Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2020 Apr 1;6(4):519-527.
doi: 10.1001/jamaoncol.2019.5570.

Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial

Alexander M M Eggermont  1 , Michal Kicinski  2 , Christian U Blank  3 , Mario Mandala  4 , Georgina V Long  5 , Victoria Atkinson  6 , Stéphane Dalle  7 , Andrew Haydon  8 , Adnan Khattak  9 , Matteo S Carlino  10 , Shahneen Sandhu  11 , James Larkin  12 , Susana Puig  13 , Paolo A Ascierto  14 , Piotr Rutkowski  15 , Dirk Schadendorf  16   17 , Rutger Koornstra  18 , Leonel Hernandez-Aya  19 , Anna Maria Di Giacomo  20 , Alfonsus J M van den Eertwegh  21 , Jean-Jacques Grob  22 , Ralf Gutzmer  23 , Rahima Jamal  24 , Paul C Lorigan  25 , Clemens Krepler  26 , Nageatte Ibrahim  26 , Sandrine Marreaud  2 , Alexander van Akkooi  3 , Caroline Robert  1 , Stefan Suciu  2
Affiliations
Randomized Controlled Trial

Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial

Alexander M M Eggermont et al. JAMA Oncol. .

Abstract

Importance: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.

Objective: To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.

Design, setting, and participants: A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017.

Interventions: Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent.

Main outcomes and measures: The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset.

Results: Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03).

Conclusions and relevance: In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.

Trial registrations: ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Eggermont reported being the study chair of the EORTC 18071 phase 3 clinical trial of ipilimumab therapy vs placebo in patients with stage III melanoma and receiving personal fees from Actelion, Agenus, Amgen, Bayer, BioInvent, Bristol-Myers Squibb, CatalYm, Celldex, Gilead Sciences, GlaxoSmithKline, HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, MedImmune, Merck Sharpe & Dohme, Nektar, Novartis, Pfizer, Polynoma, Regeneron Pharmaceuticals, Sanofi, and SkylineDx and owning equity in SkylineDx outside the submitted work. Dr Kicinski reported receiving grants from Merck during the conduct of the study. Dr Blank reported receiving grants from Bristol-Myers Squibb, NanoString Technologies, and Novartis and personal fees from AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, NanoString Technologies, Novartis, Pfizer, Pierre Fabre, and Roche during the conduct of the study. Dr Mandala reported receiving grants from Genentech/Roche and Novartis and serving as an advisor for Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, and Pierre Fabre outside the submitted work. Dr Long reported receiving personal fees from Aduro, Amgen, Array BioPharma, Bristol-Myers Squibb, Merck, Novartis, OncoSec, Pierre Fabre, and Roche outside the submitted work. Dr Atkinson reported receiving personal fees, speaking fees, and/or travel support from and/or serving on the advisory board of Bristol-Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, and Roche outside the submitted work. Dr Dalle reported receiving grants from Bristol-Myers Squibb and Merck Sharpe & Dohme outside the submitted work. Dr Haydon reported receiving personal fees from Merck outside the submitted work. Dr Carlino reported receiving personal fees from Amgen, Bristol-Myers Squibb, IDEAYA Biosciences, Merck Sharpe & Dohme, Novartis, and Roche outside the submitted work. Dr Sandhu reported receiving grants from Amgen, AstraZeneca, Bristol-Myers Squibb, Endocyte, and Merck Sharp & Dohme outside the submitted work. Dr Larkin reported receiving grants from Achilles Therapeutics, AVEO Pharmaceuticals, Bristol-Myers Squibb, Covance, Genentech/Roche, Immunocore, Merck Sharpe & Dohme, Nektar, Novartis, Pharmacyclics, and Pfizer and personal fees from Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Covance, Eisai, EUSA Pharma, Genentech/Roche, GlaxoSmithKline, Immunocore, Imugene, Incyte, iOnctura, Ipsen, Kymab, Merck Serono, Merck Sharpe & Dohme, Nektar, Novartis, Pfizer, Pierre Fabre, Secarna Pharmaceuticals, and Vitaccess during the conduct of the study. Dr Puig reported receiving patient fees for Merck Sharpe & Dohme during the conduct of the study and receiving grants from Almirall, Castle Biosciences, Leo Pharma, MelaGenix, and Novartis, personal fees and nonfinancial support from Almirall, Amgen, Bristol-Myers Squibb, ISDIN, La Roche-Posay, Leo Pharma, Lilly, Novartis, Pierre Fabre, Roche, and Sanofi, and patient fees for Biofrontera, Bristol-Myers Squibb, Philogen, and Regeneron Pharmaceuticals outside the submitted work. Dr Ascierto reported receiving grants and research funds from Array BioPharma, Bristol-Myers Squibb, and Genentech/Roche and receiving personal fees for serving as an advisor for 4SC, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche Genmab, Idera Pharmaceutials, Immunocore, Incyte, MedImmune, Merck Serono, Merck Sharp & Dohme, NewLink Genetics, Novartis, Pierre Fabre, Sandoz, Sanofi, Sun Pharma, Syndax Pharmaceuticals, and Ultimovacs outside the submitted work. Dr Rutkowski reported receiving personal fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche outside the submitted work. Dr Schadendorf reported receiving personal fees and nonfinancial support from Merck Sharp & Dohme during the conduct of the study and receiving grants from Bristol-Myers Squibb and personal fees and nonfinancial support from 4SC, Array BioPharma, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, InflaRx, NeraCare, Novartis, Philogen, Pierre Fabre, Regeneron Pharmaceuticals, Roche, Sandoz-Hexal, Sanofi, Sun Pharma, and Ultimovacs outside the submitted work. Dr Koornstra reported receiving grants from Bristol-Myers Squibb and Roche and personal fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre outside the submitted work. Dr Hernandez-Aya reported receiving grants from Merck during the conduct of the study and receiving grants from Amgen, Bristol-Myers Squibb, Corvus Pharmaceuticals, Immunocore, MedImmune, Merck Serono, Merck Sharp & Dohme, Polynoma, Roche, and Takeda, personal fees from Bristol-Myers Squibb, and speaking fees and travel support from Regeneron Pharmaceuticals and Sanofi outside the submitted work. Dr Di Giacomo reported receiving personal fees from Merck Sharp & Dohme during the conduct of the study and receiving personal fees from Bristol-Myers Squibb, Incyte, and Pierre Fabre outside the submitted work. Dr van den Eertwegh reported receiving personal fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche outside the submitted work. Dr Grob reported receiving personal fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche outside the submitted work. Dr Gutzmer reported receiving grants from Johnson & Johnson and Pfizer and personal fees and nonfinancial support from 4SC, Almirall, Amgen, AstraZeneca, Bristol-Myers Squibb, Incyte, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Sun Pharma, and Takeda outside the submitted work. Dr Jamal reported receiving grants and patient fees from Merck Sharpe & Dohme during the conduct of the study and receiving grants from Bristol-Myers Squibb, patient fees for Array BioPharma, Astellas, AstraZeneca, Bristol-Myers Squibb, the Canadian Cancer Trials Group, GlaxoSmithKline, Hoffman-La Roche, MedImmune, Merck Canada, Novartis Canada, Pfizer, and Genentech/Quintiles/Roche, and serving as an advisor for Bristol-Myers Squibb, Merck Sharpe & Dohme, and Novartis outside the submitted work. Dr Lorigan reported receiving patient fees for the European Organisation for Research and Treatment of Cancer during the conduct of the study and receiving grants from Bristol-Myers Squibb and personal fees, speaking fees, and/or travel support from or serving as an advisor for Amgen, Bristol-Myers Squibb, Incyte, Merck, NeraCare, Novartis, and Pierre Fabre outside the submitted work. Dr Ibrahim reported owning financial shares in GlaxoSmithKline and Merck outside the submitted work. Dr van Akkooi reported receiving grants from 4SC, Amgen, Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, and Pfizer outside the submitted work. Dr Robert reported receiving personal fees from Merck Sharpe & Dohme during the conduct of the study and receiving personal fees from Amgen, Bristol-Myers Squibb, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work. Dr Suciu reported receiving grants from Merck during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Figure 2.
Figure 2.. Incidence of Immune-Related Adverse Events by Treatment Arm Among All Patients and Subgroups of Patients
A, In the pembrolizumab arm (n = 509), 190 irAEs occurred, with a percentage incidence of 19.4% (95% CI, 16.1%-23.0%) at 3 months and 37.4% (95% CI, 33.2%-41.6%) at 15 months. In the placebo arm (n = 502), 45 irAEs occurred, with a percentage incidence of 4.0% (95% CI, 2.5%-6.0%) at 3 months and 9.0% (95% CI, 6.7%-11.7%) at 15 months. Vertical lines correspond to the time of censoring. B, The estimate of the subdistribution hazard ratio in the whole sample is based on an unstratified model with treatment as the only covariate. Blue boxes are centered on the estimated subdistribution hazard ratios. The green diamond is centered on the overall subdistribution hazard ratio (dashed line) and covers its 95% CI. HR indicates hazard ratio; irAE, immune-related adverse event; and LN+, positive lymph node. aFor the whole sample estimate, a 95% CI is shown. For subgroups, 99% CIs are presented. bP < .001 corresponds only to the overall comparison, performed on all patients: HR, 4.95 (99% CI, 3.58-6.85).
See this image and copyright information in PMC

Comment in

References

    1. Eggermont AM, Spatz A, Robert C. Cutaneous melanoma. Lancet. 2014;383(9919):816-827. doi:10.1016/S0140-6736(13)60802-8 - DOI - PubMed
    1. Boutros C, Tarhini A, Routier E, et al. . Safety profiles of anti–CTLA-4 and anti–PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473-486. doi:10.1038/nrclinonc.2016.58 - DOI - PubMed
    1. Hofmann L, Forschner A, Loquai C, et al. . Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti–PD-1 therapy. Eur J Cancer. 2016;60:190-209. doi:10.1016/j.ejca.2016.02.025 - DOI - PubMed
    1. Zimmer L, Goldinger SM, Hofmann L, et al. . Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti–PD-1 therapy. Eur J Cancer. 2016;60:210-225. doi:10.1016/j.ejca.2016.02.024 - DOI - PubMed
    1. Koon H, Atkins M. Autoimmunity and immunotherapy for cancer. N Engl J Med. 2006;354(7):758-760. doi:10.1056/NEJMe058307 - DOI - PubMed

Publication types

MeSH terms

Associated data