Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma

C N Owen; X Bai; T Quah; S N Lo; C Allayous; S Callaghan; C Martínez-Vila; R Wallace; P Bhave; I L M Reijers; N Thompson; V Vanella; C L Gerard; S Aspeslagh; A Labianca; A Khattak; M Mandala; W Xu; B Neyns; O Michielin; C U Blank; S J Welsh; A Haydon; S Sandhu; J Mangana; J L McQuade; P A Ascierto; L Zimmer; D B Johnson; A Arance; P Lorigan; C Lebbé; M S Carlino; R J Sullivan; G V Long; A M Menzies

doi:10.1016/j.annonc.2021.03.204

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma

Ann Oncol. 2021 Jul;32(7):917-925. doi: 10.1016/j.annonc.2021.03.204. Epub 2021 Mar 30.

Authors

C N Owen¹, X Bai², T Quah³, S N Lo⁴, C Allayous⁵, S Callaghan⁶, C Martínez-Vila⁷, R Wallace⁸, P Bhave⁹, I L M Reijers¹⁰, N Thompson¹¹, V Vanella¹², C L Gerard¹³, S Aspeslagh¹⁴, A Labianca¹⁵, A Khattak¹⁶, M Mandala¹⁷, W Xu¹⁸, B Neyns¹⁴, O Michielin¹³, C U Blank¹⁰, S J Welsh¹¹, A Haydon⁹, S Sandhu⁸, J Mangana¹⁹, J L McQuade²⁰, P A Ascierto¹², L Zimmer²¹, D B Johnson²², A Arance⁷, P Lorigan²³, C Lebbé⁵, M S Carlino²⁴, R J Sullivan²⁵, G V Long²⁶, A M Menzies²⁷

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
² Massachusetts General Hospital, Boston, USA; Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.
³ Westmead and Blacktown Hospitals, Sydney, Australia.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
⁵ Dermatology Department, Université de Paris, AP-HP Saint-Louis Hospital, INSERM, Paris, France.
⁶ The Christie NHS Foundation Trust, Manchester, UK.
⁷ Hospital Clinic Barcelona, Barcelona, Spain.
⁸ Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Australia.
⁹ The Alfred Hospital, Melbourne, Australia.
¹⁰ Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹¹ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹² Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.
¹³ Lausanne University Hospital, Lausanne, Switzerland.
¹⁴ University Hospital Brussels, Brussels, Belgium.
¹⁵ Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
¹⁶ Fiona Stanley Hospital and Edith Cowan University, Perth, Australia.
¹⁷ University of Perugia, Unit of Medical Oncology, Santa Maria misericordia hospital, Perugia, Italy.
¹⁸ Princess Alexandra Hospital and The University of Queensland, Brisbane, Australia.
¹⁹ Dermatology, Department of Dermato-Oncology, University Hospital Zurich, Zürich, Switzerland.
²⁰ The University of Texas MD Anderson Cancer Center, Houston, USA.
²¹ Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²² Vanderbilt University Medical Center, Nashville, USA.
²³ The Christie NHS Foundation Trust, Manchester, UK; The University of Manchester, Manchester, UK.
²⁴ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Westmead and Blacktown Hospitals, Sydney, Australia.
²⁵ Massachusetts General Hospital, Boston, USA.
²⁶ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Royal North Shore Hospital, Sydney, Australia; Mater Hospital, Sydney, Australia. Electronic address: [email protected].
²⁷ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Royal North Shore Hospital, Sydney, Australia; Mater Hospital, Sydney, Australia.

PMID: 33798657
DOI: 10.1016/j.annonc.2021.03.204

Abstract

Background: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.

Patients and methods: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.

Results: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%).

Conclusions: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Keywords: Immunotherapy; anti-PD-1; delayed; irAE; melanoma; toxicity.

MeSH terms

Humans
Immunologic Factors
Immunotherapy / adverse effects
Melanoma* / drug therapy
Pneumonia*
Retrospective Studies

Substances

Immunologic Factors

Grants and funding

MR/T024097/1/MRC_/Medical Research Council/United Kingdom