Virtual Library

Abstract not provided

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Background:
Atezolizumab (atezo) prevents binding of PD-L1 to its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously treated NSCLC showed superior survival with atezo vs docetaxel (doc) in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in pts expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.

Methods:
OAK evaluated atezo vs doc in PD-L1 unselected NSCLC pts who had failed prior platinum-containing chemotherapy. Pts were stratified by PD-L1 expression, prior chemotherapy regimens and histology and randomized 1:1 to atezo (1200 mg) or doc (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.

Results:
In the first 850 of 1225 randomized pts (primary study population), OS was improved with atezo vs doc regardless of histology, and this benefit was seen across PD-L1 subgroups within each histology (Table). Similar OS was seen regardless of PD-L1 expression as assessed by mRNA and IHC. ORR was 14.4% vs 15.2% in non-squamous (non-sq) pts and 11.6% vs 8.2% (atezo vs doc) in squamous (sq) pts. Improved OS was seen with atezo vs doc across subgroups, including pts with treated baseline brain metastases (n = 85; mOS, 20.1 vs 11.9 mo; HR, 0.54; 95% CI, 0.63, 0.89) and never smokers (n = 156; mOS, 16.3 vs 12.6 mo; HR, 0.71; 95% CI, 0.47, 1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.

Conclusions:
OAK demonstrated clinically relevant improvements with atezo in the ITT population, including in both histology subgroups, regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups, including never smokers and pts with baseline brain metastases.rnTable: 89PDrn

rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn

rn	OS
	Atezo		Doc		HR[a] 95% CI
	n	Median, mo	n	Median, mo
Non-sq population
TC3 or IC3	49	22.5	47	8.7	0.35 (0.21, 0.61)
TC2/3 or IC2/3	89	18.7	99	11.3	0.61 (0.42, 0.88)
TC1/2/3 or IC1/2/3	171	17.6	162	11.3	0.72 (0.55, 0.95)
TC0 and IC0	140	14.0	150	11.2	0.75 (0.57, 1.00)
All non-sq	313	15.6	315	11.2	0.73 (0.60, 0.89)
Sq population
TC3 or IC3	23	17.5	18	11.6	0.57 (0.27, 1.20)
TC2/3 or IC2/3	40	10.4	37	9.7	0.76 (0.45, 1.29)
TC1/2/3 or IC1/2/3	70	9.9	60	8.7	0.71 (0.48, 1.06)
TC0 and IC0	40	7.6	49	7.1	0.82 (0.51, 1.32)
All sq	112	8.9	110	7.7	0.73 (0.54, 0.98)

rnaUnstratified HRs.rnTC, tumor cell; IC, tumor-infiltrating immune cell.rn

Clinical trial identification:
NCT02008227

Legal entity responsible for the study:
F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

Funding:
F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

Disclosure:
S.M. Gadgeel: Speaker\'s bureau from Astra-Zeneca, Genentech/Roche and Advisory Boards from Astra-Zeneca, Ariad, Pfizer, Bristol Myers- Squibb and Genentech/Roche. A. Rittmeyer: Grants as an advisor or speaker by Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, Pfizer and Roche Genentech. F. Barlesi: Honarium from Roche. T. Hida: Corporate-sponsored research from Chugai Pharmaceutical. P. He: Employee of Roche/Genentech, and has stocks for Roche and Amgen. Her husband has stocks for Allergan and Gilead. M. Ballinger: Genentech/Roche employee and has Roche stock. D.R. Gandara: Consultant for Genentech and clinical trial grant from Genentech. J. von Pawel: Adboard with fees paid to the institution from AbbVie, Pfizer, Bristol Myers Squibb, and Novartis. All other authors have declared no conflicts of interest.

Background:
R (anti-VEGFR2) and P (anti-PD-1) are active in previously treated advanced NSCLC. Median progression-free survival (PFS) reported in KEYNOTE-001 (previously treated; PD-L1 all comers) was 3.0 months (95%CI, 2.2-4.0) and ORR was 18%. This is the first study to combine R with P.

Methods:
Ongoing, multi-cohort, phase 1a/b trial enrolled pts with confirmed NSCLC with prior progression on systemic therapy, measurable disease, ECOG PS 0-1 and baseline tumor tissue. PD-L1 was classified strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS=1-49%), or negative (TPS <1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. Primary objective- assess safety and tolerability of R + P; preliminary efficacy will be examined.

Results:
As of 21-Nov-2016, 27 pts with previously treated advanced NSCLC received R at 10 mg/kg on Day 1 with P 200 mg on Day 1 q3W. Median age was 65, 78% male, 96% had a history of smoking, 78% had adenocarcinoma and 15% had squamous-cell carcinoma. Sixteen (59%) pts received ≥2 and 4 (15%) received ≥3 prior treatment regimens for their disease. Median duration of treatment was 7.0 mo (IQR 3.0-12.4) and 8.3 mo (IQR 3.3-12.4) for R and P, respectively. Treatment related adverse events (TRAEs) occurred in 25 (93%) pts, most commonly hypertension (26%) and asthenia (19%). Five (19%) pts experienced grade 3 TRAEs (adrenal insufficiency, delirium, hypertension [n = 2], hyponatremia, infusion related reaction, proteinuria, and respiratory failure). No grade 4-5 TRAEs occurred. ORR was 30% with a median time to response of 2.1 mo. Duration of response has not been reached. Responses occurred in PD-L1 unknown (n = 1), negative (n = 2), and strong positive (n = 5) groups as well as both histologies. Median PFS was 9.7 mo (95% CI 4.6-11.5) and overall survival rate at 6 mo was 84.9%. Disease control rate was 85%. Ten (37%) pts remain on study treatment, including all responders.

Conclusions:
R + P demonstrated encouraging antitumor activity independent of PD-L1 and histology. The safety profile was consistent with monotherapy treatment for each drug, with no additive toxicities. The study was amended and is now enrolling pts with treatment naïve advanced NSCLC.

Clinical trial identification:
NCT02443324 JVDF

Legal entity responsible for the study:
Eli Lilly and Company, Indianapolis, IN

Funding:
Eli Lilly and Company, Indianapolis, IN

Disclosure:
R.S. Herbst: Personal fees from Eli Lilly, outside the submitted work. E. Calvo: Institutional research funding: multiple- available upon request; Travel expenses: Lilly, PsiOxus, Novartis; Consultant: Novartis, GSK, Astellas, Genentech, Lilly, Nanobiotich, Pfizer; SB: Novartis. N. Isambert: Honoraria: Pfizer, Novartis; Consulting/Advisory: Merck Serono. J. Bendell: Institutional research funding: From multiple and available upon request, including Lilly and Merck. P. Cassier: Personal fees from Roche/Genentech, Novartis, Astra-Zeneca, Amgen, Plexxikon; non-financial support from Roche/Genentech, Merck Sharp Dohme, Astra-Zeneca, Plexxikon; and grants from Merck Sharp Dohme and Astra-Zeneca, outside the submitted work. J. Jin, G. Mi, J. Rege: Employee and stock holder at Eli Lilly and Company. L. Paz-Ares: Consultant/Advisory role: Roche, Lilly, Novartis, MSD, BMS, Amgen, Clovis, AZ, BI, Pfizer. All other authors have declared no conflicts of interest.

Background:
Immune checkpoint inhibitors are active for patients with stage IV NSCLC who have progressed following platinum-based chemotherapy. We evaluated responses to chemotherapy in patients with NSCLC who had progressed on a checkpoint inhibitor.

Methods:
Eligible patients were adults with NSCLC who received salvage chemotherapy following PD-1/PD-L1 inhibitors (cases) versus no PD-1/PD-L1 inhibitors (controls). CT-imaging was done within 4 weeks of initiation of salvage chemotherapy and every 6 weeks thereafter. Revised RECIST guidelines were used to define response. Clinical and imaging data were abstracted from review of electronic medical records. Multivariate logistic regression analysis was used to calculate probability of response.

Results:
355 patients’ charts were reviewed and 82 patients met eligibility criteria. Among evaluable patients, 46 were males versus 36 females. 67 patients were classified as cases versus 15 controls. 56 patients received nivolumab, 7 pembrolizumab and 4 atezolizumab. 63 (77%) patients had adenocarcinoma, 18 (22%) squamous cell carcinoma and 1 (1%) large cell carcinoma. The mean number of chemotherapy regimens prior to salvage chemotherapy was 2.37 (95% CI: 2.10-2.64) in cases versus 1.93 (95% CI: 1.32-2.54) in controls. Salvage drugs used included docetaxel (62%), pemetrexed (20%), gemcitabine (12%) and paclitaxel (6%). 18 (27%) cases had partial response to chemotherapy versus 1 (7%) controls. 15 (22%) cases had progressive disease versus 6 (40%) controls. 34 (51%) cases had stable disease versus 8 (53%) controls. The odds ratio for achieving a partial response was 0.30 (95% CI: 0.18 to 0.50, p = 0.000). In multiple logistic regression model, age, gender, number of prior chemotherapy regimens, tumor histology, smoking status, different salvage chemotherapy regimens were not associated with the likelihood of achieving a partial response.

Conclusions:
The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference however warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity.

Clinical trial identification:


Legal entity responsible for the study:
N/A

Funding:
N/A

Disclosure:
All authors have declared no conflicts of interest.

Abstract not provided

Background:
In the Phase III LL3 and LL6 trials, first-line afatinib significantly improved PFS and ORR versus platinum-doublet chemotherapy in pts with EGFRm+ NSCLC. In the Phase IIb LL7 trial, afatinib significantly improved PFS, time to treatment failure, and ORR versus gefitinib in this setting. Here we present post-hoc analyses of afatinib LTRs (treated with afatinib ≥3 years) in LL3/6/7.

Methods:
Treatment-naïve pts with stage IIIB/IV EGFRm+ NSCLC who were randomized to 40 mg/day afatinib in LL3/6/7 were included.

Results:
24/229 (10%), 23/239 (10%) and 19/160 (12%) afatinib-treated pts in LL3, LL6 and LL7 were LTRs; 6, 9 and 14 LTRs were still on treatment at the time of analysis. In LL7, 4% of gefitinib-treated pts were LTRs. Baseline characteristics were generally consistent with the overall study populations, with the exception of greater proportions of women (LL3/6 only; 92/78% vs 64% in the overall populations) and Del19+ pts (63–79% vs 49–58% overall) among LTRs. The table shows treatment duration and outcomes. The median OS values for LL3/6 were >30 months longer than those reported in the overall populations. ORRs ranged from 70.8% in LL3 to 89.5% in LL7. Frequency and duration of subsequent therapy was similar to the overall population. Frequency of afatinib dose reduction due to TRAEs was broadly consistent with the overall populations; final afatinib doses of 20/30/40/50 mg were observed in 50/25/21/4% in LL3, 13/22/61/4% in LL6, and 32/21/47/0% in LL7.

Conclusions:
In the LL3/6/7 studies, 10–12% of afatinib-treated pts were LTRs (treated ≥3 years). Among these pts, greater proportions of women (LL3/6 only) and Del19+ NSCLC were observed. In LTRs, afatinib conferred a long-term survival benefit of ∼5 years and was well tolerated. Long-term treatment was independent of tolerability-guided dose adjustment, or the presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment.rnTable: 92PDrn

rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn

Characteristic	LL3 (n = 24)	LL6 (n = 23)	LL7 (n = 19)
Median follow-up for OS, months	64.6	57.0	42.1
Median duration of treatment, months (range)	50 (41–73)	56 (37–68)	42 (37–50)
Median PFS (central review), months	37.5	30.6	27.6
Median OS, months	63.2	55.3	40.8
Overall response rate (CR+PR), n (%)	17 (70.8)	18 (78.3)	17 (89.5)
CR, n (%)	1 (4.2)	3 (13.0)	1 (5.3)
PR, n (%)	16 (66.7)	15 (65.2)	16 (84.2)
SD, n (%)	5 (20.8)	2 (8.7)	2 (10.5)
NN, n (%)	2 (8.3)	3 (13.0)	–
Median duration of response, months	34.5	28.3	19.4

rnCR, complete response; NN, not-PR/not-SD; PR, partial response; SD, stable diseasern

Clinical trial identification:
LUX-Lung 3: EudraCT No: 2008-005615-18 LUX-Lung 6: clinicaltrials.gov ref: NCT01121393 LUX-Lung 7: EudraCT No: 2011-001814-33

Legal entity responsible for the study:
Boehringer Ingelheim

Funding:
Boehringer Ingelheim

Disclosure:
M. Schuler: Advisory boards: AstraZeneca, Boehringer Ingelheim, Celgene, Eli Lilly, Novartis; Corporate-sponsored research: Boehringer Ingelheim, Bristol-Myers Squibb, Novartis; Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Novartis, Roche, MSD, Alexion; Patents: University Duisburg-Essen. L. Paz-Ares: Honoraria from Pfizer, Bristol-Myer Squibb, MSD, Novartis, Roche, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, AstraZeneca, and Amgen. L.V. Sequist: Participated on advisory boards for Boehringer Ingelheim, AstraZeneca, Novartis, Clovis Oncology, Genentech, Merrimack, Ariad, and Bristol-Myers Squibb. S.L. Geater: Participated in advisory boards for Novartis and Boehringer Ingelheim, and has also received honoraria from Roche, AstraZeneca, Boehringer Ingelheim, and Novartis. A. Märten: Employee of Boehringer Ingelheim. J. Fan: Boehringer Ingelheim Pharmaceuticals Inc. employee. K. Park: Participated on advisory boards for Astellas, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Hanmi, MSD, Novartis, and Roche. J.C-H. Yang: Ad board and honoraria: BI, Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical Daiichi, Sankyo, and AZ. All other authors have declared no conflicts of interest.

Background:
A, an irreversible ErbB family blocker, and G, a reversible EGFR TKI, are approved for 1st-line treatment (tx) of advanced EGFRm+ NSCLC. In LL7, A (40 mg/d) significantly improved PFS (HR 0.73 [95% CI 0.57–0.95], p = 0.017), ORR (70 vs 56%, p = 0.008) and time to tx failure (TTF; HR 0.73 [0.58–0.92], p = 0.007) vs G (250 mg/d) in this setting; the primary OS analyses (data cut-off 8 Apr 16) showed a non-significant difference in OS between A and G (median 27.9 vs 24.5 mos; HR 0.86 [0.66–1.12], p = 0.258) that was consistent across subgroups. Here, we present updated OS data.

Methods:
LL7 assessed A vs G in tx-naïve pts with EGFRm+ (Del19/L858R) stage IIIb/IV NSCLC. Co-primary endpoints were PFS, TTF and OS. Other endpoints: ORR and AEs.

Results:
Data cut-off for the updated OS analysis was 12 Dec 16. Median follow-up for OS was 49.2 mos. 73/77% (A/G) of pts had ≥1 subsequent systemic anti-cancer tx after discontinuation of A/G. 48/56% (A/G) received a subsequent EGFR TKI; 31 (19%)/26 (16%) pts (A/G) received a 3[rd]-gen EGFR TKI. Updated median OS was 27.9 vs 24.5 mos with A vs G (HR 0.85 [0.66–1.09], p = 0.1950). Landmark 24-mo and 30-mo OS with A vs G was 61 vs 51% and 48 vs 40%, respectively; 48-mo OS was 28% with A vs 20% with G. In patients treated with A, ≥30-mo survival rates were generally similar across countries of origin and mean average dose received. Similar OS trends were observed with A vs G in pts with Del19 (30.7 vs 26.4 mos; HR 0.82 [0.59–1.15]) and L858R (25.0 vs 21.2 mos; HR 0.89 [0.61–1.31]) mutations. There was a trend towards improved OS with A vs G in pts who received a 3[rd]-gen EGFR TKI (NE vs 48.3 mos; HR 0.49 [0.20–1.19]). In patients treated with A, consistent OS outcomes were observed across age groups (median, mos: 28.9 [<60 years]; 30.1 [<65 years]; 28.9 [<75 years]; 27.9 [≥75 years]). Updated PFS, TTF and ORR (at primary OS data cut-off, 8 Apr 16) were similar to the primary analyses, and all were significantly improved with A vs G; the AE profile of A and G was virtually unchanged since the primary analysis.

Conclusions:
In this updated OS analysis, there was no significant difference in OS with A vs G. A trend favouring A, generally consistent across subgroups, was observed.

Clinical trial identification:
Clinical Trials.gov Identifier: NCT01466660

Legal entity responsible for the study:
Boehringer Ingelheim

Funding:
Boehringer Ingelheim

Disclosure:
K. Park: Participated on advisory boards for Astellas, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Hanmi, Merck & Co., Inc., Novartis, and Roche. J.C-H. Yang: Ad board and honoraria: BI, Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical Daiichi, Sankyo, AZ. T. Mok: Receipt of grants/research supports: AstraZeneca, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS. Receipt of honoraria or consultation fees: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, AVEO & Biodesix, Prime Oncology, Amgen. Participation in a company sponsored speaker’s bureau: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Amgen, Janssen, Clovis Oncology, GSK, Novartis, BMS, PrIME Oncology. Stock shareholder: Sanomics Limited. K. O\'Byrne: Ad board, speaker bureau, travel to international conferences and honoraria: AZ, BMS, Roche-Genentech, MSD, Pfizer, BI. Ad board and speaker bureau: Novartis. 3 Patents: 1 on novel drugs, 2 on biomarkers, IP held by Queensland University of Technology. V. Hirsh: Has received advisory board honoraria from Boehringer Ingelheim, AstraZeneca, Roche, Merck, Eli Lilly, Pfizer, Amgen, and Bristol-Myers Squibb. M. Boyer: Ad board: BMS, Merck Sharpe and Dohme, Pfizer Board of Directors: IASLC Research: Pfizer, Genentech, BI, AZ, Novartis, Merck Sharpe and Dohme, Clovis Honoraria: Merck Sharpe and Dohme, BI, BMS, AZ. J. Fan: Boehringer Ingelheim employee. All other authors have declared no conflicts of interest.

Background:
The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) complements standard adverse event (AE) reporting in oncology trials. We assessed patient-reported symptomatic AEs in individuals receiving osimertinib 80mg once daily or chemotherapy for advanced non-small cell lung cancer (NSCLC) in the AURA3 trial, using the PRO-CTCAE.

Methods:
AURA3 (NCT02151981) was a multinational, open-label, randomized phase III trial involving 419 patients.1 As part of exploratory analyses, individuals for whom validated local language versions were available (in English, German, Japanese or Spanish) were asked to complete the PRO-CTCAE by e-device, weekly for 18 weeks and then every 3 weeks.

Results:
In total, 161 patients (38%; 102 osimertinib, 59 chemotherapy) provided data for PRO-CTCAE analysis (mean age: 64 years; 63% women). The number of patients providing PRO-CTCAE data fluctuated between different items and time points, and decreased over the study period. Of patients on osimertinib providing information on acne/pimples, 37%, 38%, 32% and 29% reported having acne/pimples at baseline, 4 weeks, 12 weeks and 24 weeks, respectively, compared with 30%, 19%, 14% and 12% on chemotherapy. Most cases (>90%) were mild. Reported rates of diarrhoea changed little over time post-baseline and were higher with osimertinib than with chemotherapy (32% vs 36% at baseline, 47% vs 28% at 4 weeks, 53% vs 33% at 12 weeks, 45% vs 21% at 24 weeks). Most cases were mild or moderate. Fatigue (64% vs 72% at baseline, 72% vs 89% at 4 weeks, 55% vs 89% at 12 weeks, 60% vs 79% at 24 weeks) and decrease in appetite (54% vs 53% at baseline, 42% vs 75% at 4 weeks, 35% vs 69% at 12 weeks, 33% vs 46% at 24 weeks) were reported less commonly with osimertinib than with chemotherapy. Most cases were mild.

Conclusions:
Self-reported data from patients with NSCLC treated with osimertinib or chemotherapy showed changes over time in AE rates from start of treatment and differences in prevalence of patient-reported AEs (PRO-CTCAEs) with osimertinib versus chemotherapy.

Clinical trial identification:
NCT02151981

Legal entity responsible for the study:
AstraZeneca

Funding:
AstraZeneca

Disclosure:
M. Sebastian: Honoraria: Novartis, BMS, Roche, Lilly, Boehringer-Ingelheim, Pierre-Fabre, Pfizer, MSD, AstraZeneca. Consultant: Novartis, BMS, Roche, Lilly, Boehringer-Ingelheim, Pfizer, MSD, AstraZeneca, Celgene. V. Papadimitrakopoulou: Advisory: Eli Lilly&Co, Genentech, Janssen Global Sevices, Bristol-Myers Squibb, ARIAD, AstraZeneca Pharmaceuticals, Novartis, Merck Corporate-sponsored. Research: Novartis, AstraZeneca, Genentech, Merck, Janssen, ACEA, Bristol-Myers Squibb. A. Walding: AstraZeneca employee and shareholder. S. Ghiorghiu: AstraZeneca employee and shareholder. A. Ryden: AstraZeneca employee and shareholder. K. Rudell: Former AstraZeneca employee and shareholder. All other authors have declared no conflicts of interest.

Abstract not provided

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Background:
≈ 20%-40% patients (pts) with advanced NSCLC develop brain metastases (mets), which are associated with poor survival. Atezolizumab (atezo; anti–PD-L1) monotherapy has shown clinical benefit in pts with NSCLC regardless of PD-L1 expression status. Here we compare the safety and efficacy of atezo in NSCLC pts with or without baseline brain mets.

Methods:
Safety analyses were conducted on pts who received atezo as 2L+ treatment in 5 studies: PCD4989g, BIRCH, FIR, POPLAR and OAK. Pts had previously treated stable/asymptomatic or no brain mets at baseline. Efficacy analyses were conducted on pts in the atezo and docetaxel (doc) arms of OAK.

Results:
The pooled safety cohort included 1452 pts; 79 (5%) had brain mets. The incidence of all AEs and SAEs was similar in pts with or without brain mets (Table). A numerically higher rate of neurological AEs and SAEs was reported in pts with vs those without brain mets. No treatment-related G4-5 neurological AEs or SAEs were seen in pts with brain mets. The most common treatment-related neurological AE was headache in 6 (8%) pts with and 42 (3%) pts without brain mets. Efficacy cohort included the first 850 pts with or without brain mets from OAK who were randomized to atezo or doc. Atezo showed survival benefit vs doc in pts with brain mets (HR = 0.54, 95% CI: 0.31, 0.94; mOS 20.1 mo [n = 38] vs 11.9 mo [n = 47] with atezo vs doc) as well as in pts without brain mets (HR = 0.75, 95% CI: 0.63, 0.89; mOS 13.0 mo [n = 387] vs 9.4 mo [n = 378] with atezo vs doc). The risk of developing new CNS lesions appeared to be lower with atezo vs doc (HR = 0.42, 95% CI: 0.15, 1.18; median time to develop new CNS lesion, not reached vs 9.5 mo) in pts with baseline brain mets.

Conclusions:
Atezo demonstrated an acceptable safety profile and encouraging survival benefit in pts with NSCLC who had previously treated stable/asymptomatic brain mets. Results of this analyses warrant further investigation of atezo in advanced NSCLC pts with CNS mets.rnTable: 81OSummary of safety data in advanced NSCLC patients with and without baseline brain metastases following atezolizumab as 2L+ treatmentrn

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Safety	Pooled cohort[a] (N = 1452)
	Patients with baseline brain mets (n = 79) n (%)	patients without baseline brain mets (n = 1373) n (%)
Any AE	75 (95%)	1261 (92%)
Any neurological AE	37 (47%)	414 (30%)
Treatment-related AEs	55 (70%)	876 (64%)
Treatment-related neurological AEs	14 (18%)	128 (9%)
Any SAE	26 (33%)	492 (36%)
Any neurological SAEs	5 (6%)	36 (3%)
Treatment-related SAEs	7 (9%)	135 (10%)
Treatment-related neurological SAEs	0	7 (0.5%)
Discontinued treatment due to AE	8 (10%)	99 (7%)

rnaFrom PCD4989g (NCT01375842), BIRCH (NCT02031458), FIR (NCT01846416), POPLAR (NCT01903993) and OAK (NCT02008227) trials.rn

Clinical trial identification:
NCT01375842, NCT02031458, NCT01846416, NCT01903993, NCT02008227

Legal entity responsible for the study:
F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

Funding:
F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

Disclosure:
R.V. Lukas: Advisory board (2016) for Astra-Zeneca and advisory Board (2013) for Novocure. M. Gandhi: Genentech employee. C. O’Hear: Employee of Genentech and have stock in Roche. S. Hu: Employee and stockholder in Roche. C. Lai: Employee of and have stock in Roche. All other authors have declared no conflicts of interest.

Background:
Anti-PD-1/PD-L1 therapies have demonstrated meaningful clinical benefit in pts with EGFR/ALK wild-type (WT) advanced NSCLC. However, to our knowledge these agents have never been investigated in a study prospectively focusing on NSCLC pts with EGFR mutations or ALK alterations (EGFRmut/ALK+), a distinct subgroup with clear biological and treatment outcome differences compared with EGFR/ALK WT pts. Durvalumab is an engineered human IgG1 mAb targeting PD-L1.

Methods:
ATLANTIC (NCT02087423) was a Phase 2, open-label, single-arm trial in pts with locally advanced or metastatic Stage IIIB–IV NSCLC (WHO PS 0 or 1; ≥2 prior systemic regimens, including 1 platinum-based and 1 TKI [EGFRmut/ALK+ pts]). There was no maximum number of prior treatments. The study initially enrolled all-comers and then was restricted to pts with PD-L1 high tumours (≥25% of tumour cells with membrane staining). The study included 3 pt cohorts defined by EGFR/ALK status and tumor PD-L1 expression; here we report results from EGFRmut/ALK+ pts (Cohort 1). The primary outcome was ORR (RECIST v1.1). Secondary outcomes included DCR, DoR, PFS, OS, and safety (CTCAE v4.03).

Results:
As of 3 June 2016, 111 pts (median age 61 years, 63% female, 59% WHO PS 1, 99% non-squamous histology; 59% never smokers; mean prior therapies 3.8) had received durvalumab (10 mg/kg i.v. q2w for ≤12 months). Responses were durable. Most AEs were low grade. Immune-mediated AEs were manageable with standard treatment guidelines; 5.4% of pts had Grade ≥3 treatment-related (TR) AEs and 0.9% had TRAEs leading to discontinuation.rnTable: 82Orn

rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn

rn	PD-L1 high (≥25%)	PD-L1 low/negative (<25%)
	n = 74[a]	n = 28[a]
ORR,[b] % (95% CI)	12.2 (5.7, 21.8)	3.6 (0.1, 18.3)
DCR, % (95% CI)	20.3 (11.8, 31.2)	7.1 (0.9, 23.5)
mDoR, months (95% CI)	7.4 (5.4, 9.2)	NC[c]
rn	n = 77[d]	n = 30[d]
mPFS, months (95% CI)	1.9 (1.8, 3.6)	1.9 (1.8, 1.9)
mOS, months (95% CI)	13.3 (8.1, NC)	9.9 (4.2, 13.0)
1-year OS, % (95% CI)	54.8 (41.5, 66.3)	40.0 (22.1, 57.4)
mFollow-up for OS, months	6.5	8.2

rnNote: 4 patients had PD-L1 expression unknown or missing.rnaFull analysis set - evaluable for response per independent central review (ICR).rnbConfirmed response per ICR.rncNot calculated due to small number of responders.rndFull analysis set.rnDCR=disease control rate (complete response, partial response or stable disease ≥24 weeks); DoR=duration of response; m=median; NC=not calculated; ORR=objective response rate; OS=overall survival; PFS=progression-free survivalrn

Conclusions:
Although the ORR was somewhat lower compared with that reported in Cohort 2 (EGFR/ALK WT), durable responses were still observed in this heavily pretreated metastatic EGFRmut/ALK+ NSCLC population. However, the data were limited by the short duration of follow up and further confirmation is needed. Activity was greater for pts with high PD-L1 expression. The tolerability profile was manageable.

Clinical trial identification:
NCT02087423 (March 4, 2014)

Legal entity responsible for the study:
AstraZeneca PLC

Funding:
AstraZeneca

Disclosure:
M.C. Garassino: Grants/research support: Pfizer; Consultant: Eli Lilly; AZ, BMS, MSD, Roche, Celgene. B-C. Cho: Grants/Research: AZ, BI, Yuhan, Roche, MSD, BMS Ono, Eli Lilly, Pfizer, Bayer Consultant: AZ, BI, Yuhan, Roche, MSD, BMS Ono, Eli Lilly, Pfizer Honoraria: AZ, BI, Yuhan, Roche, MSD, BMS Ono, Eli Lilly, Pfizer. J. Mazières: Advisory board: AZ. K. Park: Advisory role: Astellas, AZ, BI, Clovis, Lilly, Hanmi, AZ, Kyowa Hakko Kirin, Novartis, Ono, Roche Speaker bureau: BI Research: AZ. R.A. Soo: Grants/research support: AZ Honoraria: AZ, BI, BMS, Lilly, Pfizer, Roche, Taiho, Novartis, Merck. P. Dennis, Y. Huang: Employment: AZ. C. Wadsworth: Employment: AZ; Stock ownership: AZ. N. Rizvi: Consulting: AZ, Roche, Novartis, Merck, Pfizer, Lilly, AZ, BMS, Merck Stock ownership: Gritstone Oncology. All other authors have declared no conflicts of interest.

Abstract not provided

Background:
The ROS1 fusion tyrosine kinase that results from rearrangements of the ROS1 gene is a new targetable driver oncogene. It is detected in 1-2% of lung adenocarcinoma patients. Crizotinib recently received US FDA approval for the treatment of patients with lung cancer carrying ROS1 rearrangements. Fluorescent in situ hybridization (FISH) is the gold standard for detecting ROS1 rearranged tumors. Immunohistochemistry (IHC) has been considered as a screening assay to identify ROS1 rearranged lung cancers. However, published reports suggested that ROS1 IHC shows high sensitivity but moderate specificity, thus resulting in a high percentage of cases that require confirmatory FISH testing. This may negatively impact on the cost of ROS1 screening by IHC.

Methods:
Sensitive and highly specific IHC protocols for ROS1 testing using D4D6 antibody (Cell Signaling, Danver, MA) on the Ventana and Dako autostainers were developed. A FISH protocol for detecting ROS1 gene rearrangements using a ROS1 (6q22) Break Apart FISH Probe (Biocare, Concord, CA) was also established. A network of 14 pathology laboratories participated in the validation of these protocols to detect ROS1 rearranged lung cancers. Validation involved 9 confirmed ROS1 FISH positive (+) and 15 ROS1 FISH negative (-) tumor samples.

Results:
Among 10 laboratories that completed FISH testing, 11 (4.6%) of 240 tests failed. The overall sensitivity of the laboratories to detect FISH+ cases was 88.9% (80/90), and the misclassification rate was 3.5% (8/229). Among 11 laboratories that completed the IHC testing, results from 14/264 (5.3%) tests were unavailable. Using the H-score cut-off of 80 (that completely distinguished between the mean H-score of FISH+ and FISH- cases), the overall sensitivity to detect FISH+ sample was 97%, with 94% specificity, 91% positive predictive value, and 98% negative predictive value. Eight laboratories achieved 100% sensitivity; only one laboratory had specificity below 90%. ROS1 IHC positive tumor showed homogeneous staining in practically all tumor cells.

Conclusions:
This pan-Canadian consortium established the criteria to enable clinical implementation of IHC screening and FISH testing for ROS1 rearranged lung cancers using optimized protocols with high sensitivity and specificity.

Clinical trial identification:


Legal entity responsible for the study:
University Health Network

Funding:
Pfizer Canada

Disclosure:
M.S. Tsao: Received advisory board honoraria and research grant from Pfizer Canada, AstraZeneca, Merck Canada. Received advisory board honoraria from Bristol-Myers Squibb, Hoffmann La Roche and Boehringer Ingelheim Canada. E. Torlakovic: Received advisory board honoraria from Pfizer Canada, Merck Canada, Bristol-Myers Squibb. G. Bigras: Received advisory board honoraria from Pfizer Canada, Merck Canada, Bristol-Myers Squibb. H. Wang: Received advisory board honoraria from Pfizer Canada, Merck Canada, Bristol-Myers Squibb and Hoffmann La Roche Canada. G. Qing: Received advisory board honoraria from Pfizer Canada, Merck Canada, Bristol-Myers Squibb. C.C. Cheung: Received advisory board honoraria from Merck Canada and Bristol-Myers Squibb. Z. Xu: Received advisory board honoraria from Pfizer Canada, Merck Canada, Bristol-Myers Squibb, Hoffmann La Roche. C. Couture, D. Ionescu: Received advisory board honoraria from Pfizer Canada, AstraZeneca, Merck Canada, Bristol-Myers Squibb, Hoffmann La Roche. A. Smith: Received advisory board honoraria from Pfizer Canada

Background:
Non-squamous (ns)-NSCLC is often driven by (targetable) molecular alterations, such as EGFR mutations (EGFR+), KRAS mutations (KRAS+), or ALK translocation (ALK+). Patterns of mets may differ between alterations, which may have implications for mets screening or treatment decisions. We assessed in a nationwide stage IV ns-NSCLC cohort whether molecular status is associated with anatomic sites of mets sites at Dx.

Methods:
All patients (pts) with stage IV ns-NSCLC from 2013, without a recent history of cancer, were identified from the Netherlands Cancer Registry, in which anatomic sites of mets before treatment initiation are recorded. Tumors were matched to the Dutch Pathology Registry (PALGA), and data on molecular testing (EGFR, KRAS, ALK) were extracted. Correlation between molecular status and anatomic sites of mets was assessed. Multivariable logistic regression analyses were performed to calculate adjusted odds ratios (OR) with 95% confidence intervals (CI).

Results:
In total, 2884 pts with stage IV ns-NSCLC were identified. Included for analysis were: EGFR + (n = 220; 7.6%), KRAS + (n = 775; 26.9%), ALK + (n = 42; 1.5%) and triple-negative (n = 1117; 38.7%). Most frequent mets sites were bone (33.7%), lung (23.6%), pleura (23.4%), and brain (22.5%). EGFR+ tumors significantly more often had bone mets (49.1%) than KRAS + (OR 2.01, 95% CI 1.48-2.72), ALK + (OR 2.22, 95% CI 1.09-4.50), and triple-negative tumors (OR 2.09, 95% CI 1.56-2.81). Compared to triple-negative tumors, EGFR+ tumors more often had metastasized to the pleura (OR 1.50, 95% CI 1.08-2.08) and liver (OR 1.52, 95% CI 1.00-2.25), and less often to the brain (OR 0.67, 95% CI 0.45-0.99) and adrenal gland (OR 0.49, 95% CI 0.31-0.79). KRAS+ and ALK+ tumors significantly more often had metastasized to the lung (OR 1.35, 95% CI 1.09-1.68) and liver (OR 2.09, 95% CI 1.00-4.35) than triple-negative tumors.

Conclusions:
Molecular status of NSCLC is associated with biological behavior. At diagnosis, 49.1% of EGFR+ pts had bone mets. In particular, because EGFR+ pts have a notably better prognosis, screening for and prevention of skeletal-related events in NSCLC pts with an EGFR mutation is reasonable.

Clinical trial identification:


Legal entity responsible for the study:
University Medical Centre Utrecht

Funding:
The research is sponsored by Roche and Pfizer.

Disclosure:
C. Kuijpers, S. Willems: The research is sponsored by Roche and Pfizer. A-M. Dingemans: Attended advisory boards from Roche, Lilly, Clovis, AstraZeneca, MSD, Boehringer Ingelheim, fees were paid to institute. All other authors have declared no conflicts of interest.

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