Adverse Events in Anti-PD-1-Treated Adjuvant and First-Line Advanced Melanoma Patients

Cancers (Basel). 2024 Jul 26;16(15):2656. doi: 10.3390/cancers16152656.

Authors

Daan Jan Willem Rauwerdink¹, Olivier van Not^{1

2}, Melissa de Meza³, Remco van Doorn¹, Jos van der Hage⁴, A J M van den Eertwegh⁵, John B Haanen^{6

7

8}, Maureen J B Aarts⁹, Franchette W P J van den Berkmortel¹⁰, Christiaan U Blank^{6

7

8}, Marye J Boers-Sonderen¹¹, Jan Willem B de Groot¹², Geke A P Hospers¹³, Djura Piersma¹⁴, Rozemarijn S van Rijn¹⁵, A M Stevense-den Boer¹⁶, Astrid A M van der Veldt¹⁷, Gerard Vreugdenhil¹⁸, Michel W J M Wouters^{2

4

19}, Karijn P M Suijkerbuijk²⁰, Ellen Kapiteijn⁸

Affiliations

¹ Department of Dermatology, Leiden University Medical Center, Leiden University, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
² Scientific Bureau, Dutch Institute for Clinical Auditing, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands.
³ Department of Ear-Nose-Throat ENT, Leiden University Medical Center, Leiden University, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
⁴ Department of Surgical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
⁵ Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081 HZ Amsterdam, The Netherlands.
⁶ Department of Medical Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
⁷ Department of Molecular Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
⁸ Department of Medical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
⁹ Department of Medical Oncology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
¹⁰ Department of Medical Oncology, Zuyderland Medical Centre Sittard, Dr. H. van der Hoffplein 1, 6162 BG Sittard-Geleen, The Netherlands.
¹¹ Department of Medical Oncology, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
¹² Isala Oncology Center, Isala, Dokter van Heesweg 2, 8025 AB Zwolle, The Netherlands.
¹³ Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
¹⁴ Department of Internal Medicine, Medisch Spectrum Twente, Koningsplein 1, 7512 KZ Enschede, The Netherlands.
¹⁵ Department of Internal Medicine, Medical Centre Leeuwarden, Henri Dunantweg 2, 8934 AD Leeuwarden, The Netherlands.
¹⁶ Department of Internal Medicine, Amphia Hospital, Molengracht 21, 4818 CK Breda, The Netherlands.
¹⁷ Department of Medical Oncology and Radiology & Nuclear Medicine, Erasmus Medical Centre, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
¹⁸ Department of Internal Medicine, Maxima Medical Centre, De Run 4600, 5504 DB Eindhoven, The Netherlands.
¹⁹ Department of Biomedical Data Sciences, Leiden University Medical Centre, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
²⁰ Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Abstract

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 in adjuvant or advanced settings between 2015 and 2021. Comorbidities and ECOG performance status were assessed before treatment, and grade III-IV irAEs were monitored during treatment. Univariate and multivariate regression analyses were conducted to identify factors associated with irAE development. Results: A total of 1465 advanced melanoma patients and 908 resected melanoma patients received anti-PD-1 therapy. Adjuvant-treated patients were younger, with a median age of 63 years compared to 69 years in the advanced group (p < 0.01), and had a better ECOG performance status (p < 0.01). Comorbidities were seen more frequently in advanced melanoma patients than in those receiving adjuvant treatment, 76% versus 68% (p < 0.01). Grade III-IV irAEs occurred in 214 (15%) advanced treated patients and in 119 (13%) adjuvant-treated patients. Multivariate analysis showed an increased risk of severe irAE development with the presence of any comorbidity (adjusted OR 1.22, 95% CI 1.02-1.44) and ECOG status greater than 1 (adjusted OR 2.00, 95% CI 1.20-3.32). Adjuvant therapy was not associated with an increased risk of irAE development compared to advanced treatment (adjusted OR 0.95, 95% CI 0.74-1.21) after correcting for comorbidities and ECOG performance score. Anti-PD-1 therapy was halted due to toxicity (any grade irAE) more often in the adjuvant setting than in the advanced setting, 20% versus 15% (p < 0.01). Conclusions: Higher ECOG performance status and presence of any comorbidity were independently associated with an increased risk of Grade III-IV irAE in adjuvant and advanced treated melanoma patients. Patients treated in the adjuvant setting did not have an increased risk of developing severe irAEs compared to advanced melanoma patients. These findings are of clinical significance in consulting patients for adjuvant anti-PD-1 treatment.

Keywords: immune checkpoint inhibitors; melanoma; side-effects.

Grants and funding

For the Dutch Melanoma Treatment Registry (DMTR), the Dutch Institute for Clinical Auditing Foundation received a start-up grant from the governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002). The DMTR is structurally funded by Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche Pharma. Roche Pharma stopped funding in 2019, Novartis stopped funding in 2024, and Pierre Fabre started funding the DMTR in 2019. For this work, no funding was granted.