Prognostic and predictive value of an immune-related adverse event among stage III melanoma patients included in the EORTC 1325/KEYNOTE-054 pembrolizumab versus placebo trial.
Abstract
2517 Background: Several studies suggested that patients (pts) with an immune-related adverse event (irAE) during immunotherapy have better outcomes than those without. It remains uncertain whether these observations can be explained by guarantee-time bias or the role of irAE as an indicator of drug activity. Here, we investigated the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 trial that compared pembrolizumab and placebo in high-risk stage III melanoma pts. Methods: Eligible pts included adults with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (lymph node metastasis > 1 mm), IIIB or IIIC (without in-transit metastasis) and with no active autoimmune disease that required systemic treatment in past 2 years. We used a Cox model adjusted for sex, age, and stage with a time-varying covariate taking a value zero before the irAE onset and a value one afterwards to estimate the association between the occurrence of irAEs and RFS. Results: Consistent with the main analysis in the ITT population (n = 1019, Eggermont et al, NEJM, 2018), RFS was longer in the pembrolizumab than in the placebo arm (HR = 0.56, 98.4% CI: 0.43-074) among pts who started the treatment (n = 1011). The incidence of irAE on study was 37.3% in the pembrolizumab (n = 509) and 9.0% in the placebo arm (n = 502) and, in each treatment group, it was similar in males and females. The occurrence of an irAE was significantly associated with a longer RFS in the pembrolizumab arm (HR = 0.61, 95% CI: 0.39-0.95, P = 0.03). This was true for both males and females. However, in the placebo arm, no association was observed (HR = 1.39, 95% CI: 0.83-2.32, P = 0.21). Compared to the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater (P = 0.028) after an onset of an irAE (HR = 0.37, 95% CI: 0.24-0.57) than without/before an irAE (HR = 0.61, 95% CI: 0.49-0.77). Conclusions: In the EORTC 1325/KEYNOTE-054 study conducted in high-risk stage III melanoma pts, the occurrence of an irAE was strongly associated with a longer RFS in those treated with pembrolizumab, but not with placebo. Clinical trial information: NCT02362594.
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No association between IRAE onset and RFS was witnessed in the placebo arm.
“No association between IRAE onset and RFS was witnessed in the placebo arm.”
From Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors (2019) · cites this paper as [50]
Adjuvant studies, with their low rates of on-treatment relapses, present one setting where guarantee-time bias may be substantially mitigated.
“Adjuvant studies, therefore, with their low rates of on-treatment relapses, present one setting where this bias may be substantially mitigated [50].”
From Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors (2019) · cites this paper as [50]
In an adjuvant study of 1019 resected Stage IIIA, IIIB and IIIC melanoma patients treated with pembrolizumab or placebo, patients who experienced IRAEs in the treatment arm experienced prolonged relapsed-free survival (RFS) compared to those who did not (HR 0.61; 95% CI 0.39-0.95; p = .03).
“In an adjuvant study of 1019 resected Stage IIIA, IIIB and IIIC melanoma patients treated with pembrolizumab or placebo, patients who experienced IRAEs in the treatment arm experienced prolonged relapsed-free survival (RFS) compared to those who did not (HR 0.61; 95% CI 0.39–0.95; p = .03).”
From Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors (2019) · cites this paper as [50]
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- Authors
- Eggermont, A. M. M., Kicinski, M., Blank, C. U., Mandalà, M., Long, G. V., Atkinson, V., Dalle, S., Haydon, A. M., Lichinitser, M., Khattak, M., Carlino, M. S., Sandhu, S. K., Puig, S., Ascierto, P. A., Krepler, C., Ibrahim, N., Marreaud, S., Van Akkooi, A. C. J., Robert, C., & Suciu, S.
- Affiliations
- Université Paris-Saclay (FR)
- EORTC Headquarters, Brussels, Belgium;
- The Netherlands Cancer Institute (NL)
- Ospedale Papa Giovanni XXIII (IT)
- The University of Sydney (AU)
- The University of Queensland (AU)
- Hospices Civils de Lyon (FR)
- The Alfred Hospital (AU)
- Russian Cancer Research Center NN Blokhin (RU)
- The University of Western Australia (AU)
- The University of Melbourne (AU)
- Hospital Clínic de Barcelona (ES)
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- European Organisation for Research and Treatment of Cancer (BE)
- Netherlands Cancer Institute, Amsterdam, Netherlands;
- Institut Gustave Roussy (FR)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-20
- Volume
- 37
- Issue
- 15_suppl
- Pages
- 2517-2517
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2947435541
- Cited by
- 14
- References
- 0
- Citations by year
- 2024: 1 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 5
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immune-related adverse events, pembrolizumab, stage III melanoma, recurrence-free survival, predictive biomarkers, immune checkpoint inhibitors, lymph node metastasis, prognostic value, sex differences, anti-PD-1 therapy, time to progression, time to treatment failure
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