A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma

Joseph I Clark, Jatinder Singh, Marc S Ernstoff, Christopher D Lao, Lawrence E Flaherty, Theodore F Logan, Brendan Curti, Sanjiv S Agarwala, Bret Taback, Lee Cranmer, Jose Lutzky, Theresa L Luna, Sandra Aung, David H Lawson, Joseph I Clark, Jatinder Singh, Marc S Ernstoff, Christopher D Lao, Lawrence E Flaherty, Theodore F Logan, Brendan Curti, Sanjiv S Agarwala, Bret Taback, Lee Cranmer, Jose Lutzky, Theresa L Luna, Sandra Aung, David H Lawson

Abstract

Background: Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes.

Methods: Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7-18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2.

Results: Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure.

Conclusions: Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone.

Trial registration: NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188.

Keywords: BRAF-mutated metastatic melanoma; High-dose interleukin-2; Multicenter; Phase II; Vemurafenib.

Conflict of interest statement

Ethics approval and consent to participate

Human investigations were performed after approval by an institutional review board or ethics committee at each participating institution and in accordance with an assurance filed with and approved by the U.S. Department of Health and Human Services. Written informed consent was obtained on all patients.

Consent for publication

Not applicable.

Competing interests

J.I. Clark: non-paid advisory role – PROCLIVITY registry, Prometheus; advisory board – Exelixis; speakers’ bureau – Bristol-Myers Squibb, Merck; research funding to institution – Acceleron Pharma, Argos Therapeutics, AVEO, Bristol-Myers Squibb, Prometheus, Roche.

J. Singh: no competing interests reported.

M.S. Ernstoff: no competing interests reported.

C.D. Lao: research funding to institution: Bristol-Myers Squibb, Merck, GlaxoSmithKline, Norvatis; travel reimbursement: Bristol-Myers Squibb.

L.E. Flaherty: non-paid DSMB role – Merck.

T.F. Logan: consulting/advisory role – Prometheus; research funding to institution – Abbott Laboratories, Abraxis BioScience, Acceleron Pharma, AMGEN, Argos Therapeutics, AstraZeneca, AVEO, BioVex, Bristol-Myers Squibb, Eisai, Lilly, GlaxoSmithKline, Roche, immatics, Merck, Novartis, Pfizer, Prometheus, Synta, Thrshold Pharmaceuticals, Millennium, TRACON Pharma, Cerulean, EMD Serono.

B. Curti: consulting/advisory role – Prometheus; research support – Prometheus, Galectin Therapeutics, Viralytics; research funding to institution – Bristol-Myers Squibb, MedImmune; speakers’ bureau – Prometheus, Bristol-Myers Squibb.

S.S. Agarwala: no competing interests reported.

B. Taback: no competing interests reported.

L. Cranmer: no competing interests reported.

J. Lutzky: no competing interests reported.

T.L. Luna: no competing interests reported.

S. Aung: no competing interests reported.

D.H. Lawson: no competing interests reported.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Treatment Schema
Fig. 2
Fig. 2
Progression-Free Survival by Cohort
Fig. 3
Fig. 3
Overall Survival by Cohort

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