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

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

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

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Also Published In

Title
Journal for ImmunoTherapy of Cancer
DOI
https://doi.org/10.1186/s40425-018-0387-x

More About This Work

Academic Units
Irving Comprehensive Cancer Center
Surgery
Published Here
October 1, 2018

Notes

High-dose interleukin-2, Vemurafenib, BRAF-mutated metastatic melanoma, Multicenter, Phase II