiratory disease, history of hay fever, and smoking history variables. These variables have strong biologically plausibility and are relatively easy to ascertain through patient interview. However, the validated area under the curve (AUC) statistics for former and current smoker models were modest (0.63 and 0.58, respectively), although consistent with those from other risk prediction models. The LLP model based on data from the Liverpool Lung Project included age, sex and smoking, as well as family history of lung cancer, exposure to asbestos, prior diagnosis of pneumonia and of a malignancy other than lung cancer. Prior diagnoses of emphysema and lung cancer lost significance in the multivariate model. Young et al. developed a risk model using a 20-single nucleotide polymorphism (SNP) panel including cell-cycle control, oxidant response, apoptosis, and inflammation genes, as well as age, history of COPD, family history of lung cancer, and gender. When numeric scores were assigned to both the SNP and demographic data, and sequentially combined by a simple algorithm in a risk model, the composite score was linearly related to risk with a bimodal distribution. These data have not been well replicated. In 2011,Tammemagi published a carefully constructed risk prediction model based on data from 70,962 control subjects in the Prostate, Lung, Colorectal, Ovarian cancer screening trial (PLCO). Model 1 included age, education, body mass index (BMI), family history of lung cancer, chronic obstructive pulmonary disease (COPD), recent chest x-ray, smoking status (never, former, current), pack-years smoked, and smoking duration. Model 2 also included time in years since ever-smokers permanently quit smoking. In external validation, performed with 44,223 PLCO intervention arm participants, Models 1 and 2 had area under the curves of 0.84 and 0.78, respectively. Tammemagi and colleagues also showed that their risk prediction model for lung cancer incidence was a more sensitive indicator of pre-screening risk of developing lung cancer than were NLST eligibility criteria. Kovalchik et al. subsequently showed that 88% of LDCT-prevented lung cancer deaths occurred among the 60% of NLST participants with highest pre-screening risk, while just 1% occurred among the 20% at lowest risk. This finding reinforces the role for risk-based screening. Maisonneuve et al. incorporated lung nodule characteristics and CT diagnosed emphysema into the Bach model. Presence of nonsolid nodules (RR = 10.1), nodule size > 8 mm (RR = 9.89), and emphysema (RR = 2.36) at baseline CT were all significant predictors of subsequent lung cancers. Incorporation of these variables into the Bach model increased the predictive value of the model (c-index = 0.759). Hoggart et al used prospective data from the European EPIC cohort. Using smoking information alone gave good predictive accuracy: the AUC and 95% CI in ever smokers was 0.843 (0.810-0.875). Adding other risk factors (10 occupational/environmental exposures previously implicated with lung cancer, and SNPs at two loci identified by GWAS of lung cancer) had a negligible effect on the AUC. An extended model was constructed incorporating two markers of DNA repair capacity that have been shown in case-control analyses to be associated with increased lung cancer risk. Addition of the biomarker assays improved the sensitivity of the models over epidemiologic and clinical data alone. These in vitro lymphocyte culture assays, however, are time-consuming and require technical expertise, and are not applicable for widespread population-based implementation. Spitz et al. added 3 SNPS that were most significant in their GWAS data – rs1051730 from 15q25 and two SNPs from the 5p15.33 locus (rs2736100 and rs401681 that were not in strong LD) to the baseline model. The AUC for the baseline epidemiologic/clinical model including 1016 cases and 1111 controls (all ever smokers) was 0.59. There was evidence of a gene dosage effect with an odds ratio over threefold elevated in the highest genetic risk score (GRS) stratum. With addition of the GRS to the model, the AUC showed modest improvement, to 0.61, although this was significantly improved over the baseline model, (P< 0.001). Current lung cancer risk prediction models are hampered by a restricted number of potential predictors, generally low overall predictive performance, and methodological limitations. To date, one can argue that the Tammemagi 2013 model exhibits the highest AUC among all the prediction models. It is important to conduct additional external validations of all models in diverse populations.

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Abstract
In this presentation, we describe the process that our laboratory followed that led to successful accreditation, by the Australian National Association of Testing Authorities (NATA), for medical use of NGS in clinical practice. First, we evaluated three different amplicon –based MPS technologies in order to choose the platform of choice for clinical use. We compared the performance of two commercial somatic mutation panels (Life Technology’s AmpliSeq cancer panel and Illumina’s TruSeq amplicon panel) and a customized panel (Agilent’s HaloPlex). The panels shared 31 genes in common. The AmpliSeq panel was sequenced using the Ion Torrent platform and the TruSeq and HaloPlex panels were sequenced using the Illumina MiSeq platform. In-house bioinformatics and variant annotation and reporting pipeline were developed to allow data from all three panels to be compared. A training set of 28 FFPET samples with known missense or deletion mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA and KIT were tested by all three panels. These samples, previously tested using NATA - accredited Sanger sequencing, SNaPshot and fragment analysis performed on an ABI3730, were used to empirically determine the parameters required for accurate mutation detection by MPS. Sample acceptance criteria included samples with at least 1mg of extractable DNA following macrodissection from tumour areas with at least 70% purity. Library quality was assessed by BioAnalyser and libraries were sequenced to a median depth of 2000x. The panels and platforms were compared for % aligned reads, % on - target reads, median and range of coverage, input DNA quantity and quality requirements, data quality and variability, cost, turn around time, ease of use, and accuracy of mutation detection. There was marked variation in the number and types of variants identified across the three panels. With minimum variant calling criteria of depth >50x, variant depth >20x, variant frequency >5% and base quality >15, we identified 18557 variants with AmpliSeq, 15064 variants with TruSeq and 3326 variants with Haloplex. 14229 of the TruSeq variants were SNPs (9319 were C>T), indicating DNA polymerase errors, while 12370 of the AmpliSeq variants were small indels (mostly in homopolymeric tracts) indicating errors in calling repetitive sequences. In total, 59 variants were identified by all three panels. The TruSeq and Ampliseq panels detected all 31 known somatic mutations, where as the HaloPex panel missed four mutations due to patchy on - target coverage. In panels with adequate coverage of regions of interest, the assay sensitivity was 100%. The TruSeq panel was chosen for clinical use, despite the requirement for higher DNA input (150ng compared to 10ng for AmpliSeq), primarily due to ease of use and less hands - on time by laboratory staff. We then performed reproducibility, repeatability, robustness and limit of detection experiments using the TruSeq panel. Initially, there was poor reproducibility of all variants, particularly SNVs, especially in samples with low input DNA (<50ng) or poor quality DNA (fragment size <250 bp). Most of the identified variants were random and present at low frequency, most being present at <1-2% allele frequency. These showed characteristics suggestive sequencing and polymerase errors, formalin – induced artifacts and misaligned repetitive sequences. To reduced the great excess of false positives, we restricted variant calling by establishing minimum allele frequencies, by eliminating unreported variants and by limiting alignment to clinically- relevant or actionable mutations. Variant reproducibility was increased to 38% by only calling SNVS >5% and indels >1% allele frequency that were contained within the COSMIC database. This was further increased to 92% by restricting variant calling to known clinically - relevant mutations listed on the www.mycancergenome web site. Reproducibility was increased further by strict adherence to sample and library quality control criteria (DNA amount 150ng DNA fragment size at least 250bp, minimum library concentration of 1nM, and minimum of 400,000 reads per sample) and by only calling mutations if present with allele frequency above 5% for FFPET samples and 1% for AML samples. Notabily, non - reproducible “mutations” in clinically relevant genes (eg KRAS G12A) were not infrequently encountered below these cut off values. A second independent test set of 82 FFPET samples with known missense and deletion mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, KIT and PDGFRA were analysed by the TruSeq panel. By strict adherence to the above criteria and restricting variant calling to clinically relevant mutations, 100% sensitivity and 100% specificity was achieved in the samples that met the criteria. In all, only 71% of the samples tested passed all quality control criteria. 12% of the samples failed the library preparation and were not processed. 17% of the samples passed the library QC criteria but failed the sample QC criteria. In each case the known mutation was identified. In conclusion, by strict adherence to sample and library QC and by restricting analysis to clinically-relevant mutations, the TruSeq amplicon cancer panel was able to detect common somatic missense and deletion mutations with an allele frequency >5% in FFPET samples with 100% specificity and sensitivity without the need for confirmation by an orthogonal method. However, confirmation by an orthogonal methods would be required for suspected mutations present at an allele frequency <5%, for mutations not known to be of clinical – relevance and for samples with low tumour purity, low DNA input or poor quality DNA. This study showed that deep sequencing of tumour tissue from FFPETs generated many low frequency artifacts due to sequencing, polymerase, formalin – induced chemical modifications and well as frequent mapping and variant calling errors. These artifacts and errors mostly occur at low allele frequency and can be difficult to distinguish from low frequency somatic mutations. Strict adherence to sample and library quality control criteria, allele frequency thresholds and clinically relevant mutations allows highly accurate mutation calling without the need for confirmation by an orthogonal method.

Abstract
Over the past decade, significant progress has been made in the characterization of molecular and genetic abnormalities tumors from patients with non-small cell carcinoma (NSCLC) that are being used as molecular targets and predictive biomarkers to select patients for targeted therapy. Recent advances in expanding the available NSCLC targeted therapies require the analysis of a broad panel of molecular abnormalities in tumor specimens, including gene mutations, gene amplifications, gene fusions and protein expression by applying different methodologies to tumor tissue (biopsy) and cell (cytology) samples. The rapid development of technologies for large-scale sequencing (next-generation sequencing, NGS) has facilitated high-throughput molecular analysis holding various advantages over traditionally sequencing including the ability to fully sequence large numbers of genes in a single test and simultaneously detect deletions, insertions, copy number alterations, translocations, and exome-wide base substitutions (including known hot-spot mutations) in all known cancer-related genes [1,2]. Currently, NGS platforms, including whole genome, whole exome and targeted gene sequencing, represent emerging diagnostic methodologies for the detection of oncogenes fusions and mutations in tumor tissue specimens, including formalin-fixed and paraffin-embedded (FFPE) samples [3]. Technical challenges include sequencing samples of low quality and/or quality, reliable identification of structural and copy number variation, and assessment of intratumoral heterogeneity. In addition, the clinical use of the NGS sequencing data is not straightforward and there are several challenges related to data analysis, data storage and report generation [4]. There is growing consensus that tumor tissue specimens must represent the setting of the disease to be treated, and increasingly, more tissue samples are being obtained for molecular testing of advanced, metastatic and chemo-refractory NSCLC tumors (e.g., MD Anderson BATTLE Lung Cancer Program) [5]. However, the biopsy and cytology samples available for molecular testing in those metastatic refractory NSCLC tumors are likely to be more challenging samples for molecular testing, including NGS platforms. The role of the pathologist is becoming increasingly important to adequately integrate routine histopathology assessments and molecular testing, including NGS, with clinical pathology for the most accurate tumor diagnosis and subsequent selection of the most appropriate therapy. References: 1. Meyerson M, Gabriel S, Getz G: Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 11:685-96, 2010 2. Mwenifumbo JC, Marra MA: Cancer genome-sequencing study design. Nat Rev Genet 14:321-32, 2013 3. Ross JS, Cronin M: Whole cancer genome sequencing by next-generation methods. Am J Clin Pathol 136:527-39, 2011 4. Ulahannan D, Kovac MB, Mulholland PJ, et al: Technical and implementation issues in using next-generation sequencing of cancers in clinical practice. Br J Cancer 109:827-35, 2013 5. Kim ES, Herbst RS, Wistuba, II, et al: The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 1:44-53, 2011

Abstract
As molecular biomarkers are becoming routine in the clinical management of lung cancer patients, there is an increasing need to establish standards or guidelines for the reporting of molecular results. In the most ideal situation, reporting of tissue based molecular biomarker results should be integrated into the histopathology report of the tissue sample, to provide a more complete genotype-phenotype characterization of the tumor. This is particularly important for lung cancer as molecular profiling to date has clearly shown that many “driver” genomic aberrations are often closely associated with specific tumor histology. In fact, the current CAP/IASLC/AMP guideline on molecular testing in lung cancer recommends the use of histology (adenocarcinoma containing tumors) as a primary criterion to select lung cancer samples for EGFR and ALK testing. However, until reflex molecular testing becomes routine in pathology practice, molecular testing is often conducted at a laboratory that is separate from the one where the original tissue histopathological diagnosis was made. In such cases, it is important that the stand alone molecular report should also include some histopathological data that may be highly relevant to the interpretation of the results, or at the very least, refer to the relevant Pathology report. In the Pathology report, the data should include: (a) type of sample, whether it is paraffin embedded or fresh (e.g. fluid), (b) tumor diagnosis, subtypes and variants when applicable, (c) essential immunohistochemical markers that were assessed to support the diagnosis, (d) use of tissue processing solution or fixative that could adversely affect the quality of DNA for sequencing, e.g. acid and Bouin’s solution, (e) the approximate size of the tissue, (f) whether a tumor cell enrichment strategy was used, and (g) estimated tumor cellularity in the tissue area marked for isolation of DNA for testing. It is of utmost important that molecular reports are written in language that can be understood by the treating physicians and the pathologists, who are the end-users of the report. Typical laboratory reports should include patient identification codes, the date the sample was acquired (biopsy or resection) from the patient, the date the sample is received in the molecular testing laboratory, and the date the report is signed out. All this information provides not only important sample identification information, but also the real turnaround time of the reported results. Aside from a summary of the molecular results themselves, the report should include a concise but reasonable detailed methodological section, which also provides the performance features of the assay platform being used. It should specify the list of genes included in the assay, the type of aberrations that can be reliably detected, e.g. single nucleotide mutations, deletions, insertions, rearrangements, copy number changes, etc, and the sensitivity and specificity of the assay. The methodology section should also include the analytical software used for processing the data and identifying the genomic aberrations and the version of the normal reference sequence used for comparison with the sequence in question. If the methodology used is fairly new or represent emerging technology, such as next generation sequencing (NGS), then information about mutation verification technology or process may also be required (1). While molecular aberrations are integral to the complete pathological diagnosis of a tumor, in lung cancer their main clinical relevance is for their ability to predict patient response to a specific therapeutic agent, or for patient prognosis. In this context, especially if there are a number of genetic changes being reported (as example with NGS); it may be useful if the aberrations (often called variants) are classified into categories, which reflect their clinical utility. Although there is as yet no universally acceptable classification framework for reporting genomic aberrations identified by NGS platforms, broad categories that establish prognostic, biological or treatment relevance to the aberrations have been proposed or used. These variants have been classified into several “Levels” or “Tiers”, depending on the level of evidence for their predictiveness of response to specific drug. These levels have been derived from widely accepted classification schemes, such as those published by the American College of Medial Genetics (ACMG) for use in diseases such as Breast Cancer. The “actionable” aberrations are those demonstrating proven evidence for their association with high response rates to a specific drug or treatment strategy. The “potentially actionable” alterations are those with strong rationale but as yet proven clinical evidence for being associated high response rate to a specific drug. This group also include aberrations that have demonstrated evidence for response to a specific drug in one type of cancer, yet of unproven response pattern in a different tumor being studied. However, as NGS enables the discovery of a large number of genetic aberrations that typically occur in sporadic adult cancers, many aberrations fall into the category of “unknown therapeutic or biological significance”. While some of these could potentially be predictive markers of drugs that are already available for other reasons, most may not even be pharmacologically targetable. An important risk of conducting comprehensive genomic profiling in patient samples is the identification of “incidental” aberrations, which require clinical management that is not originally planned or anticipated (2). These aberrations could involve genes/mutations with known hereditary roles in cancer or non-cancer conditions, with potentially significant implication on patient and/or other family members. For these reasons, the ACMG recently convened a working group of experts to publish recommendations for reporting of incidental findings in clinical exome and genome sequencing. While these recommendations have been provided primarily as educational resources for medical geneticists and other health care providers (and are still quite controversial), the issues discussed should be considered when deciding upon the reporting strategy for profiling cancer samples using NGS technology. References: 1. Rehm HL, Bale SJ, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013 Jul 25. doi: 10.1038/gim.2013.92. [Epub ahead of print] 2. Green RC, Berg JS, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013 Jul;15(7):565-74. doi: 10.1038/gim.2013.73. Epub 2013 Jun 20.

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Abstract
With the recent popularization of computed tomography (CT) screening, small malignant nodules are increasingly detected. In Japanese cases of lung cancer surgery, tumors in more than 60% of lung cancer patients were under 3cm in diameter. Stereotactic ablative radiotherapy (SABR) is a new treatment modality where narrow beams from several directions focus on the target while sparing the adjacent normal tissues with high accuracy. By SABR, the biological effect of radiation on tumors was increased and the overall treatment time was shortened. SABR has emerged as one of the radical treatment options for stage I non-small cell lung cancer (NSCLC), mainly in medically inoperable patients. First of all, Uematsu et al reported in 2001, that 3-year local control and overall survival rates of SABR (50-60Gy in 10 fractions) were 94% and 66%, respectively. Then Nagata et al reported in 2005, that 3-year overall survival rate of SABR (48Gy in 4 fractions) was 83% in stage IA and 72% in stage IB. In Japanese multi-centers large database of more than 2000 patients treated with SABR for stage I NSCLC, overall survival rate at three year (OS-3y) and disease-specific survival rate at three year of total patients was 72% and 85%, respectively. Locally progression free rate at three year of T1 and T2 tumors were 87% and 72%, respectively. In USA, Timmerman et al reported in 2010, that 3-year overall survival rate of SABR (54Gy in 3 fractions) was 55.8%. In Europe, Bauman et al reported in 2009, that 3-year overall survival rate of SABR (45Gy in 3 fractions) was 60%. According to a lot of previous studies demonstrating better results of SABR compared with conventional radiotherapy, a consensus that SABR is a standard radical treatment for inoperable patients with stage I NSCLC has been generally accepted. The overall survival rate for subgroup of medically operable patients who rejected surgery in retrospective and prospective studies was almost comparative to that of surgical series considering the same age range though its evidence level is not high. Onishi et al reported five-year overall survival of 87 patients with stage I NSCLC was 69% according to the multicenter retrospective study,. In the phase II trial of SABR with 48Gy in 4 fractions for stage IA (JCOG0403), Nagata et al reported three-year overall of 65 operable patients was 76%. For patients with stage I NSCLC, resection of full lobe and systemic lymph nodes represents standard treatment but can be associated with significant morbidity and even mortality, particularly because patients suffering from lung cancer are often elderly with high comorbidity rates. For such high-risk operable patients, SABR is considered as an alternative option of radical treatment. According to American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, SABR and surgical wedge resection are suggested over no therapy for patients with clinical stage I NSCLC who cannot tolerate a lobectomy or segmentectomy (Grade 2C), but surgical resection has the potential benefit of definitive histologic analysis and pathologic nodal information. In compromised patients for whom such information would not change management and also in patients for whom an adequate margin in unlikely with a surgical wedge resection, SABR is a preferred option. According to good results of these retrospective or prospective studies, some phase III prospective trials comparing SABR versus surgery (lobar resection) have been started, but the patient accrual seems to be difficult. Patient accrual of a trial exploring the efficacy and safety of sublobar resection for patients with smaller tumors has been completed by surgeon recently. SABR is a just local therapy, therefore it essentially should be compared with sublobar resection in high-risk operable patients for lobar resection with such small peripheral tumors. In the meantime, SABR represents a recent trend in radiation oncology also for oligometastases. Local aggressive therapy for oligometastases may improve outcomes, including survival in some cases. SABR has emerged as one option for local therapy against oligometastases in various body sites, most commonly in the lungs and liver. According to published papers of SABR for lung metastases, local control with SABR distributed from 70 to 90% with very low rates of serious toxicities. Although further investigation should be undertaken to clarify the benefits of SABR for the treatment of oligometastases, SABR may be worthwhile for patients who hope for treatment to acquire better local control and possible longer survival. Concerning toxicities, SABR for peripheral tumors is an almost safe and comfortable treatment. Rib fracture is a common adverse effect after SABR but the symptom is generally mild. But severe radiation-related pneumonitis occurs occasionally in the patients having pulmonary fibrosis. As the clear dose-constraint for mediastinal organs has not been demonstrated, the safety of SABR for cases with a central lesion has not been assured. When the tumor recurred only locally after SABR in operable patients, salvage radical surgery was mostly operated safely. Primary radiation therapy remains the primary curative intent approach generally for patients who refuse surgical resection or are determined by a multidisciplinary team to be inoperable or high-risk operable. However, good tumor control, less toxicity, and fewer treatment courses of SABR decrease the indirect costs of cancer care, including lost time and economic productivity secondary to treatment-related and cancer-related illness and death. On the other hand of promising results and advantages of SABR, it is imperative to assess its cost-effectiveness as well as its efficacy because SABR is becoming used in more clinical situations. SABR employing image guidance, high-precision dose delivery, more accurate target definition with better anatomical and biological imaging, and the possibility of dose verification during treatment via dose-adaptive radiation therapy permits a higher probability of tumor control. Such major technological progress certainly comes at a higher cost, and there are many concerns regarding the value of that progress. In the symposium, we will discuss what the benefits and disadvantages of SABR compared to surgical treatment in high or low risk surgical patients with early-stage NSCLC or pulmonary oligometastases are, and how we can decide best to proceed with treatment.

Abstract
Very recently, the revised international multidisciplinary classification of lung adenocarcinoma was published by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society, and European Respiratory Society.[1,2] This new classification is characterized by the creation/abandonment of some terminology for early and advanced adenocarcinomas and by a multidisciplinary approach for the application of the new classification in a clinical setting. In particular, the term "bronchioloalveolar carcinoma (BAC)" is no longer used and, instead, new concepts are introduced, such as “adenocarcinoma in situ (AIS)” and “minimally invasive adenocarcinoma (MIA)”. Invasive adenocarcinomas are classified according to the predominant pattern after comprehensive histologic subtyping with lepidic, acinar, papillary, micropapillary, and solid patterns. The term of mixed subtype adenocarcinoma is no longer used. The gold standard surgery for documented lung cancer has been lobectomy with lymph node sampling/dissection. The randomized, prospective study was performed between lobectomy and sublobar, limited resection in 1980’s by North American Lung Cancer Study Group (LCSG) and the results of this study justified the lobectomy as the standard surgical mode.[ 3] However, looking back this study from the present view point, it is obvious that the earlier forms of lung cancer, as mentioned above as adenocarcinomas of AIS or MIA, were not involved in the LCSG study, and its conclusion could not be applied for these tumors. The present-day issue of lung cancer surgery is to define the role of lobectomy or limited, sublobar resection in relation to newly defined pathological entities. The Japan Clinical Oncology Group (JCOG) has been focusing upon defining the most appropriate surgical approach for tumors of relatively early stages in recent series of clinical trials. JCOG 0201 was intended to define the radiological non-invasive lung cancer on the high-resolution CT image, and it has shown that a consolidation/tumor ratio (C/T ratio) on thin-section computed tomography (TSCT) ≤0.25 in cT1a (≤2.0 cm) could be used as a radiological criterion for a noninvasive pathology.[4] Further prognostic analyses have also indicated that according to this radiological definition of non-invasive lung cancer the 5-year overall survival rate at 97.1% could be achieved.[5] JCOG 0804 is a prospective phase II trial, targeting the radiological non-invasive lung cancers of a diameter of 2.0 cm.[6] Again, the radiological criteria of non-invasive lung cancer were defined as those with a consolidation/tumor ratio (C/T ratio) on thin-section computed tomography (TSCT) ≤0.25. For these tumors, the wide wedge resection or segmentectomy was performed. Targeted number of accrual is 340 patients, and accrual has been already over, awaiting the data maturation. JCOG 0802 is a prospective, randomized phase III trial between lobectomy and segmentectomy for peripheral lung cancers with a diameter of 2 cm or less in a non-inferiority setting.[6] The endpoints are overall survival (primary) and postoperative pulmonary function (secondary), and the targeted accrual is 1,100 patients. As of June, 2013, more than 800 patients were registered. In case that the prognosis of patients undergoing segmentectomy was not significantly inferior to that of those undergoing lobectomy and that the postoperative pulmonary function is significantly better for those undergoing segmentectomy, it can be definitively concluded that standard surgical mode for these early tumors are segmentectomy. The similar randomized trial is also underway in US (CALGB), and the sooner launch of these data is expected to change the daily practice of lung cancer surgery. Oligometastases are the state in which the patients show distant relapse in only a limited number of organs/sites. These distant, metastatic lesions are found both before and immediately after surgery, and obviously these indicate the systemic spread of the cancer cells as stage IV disease. The gold standard treatment for systemic disease has been systemic therapy (chemotherapy). However, it has been anecdotally reported that local treatment modality such as surgery for both primary and metastatic sites cure the patients. The present-day issue for patients with oligometastatic disease is the proper selection of surgical candidate who might benefit from such aggressive treatment in lung cancer. REFERENCES 1. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:144-85. 2.Van Schil P, Asamura H, Rusch VW, et al. Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification. Eur Respir J 2012;39:478-86. 3. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22. 4. Suzuki K, Koike T, Asakawa T, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6. 5. Asamura H, Hishida T, Suzuki K, Japan Clinical Oncology Group Lung Cancer Surgical Study Group. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg. 2013 [Epub ahead of print]. 6. Nakamura K, Saji H, Nakajima R, Okada M, Asamura H, Shibata T, et al. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-4. 7. Niibe Y, Hayakawa K. Oligometastases and oligorecurrence: the new era of cancer therapy. Jpn J Clin Oncol 2010;40:107-11.

Abstract
Lung cancer is the number one cancer killer worldwide accounting for more cancer deaths than colorectal cancer, breast cancer and prostate cancer combined. While the outlook is dismal in advanced lung cancer, when patients are diagnosed once they have become symptomatic, the prognosis is more favourable in early stage node-negative disease. Small lung cancers are increasingly diagnosed as incidental findings on cross-sectional imaging such as CT-coronary angiogram (CTCA), CT-pulmonary angiogram (CTPA), CT angiograms for vascular conditions or CT -intravenous pyelogram (CT-IVP). As many as 15% of patients with early stage NSCLC are not eligible for surgery due to comorbidities, usually poor cardio-respiratory reserve. This number doubles in the patient population 75y and older. Approximately 30% of patients dying of malignancy have pulmonary metastases at autopsy with some primary cancers metastasising exclusively to the lungs. In the setting of primary cancer site being under control, reasonably long disease free interval (DFI) and oligometastatic lung disease with metastases of reasonable size and in amenable positions, data shows a survival benefit for metastasectomy in a selected patient population. Metastasectomies, even if performed as sub-lobar or wedge resections, often carry a substantial morbidity and have a major impact on quality of life. Thermal ablations can be performed in an outpatient setting, they spare healthy tissue, are repeatable and are extremely well tolerated. Thermal ablation has been applied to lung tumours for over a decade and has managed to become an established minimally invasive therapy option for a selected patient population. It is used as a therapeutic means in primary and secondary lung cancer, both with a curative and palliative intent. Combination of thermal ablation with radiotherapy for NSCLC should be a viable consideration in the therapy planning pathway, with available radiofrequency ablation (RFA)/external radiation therapy (XRT) data showing convincing 5y cumulative survival rates of 39% at no additional toxicity. Microwave ablation (MWA) represents the most recent addition to the growing armamentarium of minimally invasive thermal ablation therapies. Advantages of microwave over RF energy are perceived to be many. RF heating requires an electrical conduction path and is therefore less effective in areas of low electrical conductivity and high baseline impedance such as lung parenchyma. Unlike RF and laser, microwaves can even penetrate through the charred or desiccated tissues that build up around all hyperthermic ablation applicators, resulting in limited power delivery for non-microwave energy systems. Further advantages of MWA over RFA are that the system does not require grounding pads, thus avoiding pad site burns, that implanted cardiac devices are less prone to malfunction during MWA than during RFA and that heating occurs faster with is less susceptibility to heat sink, allowing for larger and more homogenous ablation volumes. Multiple microwave antennas can be powered simultaneously to maximise the ablation volume when placed in close proximity to each other, or when widely spaced, to ablate several tumours simultaneously, particularly helpful in the case of multiple metastatic ablations. This presentation will focus on the indications for pulmonary thermal ablation, the limitations of the procedure and the advantages of MWA over RFA.

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Abstract
Dramatic response has been achieved by EGFR inhibitors in lung cancer expressing EGFR activating mutations. However, cancer cells show either intrinsic or acquire resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, and cause disease progression. Known major mechanisms for acquired resistance to EGFR-TKI include T790M gatekeeper mutation in the EGFR gene and activation of bypass survival signal via receptors other than EGFR. The latter mechanism can involve Met gene amplification and ligand-triggered receptor activation as well. For example, HGF, the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant cancer cells. Moreover, common polymorphism in BIM gene was recently reported to be found specifically in East Asian and confer intrinsic resistance to EGFR-TKI. These accumulating evidences suggest that mechanisms of EGFR-TKI resistance are complicated and heterogenous even in one individual. In this session, the resistance mechanisms will be introduced and therapeutic strategies will be discussed.

Abstract
ALK gene rearrangements occur in approximately 5% of lung adenocarcinomas and less frequently in other histologic subtypes. Crizotinib is currently the standard of care for ALK+ NSCLC (1). Treatment with crizotinib leads to remarkable objective response rates, durable progression free-survival and superiority over standard second line chemotherapy. Unfortunately, patients eventually experience disease progression on crizotinib. Disease progression may occur primarily in the central nervous system (CNS) alone, likely because of poor penetration of crizotinib into this space, or simultaneously with systemic progression outside of the CNS (2). Systemic disease progression likely occurs via cellular resistance that occurs by multiple mechanisms, which have been observed in vitro or in patient tumor samples derived following progression on crizotinib. Mutations in the kinase domain of ALK currently account for approximately 25% of observed drug resistance (3-5). Resistance mutations occur at the ‘gatekeeper’ position, L1196M, but multiple other ALK kinase domain mutations have been observed in patient samples or in cell lines with induced drug resistance. Indeed, in the first case of published crizotinib resistance, the tumor harbored two separate ALK mutations (6). This pattern stands in contrast to EGFR mutant lung cancer, where the observed rate of resistance mutations is 50-60% and the majority of resistance mutations occur at the gatekeeper position, T790M (7). Also in contrast to EGFR mutant lung cancer, resistance mutations in ALK do not appear to confer a fitness disadvantage to the tumor cell (3). Mutations induce resistance by allowing persistent ALK signaling despite the presence of crizotinib. Copy number gain of the ALK fusion has also been observed in both cell line models and in patient tumor samples following crizotinib resistance (3, 4). It is hypothesized that that a fraction of ALK fusion proteins are not inhibited by clinically achievable doses of crizotinib and that increased expression may allow sufficient downstream signaling for tumor cell survival. Collectively, we have termed resistance mutations and copy number gain as ‘ALK-dominant’ mechanisms of resistance, because the tumor cells are still predicted to be ‘addicted’ to ALK signaling. Multiple mechanisms of ‘bypass’ signaling have been observed in both cell line models and post-progression tumor biopsies. These include activating mutations in EGFR and KRAS, and ligand dependent activation of EGFR or KIT (3, 4). In some cases the ALK gene rearrangement is no longer observed in post-crizotinib biopsy, also suggestive of an alternate or bypass signaling pathway. We have termed these bypass signaling mechanisms as ‘ALK non-dominant’ resistance as the tumor cells may no longer be dependent on ALK signaling. Approximately 50% of patients have been shown to harbor each class (dominant vs. non-dominant) resistance and this may have implications for post-progression therapy in these patients (1). Next generation ALK inhibitors such as LDK378, AP26113, and CH/RO5424802 which potently inhibit the ALK kinase and have activity against many of the resistance mutations in vitro, may be the favored post-progression therapy for patients with ALK dominant resistance. All of these drugs have also demonstrated anecdotal evidence of activity in the CNS. Although not ALK-specific, HSP90 inhibitors, such as ganetespib, IPI-504, and AUY-922, can inhibit ALK signaling by decreasing proper folding of the chimeric ALK fusion proteins and may also overcome ALK dominant resistance (8). ALK non-dominant resistance may require dual inhibition of ALK and a bypass signaling pathway to overcome resistance and the selection of drugs would be dependent on the alternate signaling pathway. Currently, no post-crizotinib therapies are approved in ALK+ lung cancer, but systemic chemotherapy remains as useful treatment strategy and some evidence suggests that pemetrexed-based regimens may be an optimal initial choice in the absence of a clinical trial (9). References 1. Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future challenges. Nat Rev Clin Oncol. 2012;9:268-77. 2. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443-5. 3. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472-82. 4. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4:120ra17. 5. Huang D, Kim DW, Kotsakis A, Deng S, Lira P, Ho SN, et al. Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics. 2013. 6. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734-9. 7. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-7. 8. Normant E, Paez G, West KA, Lim AR, Slocum KL, Tunkey C, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30:2581-6. 9. Camidge DR, Kono SA, Lu X, Okuyama S, Baron AE, Oton AB, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6:774-80.

Abstract not provided

Abstract
Lung cancer therapy in the metastatic setting is invariably characterized by the emergence of resistance. This applies both to conventional chemotherapy and molecular targeted agents. This presentation will focus on the biological background and subsequent trial designs as it applies to resistance regarding molecular targeted agents (MTA). In the clinical setting when a patient develops progressive disease while exposed to a MTA some key basic considerations should be taken into account before considering acquired biological resistance. Compliance of the patient to the prescribed therapy is an obvious one. Indeed chronic exposure to tyrosine kinase inhibitors (TKI) exposes the patient to chronic toxicities. Some of these toxicities can become intolerable for the patient, thus leading to patient-driven therapeutic breaks that are frequently not specified to the clinician. This is notably true for week-end breaks as well holiday breaks. Honest dialogue with the patient is necessary to identify compliance issues and pharmacological (PK) dosage in the blood of the relevant TKI is an approach to be discussed. Further pharmacokinetic interactions represent a real issue with TKI: many TKI are metabolized by the liver and can have CYP liabilities (ie erlotinib, gefitinib are susbtrated of CYP3A4). Inter-individual PK variability due to genotypic background (polymorphisms in genes encoding drug metabolizing enzymes), inflammatory and nutritional status, may result in suboptimal drug concentrations and decreased efficacy. Significant decrease in drug exposure over time have also been described for and may result in secondary progression despite preserved sensitivity to these agents, with a potential role for subsequent dose escalation. From a biological perspective, 3 main mechanisms have been described to explain resistance to TKI: a) mutation/amplification in the target (ie T790M for EGFR or ALK L1196M), bypass mechanism (ie Met amplification, PI3K mutation, HER 3 activation,) and growth survival/apoptosis resistance (ie loss of BIM, SCLC, EMT). Stronger kinase inhibitors and use of combinations appear as potential solutions to deal with these resistance mechanisms. Some of the potential designs to address acquired resistance include: a) upfront combinations, b) use of third generation inhibitors or mutant-specific inhibitors, c) rolling trials (ie the use of sequential TKI therapies), c) alternating therapeutic approaches (TKI followed by chemotherapy or TKI followed by immunotherapy).

Background
Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

Methods
We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

Results
Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

Conclusion
Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

Background
Necitumumab is a human IgG1 anti-EGFR1 monoclonal antibody that competes for the binding of natural ligands to this receptor and prevents receptor activation. EGFR1 is detectable in approximately 85% of advanced NSCLC tumors. This phase 3 study investigated necitumumab in combination with first-line chemotherapy in advanced non-squamous NSCLC.

Methods
Patients with histologically or cytologically proven stage IV non-squamous NSCLC were randomized 1:1 to either Arm A: cisplatin 75mg/m[2] i.v.-pemetrexed 500mg/m[2] i.v. (Cis + PEM) on Day 1+ necitumumab 800mg i.v. on Days 1 and 8 of a 21-day cycle or Arm B: Cis+PEM alone. Patients received these regimens for up to six cycles. For patients in Arm A with at least stable disease, necitumumab continued until PD or intolerable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and EGFR protein expression level by immunohistochemistry (H-score) utilizing archived tumor tissue based on a mandatory tissue collection. The planned sample size of this study was 947 patients (assuming a hazard ratio [HR] of 0.8 would allow 85% power at 2-sided alpha level of 0.05). After 633 patients, enrollment was stopped (after Feb 2011) following an Independent Data Monitoring Committee (IDMC) recommendation.

Results
Between Nov 2009 and Feb 2011 633 patients were randomized (315 Arm A; 318 Arm B). Baseline characteristics were balanced between the arms; 67.0% were male and 33.0% female; ECOG-PS 0/1 94.2 % and PS 2 5.7 %. No difference between treatment arms was observed for OS (median 11.3 vs 11.5 months; HR 1.01 95%-CI [0.84, 1.21]), PFS (median 5.6 vs 5.6 months, HR 0.96 95%-CI [0.80, 1.16]) and ORR (31.1 vs 32.1%; Odds ratio 0.96 95%-CI [0.68, 1.34]). The exploratory analysis in 490 patients assessable for H-score revealed no association between H-score and differences in efficacy between treatment arms (H-score < 200: mOS 8.97 vs 9.72 months, HR 1.07, mPFS 4.90 vs 4.76 months, HR 0.95, ORR 27.1 vs 26.0%; H-score ≥ 200: mOS 15.01 vs 13.34 months, HR 1.03, mPFS 5.59 vs 5.62 months, HR 0.94, ORR 39.6 vs 39.4%). Grade ≥ 3 treatment-emergent adverse events (AEs) occurring more frequently in Arm A included skin or subcutaneous disorders (14.1 vs 0.3%), thromboembolic events (9.5 vs 6.4%), hypomagnesaemia (7.6 vs 2.2%), asthenia (6.9 vs 1.9%), vomiting (6.6 vs 3.2%), dyspnea (5.3 vs 2.6%) and diarrhea (4.3 vs 2.2%). The frequency of study drug related deaths was 4.9% and 2.9% in Arms A and B, respectively.

Conclusion
In this study, the addition of necitumumab did not improve the efficacy outcome over cisplatin plus pemetrexed alone in advanced non-squamous-NSCLC. The EGFR H-score did not seem to predict the efficacy outcomes of necitumumab in combination with cisplatin plus pemetrexed. The addition of necitumumab resulted in a higher frequency of grade ≥ 3 AE (skin reaction, GI, asthenia and other) and an imbalance of grade ≥ 3 thromboembolic events. Further biomarker studies are ongoing.

Background
With recent successes of targeted therapeutics, there has been increased enthusiasm to enroll patients with NSCLC into phase I trials. Most phase I prognostic indices have been derived from patient populations where NSCLC is underrepresented.

Methods
Retrospective review of NSCLC patients enrolled between 2005-2012 at National Cancer Centre Singapore was performed, collating data on demographics, molecular profiles, trial characteristics and clinical outcomes (using RECIST criteria) to identify prognostic factors to improve patient selection.

Results
167 patients were treated on 20 phase I trials. Median (range) age 60.7 years (22.7–84.7), 58% male, adenocarcinoma/squamous/NOS/others (75.4%/9.6%/12.6%/2.4%). 13% were at high risk of nutritional deficiency (BMI<18.5), and ECOG 0(21%)/1(77%)/2(2.4%). Median (range) prior chemotherapy was 2 (0-6) and 99% received at least one treatment line. Class of agents include anti-angiogenics (50.3%), signal transduction pathway inhibitors (STPi) 46%. Only 4.2% received cytotoxics alone. 86.2% were on combination regimens, of which two-thirds on combinations of chemotherapy and small molecule. Between 2008-2012, proportion of patient tumors with molecular alterations identified increased from 5.5% to 62.5%, facilitating enrolment into trials designed for a specific genotype (or “matched” trials). 35% and 7.8% of patients participated on trials targeting EGFR and ALK alterations respectively. With a median follow up of 8.7 months, progression free survival was 3.9m (95%CI:3.4–5.8), overall survival (OS) 10.4m (95%CI:8.0–11.7). Among evaluable patients, 24.8% (95%CI:18.2–32.5) had complete/partial response; clinical benefit rate (CBR) 75.8% (95%CI:68.2–82.4). 90-day mortality (90DM) was 15%. Patients participating in “matched” trials had a lower risk of death (HR 0.55 [95%CI:0.38-0.78] p<0.001) compared to those on unselected or “unmatched” trials (median OS 11.9 v 7.6). On univariate analysis, low BMI<18.5, ECOG>0, ≥3 metastatic sites, presence of bone metastasis, low albumin (<35), low Hb (<12), ≥ 3 prior lines of chemotherapy and non-participation in a "matched" trial were significant negative prognostic factors for OS. On multivariate analysis, ECOG, number of metastatic sites, albumin and trial type (targeting EGFR/ALK/others), emerged as independent variables. These factors were used to construct a prognostic nomogram to predict OS at 3, 6 and 12m. Of 12 published prognostic indices, 8 models were validated in our patient cohort, with the highest c-index being 0.66. Pairwise comparison against these 8 (7 tumor agnostic; 1 NSCLC) prognostic indices, found the nomogram to be superior in predicting OS, with a c-index of 0.74.

Conclusion
This is the largest analysis of phase I NSCLC patients using individual patient data. Outcome of NSCLC patients in phase I trials is promising with CBR 76% and median OS 10.8m. Our nomogram – comprising of ECOG, albumin, number of metastatic sites, participation in a “matched” trial – is uniquely derived from NSCLC patients and was a better predictor of OS compared to 8 published phase I prognostic scores.

Abstract not provided

Background
EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18–21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Here we present the first prospective data series on activity of afatinib, the irreversible ErbB Family Blocker, in patients with tumours harbouring uncommon EGFR mutations.

Methods
This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit (TheraScreen29) in LUX-Lung 3 and 6. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorized into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.

Results
Seventy-five patients (LUX-Lung 2: n=23; LUX-Lung 3: n=26; and LUX-Lung 6: n=26) had uncommon mutations, accounting for 12.5% of all afatinib patients in these studies. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was T790M: n=14; Exon 20 insertions: n=23; other: n=38 (most frequent types were L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3). Efficacy results for each group are shown below. Further details by mutation status will be presented.

Conclusion
Afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q, S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients. To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations; treatment options in this heterogeneous group of tumours will be discussed.

Background
Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest greatest efficacy when plasma concentrations exceed 200ng/ml for >16hrs/day.

Methods
This is an ongoing first-in-human dose finding study (3+3) of oral CO-1686 administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. All patients must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Endpoints include safety, pharmacokinetics (PK), and efficacy.

Results
As of 12 June 2013, 45 patients have been treated with CO-1686. 31/42 (74%) were T790M+; data for three patients is pending. The median age is 58 years, 82% are female, 75% are white, and 73% ECOG 1. The median number of previous therapies was 4 (range: 1- 6), with a median of 1 (range: 1- 4) previous EGFR TKI therapies. Dosing started at 150mg QD and escalated to 900mg QD, 900mg BID and 400mg TID, with a maximum tolerated dose not yet reached. Treatment-related AEs (all grades) occurring in > 5% patients were: fatigue (19%), diarrhea (15%), nausea (14%), anemia (10%), arthralgia (7%), muscle spasms (10%), myalgia (7%), headache (7%). The majority of events were mild or moderate. Unlike other EGFR inhibitors, rash and diarrhea were not commonly seen. This AE profile is consistent with the expected lack of wild type EGFR inhibition with CO-1686. The PFS for T790M+ patients with CO-1686 plasma concentrations > 200ng/mL for > 16 hours was 194 days compared with 72.5 days for those that achieved these concentrations for < 16 hours (Figure 1). At the highest evaluated dose, 900mg BID, four T790M+ patients were evaluable for response; 3 of the 4 achieved PRs, one achieved SD. One patient at a lower dose cohort also achieved a PR. Further safety and efficacy data will be presented at the meeting. Figure 1

Conclusion
CO-1686 has demonstrated good tolerability and efficacy against proven T790M+ EGFR mutant NSCLC with a strong suggestion of a dose-response relationship. Additional evaluation of the optimal dose and formulation of CO-1686 are underway to further explore its potential for improved activity and better tolerability over other existing EGFR TKIs.

Background
A large-scale surveillance study (POLARSTAR) was implemented to investigate erlotinib safety and efficacy in Japanese patients, focusing on the pattern of occurrence of interstitial lung disease (ILD) and specific factors that may contribute to the onset of ILD in patients receiving erlotinib. The following risk factors for erlotinib-induced ILD have been previously reported: concurrent/previous ILD (adjusted hazard ratio [HR] =3.2), existing emphysema/chronic obstructive pulmonary disease (COPD) (HR=1.9) or lung infection (HR=1.6), smoking status (HR=2.2) and ECOG performance status 2–4 (HR=1.4). These were identified as the primary risk factors for ILD by multivariate analysis. The current analysis was carried out to identify factors linked with poor prognosis in terms of ILD-related death within the POLARSTAR surveillance study.

Methods
Enrolment of all patients in Japan receiving erlotinib for NSCLC took place between December 2007 and October 2009; the observation period was 12 months. All ILD-like events were assessed by an independent ILD review committee. ILD was defined as all ILD-like events excluding those events deemed non-ILD by the independent ILD review committee. Risk factors for poor prognosis concerning ILD death were analyzed by multivariate analysis using a logistic regression model.

Results
A total of 10,708 patients were enrolled by the data cut-off of 12 October 2009, with data available for 9,909 patients. The majority of ILD cases were reported within 4 weeks of receiving erlotinib. Among the 491 patients who experienced ‘ILD-like’ events, 93 could not be evaluated by the independent ILD review committee due to lack of imaging data; the remaining 398 patients were referred to the committee for evaluation. A total of 310 patients had confirmed ILD by the ILD review committee, based on image evaluation or clinical investigation; 125 had died as a result of ILD. These patients were assessed by multivariate analysis. Sixty-two events were deemed non-ILD and 26 events could not be evaluated due to a lack of clear clinical evidence (e.g. ILD could not be distinguished from progression or pneumonitis, or insufficient imaging data were available). The multivariate analysis identified ECOG performance status 2–4 (adjusted odds ratio [OR] =2.45 [95% CI 1.41–4.27]; p=0.0016), <50% remaining normal lung area (OR=3.12 [1.48–6.58]; p=0.0029) and interstitial pneumonia with concomitant honeycomb lung (OR=6.67 [1.35–32.94]; p=0.02) as poor prognostic factors for ILD death. However, pre-existing interstitial pneumonia by grade of severity was not identified as one of these factors. This result could be attributed to practical bias in this surveillance study, such as selection or treatment bias for patients with pre-existing interstitial pneumonia within the condition of careful dosage specified in the erlotinib label.

Conclusion
These final data from this large surveillance study in Japanese patients with recurrent and advanced NSCLC provide further information on the risk factors for poor prognosis with ILD, identifying those patients at greatest risk of ILD-related death. Improved awareness of these prognostic factors will help clinicians in monitoring those patients at highest risk.

Abstract not provided