Background

Risk of recurrence and death remain high for pts with advanced melanoma after resection. TVEC, an intralesional immunotherapy for advanced melanoma, selectively replicates in tumors and enhances systemic antitumor immune response. We examined the impact of neo T-VEC in resectable metastatic melanoma.

Methods

Pts with resectable stage IIIB-IVM1a melanoma and ≥ 1 injectable cutaneous, subcutaneous or nodal lesions were randomized 1:1 to 6 doses/12 wks of neo T-VEC then surg (Arm 1) vs surg alone (Arm 2). T-VEC was given until surg, no remaining injectable tumors or intolerance. The primary endpoint per protocol was recurrence-free survival (RFS) at 2-yrs, with events defined as first of local, regional or distant recurrence or death due to any cause after surg in the ITT set. Per protocol, pts who withdrew prior to surg or had a non-R0 resection were counted as an RFS event at randomization. An additional sensitivity analysis that did not count non-R0 events at baseline per conventional RFS calculation was also conducted.

Results

Demographics, tx status and safety for the 150 pts analyzed has been reported (Dummer et al., ASCO 2019). Median follow-up (range) was 31.2 (0.1, 49.9) mos. Per protocol, 29.5% of pts in Arm 1 and 16.5% of pts in Arm 2 remained recurrence free at 2 yrs (HR 0.75, P = 0.07). 50.5% of pts in Arm 1 and 30.2% of pts in Arm 2 (HR 0.66, P = 0.038) remained recurrence free at 2 yrs in the additional sensitivity analysis. 2-yr overall survival (OS) rates were 88.9% in Arm 1 and 77.4% in Arm 2 (overall HR 0.49, P = 0.050). In Arm 1, T-VEC resulted in a 3x increase in intratumoral CD8+ cell density (P < 0.001) and an increase in PD-L1 (P ≤ 0.05). CD8+ density and PD-L1 H-score were higher post-tx in Arm 1 vs Arm 2 (P < 0.001). Increased intratumoral CD8+ density post-tx correlated with longer RFS in the sensitivity analysis and OS.

Conclusions

In the largest randomized trial of neo tx in resectable stage IIIB-IVM1a melanoma, neo T-VEC improved 2-yr RFS and OS. T-cell influx and PD-L1 upregulation after T-VEC tx support a role for the adaptive immune system consistent with the mechanisms of action.

Clinical trial identification

NCT02211131, release date: August 7, 2014; EudraCT: 2014-001146-13.

Editorial acknowledgement

Medical writing support was provided by Sarah K Madsen (Amgen Inc.).

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

R. Dummer: Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Novartis; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Merck Sharp & Dohme (MSD); Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work.: BMS; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Roche; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Amgen Inc; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Takeda; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work.: Pierre Fabre; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Sun Pharma; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Sanofi; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Catalym. D.E. Gyorki: Honoraria (self), Travel / Accommodation / Expenses: Amgen Inc.. J. Hyngstrom: Advisory / Consultancy, Reviews of general surgery research articles every 2 months for Practical Reviews of General Surgery: Ebix. A. Berger: Speaker Bureau / Expert testimony: Cardinal Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Castle Biosciences. R. Conry: Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Amgen Inc.; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Array; Speaker Bureau / Expert testimony: Regeneron-Sanofi. L. Demidov: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Roche. A. Sharma: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. S.A. Treichel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. K. Gorski: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. A. Anderson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. M. Faries: Advisory / Consultancy: Delcath Systems Inc.; Advisory / Consultancy: Pulse Bioscience; Advisory / Consultancy: Novartis. M.I. Ross: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Amgen Inc.; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Research grant / Funding (self), Travel / Accommodation / Expenses: Provectus; Travel / Accommodation / Expenses: Castle Biosciences; Travel / Accommodation / Expenses: Novartis.

Background

The PD1 inhibitor NIVO has been approved for the adjuvant treatment of high-risk stage III and IV resected melanoma based on a phase III trial demonstrating improved recurrence-free survival (RFS) compared to IPI. We conducted a phase II double-blind, randomized, multicenter trial to determine the efficacy of NIVO alone or in combination with IPI vs. placebo for adjuvant therapy in stage IV melanoma pts with NED.

Methods

Pts ≥18 yrs of age with stage IV cutaneous or unknown primary melanoma and NED after surgery or radiation therapy were eligible (IMMUNED; CA209-184, NCT02523313, supported by BMS). They were randomly assigned 1:1:1 (stratified by trial site, site of metastasis and PD-L1 status) to receive either NIVO 3 mg/kg Q2W (n = 59) or NIVO 1 mg/kg plus IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W (n = 56) or placebo (n = 52) for a period of up to 1 year, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS in the intent-to-treat population.

Results

Between September 2015 and September 2018, 167 pts were randomized at 20 German centers and 162 pts received at least one infusion. At a median follow-up of 28.4 months, the RFS was significantly longer for NIVO compared to placebo (hazard ratio (HR) 0.56, 95% CI 0.36 to 0.88), and for NIVO plus IPI compared to placebo (HR 0.23, 95% CI, 0.13 to 0.41). Results from prespecified subgroup analyses demonstrated consistent HR favoring NIVO and NIVO plus IPI over placebo. Treatment-related grade 3/4 adverse events (AE) were reported in 27% pts of the NIVO group and in 71% of the NIVO plus IPI group. Treatment-related AEs of any grade led to treatment discontinuation in 13%, 62% and 2% of the NIVO, NIVO plus IPI and placebo group, respectively. No treatment-related deaths were reported.

Conclusions

Among stage IV melanoma pts with NED adjuvant therapy with NIVO alone or in combination with IPI resulted in significantly longer RFS compared to placebo. The rate of grade 3/4 treatment-related AEs in the NIVO and in the NIVO plus IPI group was higher than the rate reported in the CheckMate 067 trial in pts with unresectable melanoma.

Clinical trial identification

IMMUNED; CA209-184, NCT02523313.

Legal entity responsible for the study

University Hospital Essen, Prof. Dirk Schadendorf.

Funding

Funding in part by Bristol-Myers Squibb.

Disclosure

D. Schadendorf: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Amgen; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Leo Pharma; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (self): Incyte; Honoraria (self), Honoraria (institution): Regeneron; Honoraria (self), Honoraria (institution): 4SC; Honoraria (self): AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Honoraria (institution): Merck-EMD; Honoraria (self): Pfizer; Honoraria (self), Honoraria (institution): Philogen; Honoraria (self): Array. J.C. Hassel: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Payments to institution for treating patients within clinical trials: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Pierre Fabre. M. Fluck: Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Pierre-Fabre. T. Eigentler: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Sanofi Genzyme; Advisory / Consultancy: Leo Pharma; Honoraria (self), Advisory / Consultancy: MSD. C. Loquai: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sun Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Biontech; Advisory / Consultancy, Travel / Accommodation / Expenses: Almirall; Travel / Accommodation / Expenses: Kyowa Kirin. R. Gutzmer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Serono; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Sanofi; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: Novartis; Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Almirall Hermal; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Leo; Honoraria (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: SunPharma; Advisory / Consultancy: 4SC; Research grant / Funding (institution): Johnson & Johnson. P. Mohr: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: GSK; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Sanofi. A. Hauschild: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Philogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Provectus; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Regeneron; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: OncoSec; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi-Genzyme; Advisory / Consultancy: Sun Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis. J.C. Becker: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (institution): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC; Advisory / Consultancy: CureVac; Advisory / Consultancy: eTheRNA; Advisory / Consultancy: Lytix; Advisory / Consultancy: Novartis; Advisory / Consultancy: ReProTHer; Advisory / Consultancy: Rigontec; Research grant / Funding (institution): Alcedis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): IQVIA; Travel / Accommodation / Expenses: Incyte. F. Kiecker: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Pierre Fabre. C. Garbe: Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): NeraCare; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Philogen; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi. E. Livingstone: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Medac; Honoraria (self): Janssen; Advisory / Consultancy: Actelion; Travel / Accommodation / Expenses: Pierre Fabre. L. Zimmer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.

Background

The phase III study CheckMate 238 demonstrated improved relapse-free survival (RFS) with NIVO 3 mg/kg vs IPI 10 mg/kg in patients (pts) with resected stage III/IV melanoma. Sustained efficacy benefit at 24 mo of follow-up with NIVO vs IPI was previously reported. Here we present a 36mo analysis of efficacy and biomarker data from this study.

Methods

Pts aged ≥ 15 y with completely resected stage IIIB/C or IV melanoma were randomized 1:1 to receive NIVO (3 mg/kg Q2W; N = 453) or IPI (10 mg/kg Q3W for 4 doses; Q12W thereafter; N = 453) for ≤ 1 y or until disease recurrence/unacceptable toxicity. RFS was the primary endpoint; exploratory endpoints included distant metastases-free survival (DMFS) in pts with stage III disease and potential biomarkers of efficacy.

Results

With 36 mo of follow-up, NIVO continued to demonstrate superior RFS vs IPI (HR, 0.68; P < 0.0001; 3-y RFS rates, 58% vs 45% and 188/453 vs 239/453 pts with events, respectively). Prespecified subgroup analyses demonstrated a consistent pattern similar to that of the 24-mo analysis, with HRs favoring NIVO (Table). DMFS analysis also continued to favor NIVO (Table). High levels of all biomarkers analyzed (interferon-gamma gene expression signature, tumor mutational burden, and CD8+ T-cell infiltration by immunohistochemistry) showed an association with improved RFS for both NIVO and IPI. Median RFS (mo; 24-mo follow-up) by high vs low values for each biomarker for NIVO was 30.8 vs 24.1, not reached (NR) vs 30.8, and 30.8 vs 24.9, respectively; and for IPI was NR vs 15.9, NR vs 18.3, and NR vs 13.8, respectively.Table:

1310O

Conclusions

With 36 mo of follow-up, NIVO continued to demonstrate superior efficacy over IPI in pts with stage III/IV melanoma at high risk of recurrence across pt subgroups. Additional analyses using composite scoring of biomarker combinations will be presented.

Clinical trial identification

NCT02388906.

Editorial acknowledgement

Wendy Sacks, PhD, and Cara Hunsberger, MS, of StemScientific, an Ashfield company, funded by Bristol-Myers Squibb.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

J.S. Weber: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celldex; Honoraria (self), Advisory / Consultancy: Ichor Medical Systems; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: cCam Biotherapeutics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lion Biotechnologies; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pieris Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: Altor BioScience; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: GSK; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: CytomX Therapeutics; Honoraria (self), Advisory / Consultancy: Nektar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Sellas Life Sciences; Honoraria (self), Advisory / Consultancy: WindMIL; Non-remunerated activity/ies, named on a patent for an ipilimumab biomarker: Moffitt Cancer Center; Non-remunerated activity/ies, named on a patent for a PD-1 antibody biomarker: Biodesix; Shareholder / Stockholder / Stock options: Biond; Honoraria (self): AbbVie; Research grant / Funding (institution): InCyte; Research grant / Funding (institution): Astellas Pharma. M. Del Vecchio: Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Pierre Fabre. M. Mandala: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy: MSD Oncology. H. Gogas: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD Oncology; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre. A.M. Arance: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck. S. Dalle: Shareholder / Stockholder / Stock options, Full / Part-time employment: Sanofi Pasteur; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca. C.L. Cowey: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Regeneron; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Array; Research grant / Funding (institution): Amgen. M. Schenker: Research grant / Funding (self), Research grant / Funding (institution): BMS; Research grant / Funding (self), Research grant / Funding (institution): Roche; Research grant / Funding (self), Research grant / Funding (institution): Novartis; Research grant / Funding (self), Research grant / Funding (institution): Lilly; Research grant / Funding (self), Research grant / Funding (institution): Bayer; Research grant / Funding (self), Research grant / Funding (institution): Amgen; Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): AbbVie; Research grant / Funding (self), Research grant / Funding (institution): Astellas; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), Research grant / Funding (institution): Merck Serono; Research grant / Funding (self), Research grant / Funding (institution): Mylan; Research grant / Funding (self), Research grant / Funding (institution): Bioven. J.J. Grob: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pfizer. V. Chiarion-Sileni: Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Merck Serono; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: MSD. I. Marquez-Rodas: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Incyte; Advisory / Consultancy, Travel / Accommodation / Expenses: Bioncotech; Advisory / Consultancy: Pierre Fabre. M.O. Butler: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Immunovaccine; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: GSK; Advisory / Consultancy: Genzyme; Honoraria (self): Roche; Research grant / Funding (self): Takara Bio. M. Maio: Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Merck. M.R. Middleton: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: CytomX Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): RigonTEC; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Immunocore; Advisory / Consultancy: BiolineRx; Advisory / Consultancy: Johnson and Johnson; Advisory / Consultancy: Merck; Honoraria (self), Research grant / Funding (institution): Amgen; Honoraria (self), Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Vertex; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Replimune; Research grant / Funding (institution): Array Biopharm; Research grant / Funding (institution): TC Biopharm; Research grant / Funding (institution): Regeneron. T. Tang: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. A. Saci: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. V. De Pril: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. M. Lobo: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS; Shareholder / Stockholder / Stock options, Full / Part-time employment: Advaxis Immunotherapies. J.M.G. Larkin: Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: Sectra; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Achilles Therapeutics; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boston Biomedical; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Imugene; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: iOncologi; Advisory / Consultancy: Kyocera; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nektar; Honoraria (self), Advisory / Consultancy: Vitaccess; Honoraria (self): Secarna; Honoraria (self): Kymab; Research grant / Funding (institution): Covance; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): AVEO. P.A. Ascierto: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Incyte; Advisory / Consultancy: Genmab; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: MedImmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Idera; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Immunocore.

Background

Results from CheckMate 067 have shown significant improvements in objective response, progression-free survival (PFS), and overall survival (OS) with NIVO+IPI and NIVO alone vs IPI in patients with advanced treatment-naive melanoma. Here we present 5-year outcomes from the study.

Methods

Eligible patients with previously untreated stage III or IV melanoma (N = 945) were randomly assigned 1:1:1 and stratified by programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. Patients received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were OS and PFS; the study was not powered to compare the NIVO-containing groups. Descriptive analyses were performed to evaluate efficacy between NIVO+IPI and NIVO, treatment-free status, and health-related quality of life (HRQoL).

Results

With a minimum follow-up of 60 months, the NIVO-containing arms continued to show improved OS, PFS, and response vs IPI (table). In addition, descriptive analyses showed longer OS with NIVO+IPI (median OS, > 60.0 mo [not reached]) than with NIVO alone (median OS, 36.9 mo), as well as a higher proportion of patients alive and treatment-free with the combination. No sustained deterioration of HRQoL (EQ-5D-3L utility index) was observed during treatment or following treatment discontinuation with NIVO or NIVO+IPI.Table:

LBA68_PR

Conclusions

This 5-year analysis represents the longest phase III follow-up for checkpoint inhibitor combination therapy and demonstrates long-term survival with both NIVO-containing arms vs IPI. In descriptive analyses, NIVO+IPI was associated with improved survival and a higher likelihood of being alive and treatment-free compared with NIVO alone, both without loss of QoL.

Clinical trial identification

NCT01844505.

Editorial acknowledgement

Writing and editorial assistance was provided by Melissa Kirk, PhD, and Michele Salernitano of StemScientific, an Ashfield Company.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

J.M.G. Larkin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Achilles; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boston Biomedical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: EUSA Pharma; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Imugene; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: iOnctura; Honoraria (self), Advisory / Consultancy: Kymab; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Nektar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Secarna; Research grant / Funding (self): Aveo; Research grant / Funding (self): Covance; Honoraria (self), Advisory / Consultancy: Vitaccess. V. Chiarion-Sileni: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck-Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Incyte. R. Gonzalez: Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): Genentech/Roche; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): GSK; Honoraria (self), Research grant / Funding (self): Array; Honoraria (self), Research grant / Funding (self): Amgen; Honoraria (self), Research grant / Funding (self): Incyte; Honoraria (self), Research grant / Funding (self): NewLink Genetics; Research grant / Funding (self): Merck; Research grant / Funding (self): Takeda; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Checkmate Pharmaceuticals; Research grant / Funding (self): Tesaro; Research grant / Funding (self): Syndax; Research grant / Funding (self): Nektar. J.J. Grob: Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Roche/Genentech; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AMGEN; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Sun Pharma. P. Rutkowski: Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Blueprint Medicines . C. Lao: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Dynavax; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Immunocore. D. Schadendorf: Honoraria (self): Roche/Genentech; Honoraria (self): Merck Serono; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis, Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Immunocore, Philogen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Incyte, Regeneron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: 4SC, Mologen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Mologen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Sanofi/Regeneron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Sysmex; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Grünenthal Group; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Agenus; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Array; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: BioPharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: LEO Pharma. J. Wagstaff: Honoraria (self): Bristol-Myers Squib . R. Dummer: Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Honoraria (self): Amgen; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre; Honoraria (self): Roche; Honoraria (self): Sun Pharma; Honoraria (self): Takeda; Honoraria (self): Sanofi. P.F. Ferrucci: Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre. M. Smylie: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck; Honoraria (self): Sanofi Genzyme; Honoraria (self): Novartis. D. Hogg: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): EMD Sereno; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Merck. I. Marquez-Rodas: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Research grant / Funding (self): BIONCOTECH; Honoraria (self), Research grant / Funding (self): AMGEN; Honoraria (self), Research grant / Funding (self): Incyte; Honoraria (self): Sanofi ; Honoraria (self): Regeneron. J.B.A.G. Haanen: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Novartis; Research grant / Funding (self): MSD; Research grant / Funding (self): Neon Therapeutics . J. Rizzo: Honoraria (self), Full / Part-time employment: Bristol-Myers Squibb. A. Balogh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F..S. Hodi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Merck, EMD Serono, Takeda, Surface, ; Honoraria (self): Genentech/Roche, Compass Therapeutics,; Honoraria (self): Apricity, Bayer, Aduro, Partners Therapeutics; Honoraria (self): Sanofi, Pfizer, Pionyr, Verastem; Honoraria (self): Rheos, Kairos, Bicara; Honoraria (self), Research grant / Funding (self): Novartis; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Torque, 7 Hills Pharma, Psioxus Therapeutics ; Licensing / Royalties: patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid; a patent Tumor Antigens and Uses Thereof (#7250291) issued; a patent Angiopoiten-2 Biomarkers Predictive of Anti-Immune Checkpoint Response (#20170248603) pending; a . J. Wolchok: Patent information: Xenogeneic DNA Vaccines; Alphavirus Replicon Particles Expressing TRP2; Myeloid-derived Suppressor cell (MDSC) assay; Newcastle Disease Viruses for Cancer Therapy; Genomic Signature to Identify Responders to Ipilimumab in Melanoma; Engineered Vaccinia Viruses for Cancer Immunotherapy; Anti-CD40 agonist mAb fused to Monophosphoryl Lipid A (MPL) for cancer therapy; CAR+ T cells targeting differentiation antigens as means to treat cancer; Anti-PD1 Antibody; Anti-CTLA4 antibodies; Anti-GITR antibodies and methods of use thereof; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb ; Honoraria (self): Advaxis, Elucida, Amgen, Eli Lilly; Honoraria (self): Apricity, F Star, Array BioPharma, Imvaq; Honoraria (self): Ascentage, Janssen, Astellas, Kleo; Honoraria (self): Bayer, Merck, Adaptive Biotech, Neon Therapeutics; Honoraria (self): Beigene, ONO, Celgene, Polaris Pharma; Honoraria (self): Chugai, Polynoma, PsiOxus, Puretech; Honoraria (self): Recepta, Sellas Life Sciences; Honoraria (self): Serametrix, Surface, Syndax; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Potenza Therapeutics, Tizona Pharma; Honoraria (self), Research grant / Funding (self): Genentech, MedImmune; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Trieza, Linneaus. All other authors have declared no conflicts of interest.

Background

Treatment for pts with advanced BRAF^V600 wt melanoma includes immune checkpoint inhibitors, such as P, an anti–PD-1 antibody. MAPK activation is implicated in BRAF^V600 wt melanoma, and emerging data suggest that MAPK inhibition may enhance antitumor immune response to checkpoint inhibitors. In a phase I study, the combination of C, a MEK inhibitor, plus A, an anti–PD-L1 antibody, showed promising antitumor activity. In a phase III randomized study we evaluated whether C+A would improve efficacy compared with P monotherapy in pts with BRAF^V600 wt advanced melanoma.

Methods

Pts had previously untreated unresectable stage III or IV BRAF ^V600 wt melanoma. Pts were stratified by PD-L1 expression, LDH level, and geographic location, and were randomized 1:1 to receive C (60 mg, days 1-21) plus A (840 mg, every 2 wk) in 28-day cycles or P (200 mg, every 3 wk) until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. Primary endpoint was PFS, assessed by independent review committee (IRC). Key secondary endpoints were confirmed objective response rate (ORR), disease control rate (DCR), OS, and safety.

Results

446 pts were randomized to C+A (n = 222) or P (n = 224); 68% of pts had PD-L1–positive tumors and 25% had LDH >ULN. Median follow-up was 7 mo (range 0-15). C+A did not significantly improve IRC-assessed PFS vs P (median 5.5 vs 5.7 mo; HR 1.15; 95% CI 0.88-1.50; P = 0.295). Results were consistent across pt subgroups. Confirmed IRC-assessed ORR was 26% vs 32% with C+A vs P; DCR was 46% vs 44%. Median OS was not reached in either arm (HR 1.06; 95% CI 0.69-1.61). AEs were consistent with known safety profiles of the individual agents. Grade ≥3 AEs occurred in 67% vs 33% of pts receiving C+A vs P; AEs leading to discontinuation of all treatments occurred in 12% vs 6%.

Conclusions

IMspire170 did not meet its primary endpoint. The combination of C+A did not demonstrate an improvement in PFS vs P monotherapy in pts with BRAF^V600 wt advanced melanoma. The safety profile of C+A was consistent with that observed in previous studies of this combination.

Clinical trial identification

NCT03273153.

Editorial acknowledgement

ApotheCom, Yardley, PA, USA.

Legal entity responsible for the study

Roche.

Funding

Roche.

Disclosure

A.M. Arance: Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp and Dohme; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck. H. Gogas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (institution), Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Roche. B. Dreno: Advisory / Consultancy: Roche. K.T. Flaherty: Advisory / Consultancy, Shareholder / Stockholder / Stock options, BMS: advisory/consultancy: X4 Pharmaceuticals; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Merck: advisory/consultancy; research grant (institution): PIC Therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Takeda: advisory/consultancy: Sanofi; Advisory / Consultancy, Verastem: advisory/consultancy: Amgen; Advisory / Consultancy, Boston Biomedical: advisory/consultancy: Asana; Advisory / Consultancy, Pierre Fabre: advisory/consultancy: Adaptimmune; Advisory / Consultancy, Cell Medica: advisory/consultancy: Fount; Advisory / Consultancy, Debiopharm: advisory/consultancy; research grant (institution): Aeglea; Advisory / Consultancy, Research grant / Funding (institution), Clovis Oncology: shareholder/stock: Array BioPharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Strata Oncology: shareholder/stock: Shattuck Labs; Advisory / Consultancy, Vivid Biosciences: shareholder/stock: Tolero; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Checkmate Pharmaceuticals: shareholder/stock: Apricity; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncoceutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fog Pharma; Advisory / Consultancy: Neon; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tvardi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: xCures; Advisory / Consultancy: Monopteros; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Genentech. L. Demidov: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: BIOCAD; Research grant / Funding (self): Amgen. D. Stroyakovskiy: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis. Z. Eroglu: Advisory / Consultancy: Array; Advisory / Consultancy: Regeneron; Research grant / Funding (institution): Novartis. P.F. Ferrucci: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis. J. Pigozzo: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. P. Rutkowski: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Travel / Accommodation / Expenses: Orphan Drugs. J. Mackiewicz: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. I. Rooney: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. A. Voulgari: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. S. Troutman: Full / Part-time employment: Genentech. B. Pitcher: Full / Part-time employment: Roche. Y. Yan: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. J.M.G. Larkin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Vitaccess: honoraria (self)/advisory/consultancy/travel: Achilles; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Covance: research grant (institution): AZ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Immunocore: research grant (institution): Boston Biomedical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Pharmacyclics: research grant (institution): BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Aveo: research grant (institution): Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: GSK; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Imugene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Incyte; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: iOnctura; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Kymab; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Nektar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Secarna.

Background

Preliminary data from the ABC (76 pts, med f/u 17mo) and CheckMate 204 (94 pts, med f/u 14mo) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report the survival and updated response data from all pts enrolled (Nov 2014-Apr 2017) on the randomised Ph2 ABC trial (NCT02374242) of 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/CTLA4.

Methods

Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Secondary endpoints were best extracranial response (ECR), best overall response, IC PFS, EC PFS, overall PFS, OS, & safety.

Results

76 pts (med f/u 34 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600 BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. The ICR/ECR in A, B and C were 51%/57%, 20%/29% and 6%/25%, respectively, with complete ICR in 26%, 16% and 0%. The 12- and 24-mo IC PFS were cohort A: 49% and 49%, B: 20% and 15% and C: 6% and 6%, and the 12- and 24-mo OS were A: 63% and 63%, B: 60% and 51% and C: 31% and 19%. ICR and 24-mo IC PFS in cohort A drug treatment naïve (n = 27) were 59% and 56%, respectively. Treatment-related AEs gd 3/4 toxicity in A, B and C were 54%, 20% and 13%, respectively. There were no treatment-related deaths. Quality of life was assessed using EQ-5D-5L, QOL C30 and BM-20 questionnaires.

Conclusions

With longer follow up, upfront ipi+nivo demonstrates durable IC responses in the majority of patients, with no new AEs. A study of upfront ipi+nivo+SRS vs ipi+nivo is planned (NCT03340129).

Clinical trial identification

NCT02374242.

Editorial acknowledgement

NIL.

Legal entity responsible for the study

Melanoma Institute Australia.

Funding

Bristol-Myers Squibb.

Disclosure

G.V. Long: Advisory / Consultancy: Aduro, Amgen, BMS, Mass-Array, Merck MSD, Novartis, ONcosec, Pierre Fabre, Roche. V.G. Atkinson: Honoraria (self): BMS, MSD, Merck Serono, Pierre Fabre, Roche, Novartis; Advisory / Consultancy: BMS, MSD, Merck Serono, Pierre Fabre, Roche, Novartis; Speaker Bureau / Expert testimony: BMS, MSD, Merck Serono, Roche, Novartis; Travel / Accommodation / Expenses: BMS, MSD, Roche, Onco-Sec. S.K. Sandhu: Honoraria (self): Janssen, Bristol-Myers Squibb, Roche/Genentech, Merck Sharp and Dohme and Merck Serono; Research grant / Funding (institution): Merck, Merck Serono, Bristol-Myers Squibb, Amgen,Tolmar; Travel / Accommodation / Expenses: Genentech, Janssen, Merck. M. Brown: Honoraria (institution): BMS. A. Guminski: Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Kga, SunPharm; Advisory / Consultancy: Eisai, Regeneron, Sandofi. R.A. Scolyer: Advisory / Consultancy: Merck, Sharp & Dohme, Novartis, Myriad, NeraCare. A.M. Menzies: Advisory / Consultancy: BMS, MSD, Novartis, Roche, Pierre Fabre. G.A. McArthur: Honoraria (institution): - Genentech/Roche - MSD - BMS - Array BioPharm - Amgen - Pfizer. All other authors have declared no conflicts of interest.