[Skip to Navigation]
Sign In
Brief Report
March 25, 2021

Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-risk Resected Melanoma

Author Affiliations
  • 1School of Medicine, Vanderbilt University, Nashville, Tennessee
  • 2Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia
  • 3Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia
  • 4Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston
  • 5Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia
  • 6Ronald O. Perelman Department of Dermatology, NYU Langone Health, New York University School of Medicine, New York, New York
  • 7Division of Hematology and Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York University School of Medicine, New York, New York
  • 8Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
  • 9Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick
  • 10Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 11Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 12Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
JAMA Oncol. 2021;7(5):744-748. doi:10.1001/jamaoncol.2021.0051
Key Points

Question  What is the incidence, time course, and spectrum of chronic immune-related adverse events (irAEs) arising from adjuvant treatment with anti–programmed cell death 1 (anti–PD-1) for advanced melanoma?

Findings  In this multicenter cohort study of 387 patients with stage III to IV melanomas, 43% of patients treated with anti–PD-1 developed a chronic irAE, with only 14% resolving at last follow-up. Chronic irAEs most commonly affected nonvisceral organs (endocrine, joints, salivary glands, eye, and peripheral nerves).

Meaning  Chronic irAEs associated with anti–PD-1 therapy are more common than previously recognized and frequently persist even with prolonged follow-up.

Abstract

Importance  Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined.

Objective  To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti–PD-1 therapy.

Design, Setting, and Participants  This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti–PD-1 in the adjuvant setting were included.

Main Outcomes and Measures  Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation).

Results  Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti–PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti–PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs.

Conclusion and Relevance  In this multicenter cohort study, chronic irAEs associated with anti–PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

Add or change institution
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    RE: "Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma"
    Tomoyuki Kawada, MD | Nippon Medical School
    Patrinely et al. reported the incidence and spectrum of chronic immune-related adverse events (irAEs) arising from adjuvant anti-PD-1 therapy in patients with resected stage III and IV melanomas (1). Chronic irAEs were defined as irAEs persisting at least 12 weeks after therapy cessation. Chronic irAEs were observed in 167 (43.2%) patients, of which 161 patients presented mild (grade 1 or 2). Endocrinopathies, arthritis, xerostomia, neurotoxicities, and ocular events were main chronic irAEs. In contrast, irAEs affecting visceral organs had lower rates of chronic irAEs. Age, gender, time of onset, and need for steroids did not contribute significantly to chronic irAEs. I present information regarding the risk of irAEs.

    Rauwerdink et al. reported data regarding recurrence patterns, adjuvant therapy responses, and therapy-associated adverse events (AEs) (2). The percentages of AEs in adjuvant anti-PD-1 and adjuvant BRAF/MEKi groups were 54% and 80%, respectively. Although adjuvant anti-PD-1 and BRAF/MEKi were significantly effective in patients with resected stage 3 or 4 melanoma, the BRAF/MEKi group had significantly more AEs than the anti-PD-1 group. They presented efficacy and safety of adjuvant therapy simultaneously for clinical decision-making, although AEs should be classified into acute and chronic events.

    Regarding efficacy and safety of adjuvant anti-PD-1 therapy, Testori et al. pointed out that there is still a lack of enough data on adjuvant therapy including anti-PD-1 and BRAF/MEKi. Although adjuvant anti-PD-1 or BRAF-directed therapy for melanoma has become standard of care, more than 50% of long-term toxic side effects have been reported, which should be checked by further studies.


    References
    1. Patrinely JR Jr, Johnson R, Lawless AR, et al. Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma. JAMA Oncol 2021 Mar 25. doi: 10.1001/jamaoncol.2021.0051
    2. Rauwerdink DJW, Molina G, Frederick DT, et al. Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management. Ann Surg Oncol 2020;27(13):5128-5136.
    3. Testori AAE, Chiellino S, van Akkooi ACJ. Adjuvant Therapy for Melanoma: Past, Current, and Future Developments. Cancers (Basel) 2020;12(7):1994.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    ×