BACKGROUND: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial. METHODS: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups. RESULTS: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm. CONCLUSION: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident. TRIAL REGISTRATION NUMBER: NCT02388906.

1st Department of Medicine National and Kapodistrian University of Athens School of Medicine Athens Greece

Aix Marseille University APHM Hospital Marseille France

Bristol Myers Squibb Princeton New Jersey USA

Center for Immuno Oncology University Hospital of Siena Siena Italy

Clinical Oncology Department Hospital Universitario Virgen Macarena Sevilla Spain

Department of Cutaneous Oncology Moffitt Cancer Center Tampa Florida USA

Department of Medicine Universidad de Sevilla Sevilla Spain

Gallipoli Medical Research Foundation and University of Queensland Brisbane Queensland Australia

General University Hospital Gregorio Marañón CIBERONC Madrid Spain

Hospices Civils de Lyon Pierre Bénite France

Hospital Clínic de Barcelona Barcelona Spain

Istituto Nazionale Tumori IRCCS Fondazione Pascale Napoli Italy

Oncology Center Sf Nectarie Ltd Craiova Romania

Oncology Mount Sinai Medical Center Miami Beach Florida USA

Perlmutter Cancer Center NYU Langone Health New York New York USA

Princess Margaret Hospital Cancer Centre Toronto Ontario Canada

Rogel Cancer Center University of Michigan Ann Arbor Michigan USA

Royal Marsden NHS Foundation Trust London UK

Sir Charles Gairdner Hospital University of Western Australia Perth Western Australia Australia

Tasman Oncology Research Ltd Southport Queensland Australia

Texas Oncology Baylor Charles A Sammons Cancer Center Dallas Texas USA

Unit of Medical Oncology University of Perugia Perugia Italy

Unit of Melanoma Medical Oncology Fondazione IRCCS Istituto Nazionale dei Tumori Milano Italy

University Hospital Královské Vinohrady Czech Republic

Veneto Institute of Oncology IOV IRCCS Padua Italy

J Immunother Cancer. 2021 Nov;9(11):e003188corr1. doi: 10.1136/jitc-2021-003188corr1. PubMed

J Immunother Cancer. 2022 Jan;10(1):e004272. doi: 10.1136/jitc-2021-004272. PubMed

Zobrazit více v PubMed

Leiter U, Buettner PG, Eigentler TK, et al. . Hazard rates for recurrent and secondary cutaneous melanoma: an analysis of 33,384 patients in the German central malignant melanoma registry. J Am Acad Dermatol 2012;66:37–45. 10.1016/j.jaad.2010.09.772 PubMed DOI

Romano E, Scordo M, Dusza SW, et al. . Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol 2010;28:3042–7. 10.1200/JCO.2009.26.2063 PubMed DOI PMC

Meyers MO, Yeh JJ, Frank J, et al. . Method of detection of initial recurrence of stage II/III cutaneous melanoma: analysis of the utility of follow-up staging. Ann Surg Oncol 2009;16:941–7. 10.1245/s10434-008-0238-y PubMed DOI

Tas F, Erturk K. Recurrence behavior in early-stage cutaneous melanoma: pattern, timing, survival, and influencing factors. Melanoma Res 2017;27:134–9. 10.1097/CMR.0000000000000332 PubMed DOI

National Cancer Institute . Cancer STAT facts: melanoma of the skin. Available: https://seer.cancer.gov/statfacts/html/melan.html [Accessed 30 Apr 2019].

Gershenwald JE, Scolyer RA, Hess KR, et al. . Melanoma staging: evidence-based changes in the American joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:472–92. 10.3322/caac.21409 PubMed DOI PMC

Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. . Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European organisation for research and treatment of cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer 2019;119:1–10. 10.1016/j.ejca.2019.07.001 PubMed DOI

Tarhini AA, Lee SJ, Hodi FS, et al. . Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American intergroup E1609. J Clin Oncol 2020;38:567–75. 10.1200/JCO.19.01381 PubMed DOI PMC

Coit DG, Thompson JA, Albertini MR, et al. . Cutaneous melanoma, version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2019;17:367–402. 10.6004/jnccn.2019.0018 PubMed DOI

Michielin O, van Akkooi ACJ, Ascierto PA, et al. . Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up†. Ann Oncol 2019;30:1884–901. 10.1093/annonc/mdz411 PubMed DOI

Weber J, Mandala M, Del Vecchio M, et al. . Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35. 10.1056/NEJMoa1709030 PubMed DOI

Ascierto PA, Del Vecchio M, Mandalá M, et al. . Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2020;21:1465–77. 10.1016/S1470-2045(20)30494-0 PubMed DOI

Balch CM, Gershenwald JE, Soong S-J, et al. . Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–206. 10.1200/JCO.2009.23.4799 PubMed DOI PMC

National Cancer Institute . Cancer therapy evaluation program. common terminology criteria for adverse events (CTCAE). Available: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 [Accessed 2 Jan 2020].

Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J Clin Oncol 2013;31:2963–9. 10.1200/JCO.2013.49.5283 PubMed DOI PMC

Weber JS, Hodi FS, Wolchok JD, et al. . Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 2017;35:785–92. 10.1200/JCO.2015.66.1389 PubMed DOI

Teufel A, Zhan T, Härtel N, et al. . Management of immune related adverse events induced by immune checkpoint inhibition. Cancer Lett 2019;456:80–7. 10.1016/j.canlet.2019.04.018 PubMed DOI

Freeman-Keller M, Kim Y, Cronin H, et al. . Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 2016;22:886–94. 10.1158/1078-0432.CCR-15-1136 PubMed DOI PMC

Hua C, Boussemart L, Mateus C, et al. . Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 2016;152:45–51. 10.1001/jamadermatol.2015.2707 PubMed DOI

Grimaldi A, Simeone E, Festino L, et al. . Correlation between immune-related adverse events and response to pembrolizumab in advanced melanoma patients. J Immunother Cancer 2015;3:P186. 10.1186/2051-1426-3-S2-P186 DOI

Lutzky J, Wolchok J, Hamid O, et al. . Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (PTS) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials. JCO 2009;27:9034. 10.1200/jco.2009.27.15_suppl.9034 DOI

Eggermont AMM, Kicinski M, Blank CU, et al. . 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. JAMA Oncol 2020;6:519–17. 10.1001/jamaoncol.2019.5570 PubMed DOI PMC

Zobrazit více v PubMed

ClinicalTrials.gov
NCT02388906