Background

Vemurafenib has previously demonstrated robust clinical activity in BRAF^V600+ advanced/metastatic melanoma. We evaluated adjuvant vemurafenib in pts with BRAF^V600+ melanoma with high recurrence risk.

Methods

This 2-cohort (C) study randomized 498 adult pts with fully resected stage IIC, IIIA, or IIIB (C1) melanoma or Stage IIIC melanoma (C2) 1:1 to vemurafenib 960 mg twice daily or placebo for 52 weeks. Stratification was by geographic region and additionally by disease stage in C1. The primary endpoint was disease-free survival (DFS). Hierarchical analysis of C2 before C1 was prespecified. Secondary objectives included safety, distant metastasis–free survival (DMFS), and overall survival (OS).

Results

Median study followup was 34 months in C2 and 31 months in C1. In C2, median DFS was greater, though not statistically significant, with adjuvant vemurafenib vs placebo (Table). Adjuvant vemurafenib substantially improved DFS vs placebo in C1. Subgroup analyses by common disease and demographic covariates were consistent with the overall analysis. Results for DMFS were similar to that of DFS; OS data are immature. Median exposure to study drug was similar in both cohorts (median duration = 364.0 days; median dose intensity of ≈80% in both). Vemurafenib-treated pts in C1 and C2 had similar incidences of serious adverse events (AEs) (16.2% and 16.1% respectively); the rate of treatment discontinuation because of AEs was slightly higher in C1 (22.7%) than C2 (15.1%). Overall, the safety profile of adjuvant vemurafenib was consistent with previous data and no new safety signals were observed.

Conclusions

Although the study did not meet the primary DFS endpoint in pts with stage IIIC disease (C2), adjuvant vemurafenib appears to be effective and well tolerated in pts with resected stage IIC–IIIB BRAF^V600+ melanoma (C1). Further followup is needed to assess OS benefit.Table:

LBA7_PR Summary of efficacy

Clinical trial identification

Trial protocol number: GO27826 v9 (14 March 2017). Data available from 12 July 2017.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

K. Lewis: Grants from Roche/Genentech, Amgen, Incyte, and EMD Serono, and personal fees from Roche/Genentech, Incyte, and SunPharma, grants from Amgen, grants from EMD Serono. L. Demidov: Honoraria with MSD, Novartis (GSK), Roche, BMS; participated in a consulting or advisory role with BMS, MSD; received research funding with MSD, GSK, Roche, BMS, Novartis; and provided expert testimony for Amgen. M. Mandala: Grants and personal fees from Roche, and personal fees from Novartis, BMS, and MSD. P.A. Ascierto: Grants and personal fees from Roche-Genentech, BMS, and Array, and personal fees from MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte. P. Rutkowski: Grants and personal fees from Novartis, and personal fees from Roche, MSD, BMS, Amgen, Pfizer, and Blueprint. A. Guminski: Personal fees and other from BMS, personal fees from MSD, Merck, and Eisai, and travel support from Astellas. G. Goodman, B. Simmons, Y. Yan: Employee of and owns stock in Roche/Genentech. C. Ye: Employee of and owns stock and stock options in Roche/Genentech. D. Schadendorf: Patients\' fees from Novartis, Roche, Merck/MSD, GSK, and BMS, and personal fees from Amgen, Boehringer Ingelheim, Leo Pharma, Roche, Merck/MSD, and BMS. All other authors have declared no conflicts of interest.

Background

Surgery is curative for most patients (pts) with localized melanoma; however, those with regional nodal involvement (stage III disease) are at a higher risk for relapse and death after resection. In phase 3 trials of advanced or metastatic BRAF V600–mutant melanoma, D+T combination therapy improved clinical outcomes and was well tolerated.

Methods

In this randomized, double-blind, placebo-controlled, phase 3 study (COMBI-AD [NCT01682083]), pts with high-risk, stage III, BRAF V600E/K–mutant melanoma without prior anticancer therapy were randomized 1:1 within 12 weeks of complete surgical resection to receive D 150 mg twice daily plus T 2 mg once daily or matching placebos. Pts were treated for 12 months and stratified based on BRAFmutation (V600E vs V600K) and stage (IIIA vs IIIB vs IIIC). The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety.

Results

A total of 870 pts (stage IIIA, 18%; IIIB, 41%; IIIC, 40%; unknown, 1%) were randomized (D+T, n = 438; placebo, n = 432). The primary endpoint was met. At the time of the data cutoff for the primary analysis (June 30, 2017; median follow-up, 2.8 years), D+T significantly reduced the risk of disease recurrence or death by 53% vs placebo (HR, 0.47 [95% CI, 0.39-0.58]; median not reached vs 16.6 months, respectively; P<0.001). RFS benefit with D+T was observed across all patient subgroups. D+T also improved secondary endpoints of OS (HR, 0.57 [95% CI, 0.42-0.79]), DMFS (HR, 0.51 [95% CI, 0.40-0.65]), and FFR (HR, 0.47 [95% CI, 0.39-0.57]). With D+T, 97% of pts had an adverse event (AE), 41% had grade 3/4 AEs, and 26% had AEs leading to treatment discontinuation (vs 88%, 14%, and 3%, respectively, with placebo).

Conclusions

Combination D+T adjuvant therapy was associated with improvements in RFS, OS, DMFS, and FFR, and manageable safety in pts with high-risk, resected, stage III, BRAF V600E/K–mutant melanoma. This regimen represents a new adjuvant treatment option in this setting.

Clinical trial identification

ClinicalTrials.gov number: NCT01682083, EudraCT number: 2012-001266-15 Release date: May 31, 2017

Legal entity responsible for the study

GlaxoSmithKline

Funding

GlaxoSmithKline

Disclosure

A. Hauschild: Clinical trial support or speakeŕs honoraria or consultancy fees from Amgen, BMS, MerckSerono, MSD, Novartis, OncoSec, Philogen, Pierre Fabre, Provectus, Regeneron, Roche during the conduct of the study. G.V. Long: Personal fees as a consultant advisor to BMS, Novartis, Roche, Amgen, Merck MSD, Pierre Fabre, and Array outside the submitted work. V. Atkinson: Travel reimbursement and advisory board speaker\'s fees from MSD, BMS, and Novartis, speaker\'s fees from Roche, and advisory board fees from Pierre Fabre outside the submitted work. M. Mandala: Advisory board, lectures, and research activity fees from Roche; and advisory board and lecture fees from Novartis, MSD, and BMS outside the submitted work. V. Chiarion Sileni: Assistance with manuscript preparation from ArticulateScience, LLC, and advisory board fees from BMS, MSD, Roche, Novartis, and Merck Serono during the conduct of the study. M.S. Nyakas, C. Dutriaux: Assistance with manuscript preparation from ArticulateScience, LLC, during the conduct of this study. A. Haydon: Lecture fees from Novartis during the conduct of the study. C. Robert: Advisory board fees from BMS, MSD, Novartis, and Roche during the conduct of the study. L. Mortier: Assistance with manuscript preparation from ArticulateScience, LLC, and medical board fees from Novartis during the conduct of this study; and medical board fees from Roche outside the submitted work. R. Ji, P. Zhang: Employment by Novartis during the conduct of the study. B. Mookerjee: Employment and stock options from Novartis and stock options from GlaxoSmithKline during the conduct of the study; employment and stock options from Novartis and GlaxoSmithKline outside the submitted work. J. Legos: Employment by and shareholder of Novartis and non-financial support from ArticulateScience, LLC, during the conduct of the study. R. Kefford: Institutional reimbursement advisory boards fees from Novartis during the conduct of the study and institutional reimbursement advisory boards fees from BMS, Merck, Amgen, and Teva outside the submitted work. R. Dummer: Intermittent, project-focused consulting and/or advisory relationships with Novartis, MSD, BMS, Roche, Amgen, Takeda, and Pierre Fabre outside the submitted work. J. Kirkwood: Grants from Merck and Prometheus and personal fees from Prometheus, BMS, Novartis, Roche, Genentech, EMD Serono, and ArrAY Biopharma outside the submitted work. All other authors have declared no conflicts of interest.

Background

NIVO and IPI are immune checkpoint inhibitors approved for advanced melanoma. IPI is also approved in the US for resected stage III melanoma, based on a phase 3 trial demonstrating an improvement in recurrence-free survival (RFS). We report the first results of a phase 3 trial designed to evaluate NIVO vs IPI for resected stage III/IV melanoma at high risk of recurrence.

Methods

In this randomized, double-blind trial, eligible patients (pts) included those ≥15 yrs of age who underwent complete resection of stage IIIb/c or IV melanoma. 906 pts were randomized (stratified by stage and PD-L1 status) 1:1 to receive NIVO 3 mg/kg (n = 453) every 2 wks or IPI 10 mg/kg (n = 453) every 3 wks for 4 doses, then every 12 wks (from week 24) for up to 1 yr, disease recurrence, or unacceptable toxicity. The primary endpoint was RFS in the intent-to-treat population.

Results

Overall, 34%/47%/19% of pts had stage IIIb/IIIc/IV; 32%, ulcerated primary; 48%, macroscopic lymph node involvement; and 42%, BRAF mutation. At a median follow-up of 18.5 mo, NIVO significantly improved RFS vs IPI (Table). Results from prespecified subgroup analyses demonstrated consistent hazard ratios favoring NIVO.

Table:

LBA8_PR

Conclusions

NIVO as adjuvant therapy significantly improved RFS vs IPI for pts with stage III/IV melanoma at high risk of recurrence and demonstrated a superior safety profile. Acknowledgement: The co-senior authors for this abstract are Dr. J. Larkin and Dr. P.A. Ascierto.

Clinical trial identification

NCT02388906

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

J. Weber: Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris Pharmaceuticals, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai, CytomX Therapeutics, Nektar, Novartis, Medivation: consulting or advisory role; Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris Pharmaceuticals, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis: travel, accommodations, expenses; Named on a patent submitted by Moffitt Cancer Center for an ipilimumab biomarker; Altor BioScience, Celldex, CytomX Therapeutics: stock and other ownership interests; Bristol-Myers Squibb, Merck, Genentech, Abbvie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris Pharmaceuticals, CytomX Therapeutics, Nektar, Novartis, Medivation: honoraria; Bristol-Myers Squibb, Merck, Gla. M. Mandala: Roche: personal fees, grant; BMS, MSD, Novartis: personal fees. M. Del Vecchio: BMS: personal fees, honoraria; Roche: personal fees, honoraria, advisory board, research funding; GSK: personal fees, honoraria. H. Gogas: Roche, Amgen MSD, BMS, Novartis: consulting or advisory role, research funding; BMS, Roche, MSD: travel accommodations, expenses. A.M. Arance: GSK, Roche, personal fees, Consultant, speakers\' bureau; BMS: personal fees & non-financial support, Speakers\' bureau, travel funding. L.C. Cowey: BMS, Genentech: grant, personal fees, consultant, Speaker, Research funding; Merck, GSK: grant, consultant, Research funding. S. Dalle: BMS: research grants and travel expenses; BMS, MSD, Novartis, Roche: principal investigator V. Chiarion-Sileni: BMS, Roche, GSK: personal fees, consulting, speakers\' bureau, travel; MSD: personal fees, consulting, travel. I. Márquez-Rodas: Novartis, Roche, MSD, BMS: honoraria; Novartis, Roche, MSD, BMS, Amgen, Bioncotech: consulting or advisory role; MSD, BMS, Amgen: travel, accommodations, expenses. J-J. Grob: BMS: personal fees, consultant, speakers\' bureau, research funding; GSK: personal fees, consultant, speakers\' bureau; Novartis: personal fees, consulting; Roche: personal fees, non-financial support, consulting, speakers\' bureau, research funding, travel; Merck, Amgen: personal fees, consulting M. Butler: Bristol Myers Squib, EMD Serono, Immunocore, Immunovaccine: personal fees, advisory boards; Merck: grant, personal fees, advisory boards, grant support for clinical trial. M.R. Middleton: Amgen, Bristol-Myers Squibb, Clovis, GlaxoSmithKline, Immunocore (uncompensated), Merck, Roche (all compensated): consulting or advisory role; Amgen, AstraZeneca, Bristol-Myers Squibb, Clovis, Eisai, GlaxoSmithKline, Immunocore, Medimmune, Merck, Pfizer, Roche, Vertex: research funding; Merck, Roche: travel, accommodations, expenses. M. Maio: BMS, Roche, MedImmune, MSD, GSK: honoraria, consulting or advisory role, travel, accommodations, expenses; BMS, MedImmune: research funding. V. Atkinson: BMS, MSD, Novartis: honoraria, consulting or advisory role, speakers\' bureau, travel, accommodations, expenses. P. Queirolo: Roche, MSD, BMS, Novartis: personal fees. V. de Pril, A. Qureshi: employment – Bristol-Myers Squibb and stock/ownership – Bristol-Myers Squibb J. Larkin: BMS, MSD, Novartis, Pfizer: research funding; BMS, MSD, Pfizer, Eisai, GSK, Roche: travel, accommodations, expenses. P.A. Ascierto: Bristol-Myers Squibb, Roche-Genentech: grant, personal fees, honoraria, consultant, institutional research funding; GSK: personal fees, honoraria, consultant; MSD, personal fees, consultant; Ventana: grant, consultant, institutional research funding; Novartis: Consultant. All other authors have declared no conflicts of interest.