Nivolumab shows signs of superior response rate compared to standard chemotherapy in advanced melanoma

Preliminary data from a phase III trial suggest drug is well tolerated and leads to a sustained response in patients who have progressed after ipilimumab therapy

Lugano/Madrid, 29 September 2014 -- The monoclonal antibody nivolumab achieves superior response rates and a longer duration of response than standard chemotherapy[1] in patients whose melanoma has progressed after treatment with ipilimumab, according to phase III data presented at the ESMO 2014 Congress in Madrid, Spain.

“Previously-treated advanced melanoma patients have limited options,” says the study’s principal investigator, Professor Jeffrey Weber, Director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at the Moffitt Cancer Centre, Tampa, Florida.

Nivolumab is an antibody in a class of drugs called ‘checkpoint inhibitors’, that act to relieve a critical brake placed on the immune system by the tumour itself. The drug then reinvigorates patients’ anti-tumour immune response and promotes shrinkage of the tumour.

In this first phase III trial of nivolumab among melanoma patients whose disease has progressed even after treatment with ipilimumab, 405 patients with unresectable metastatic melanoma were randomized in a ratio of 2:1 either to intravenous nivolumab (3 mg/kg) or the investigator’s choice of chemotherapy regimens: dacarbazine (1000 mg/m2), or carboplatin AUC6 plus paclitaxel (175 mg/m2).

The primary endpoints of the study were objective response rate to treatment and overall survival, but researchers are also looking at the impact of treatment on secondary objectives of safety, progression-free survival, health-related quality of life and expression of the programmed death-1 ligand (PD-L1), which is the ligand of PD-1 targeted by nivolumab.

Preliminary data from a sub-group of the nivolumab-treated patients in the open-label trial show that nivolumab has markedly higher clinical activity with a 32% response rate, as well as lower toxicity compared to the chemotherapy reference arm, with a 11% response rate.

Treatment responses were also longer-lasting in the nivolumab group compared to the chemotherapy group, and there was a 31% incidence of higher-grade treatment-related side effects in the chemotherapy group compared to only 9% incidence in the nivolumab group.

“The impressive data on duration of response suggest that there will be significant prolongation of progression-free and overall survival when the analysis of those data is mature,” says Weber.

In summary, Weber says, “The differences in response rate and toxicity markedly favour the use of the PD-1 blocking antibody nivolumab compared to results seen with chemotherapy in patients that have failed ipilimumab.”

Commenting on the findings, Professor Olivier Michielin of the Department of Oncology, University of Lausanne, Switzerland, says, “These results add another piece of evidence that PD blockade is rapidly becoming a central part in our armamentarium against melanoma, progressively replacing chemotherapy with more effective and less toxic options.”

“These results demonstrate that PD blockade, contrary to a common and old dogma of immunotherapy, can produce rapid and deep responses even in advanced and bulky disease. This opens exciting new opportunities to widen the scope of application of immuno-oncology for the treatment of stage IV melanoma,” says Michielin.

-END-

Notes to Editors

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 previously treated advanced melanoma

[1] Actual numbers for responses: 32% for nivolumab versus 11% for chemotherapy

Disclaimer

Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.

Session info

LBA3_PR              Monday, September 29, 2014 – 16:00 PM – 17:20 PM  - Madrid

Abstract: 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 previously treated advanced melanoma

J.S. Weber¹, D.R. Minor², S.P. D'Angelo³, F.S. Hodi⁴, R. Gutzmer⁵, B. Neyns⁶, C. Hoeller⁷, N.I. Khushalani⁸, W.H. Miller⁹, J-J. Grob¹⁰, C. Lao¹¹, G. Linette¹², K. Grossmann¹³, J.C. Hassel¹⁴, P. Lorigan¹⁵, M. Maio¹⁶, M. Sznol¹⁷, A. Lambert¹⁸, A. Yang¹⁹, J. Larkin^20
1Medical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA, ²Medical Oncology, California Pacific Medical Center, San Francisco, USA,³Internal Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA, ⁴Melanoma Center, Dana-Farber Cancer Institute, Boston, MA, USA, ⁵Dermatology and Allergy, Skin Cancer Center, Hannover Medical School, Hannover, GERMANY, ⁶Medical Oncology, Vrije Universiteit Brussel, Brussels, BELGIUM, ⁷Dermatology, Medical University of Vienna, Vienna, AUSTRIA, ⁸Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA, ⁹Oncology, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital , McGill University, Montreal, QC, Canada, ¹⁰Dermatology, Aix-Marseille University, Hopital de la Timone, Marseille, FRANCE, ¹¹Medical Oncology, University of Michigan, Ann Arbor, MI, USA, ¹²Internal Medicine/oncology, Washington University, St. Louis, MO, USA, ¹³Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA, ¹⁴Dermatology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, GERMANY,¹⁵Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK, ¹⁶Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, ITALY, ¹⁷Section of Medicine Oncology, Yale Cancer Center, New Haven, CT, USA, ¹⁸Biostatistics, Bristol-Myers Squibb, Braine-l’Alleud, BELGIUM, ¹⁹Immuno-oncology, Bristol-Myers Squibb, Princeton, NJ, USA, ²⁰Department of Medicine, Royal Marsden Hospital, London, UK

Aim: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Disclosure: 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-renumerated). Research funding: Pfizer, Novartis (payment to institution). All other authors have declared no conflicts of interest.

Keywords: immunotherapy, melanoma, anti-PD-1 antibody, 1. nivolumab