LBA3_PR - A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator's choice chemotherapy (ICC) in patients w...

Date 29 September 2014
Event ESMO 2014
Session Presidential Symposium 2
Topics Anticancer Agents
Skin Cancers
Biological Therapy
Presenter Jeffrey Weber
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors J.S. Weber1, D.R. Minor2, S. D'Angelo3, F.S. Hodi4, R. Gutzmer5, B. Neyns6, C. Hoeller7, N.I. Khushalani8, W.H. Miller9, J. Grob10, C. Lao11, G. Linette12, K. Grossmann13, J. Hassel14, P. Lorigan15, M. Maio16, M. Sznol17, A. Lambert18, A. Yang19, J. Larkin20
  • 1Medical Oncology, H. Lee Moffitt Cancer Center & Research Institute, 33612 - Tampa/US
  • 2Medical Oncology, California Pacific Medical Center, San Francisco/US
  • 3Internal Medicine, Memorial Sloan Kettering Cancer Center, New York/US
  • 4Melanoma Center, Dana-Farber Cancer Institute, Boston/US
  • 5Dermatology And Allergy, Skin Cancer Center, Hannover Medical School, Hannover/DE
  • 6Medical Oncology, Vrije Universiteit Brussel, BE-1090 - Brussels/BE
  • 7Dermatology, Medical University of Vienna, Vienna/AT
  • 8Medical Oncology, Roswell Park Cancer Institute, US-14263 - Buffalo/US
  • 9Oncology, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital , McGill University, Montreal/CA
  • 10Dermatology, Aix-Marseille University, Hopital de la Timone, Marseille/FR
  • 11Medical Oncology, University of Michigan, Ann Arbor/US
  • 12Internal Medcine/oncology, Washington University, St. Louis/US
  • 13Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City/US
  • 14Dermatology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg/DE
  • 15Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 16Division Of Medical Oncology And Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, 53100 - Siena/IT
  • 17Section Of Medicine Oncology, Yale Cancer Center, New Haven/US
  • 18Biostatistics, Bristol-Myers Squibb, Braine-l’Alleud/BE
  • 19Immuno-oncology, Bristol-Myers Squibb, Princeton/US
  • 20Department Of Medicine, Royal Marsden Hospital, SW3 6JJ - London/GB




Effective therapies are needed for patients (pts) with melanoma (MEL) who progress on or after anti-CTLA-4 therapy and a BRAF inhibitor. This phase 3 open-label trial evaluated the efficacy of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, which demonstrated durable antitumor activity and promising overall survival (OS) in phase 1 trials in pretreated patients.


Pts with metastatic MEL who progressed on or after anti-CTLA-4 therapy (and a BRAF inhibitor if BRAF V600 mutation positive) were randomized 2:1 to receive nivolumab 3 mg/kg IV Q2W (n = 268 treated) or ICC (dacarbazine 1000 mg/m2 Q3W, or carboplatin AUC 6 + paclitaxel 175 mg/m2 Q3W; n = 102 treated) until progression or unacceptable toxicity. Pts were stratified by PD-1 ligand expression, BRAF status and best response to prior anti-CTLA-4 therapy. Co-primary endpoints were objective response rate (ORR) by independent radiology review committee (IRC) and OS of nivolumab- versus ICC-treated pts. Response (RECIST 1.1) was assessed 9 W after randomization, followed by Q6W for the first 12 mo and then Q12W.


ORR was assessed as planned in the first 120 nivolumab and 47 ICC pts with follow-up of ≥6 mo. Baseline age, sex and M stage were balanced between arms. Confirmed ORR (IRC) in nivolumab and ICC pts was 32% (95% CI: 24, 41) and 11% (95% CI: 3.5, 23), with median time to response of 2.1 mo (range: 1.6, 7.4) and 3.5 mo (range: 2.1, 6.1), respectively. Reduction of ≥50% in target lesion burden occurred in 82% (31/38) of nivolumab responders and 60% (3/5) of ICC responders. Median duration of response for nivolumab was not reached (range: 1.4 +, 10+ mo) with 36 (95%) pts still in response. Median duration of response for ICC was 3.6 mo (range: 1.3 + , 3.5) with 4 (80%) pts still in response. Among nivolumab-treated pts, an additional 10 (8.3%) pts had immune-related response patterns observed. Grade 3-4 drug-related adverse events (AEs) were seen in 9.0% and 31% of pts treated with nivolumab and ICC, respectively. Discontinuations due to drug-related AEs, any grade, occurred in 2.2% and 7.8% of treated pts, respectively.


In pts with metastatic MEL who progressed on or after anti-CTLA-4 therapy (and BRAF inhibitors), nivolumab was well tolerated and showed higher ORR as compared with ICC, with durable tumor regression in the majority of responders.


J.S. Weber: Advisory board-BMS, Merck, Genentech, all less than $5000 USD annually Corporate sponsored research-BMS, Merck, Genentech, all to my institution, not me personally; D.R. Minor: I am a speaker for BMS and I own stock in BMS (approx $26,000). I also am a speaker for Glaxo; F.S. Hodi: Consultant, not paid: Bristol-Myers Squibb Corporate-sponsored research: Bristol-Myers Squibb; R. Gutzmer: Consultant: BMS, Merck/MSD, Roche, GSK, Novartis, AlmirallHermal Honoraria: same as above + Janssen, Amgen, Pfizer, Boehringer Ingelheim Corporate-sponsored research: Roche, Novartis, Pfizer, Johnson & Johnson (payment to institution); B. Neyns: Consultant: BMS, GSK, Merck-Serono, Novartis Honoraria: BMS, GSK Research funding: GSK, Pfizer (payment to institution); C. Hoeller: Advisory board: BMS; N.I. Khushalani: Advisory board: Amgen, Genentech, Provectus Speaker's bureau: Prometheus Research funding: BMS, Biovex, Eisai, Genentech, Celgene, Merck, Pfizer, Threshold, and Roche, Allos, and Pfizer for NCCN trials; W.H. Miller: Consultant and Honoraria: BMS, Roche, Novartis, Merck Stock holdings: BMS; J-J. Grob: Advisor: BMS, Roche, GSK, Merck, Celgene; G. Linette: Consultant: BMS, Genentech, Ziopharm Honoraria: Genentech K. Grossmann: Research funding: BMS (payment to institution); J.C. Hassel: Consultant: BMS, GSK Honoraria: BMS, Roche, Amgen, MSD; P. Lorigan: Consultant and honoraria: BMS, Merck, Roche, GSK, Celgene, Novartis, Amgen; M. Maio: Consultant and honoraria: BMS, Roche, MSD, GSK Research funding: BMS, MedImmune (payment to institution); M. Sznol: Consultant: Bristol-Myers Squibb, Genentech/Roche, Amgen, AstraZeneca/MedImmune, Symphogen, Merus, Immune Design, Anaeropharma, Kyowa-Hakko Kirin, Lion Biotechnologies, Nektar, and Seattle Genetics. Other: Haymarket Media; A. Lambert and A. Yang: Employment: Bristol-Myers Squibb Stock holdings: Bristol-Myers Squibb; J. Larkin: Consultant: BMS, Pfizer, Novartis, GSK, MSD, Roche/Genentech (non-remunerated). Research funding: Pfizer, Novartis (payment to institution). All other authors have declared no conflicts of interest.