Adjuvant PD-1 Inhibitor Chronic Immune-Related AEs Highlighted In Advanced Melanoma

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: A study of patients with stage III–IV melanoma indicates that around 40% of individuals may experience chronic immune-related adverse events (irAEs) associated with PD-1 inhibitors after surgery.

On finding that chronic irAEs were “more common than previously recognized and frequently persist even with prolonged follow-up” in this population, the investigators say that it is “paramount” to characterise these effects for the increasing numbers of long-term melanoma survivors.

Douglas Johnson, from Vanderbilt University Medical Center in Nashville, Tennessee, USA, and co-workers reviewed medical records for 387 patients, aged a median 63 years, who received nivolumab (84.2%) or pembrolizumab (15.8%) at one of eight US and Australian medical centres between 2015 and 2020.

The patients commonly had stage IIIb (33.1%) or IIIc (39.5%) disease, with just 11.1% at stage IV; the majority (85.8%) of cases were cutaneous primary disease and around half (51.2%) were wild-type for BRAF or NRAS.

Writing in a brief report to JAMA Oncology, the team says that 50.0% of patients completed adjuvant PD-1 inhibitor therapy, 25.3% discontinued treatment after developing irAEs and 20.9% discontinued after progression.

The patients were followed up for a median 529 days, including a median 287 days after ending treatment, and 93.0% were alive at the last follow-up. Overall, 69.3% of patients were free from recurrence, 17.8% had metastatic disease and 12.9% regional recurrence.

Acute irAEs occurred in 69.0% of patients, with 13.4% at grade 3–5. The most common acute irAEs were dermatitis or pruritus (25.8%), followed by thyroiditis or hypothyroidism (16.3%), arthralgia (10.6%), colitis or diarrhoea (9.8%), hepatitis (6.2%), pneumonitis (4.4%) and xerostomia (4.1%). There were two deaths from myocarditis and Guillain-Barré-like syndrome.

Overall, 43.2% of patients had irAEs lasting for at least 12 weeks after treatment discontinuation, 96.4% of which were grade 1 or 2 events. Half (49.1%) of the chronic irAEs were symptomatic and a third (32.9%) of patients required glucocorticoids for chronic irAEs. Of concern, just 14.4% of chronic irAEs resolved during follow-up, the researchers say.

They observe that the incidence of chronic irAEs differed among people with acute irAEs; all eight cases of acute neurotoxicity became chronic irAEs, as did 83.0% of endocrinopathies, 63.0% of ocular events, 52.9% of xerostomias and 48.9% of arthritis irAEs.

But acute irAEs affecting the visceral organs appeared to be less likely to become chronic conditions, with colitis, hepatitis and pneumonitis affecting 13.6%, 16.0% and 33.3% of cases, respectively.

Douglas Johnson and co-workers add that patients with and without chronic irAEs were comparable in terms of age and sex, the timing of acute irAE onset, and use of glucocorticoids for acute irAEs (when excluding endocrinopathy patients).

Acknowledging that adjuvant PD-1 therapy “significantly extends” recurrence-free survival, the team remarks that “[t]he adjuvant patient population presents unique considerations; they may have been cured by surgery alone and have longer or normal life expectancies.”

The study authors therefore recommend that “persistent, life-altering, or life-threatening irAEs should be characterized in detail and integrated into patient counseling and treatment decision-making.”

Reference

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; Advance online publication 25 March 2021. DOI:10.1001/jamaoncol.2021.0051