Adjuvant Nivolumab Superior to Ipilimumab in Surgically Resected Stage III/IV Melanoma

LUGANO-MADRID – Adjuvant nivolumab is superior to standard of care ipilimumab in patients with surgically resected stage III/IV melanoma who are at high risk of relapse, according to late-breaking results from the CheckMate 238 trial presented today at the ESMO 2017 Congress in Madrid (1) and published in the New England Journal of Medicine (NEJM). (2) The anti-programmed death-1 (PD-1) antibody nivolumab led to better relapse-free survival, with fewer side effects than ipilimumab.

Adjuvant therapy is given after initial cancer treatment with the goal of preventing metastases. Drugs that are effective in metastatic disease may be given as adjuvant therapy to patients who have been surgically resected of their disease and are at high risk of relapse.

Nivolumab and ipilimumab are immune checkpoint inhibitors approved for metastatic melanoma. Ipilimumab is also the Food and Drug Administration (FDA)-approved standard of care adjuvant therapy for resected stage III melanoma in the US. Nivolumab was well tolerated and showed promising survival results when investigated as adjuvant therapy in a pilot study of 33 patients with resected stage IIIC and IV melanoma. (3)

The benefit shown for nivolumab in metastatic disease and those pilot data provided the impetus for CheckMate 238, a randomised, double-blind, phase III trial comparing adjuvant treatment with nivolumab versus standard of care ipilimumab. The trial included 906 patients with stages IIIB, IIIC, and IV resected melanoma who had a greater than 50% risk of relapse over five years. Patients were randomised 1:1 to either treatment.

The primary endpoint was relapse-free survival. Overall survival was a secondary endpoint which will be complicated by the anticipation that patients will cross over to the alternative drug upon relapse.

The trial was stopped early by the data safety monitoring committee due to clear evidence of benefit for nivolumab. The planned interim analysis which occurred at a minimum follow-up of 18 months, presented today, shows that the rate of relapse-free survival was significantly improved with nivolumab (66.4%) compared to ipilimumab (52.7%), with a hazard ratio of 0.65 (p < 0.0001). There were similar results across prespecified subgroups of patients.

There were fewer treatment-related, clinically relevant side effects (grade 3/4) in the group treated with nivolumab (14%) compared to those treated with ipilimumab (46%). Just 10% of patients taking nivolumab had to stop treatment due to side effects compared to 43% taking ipilimumab.

First author Dr Jeffrey Weber, deputy director, Perlmutter Cancer Center, NYU Langone Health, New York, USA, said: “The results clearly show that relapse-free survival is more favourable with nivolumab. The majority of patients had higher risk disease than in most prior adjuvant melanoma trials, which makes the findings even more encouraging.”

“A previous trial found that ipilimumab had a significant relapse-free and overall survival advantage compared to placebo,” continued Weber. (4) “CheckMate 238 shows that nivolumab is superior to ipilimumab, so extrapolating these results, nivolumab is far better than no adjuvant treatment for high-risk melanoma. It is also much less toxic than ipilimumab.”

He concluded: “Nivolumab looks like a superior adjuvant melanoma regimen compared to ipilimumab from every angle. It leads to better relapse-free survival, has fewer side effects, and is well tolerated.”

Professor John Haanen, head, Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands, said: “An adjuvant trial presented at the ESMO 2016 Congress showed that ipilimumab gave an overall survival advantage over placebo but it was highly toxic. In the US it has become standard of care but this is still being debated in Europe.”

Commenting on the findings presented today, he said: “The results of CheckMate 238 are very exciting. They show for the first time that an anti-PD-1 drug is superior in the adjuvant setting and because of its lower toxicity nivolumab is much easier to give than ipilimumab. The same occurs in the metastatic setting where anti-PD-1 treatment is more efficacious and has a much better safety profile and has replaced ipilimumab as first line treatment.”

Another anti-PD-1 drug, pembrolizumab, is being tested as adjuvant therapy against placebo in patients with resected stage III melanoma in a phase III European Organisation for Research and Treatment of Cancer (EORTC) trial. Haanen said: “If relapse-free survival is better with pembrolizumab, it is likely that adjuvant anti-PD-1 will become standard of care for high-risk melanoma in the near future, provided an overall survival benefit is also shown.”

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

1. Abstract LBA8_PR ‘Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238)’ will be presented by Dr Jeffrey Weber during Presidential Symposium III on Monday, 11 September, 16:30 to 17:45 (CEST), in Madrid Auditorium.
2. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. DOI: 10.1056/NEJMoa1709030
3. Gibney GT, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res. 2015;21:712–720. doi: 10.1158/1078-0432.CCR-14-2468.
4. Eggermont AM, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–1855.

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Abstract LBA8_PR

Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238)

J. Weber¹, M. Mandala², M. Del Vecchio³, H. Gogas⁴, A.M. Arance⁵, L.C. Cowey⁶, S. Dalle⁷, M. Schenker⁸, V. Chiarion-Sileni⁹, I. Márquez-Rodas¹⁰, J.-J. Grob¹¹, M. Butler¹², M.R. Middleton¹³, M. Maio¹⁴, V. Atkinson¹⁵, P. Queirolo¹⁶, V. de Pril¹⁷, A. Qureshi¹⁷, J. Larkin¹⁸, P.A. Ascierto^19
1Perlmutter Cancer Center, NYU Langone Health, New York, USA, ²Oncology, Papa Giovanni XIII Hospital, Bergamo, Italy, ³Medical Oncology, National Cancer Institute, Milan, Italy, ⁴Oncology, University of Athens, Athens, Greece, ⁵Oncology, Hospital Clinic de Barcelona, Barcelona, Spain, ⁶Oncology, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA, ⁷Oncology, Hospices Civils de Lyon, Pierre Bénite, France, ⁸Oncology, Oncology Center sf. Nectarie Ltd., Craiova, Romania, ⁹Oncology, Oncology Institute of Veneto IRCCS, Padua, Italy, ¹⁰Medical Oncology, Hospital Gregorio Marañón, Madrid, Spain, ¹¹Medical Oncology, Hospital de la Timone, Marseille, France, ¹²Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada, ¹³Oncology, Churchill Hospital, University of Oxford, Oxford, UK, ¹⁴Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy, ¹⁵Oncology, Gallipoli Medical Research Foundation and Princess Alexandra Hospital, and University of Queensland, Queensland, Australia, ¹⁶Oncology, IRCCS AOU San Martino - IST, Genova, Italy, ¹⁷Global Clinical Research - Oncology, Bristol-Myers Squibb, Princeton, NJ, USA, ¹⁸Oncology, The Royal Marsden Hospital, London, UK, ¹⁹Oncology, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy

Background: NIVO and IPI are immune checkpoint inhibitors approved for advanced melanoma. IPI is also approved in the US for resected stage III melanoma, based on a phase 3 trial demonstrating an improvement in recurrence-free survival (RFS). We report the first results of a phase 3 trial designed to evaluate NIVO vs IPI for resected stage III/IV melanoma at high risk of recurrence.

Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥15 yrs of age who underwent complete resection of stage IIIb/c or IV melanoma. 906 pts were randomized (stratified by stage and PD-L1 status) 1:1 to receive NIVO 3 mg/kg (n=453) every 2 wks or IPI 10 mg/kg (n=453) every 3 wks for 4 doses, then every 12 wks (from week 24) for up to 1 yr, disease recurrence, or unacceptable toxicity. The primary endpoint was RFS in the intent-to-treat population.

Results: Overall, 34%/47%/19% of pts had stage IIIb/IIIc/IV; 32%, ulcerated primary; 48%, macroscopic lymph node involvement; and 42%, BRAF mutation. At a median follow-up of 18.5 mo, NIVO significantly improved RFS vs IPI (Table). Results from prespecified subgroup analyses demonstrated consistent hazard ratios favoring NIVO.

Treatment-related grade 3/4 adverse events (AEs) occurred in 14% of pts in the NIVO group and 46% of pts in the IPI group; AEs of any grade led to discontinuation in 10% and 43%, respectively. Organ systems with the highest frequency of treatment-related grade 3/4 select (immune-related) AEs in the NIVO and IPI arms were gastrointestinal (2.0% vs 16.8%), hepatic (1.8% vs 10.8%), and skin (1.1% vs 6.0%). No deaths due to study drug toxicity were reported for NIVO, but 2 (0.4%) were reported for IPI (colitis and medullary aplasia) >100 days post-IPI.

Conclusions: NIVO as adjuvant therapy significantly improved RFS vs IPI for pts with stage III/IV melanoma at high risk of recurrence and demonstrated a superior safety profile. Acknowledgement: The co-senior authors for this abstract are Dr. J. Larkin and Dr. P.A. Ascierto.

Clinical trial identification: NCT02388906

Legal entity responsible for the study: Bristol-Myers Squibb

Funding: Bristol-Myers Squibb

Disclosure: J. Weber: Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris Pharmaceuticals, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai, CytomX Therapeutics, Nektar, Novartis, Medivation: consulting or advisory role; Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris Pharmaceuticals, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis: travel, accommodations, expenses; Named on a patent submitted by Moffitt Cancer Center for an IPILIMUMAB biomarker; Altor BioScience, Celldex, CytomX Therapeutics: stock and other ownership interests; Bristol-Myers Squibb, Merck, Genentech, Abbvie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris Pharmaceuticals, CytomX Therapeutics, Nektar, Novartis, Medivation: honoraria; Bristol-Myers Squibb, Merck, Gla
M. Mandala: Roche: personal fees, grant; BMS, MSD, Novartis: personal fees
M. Del Vecchio: BMS: personal fees, honoraria; Roche: personal fees, honoraria, advisory board, research funding; GSK: personal fees, honoraria
H. Gogas: Roche, Amgen MSD, BMS, Novartis: consulting or advisory role, research funding; BMS, Roche, MSD: travel accommodations, expenses
A.M. Arance: GSK, Roche, : personal fees, Consultant, speakers' bureau; BMS: personal fees & non-financial support, Speakers' bureau, travel funding
L.C. Cowey: BMS, Genentech: grant, personal fees, consultant, Speaker, Research funding; Merck, GSK: grant, consultant, Research funding
S. Dalle: BMS: research grants and travel expenses; BMS, MSD, Novartis, Roche: principal investigator
V. Chiarion-Sileni: BMS, Roche, GSK: personal fees, consulting, speakers' bureau, travel; MSD: personal fees, consulting, travel
I. Márquez-Rodas: Novartis, Roche, MSD, BMS: honoraria; Novartis, Roche, MSD, BMS, Amgen, Bioncotech: consulting or advisory role; MSD, BMS, Amgen: travel, accommodations, expenses
J.-J. Grob: BMS: personal fees, consultant, speakers' bureau, research funding; GSK: personal fees, consultant, speakers' bureau; Novartis: personal fees, consulting; Roche: personal fees, non-financial support, consulting, speakers' bureau, research funding, travel; Merck, Amgen: personal fees, consulting
M. Butler: Bristol Myers Squib, EMD Serono, Immunocore, Immunovaccine: personal fees, advisory boards; Merck: grant, personal fees, advisory boards, grant support for clinical trial
M.R. Middleton: Amgen, Bristol-Myers Squibb, Clovis, GlaxoSmithKline, Immunocore (uncompensated), Merck, Roche (all compensated): consulting or advisory role; Amgen, AstraZeneca, Bristol-Myers Squibb, Clovis, Eisai, GlaxoSmithKline, Immunocore, Medimmune, Merck, Pfizer, Roche, Vertex: research funding; Merck, Roche: travel, accommodations, expenses
M. Maio: BMS, Roche, MedImmune, MSD, GSK: honoraria, consulting or advisory role, travel, accommodations, expenses; BMS, MedImmune: research funding
V. Atkinson: BMS, MSD, Novartis: honoraria, consulting or advisory role, speakers' bureau, travel, accommodations, expenses
P. Queirolo: Roche, MSD, BMS, Novartis: personal fees
V. de Pril, A. Qureshi: employment – Bristol-Myers Squibb and stock/ownership – Bristol-Myers Squibb
J. Larkin: BMS, MSD, Novartis, Pfizer: research funding; BMS, MSD, Pfizer, Eisai, GSK, Roche: travel, accommodations, expenses
P.A. Ascierto: Bristol-Myers Squibb, Roche-Genentech: grant, personal fees, honoraria, consultant, institutional research funding; GSK: personal fees, honoraria, consultant; MSD, personal fees, consultant; Ventana: grant, consultant, institutional research funding; Novartis: Consultant
 All other authors have declared no conflicts of interest.

Keywords: adjuvant, nivolumab, recurrence-free survival, phase 3