Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma

Geoffrey T. Gibney, Ragini R. Kudchadkar, Ronald C. DeConti, Melissa S. Thebeau, Maria P. Czupryn, Leticia Tetteh, Cabell Eysmans, Allison Richards, Michael J. Schell, Kate J. Fisher, Christine E. Horak, H. David Inzunza, Bin Yu, Alberto J. Martinez, Ibrahim Younos, Jeffrey S. Weber

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Abstract

Purpose: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design: HLA-A-∗ 0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Results: Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4 +/CD4+, CD25+Treg/CD4 +, and tetramer specific CD8 + T-cell populations were observed with treatment (P < 0.05). Trends for lower baselinemyeloid-derived suppressor cell and CD25 +Treg/CD4+ populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Conclusions: Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. Clin Cancer Res; 21(4); 712-20.

Original languageEnglish
Pages (from-to)712-720
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number4
DOIs
Publication statusPublished - Feb 15 2015

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Combined Vaccines
Melanoma
Biomarkers
Safety
Survival
Vaccines
Maximum Tolerated Dose
Exanthema
Recurrence
Neoplasms
Subunit Vaccines
Hypokalemia
Enteritis
nivolumab
Arthralgia
Regulatory T-Lymphocytes
Colitis
Pruritus
Nausea
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. / Gibney, Geoffrey T.; Kudchadkar, Ragini R.; DeConti, Ronald C.; Thebeau, Melissa S.; Czupryn, Maria P.; Tetteh, Leticia; Eysmans, Cabell; Richards, Allison; Schell, Michael J.; Fisher, Kate J.; Horak, Christine E.; Inzunza, H. David; Yu, Bin; Martinez, Alberto J.; Younos, Ibrahim; Weber, Jeffrey S.

In: Clinical Cancer Research, Vol. 21, No. 4, 15.02.2015, p. 712-720.

Research output: Contribution to journalArticle

Gibney, GT, Kudchadkar, RR, DeConti, RC, Thebeau, MS, Czupryn, MP, Tetteh, L, Eysmans, C, Richards, A, Schell, MJ, Fisher, KJ, Horak, CE, Inzunza, HD, Yu, B, Martinez, AJ, Younos, I & Weber, JS 2015, 'Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma', Clinical Cancer Research, vol. 21, no. 4, pp. 712-720. https://doi.org/10.1158/1078-0432.CCR-14-2468
Gibney, Geoffrey T. ; Kudchadkar, Ragini R. ; DeConti, Ronald C. ; Thebeau, Melissa S. ; Czupryn, Maria P. ; Tetteh, Leticia ; Eysmans, Cabell ; Richards, Allison ; Schell, Michael J. ; Fisher, Kate J. ; Horak, Christine E. ; Inzunza, H. David ; Yu, Bin ; Martinez, Alberto J. ; Younos, Ibrahim ; Weber, Jeffrey S. / Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 4. pp. 712-720.
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AU - Gibney, Geoffrey T.

AU - Kudchadkar, Ragini R.

AU - DeConti, Ronald C.

AU - Thebeau, Melissa S.

AU - Czupryn, Maria P.

AU - Tetteh, Leticia

AU - Eysmans, Cabell

AU - Richards, Allison

AU - Schell, Michael J.

AU - Fisher, Kate J.

AU - Horak, Christine E.

AU - Inzunza, H. David

AU - Yu, Bin

AU - Martinez, Alberto J.

AU - Younos, Ibrahim

AU - Weber, Jeffrey S.

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N2 - Purpose: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design: HLA-A-∗ 0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Results: Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4 +/CD4+, CD25+Treg/CD4 +, and tetramer specific CD8 + T-cell populations were observed with treatment (P < 0.05). Trends for lower baselinemyeloid-derived suppressor cell and CD25 +Treg/CD4+ populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Conclusions: Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. Clin Cancer Res; 21(4); 712-20.

AB - Purpose: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design: HLA-A-∗ 0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Results: Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4 +/CD4+, CD25+Treg/CD4 +, and tetramer specific CD8 + T-cell populations were observed with treatment (P < 0.05). Trends for lower baselinemyeloid-derived suppressor cell and CD25 +Treg/CD4+ populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Conclusions: Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. Clin Cancer Res; 21(4); 712-20.

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