Background

The efficacy of the oral ALK inhibitor crizotinib (C) compared with pemetrexed-platinum chemotherapy (PPC) has been demonstrated in the first-line setting in patients with advanced ALK+ non–small-cell lung cancer (NSCLC). The primary objective, progression-free survival (PFS), for this phase 3 study (PROFILE 1014; supported by Pfizer [NCT01154140]) was met and was previously published in 2014¹ (data cutoff 30 Nov 2013) along with an interim analysis of the secondary endpoint of overall survival (OS), which was not mature at that time, with approximately 17 months of follow-up and 26% of OS events. Here, we report the final analysis of OS based on the last patient visit of 30 Nov 2016.

Methods

Between Jan 2011 and Jul 2013, 343 patients with previously untreated, advanced nonsquamous ALK+ NSCLC were randomized 1:1 to receive oral C 250 mg twice daily (n = 172) or PPC (n = 171). Of patients who received PPC, 144 (84%) were treated with second-line C (crossover patients).

Results

Median follow-up duration for OS was 46 months in both arms, and 41% and 47% of patients reported OS events in the C and PPC arms, respectively. There was a numerical improvement in OS with C compared with PPC (hazard ratio [HR], 0.760; 95% confidence interval [CI] 0.548, 1.053; 1-sided P = 0.0489) that did not reach statistical significance. The median OS was not reached [NR] (95% CI 45.8, NR) with C and was 47.5 months (95% CI 32.2, NR) with PPC. However, after adjusting for crossover (for both arms) with the rank-preserving structural failure time model, the HRs for OS were 0.346 (95% bootstrap CI 0.081, 0.718) and 0.353 (95% bootstrap CI 0.102, 0.739) based on the stratified log-rank test and stratified Wilcoxon test, respectively.

Conclusions

In this randomized study, which allowed crossover from PPC to C, there was long OS in both treatment arms. There was no statistically significant difference between C and PPC arms in the final OS analysis, which was impacted by the high percentage of patients randomized to PPC who received subsequent C. After adjusting for crossover, OS in the C arm was significantly longer than in the PPC arm. Reference: 1. Solomon BJ, et al. N Engl J Med. 2014;371:2167–2177.

Clinical trial identification

NCT01154140

Legal entity responsible for the study

Pfizer

Funding

Pfizer

Disclosure

T.S.K. Mok: Honoraria from AstraZeneca, Roche/Genentech, Eli Lilly and Co., Bristol-Myers Squibb Co., Boehringer Ingelheim, Novartis Pharmaceuticals, MSD, and Pfizer, fees for serving on advisory boards from AstraZeneca, Roche/Genentech, Eli Lilly and Co., Merck Serono, Bristol-Myers Squibb Co., Pfizer, Boehringer Ingelheim, Novartis, Clovis Oncology, Vertex Pharmaceuticals, SFJ, ACEA BioSciences, MSD, geneDecode Oncogenex, Celgene, and Ignyta, and research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ, Roche/Genentech, MSD, Clovis Oncology, Bristol-Myers Squibb Co., Taiho Pharmaceutical Co., Ltd., and Eisai Co., Ltd., and holding stock in Sanomics Ltd. K. Nakagawa: Honoraria from Astellas Pharma Inc., AstraZeneca K.K., EPS Holdings Inc, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd, Showa Yakuhin Kako Co., Ltd, SymBio Pharmaceuticals Ltd., Daiichi Sankyo Co., Ltd, Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Bristol-Myers Squibb Co., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K., and Ayumi Pharmaceutical Corporation, and research funding from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., EPS Associates Co., Ltd., Quintiles Inc., Daiichi Sankyo Co., Ltd, Japan Clinical Research Operations, Eisai Co., Ltd., PPD-SNBL K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., GlaxoSmithKline K.K., AstraZeneca K.K., Kyowa Hakko Kirin Co., Ltd, AbbVie Inc., Novartis Pharma K.K., Eli Lilly Japan K.K., Yakult Honsha Co., Ltd., PAREXEL International Corp., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., AC Medical Inc., and Merck Serono Co., Ltd, Y-L. Wu: Honoraria from AstraZeneca, Roche, and Eli Lilly and Co. T. Mekhail: Fees from Pfizer and Eli Lilly. E. Felip: Fees from serving on advisory boards for Eli Lilly, Pfizer, Roche, MSD, Boehringer Ingelhrim and receiving lecture fees from AstraZeneca, BMS and Novartis. F. Cappuzzo: Advisory board: Pfizer. J. Paolini, T. Usari, K. Wilner: Employee of and owning stock in Pfizer. F. Blackhall: Honoraria from Pfizer, Astra-Zeneca, Medivation, having consulting/advisory roles with Pfizer, Medivation, Amgen, Astra-Zeneca, receiving research funding from Pfizer, Astra-Zeneca, Novartis and receiving lecture fees from Pfizer. B.J. Solomon: Fees for serving on advisory boards from Pfizer, Novartis, Roche-Genentech, AstraZeneca, Merck, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Background

ALEX phase III study (NCT02075840) of alectinib (ALC) vs crizotinib (CRZ) in treatment-naïve advanced ALK+ NSCLC, met its primary endpoint of improved progression-free survival (PFS). Pts with asymptomatic brain mets at baseline (BL), treated with radiotherapy (RT) or not, were eligible. We present comprehensive CNS efficacy data.

Methods

Pts aged ≥18 years were randomized 1:1 to ALC 600mg or CRZ 250mg (both twice daily) until disease progression (PD), toxicity, withdrawal or death. CNS MRIs were done at BL and every 8 wks in all pts. An Independent Review Committee (IRC) assessed CNS endpoints (RECIST v1.1 and RANO). Endpoints (analysed by subgroup: pts with/without BL CNS disease; pts with/without prior RT) included patterns of PD, CNS objective response rates (CORR), CNS PD and PFS.

Results

Overall, 303 pts were randomised (ALC n = 152; CRZ n = 151); 122 had BL CNS mets by IRC (ALC n = 64 [42%]; CRZ n = 58 [38%]), of whom 43 had IRC-assessed measurable lesions (ALC n = 21; CRZ n = 22); 47/122 pts had received prior RT (ALC n = 26 [62% WBRT]; CRZ n = 21 [71% WBRT]). Subgroup analyses of PFS and CNS PD are in Table 1. In the CRZ arm first PD was more common in CNS than in non-CNS sites in pts with (CNS PD 57% vs non-CNS PD 24%) and without (CNS PD 38% vs non-CNS PD 20%) CNS mets at BL. In the ALC arm first PD was more common in non-CNS sites in pts without CNS mets at BL (CNS PD 6.8% vs non-CNS PD 28%); first PD in CNS and non-CNS was similar in pts with CNS mets at BL (CNS PD 19% vs non-CNS PD 17%). CORR (RECIST) in pts with measurable CNS mets at BL was ALC 85.7% vs CRZ 71.4% for pts with prior RT and ALC 78.6% vs CRZ 40.0% for pts without RT. In pts with measurable and non-measurable CNS mets at BL, CORR was ALC 36.0% vs CRZ 28.6% for pts with prior RT, and ALC 74.4% vs CRZ 24.3% for those without. Data by RANO criteria will be presented.Table:

1298O_PR Subgroup analysis of PFS and CNS PD§

Conclusions

ALC showed significantly superior CNS activity vs CRZ in previously untreated advanced ALK+ NSCLC, irrespective of prior RT, and had a protective effect in the CNS.

Clinical trial identification

NCT02075840

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

S. Gadgeel: Consulting fees from Boehringer Ingelheim, ARIAD, Novartis, Genentech, Pfizer and AstraZeneca during the conduct of the study. S. Peters: Grants and personal fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, Roche, Guardant health, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Morphotek, Pfizer, Regeneron and Takeda. T.S.K. Mok: Personal fees: AZ, MSD, Novartis, BI, Pfizer, Roche/Genentech, BMS, Eli Lilly, Eisai, SFJ, Clovis, Taiho, Merck Serono, Celgene, OncoGenex Technologies, ACEA Biosciences, Vertex, Ignyta, Cirina, GeneDecode., Ariad/Tekeda. Stock ownership: Sanomics. A.T. Shaw: Personal fees from Genentech/Roche, Pfizer, Novartis, Genentech/Roche, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint Medicines, Loxo, EMD Serono and Foundation Medicine. S-H.I. Ou: Personal fees from Pfizer, Roche, Astra Zeneca, ARIAD, Ignyta and Foundation Medicine. M. Perol: Personal fees from Roche, Lilly, BMS, Novartis, Astra-Zeneca, Boehringer-Ingelheim, Clovis Oncology, Merck, Pfizer, Pierre Fabre, Amgen. R. Dziadziuszko: Personal fees from Roche, Novartis, Tesaro, Clovis, Pfizer, Boehringer-Ingelheim, Ignyta and Astra-Zeneca. J.S. Ahn: Personal fees from BMS, Eisai, Janssen, Roche, Menarini and Boehringer Ingelheim. A. Zeaiter, E. Mitry, E. Nueesch: Full-time employee at F. Hoffmann-La Roche Ltd. B. Balas: Full-time employee at F. Hoffmann-La Roche Ltd with stock ownership. R. Camidge: Personal fees from Roche Genetech, Genoptix, G1 Therapeutics, Orion, Clovis, Ariad, Novartis, Celgene, Array, Abbvie and Eli Lilly. All other authors have declared no conflicts of interest.

Background

ALK+ NSCLC current standard of care is crizotinib. However, many pts experience progressive disease (PD) within a year, often in the central nervous system (CNS). Alectinib (ALC) has shown systemic and CNS efficacy in phase II trials of previously treated ALK+ NSCLC after crizotinib failure. The phase III ALUR study (NCT02604342) investigated efficacy and safety of ALC vs standard relapse chemotherapy (CT) in ALK+ NSCLC previously treated with platinum-based doublet CT and crizotinib.

Methods

Pts aged ≥18 years with previously treated ALK+ NSCLC were randomised 2:1 to ALC (600mg twice daily) or CT (pemetrexed 500mg/m² q3w or docetaxel 75mg/m² q3w) until PD, death or withdrawal. Crossover from CT to ALC was permitted after PD. Primary outcome was progression-free survival (PFS) by investigator (INV) assessment. Secondary outcomes included PFS by Independent Review Committee (IRC), overall response rate (ORR) and CNS ORR (CORR) by IRC, disease control rate (DCR), duration of response (DOR) and safety.

Results

107 pts were randomised (ALC n = 72; CT n = 35); 104 received ≥1 dose of study drug (ALC n = 70; CT n = 34). At data cut-off (26.01.17) median follow-up: 6.5 months ALC, 5.8 months CT. Median treatment duration: 20.1 weeks ALC, 6.0 weeks CT. Median PFS by INV was 9.6 months (95% CI 6.9–12.2) ALC, 1.4 months (95% CI 1.3–1.6) CT (HR 0.15, 95% CI 0.08–0.29; p < 0.001); median PFS by IRC was 7.1 months ALC vs 1.6 months CT (HR 0.32, 95% CI 0.17–0.59, p < 0.001). ORR by IRC was 36.1% ALC, 11.4% CT (difference 24.7%, 95% CI 0.05–0.43); CORR in pts with measurable disease was 54.2% ALC, 0% CT (difference 54.2%, 95% CI 0.23–0.78). DCR was 80.6% ALC, 28.6% CT (difference 52%, 95% CI 0.33–0.69). Median DOR was 9.3 months ALC (95% CI 6.9–not estimable [NE]) and 2.7 months CT (95% CI NE). Adverse events (AEs; all grades) occurred in 77.1% ALC and 85.3% CT, with grade 3–5 AEs in 27.1% and 41.2%, respectively. There was one fatal AE in the CT arm. AEs leading to discontinuation or dose reduction occurred in 10% ALC and 20.6% CT arm.

Conclusions

ALC significantly improved systemic and CNS efficacy, including PFS and ORR, vs CT for previously treated ALK+ NSCLC, with a favourable safety profile vs CT.

Legal entity responsible for the study

F. Hoffmann - La Roche Ltd.

Funding

F. Hoffmann - La Roche Ltd.

Disclosure

S. Novello: Speaker Bureau: Eli Lilly, BMS, MSD, Astra Zeneca, Roche. J. Mazieres: Honoraria from Novartis, Roche, Pfizer, BMS, MSD. J. de Castro: Membership on an advisory board: Astra-Zeneca, Boehringer, MSD, Novartis, Pfizer, Roche. M.R. Migliorino: Honoraria and Advisory board: Bristol Mayer Squibb, Boehringer Ingelheim, MSD, Astra Zeneca. R. Dziadziuszko: Travel accommodation: Roche. Honoraria: Novartis, Tesaro, Clovis. Honoraria and speakers bureau: Pfizer, Honoraria and consulting role: Boehringer-Ingelheim, Astra-Zeneca, Ignyta. F. Griesinger: Advisory Board and corporate sponsored research: Roche, Astra Zeneca, Lilly, BMS, MSD, Celgene, Boehringer, Pfizer, Novartis. A. Kotb, A. Cardona, B. Balas, H. Johannsdottir, A. Das-Gupta: Employee of F. Hoffmann-La Roche Ltd. A. Zeiter: Employee of F. Hoffmann-La Roche Ltd. with stock ownership. J. Wolf: Advisory boards and lecture fees: AstraZeneca, BMS, Boehringer-Ingelheim, Clovis, Lilly, MSD, Novartis, Pfizer, Roche. Research support: BMS, MSD, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.

Background

BRAF V600E mutation occurs in ≈ 1%-2% of lung adenocarcinomas. D+T showed substantial clinical activity in pts with previously treated BRAF V600E–mutant metastatic NSCLC, with an investigator (INV)-assessed confirmed overall response rate (ORR) of 67%, median progression-free survival (PFS) of 10.2 mo, and median overall survival (OS) of 18.2 mo. We report results of D+T therapy in treatment-naive pts with BRAF V600E–mutant metastatic NSCLC.

Methods

In this cohort of the phase 2 BRF113928 trial (NCT01336634), pts with BRAF V600E–mutant metastatic NSCLC without prior systemic therapy for metastatic disease received D 150 mg twice daily + T 2 mg once daily. The primary endpoint was INV-assessed ORR. Secondary endpoints included duration of response (DOR), PFS, OS, and safety.

Results

36 pts received D+T as first-line therapy. At the data cutoff (28 Apr 2017), median follow-up was 15.9 mo, and 11 pts (31%) remained on study treatment. Median age was 67 y (range, 44-91 y); most pts were female (61%), white (83%), and current/former smokers (72%). The INV-assessed confirmed ORR was 64% (95% CI, 46%-79%), with 2 complete responses (6%) and 21 partial responses (58%). Four pts (11%) had stable disease ≥ 12 wk (disease control rate, 75% [95% CI, 58%-88%]). These results were supported by independent review committee assessment. INV-assessed median DOR was 10.4 mo (95% CI, 8.3-17.9 mo), and median PFS was 10.9 mo (95% CI, 7.0-16.6 mo; 24 pts progressed or died). Median OS was 24.6 mo (95% CI, 12.3 mo-not estimable; 17 pts died). All pts experienced ≥ 1 adverse event (AE), and 69% had ≥ 1 grade 3/4 AE. Serious AEs (SAEs) in > 2 pts included alanine aminotransferase increase (14%), pyrexia (11%), aspartate aminotransferase increase (8%), and ejection fraction decrease (8%). One pt died due to an SAE (cardiorespiratory arrest) that was determined to be unrelated to study treatment.

Conclusions

D+T demonstrated clinically meaningful antitumor activity and a manageable safety profile in pts with previously untreated BRAF V600E–mutant metastatic NSCLC, supporting recent approval by the European Commission and US FDA.

Clinical trial identification

Clinical trial ID: NIH ClinicalTrials.gov NCT01336634 First received April 7, 2011

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation

Funding

Novartis Pharmaceuticals Corporation

Disclosure

D. Planchard: Consultancy/Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, MSD, Pfizer, Roche, Novartis, Chugai. E.F. Smit: Consulting/Advisory Role: Lillly Research Funding: Boehringer Ingelheiim, Bayer, Roche/Genentech, AstraZeneca. H.J.M. Groen: Consulting/Advisory Role: Pfizer, Novartis, Bristol-Meyers Squibb, MSD Oncology, Lilly, Abbvie, Roche/Genentech Research Funding: Lilly, Roche. J. Mazieres: Research Funding: Roche, Bristol-Myers Squibb. B. Besse: Research Funding: AstraZeneca, Roche/Genentech, Pfizer, Boehringer Ingelheim, Lilly, Servier, Onxeo, Bristol-Myers Squibb, Ose Pharma, Inivata, Novartis Travel/Accommodations/Expenses: Roche, Pfizer, Bristol Myers Squibb/Medarex, Novartis, Pierre Fabre. V. Giannone, P. Zhang: Employment: Novartis. A. D\'Amelio: Employment: Novartis Stock or Other Ownership: Novartis, GlaxoSmithKline. B. Mookerjee: Employment: Novartis, GlaxoSmithKline Stock or Other Ownership: Novartis, GlaxoSmithKline, Incyte, AstraZeneca. B. Johnson: Stock or Other Ownership: KEW Group Honoraria: Chugai Consulting/Advisory Role: Novartis, Eli Lilly, Amgen, Boehringer Ingelheim, AstraZeneca, Clovis, Genentech, Merck Grant: Toshiba Post Marketing Royalties (DFCI): EGFR Mutation Testing. All other authors have declared no conflicts of interest.