1085O - Survival, response duration, and activity by BRAF mutation (MT) status in a phase 1 trial of nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilim...

Date 27 September 2014
Event ESMO 2014
Session Melanoma and other skin tumours
Topics Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Translational Research
Presenter Harriet Kluger
Citation Annals of Oncology (2014) 25 (suppl_4): iv374-iv393. 10.1093/annonc/mdu344
Authors H. Kluger1, M. Sznol2, M. Callahan3, M. Postow3, R. Gordon3, N.H. Segal3, N. Rizvi3, A. Lesokhin3, M.B. Atkins4, J. Kirkwood5, M. Burke6, A. Ralabate7, A. Rivera7, S. Kronenberg3, B.U. Agunwamba3, W. Feely8, Q. Hong8, S. Krishnan8, J.D. Wolchok3
  • 1Yale Cancer Center, Yale Comprehensive Cancer Center (Smilow Cancer Hospital at Yale-New Haven), 06519 - New Haven/US
  • 2Yale Cancer Center, Yale Comprehensive Cancer Center(Smilow Cancer Hospital at Yale-New Haven), New Haven/US
  • 3Ludwig Center, Memorial Sloan Kettering Cancer Center, New York/US
  • 4Internal Medicine, Georgetown Lombardi Comprehensive Cancer Center, Washington DC/US
  • 5Division Of Hematology/oncology, University of Pittsburgh Medical Center, Pittsburgh/US
  • 6Yale School Of Nursing, Yale School of Medicine, 06519 - New Haven/US
  • 7Yale Cancer Center, Yale School of Medicine, 06519 - New Haven/US
  • 8N/a, Bristol-Myers Squibb Company, Princeton/US

 

Abstract

Aim

In a phase 1 trial, concurrent therapy with nivolumab (N) + IPI (N + I) led to an objective response rate (ORR) of 40% and evidence of clinical activity in a further 25% of patients (pts). Tumor regression was generally rapid, with >80% reduction in tumor measurements in 31% of pts. We report updated survival, efficacy and clinical activity by BRAF MT status across all pt cohorts.

Methods

MEL pts (≤3 prior therapies) received concurrent N + I IV Q3W × 4 doses (Table; n = 53) followed by N Q3W × 4 doses. At wk 24, pts without progression by immune-related criteria (iRC) and no dose limiting toxicities could continue N + I Q12W × 8 doses. An additional 41 pts (cohort 8, last pt enrolled Nov 2013) were treated with N + I 1 + 3 mg/kg Q3W × 4 doses, followed by N 3 mg/kg Q2W (selected regimen for phase 2/3 trials). Tumor responses were evaluated by WHO and iRC.

Results

Of the total 94 pts, 53% were stage M1c; 45% had prior systemic therapy. In the initially enrolled cohorts, ORR was 42% (22/53); median duration of response (DOR) not reached (NR); 9/53 (17%) demonstrated confirmed complete response. Fourteen of 22 pts (64%) with an OR had DOR ≥24 wks (range 24.7 + , 105.7+). Clinical activity was similar irrespective of BRAF MT status. Tumor reduction of ≥80% by wk 36 was observed in 22/53 pts (42%). One- and 2-yr OS rates were 85% and 79%, respectively. In cohort 8, ORR was 43% (17/40). For aggregate safety across cohorts, grade 3–4 treatment-related AEs occurred in 58/94 pts (62%); most common: increased lipase (15%), ALT (12%) and AST (11%).

Conclusions

Concurrent N + I demonstrated encouraging survival and a manageable safety profile using standard safety algorithms in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in many pts. The preliminary analysis of cohort 8 confirms the activity of N + I observed in the initially enrolled concurrent cohorts.

Nivolumab (mg/kg) + IPI (mg/kg) [n] 1-yr OS rate, % [pts at risk] Median OS, mo ACAR, % ACAR by BRAF MT status,* % [n]
Initially enrolled concurrent cohorts [53] 85 [44] 39.7 70 60 [10] 73 [26] 71 [17]
0.3 + 3 [14]  57 [8] 27.2 57 50 [4] 67 [3] 57 [7]
1 + 3 [17]  94 [15] NR 65 50 [2] 50 [6] 78 [9]
3 + 1 [16]  94 [15] NR 81 67 [3] 85 [13] – [0]
3 + 3 [6] 100 [6] NR 83 100 [1] 75 [4] 100 [1]
Cohort 8 [41] Insufficient follow-up NR 48 58 [7] 46 [12] 100 [2]

n: no. response-evaluable pts. ACAR: aggregate clinical activity rate = CR + PR + uCR + uPR + irCR + irPR + SD ≥ 24 wk+ irSD ≥24 wk. *Retrospective analysis.

Disclosure

M. Sznol: Paid consultant and scientific advisory board-Bristol-Myers Squibb, Genentech/Roche, MedImunne, Amgen, Nektar, Symphogen, Merus, Amphivena, NeoStem, Anaeropharma, BeiGene, Kyowa-Kirin, Immune Design, Lion Biotechnologies, Seattle Genetics; M. Postow: BMS-consultant advisor, research funding; R. Gordon: BMS remuneration; N.H. Segal: Ad Board-MedImmune, Alkermes Scientific, Imugene; Research Funding BMS, MedImmune, Pfizer; N. Rizvi: Consultant Advisor-BMS; Honoraria-BMS, Medimmune, Genentech/Roche; A. Lesokhin: Consultant/advisor to BMS; Research Funding BMS; M.B. Atkins: Consultant advisor, honoraria- BMS; J. Kirkwood: Consultant advisor-BMS, Merck, GSK, Celgene, Vical, Ziopharm; Research Funding Prometheus; W. Feely: BMS-employee, stock; Q. Hong: BMS-employee, stock; S. Krishnan: BMS-employee, stock; J. Wolchok: Consultant/advisor to BMS; Research Funding BMS. All other authors have declared no conflicts of interest.