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T. John
Moderator of
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MO07 - NSCLC - Targeted Therapies II (ID 114)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 14
- Moderators:T. John, J.W. Riess
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1
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MO07.01 - Clinical benefit of continuing crizotinib beyond initial disease progression in patients with advanced <em>ALK</em>-positive non-small-cell lung cancer (ID 2843)
16:15 - 16:20 | Author(s): S.I. Ou, G.J. Riely, Y. Tang, D. Kim, G.A. Otterson, L. Crinò, C.H. Bartlett, D.P. Cohen, J.W. Clark, P.A. Jänne
- Abstract
- Presentation
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 1Conclusion
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.02 - Clinical experience with crizotinib in patients with advanced <em>ALK</em>-rearranged non-small cell lung cancer and brain metastases in PROFILE 1005 and PROFILE 1007 (ID 2932)
16:20 - 16:25 | Author(s): D.B. Costa, A.T. Shaw, S.I. Ou, B.J. Solomon, G.J. Riely, M. Ahn, C. Zhou, S..M. Shreeve, R. Wiltshire, P. Selaru, A. Polli, P. Schnell, D..R. Camidge, L. Crinò
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.03 - Crizotinib therapy for patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) (ID 2777)
16:25 - 16:30 | Author(s): S.I. Ou, D. Kim, D..R. Camidge, G. Riely, R. Salgia, G. Shapiro, B. Solomon, J.A. Engelman, E.L. Kwak, J.W. Clark, L. Tye, K. Wilner, T. Usari, M. Varella-Garcia, K. Bergethon, A.J. Iafrate, A.T. Shaw
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.04 - Clinical Implication of a Population Pharmacokinetic Analysis of XALKORI (crizotinib) in 1,182 Patients with Non-Small Cell Lung Cancer (NSCLC) and 32 Patients with Other Solid Tumors (ID 3082)
16:30 - 16:35 | Author(s): D. Nickens, E. Wang, A. Bello, R. Khosravan, M. Amantea, W. Tan
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.05 - DISCUSSANT (ID 3952)
16:35 - 16:45 | Author(s): J. Soria
- Abstract
- Presentation
Abstract not provided
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MO07.06 - Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies (ID 2400)
16:45 - 16:50 | Author(s): D..R. Camidge, L. Bazhenova, R. Salgia, G.J. Weiss, C.J. Langer, A.T. Shaw, N.I. Narasimhan, D.J. Dorer, V.M. Rivera, J. Zhang, T. Clackson, F.G. Haluska, S.N. Gettinger
- Abstract
- Presentation
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. NCT01449461Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.07 - Combined pan-ERBB and ALK/ROS1/MET inhibition with dacomitinib and crizotinib in advanced non-small cell lung cancer (NSCLC): update of a phase I trial (ID 2740)
16:50 - 16:55 | Author(s): G. Giaccone, D.R. Camidge, P.A. Jänne, B. Solomon, L.P. James, Y. Tang, J. Martini, Z. Goldberg, S..M. Shreeve, A.T. Shaw
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.09 - Feasibility and clinical impact of re-biopsy in advanced non-small cell lung cancer: a prospective multicentric study in real world setting (GFPC study 12-01) (ID 1045)
17:00 - 17:05 | Author(s): C. Dujon, C. Chouaid, P. Do, I. Monnet, A. Madroszyk, H. Le Caer, J. Auliac, H. Berard, P. Thomas, H. Lena, G. Robinet, S. Hominal, N. Baize, A. Bizieux-Thaminy, G. Fraboulet, C. Locher, J. Le Treut, A. Vergnenegre
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.10 - DISCUSSANT (ID 3953)
17:05 - 17:15 | Author(s): N. Pavlakis
- Abstract
- Presentation
Abstract not provided
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MO07.11 - A randomised placebo-controlled multicentre phase II trial of erlotinib plus whole brain radiotherapy for patients with advanced non-small cell lung cancer with multiple brain metastases (TACTIC) (ID 2305)
17:15 - 17:20 | Author(s): S.M. Lee, C. Lewanski, N. Counsell, C. Ottensmeier, A.T. Bates, N. Patel, C. Wadsworth, Y. Ngai, A. Hackshaw, C. Faivre-Finn
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.13 - Efficacy of afatinib vs. chemotherapy in treatment-naïve patients with non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations with or without metastatic brain disease (ID 1923)
17:25 - 17:30 | Author(s): M. Schuler, J.C. Yang, L.V. Sequist, V. Hirsh, K. O'Byrne, N. Yamamoto, D. Massey, M. Shahidi, V. Zazulina, T. Mok
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO07.14 - DISCUSSANT (ID 3954)
17:30 - 17:40 | Author(s): M. Ahn
- Abstract
- Presentation
Abstract not provided
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MO16 - Prognostic and Predictive Biomarkers IV (ID 97)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:S. Toyooka, J.C. Yang
- Coordinates: 10/29/2013, 16:15 - 17:45, Parkside Auditorium, Level 1
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MO16.05 - DISCUSSANT (ID 3915)
16:35 - 16:50 | Author(s): T. John
- Abstract
- Presentation
Abstract not provided
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P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.05-007 - Large scale establishment of genetically diverse patient-derived primary tumor xenografts from resected early stage non-small cell lung cancer (NSCLC) patients (ID 1539)
09:30 - 09:30 | Author(s): T. John
- Abstract
Background
The fidelity of established NSCLC cell line models to reflect patient tumors has been challenged. Patient-derived primary tumor xenografts (PTXGs) established directly from patient tumors in immunodeficient mice reproduce closely the histology of the primary tumors, thus are potentially better preclinical models to investigate novel therapies. We previously reported that early stage NSCLC patients whose tumors form PTXGs have significantly greater risk of relapse after surgery (Clin Cancer Res 2011; 17: 134-141). We report here a more extended analysis of clinical-molecular-pathological features of early stage NSCLC that are associated with engraftment and its impact on patient outcome.Methods
Resected NSCLC tumors were harvested within 30 minutes after surgery and were implanted into severely immunodeficient mice to establish PTXGs. Tumors that grew were propagated for up to 3 passages. The mutational profiles of the primary tumors were assessed by the MassARRAY platform that included 133 mutations with ‘putative’ driver function, which have been reported in COSMIC database as recurrent in NSCLC. All identified mutations were verified by direct sequencing in both the primary and PTXG tumors. Engraftment rate among clinical factors were tested using the Fisher’s exact or Mann-Whitney tests. The Kaplan-Meier method was used to estimate 3-year overall (OS) and disease-free survival (DFS) probabilities. The effect of engraftment on OS and DFS adjusting for clinical variables was assessed using a Cox proportional hazards model.Results
From April 2005 to December 2010, 261 rigorously verified resected primary non-carcinoid NSCLCs were engrafted; 38 xenografts that were lymphoma were excluded from further analysis. For the remaining 223 primaries, 101 (45.3%) successfully engrafted and formed PTXG lines. Engraftment rates were 33.8% (48/142) for adenocarcinoma (AdC), 67.7% (42/62) for squamous cell carcinoma (SqCC), 66.7% (4/6) for large cell neuroendocrine carcinoma, and 53.8% (7/13) for others. The tumors forming PTXGs were more likely to be poorly differentiated (p=0.00012) and of larger tumor size and higher pT stage (p<0.0001), but were not correlated with the pN stage. Among 95/101 (94.1%) PTXG cases profiled for mutations, 6 had mutations in the EGFR tyrosine kinase domain, 18 in KRAS/HRAS, 5 in PIK3CA, 2 in paxillin and 1 in STK11/LKB gene; 56 (62.2%) were negative for mutations. The median follow-up time was 2.7 years (range 0.04 – 7.5 years). Patients whose tumors engrafted had decreased DFS (HR 2.68, 95% CI 1.16-4.60, Wald p<0.0001) and OS (HR 3.14, 95% CI 1.56-6.33, Wald p=0.0014). Significantly poorer survival was maintained in AdC. Among 33 patients with EGFR mutation, only 6 (18.2%) engrafted. Engraftment was associated with significantly poorer DFS (HR 4.76; 1.43-15.86, log-rank p=0.005) and OS (HR 8.55, 95% CI 0.77-94.3, log-rank p=0.035) in this population.Conclusion
The ability to form PTXGs of early stage NSCLC is confirmed as a very strong poor prognostic marker. Although EGFR mutant tumors usually do not engraft, engraftment of EGFR mutant tumors is associated with poor patient survival. PTXGs appear to represent biologically aggressive NSCLC.
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P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.06-034 - MET expression, copy number and oncogenic mutations in early stage NSCLC (ID 2424)
09:30 - 09:30 | Author(s): T. John
- Abstract
Background
The MET receptor tyrosine kinase and its ligand are associated with the malignant phenotype. In non-small cell lung cancer (NSCLC) MET expression increases with disease stage and is involved in de novo and acquired resistance to tyrosine kinase inhibitors. Despite this, in early stage NSCLC, conflicting data series have reported MET expression and copy number to be prognostic in some studies but not others[1,2]. We investigated a large cohort of patients who underwent curative surgical resection at our institution to determine whether MET receptor or gene amplification was prognostic.Methods
Tissue Microarrays (TMAs) were constructed using 1mm cores of FFPE primary NSCLC tissues in triplicate. TMAs were stained with the MET SP44 clone and a H-score calculated based on % cells stained and intensity; (%cellsx1)+(%cellsx2)+(%cellsx3) with a minimum of 0 and maximum of 300. The mean of triplicate values was calculated. MET gene amplification was detected using Ventana’s MET DNP probe with ultraView SISH DNP silver detection, performed on Ventana’s XT autostainer. DNA was isolated and subjected to mutational profiling using Sequenom’s LungCarta panel.Results
Data for 508 patients, 352 (69%) male, were available for analysis including 329 pathological node negative (pN0), 67 pN1, 104 pN2 and 8 patients with resected primaries and solitary brain metastases (M1). Most patients were smokers with only 33 (6%) non-smokers. The median MET H-score was 100 and consistent across N0, N1 and N2 patients, although was higher in M1 patients. Median H-scores were significantly higher in adenocarcinoma compared to squamous cell carcinoma (140 vs 91.5, p<0.0001). Increased MET expression (H-score>100) was seen in 227 (45%) patients. High quality DNA was isolated in 443/508 (87%) of samples. The commonest mutations were in KRAS (21%), TP53 (10%), EGFR (5%), PIK3CA (4%) MET (3%) and NRF2 (3%). No mutation was found in 44% of samples. EGFR and KRAS mutations were associated with significantly higher MET expression, whereas TP53 was associated with significantly lower expression (Chi square p=0.0005). These differences may reflect the higher rates of adenocarcinoma in both EGFR and KRAS mutated tumours. Increased MET copy number by SISH was only observed in 6 samples. MET expression was not associated with cancer specific survival across all stages. In tumours harbouring mutations and in wild type tumours, there were no significant differences in survival according to MET expression.Conclusion
Although increased MET expression was associated with both KRAS and EGFR mutations, it was not prognostic in this large cohort of resected NSCLC. MET expression may be both predictive and prognostic in advanced NSCLC, but its role in early stage NSCLC is unclear. References: 1. Dziadziuszko R, et al. Correlation between MET Gene Copy Number by Silver In Situ Hybridization and Protein Expression by Immunohistochemistry in Non-small Cell Lung Cancer. Journal of Thoracic Oncology. 2012 Feb;7(2):340–7. 2. Cappuzzo F, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. Journal of Clinical Oncology. 2009 Apr 1;27(10):1667–74.
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P1.12 - Poster Session 1 - NSCLC Early Stage (ID 203)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.12-018 - Overall Survival and Smoking Status in Resectable Non-Small Cell Lung Cancer (ID 2662)
09:30 - 09:30 | Author(s): T. John
- Abstract
Background
Although the carcinogenic effects of cigarette smoking are important in the pathogenesis of lung carcinoma, the impact of quantitative smoking history on survival in resectable tumours has not been well described. Using a comprehensive database in which smoking was quantitatively documented, we analysed the impact of increasing number of pack years of smoking on stage, histology, mutation status and overall survival in an Australian population. We focused on patients without nodal involvement (N0) as they were less likely to have received neoadjuvant or adjuvant therapy.Methods
Data was extracted from a large single institution database containing information on patients who underwent curative resection of non-small cell lung cancer from 1992 to 2012. Cigarette smoking history was documented in pack years. DNA was isolated and analysed using Sequenom’s LungCarta panel which interrogates 214 mutations in 26 genes. Statistical analysis was performed using Chi-square tests and the Kaplan Meier method for survival.Results
Information on pack year smoking status was available for 470 patients, 70% of whom were male. This included 311 (66%) pathological N0 (pN0), 64 (14%) pN1 and 95 (20%) pN2. Smoking history ranged between 0 (never smokers N=32, 7%) and 180 pack years, with a median of 45 and mean of 48. Patients were divided into quartiles based on their smoking history: never- and < 10 pack year smokers (N=43; 9%), 11-25 pack years (N=74; 16%), 26-50 pack years (N=180; 38%) and >50 pack years (N=173; 37%). Adequate DNA was isolated in 425 samples. Frequencies of mutations were as follows: KRAS 21%, TP53 10%, EGFR 5%, PIK3CA 4%; other mutations occurred at lower frequencies. In 44% no mutation was found. Increased pack year history of smoking was not associated with overall survival. In the pN0 wild type population, no association with smoking and survival was seen. In the pN0 mutation group (Figure 1) those with a <25 pack year history had significantly better overall survival than heavier smokers (HR 0.61, 95% CI 0.40-0.92). Figure 1: Overall Survival by smoking status in pN0 tumours with a mutationFigure 1Conclusion
Smoking status was not associated with overall survival across the entire cohort. In patients whose tumour harboured a mutation, increased smoking was associated with a less favourable mutation profile including in KRAS, TP53 and PIK3CA. In patients with pN0 disease a significant difference in overall survival was observed favouring light smokers. The presence of mutations in association with heavy smoking negatively impacts overall survival.
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P2.09 - Poster Session 2 - Combined Modality (ID 213)
- Event: WCLC 2013
- Type: Poster Session
- Track: Combined Modality
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.09-007 - Comparison of toxicity and outcomes of concurrent radiotherapy with carboplatin/paclitaxel and cisplatin/etoposide in stage III non-small cell lung cancer (ID 1497)
09:30 - 09:30 | Author(s): T. John
- Abstract
Background
Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). The comparative merits of two widely used regimens: carboplatin/paclitaxel (PC) and cisplatin/etoposide (PE), each given with concurrent radiotherapy, remain largely undefined.Methods
Records for consecutive patients with stage III NSCLC treated with PC or PE and ≥60Gy chest radiotherapy between 2000-2011 were reviewed for outcomes and toxicity. Survival was estimated using the Kaplan-Meier method and Cox modeling with the Wald test. Comparison across groups was done using the student t and chi-squared tests.Results
75 (PC: 44, PE: 31) patients were analyzed. PC patients were older (median 71 vs 63 years; p=0.0006). Other characteristics were comparable between groups. With PE, there was significantly increased grade ≥3 neutropenia (39% vs 14%, p=0.024) and thrombocytopenia (10% vs 0%, p=0.039). Radiation pneumonitis was more common with PC (66% vs 38%, p=0.033). Five treatment related deaths occurred (PC: 3 vs PE: 2, p=1.000). With a median follow up of 51.6 months, there were no significant differences in relapse free survival (median PC 12.0 vs PE 11.5 months, p=0.700) or overall survival (median PC 20.7 vs PE 13.7 months; p=0.989). In multivariate analyses, no factors predicted for improved survival for either regimen. Table 1: Non-hematological and hematological adverse events, by grade (CTCAE 4.0)Adverse events PC (n = 44) PE (n = 31) n (%) n P~χ2~ Esophagitis 1 2 3 4 3 (7) 19 (43) 10 (23) 5 (11) 5 (16) 7 (23) 10 (32) 1 (3) 0.151 Pneumonitis 1 2 3 4 5 21 (48) 6 (14) 0 (0) 1 (2) 1 (2) 4 (13) 6 (19) 1 (3) 1 (3) 0 (0) 0.033 Neuropathy 1 2 1 (2) 1 (2) 0 (0) 0 (0) 0.485 Nephropathy 1 2 3 3 (7) 0 (0) 0 (0) 4 (13) 0 (0) 1 (3) 0.314 Nausea/vomiting 1 2 3 7 (16) 8 (18) 0 (0) 7 (23) 2 (6) 1 (3) 0.291 Chest infection 1 2 3 4 5 1 (2) 1 (2) 11 (25) 1 (2) 1 (2) 0 (0) 3 (10) 5 (16) 2 (6) 1 (3) 0.534 Neutropenia 1 2 3 4 4 (9) 5 (11) 6 (14) 0 (0) 2 (6) 0 (0) 8 (26) 4 (13) 0.024 Febrile neutropenia 3 4 5 (11) 0 (0) 5 (16) 1 (3) 0.394 Anemia 1 2 3 4 12 (27) 5 (11) 1 (2) 0 (0) 10 (32) 9 (29) 0 (0) 1 (3) 0.117 Thrombocytopenia 1 2 3 1 (2) 3 (7) 0 (0) 4(13) 1 (3) 3 (10) 0.039 Treatment-related deaths 3 (7) 2 (6) 1.000 Conclusion
PC was more likely to be used in elderly patients. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes as PE. PC is an acceptable CCRT regimen, especially in older patients with multiple comorbidities.
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P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.06-039 - Expression of Mucin 1 in non-small cell lung cancer: Relationship between immunohistochemistry, tumour characteristics and survival (ID 2765)
09:30 - 09:30 | Author(s): T. John
- Abstract
Background
Mucin 1 (MUC1), a glycoprotein highly expressed in many malignancies, is being explored as an antigen for immunotherapy. How best to measure MUC1 expression in non-small cell lung cancer (NSCLC) and its prognostic value in NSCLC are under discussion.Methods
Tissue microarrays (TMAs) were constructed using triplicate 1mm cores of formalin-fixed paraffin-embedded tumour and stained with 214D4 (recognizes protein core) and MA695 (recognizes carbohydrate epitope) anti-MUC1 antibodies. TMAs were assessed for polarization, cytoplasmic and membranous staining intensity (scored 0–3) and proportion cells positive (0–100%; scored 0–5), averaged for multiple cores. A composite score (intensity x cells positive) was derived (range 0–15).Results
TMAs from 518 patients were analyzed: 69% male, 95% Caucasian, 7% never-smoking; 49% adenocarcinoma, 35% squamous cell, 7% large cell; 43% stage I NSCLC, 33% stage II, 23% stage III. Immunohistochemistry staining intensity, proportion positive cells and depolarization were very similar between antibodies, with high concordance in composite score (R2=0.71, p<0.0001). Polarization was discordant in 8%. Similar scores were seen for N0, N1 and N2 when assessed by either antibody. For 77 cases with paired primary/N2 nodal tissue, mean 214D4 composite scores were 10.7 and 10.1 and MA695 scores 9.5 and 9.4, respectively. Discordant staining in primary but not node was seen in 5.2% and 10.4% with 214D4 and MA695, respectively. For 27 cases with neoadjuvant chemotherapy vs no chemotherapy, mean 214D4 scores were 10.2 vs 10.1 and MA695 9.3 vs 9.6, respectively. Higher scores with each antibody trended toward improved survival (non-significant). Polarization was associated with improved survival (whole cohort) with 214D4 (80.6 vs 47.8 months; HR 1.37 [95%CI 1.078–1.742], p=0.01 log rank test) and MA695 (95.8 vs 45.7 months; HR 1.48 [95%CI 1.159–1.878], p=0.002). Polarization with 214D4 was strongly associated with improved survival for adenocarcinoma (HR 1.92 [95%CI 1.385–2.668], p<0.0001) but not for non-adenocarcinoma. Similarly, polarization with MA695 conferred a survival advantage in adenocarcinoma (HR 1.68 [95%CI 1.225–2.311], p=0.001) but not non-adenocarcinoma cases. Data on MUC1 immunohistochemistry and circulating soluble MUC1 will be presented.214D4 MA695 No staining 3.5% 6.2% Mean intensity - Cytoplasmic 1.8 1.7 - Membranous 2.1 2.2 Mean cells positive 3.9 3.6 Mean composite score 10.1 9.6 - Adenocarcinoma 13.1 12.0 - Squamous cell 7.1 7.0 - Large cell 7.2 7.7 Depolarization 66.7% 62.4% Conclusion
Over 93% were MUC1 immunohistochemistry positive, with higher scores in adenocarcinoma. Composite scores for the two antibodies were highly correlated and depolarization largely concordant. MUC1 expression was generally maintained in paired primary/nodal tumour and was similar across nodal stages and following neoadjuvant chemotherapy. Polarization was associated with improved survival in adenocarcinoma. Further investigation is needed to determine which antibodies best predict outcomes.
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P3.10 - Poster Session 3 - Chemotherapy (ID 210)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.10-034 - Is loss of MGMT a therapeutic target in lung cancer? (ID 2118)
09:30 - 09:30 | Author(s): T. John
- Abstract
Background
MGMT is a DNA repair protein which removes alkylating DNA adducts from the O[6] position of guanine. Expression of MGMT is often silenced by promoter methylation in human cancers. MGMT methylation is a predictive marker for prolonged survival in glioblastoma patients treated with an alkylating agent, temozolomide. As MGMT methylation has been found in lung cancers, there is an increasing interest on the clinical utility of temozomolide in the treatment of human cancers. However, it is essential to use appropriate quantitative or semi-quantitative method methods to definitively establish the methylation status of the tumour.Methods
We critically assessed MGMT methylation status in 6 lung cancer cell lines and 56 lung tumours using three different methodologies. We first assessed the MGMT methylation pattern using methylation sensitive – high resolution melting (MS-HRM). The methylation status at each CpG dinucleotide was assessed bisulfite pyrosequencing of methylated clones. The level of MGMT methylation was quantified using quantitative methylation specific PCR.Results
MGMT methylation was found in 3 lung cancer cell lines by MS-HRM. The melting profiles of all methylated samples were indicative of heterogeneous methylation pattern by melting curve analysis. To examine the methylation status at each CpG sites of individual template, two MGMT methylated lung cell lines (H1666 and H69) were further tested by limiting dilution analysis and bisulfite pyrosequencing. The number and site of methylated CpG dinucleotides greatly varied in each template, confirming the heterogeneous methylation pattern in both cell lines. In 56 lung tumours, heterogeneous MGMT methylation was detected in seven samples (13%) by MS-HRM. The level of MGMT methylation was then estimated. 17 lung tumours, including the 7 MS-HRM positives and 10 additional tumours, were positive. However, the methylated level in all of the methylated samples was low, ranging from below 1% (12 samples) and up to 12%.Conclusion
The level of MGMT promoter in lung cancer is difficult to estimate. Ideally clonal analysis should be used to estimate the proportion of methylated alleles. Alternatively, methylation profiling using MS-HRM followed by pyrosequencing can be used to identify tumours showing significant levels of methylation. If MGMT methylation is found only in a small proportion of tumour cells, it is unlikely to be a useful target for therapy. Overcalling of MGMT methylated tumours may provide the explanation for the lack of survival benefit with temozolomide treatment in MGMT-methylated lung cancer patients in a recent phase II clinical trial (NCT00423150). This indicates that incorporation of immunohistochemistry for the MGMT protein should also be part of the assessment of the MGMT status of lung cancer.
