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 D Cranmer, Jose Lutzky, Theresa L. Luna, Sandra Aung, David H. Lawson

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article number76
JournalJournal for ImmunoTherapy of Cancer
Volume6
Issue number1
DOIs
StatePublished - Jul 27 2018
Externally publishedYes

Fingerprint

Interleukin-2
Melanoma
Mutation
Antigen Presentation
Neoplasm Antigens
PLX4032
Immunotherapy
Immunity
Therapeutics
Survival

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

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 D; Lutzky, Jose; Luna, Theresa L.; Aung, Sandra; Lawson, David H.

In: Journal for ImmunoTherapy of Cancer, Vol. 6, No. 1, 76, 27.07.2018.

Research output: Contribution to journalArticle

Clark, JI, Singh, J, Ernstoff, MS, Lao, CD, Flaherty, LE, Logan, TF, Curti, B, Agarwala, SS, Taback, B, Cranmer, LD, Lutzky, J, Luna, TL, Aung, S & Lawson, DH 2018, 'A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma', Journal for ImmunoTherapy of Cancer, vol. 6, no. 1, 76. https://doi.org/10.1186/s40425-018-0387-x
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 D ; Lutzky, Jose ; Luna, Theresa L. ; Aung, Sandra ; Lawson, David H. / A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma. In: Journal for ImmunoTherapy of Cancer. 2018 ; Vol. 6, No. 1.
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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 na{\"i}ve 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.",
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T1 - A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma

AU - Clark, Joseph I.

AU - Singh, Jatinder

AU - Ernstoff, Marc S.

AU - Lao, Christopher D.

AU - Flaherty, Lawrence E.

AU - Logan, Theodore F.

AU - Curti, Brendan

AU - Agarwala, Sanjiv S.

AU - Taback, Bret

AU - Cranmer, Lee D

AU - Lutzky, Jose

AU - Luna, Theresa L.

AU - Aung, Sandra

AU - Lawson, David H.

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N2 - 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.

AB - 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.

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KW - Phase II

KW - Vemurafenib

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