Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma

Abstract

Introduction. Objective response rates (ORR) appear to be higher in melanoma patients who develop immune-related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown. Materials and Methods. Patients with advanced melanoma treated with single-agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti-programmed cell death protein 1 (PD-1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression-free survival (PFS) and ORR. Results. Among 186 patients, any-grade and grade ≥3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12 weeks, the median follow-up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p = .006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p = .001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ≥3 irAEs and no grade ≥3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p = .001), whereas each additional cycle of treatment received (HR, 0.94; p < .001) and development of grade ≥3 irAEs (HR, 0.29, p = .024) were significantly associated with longer OS. Conclusion. Anti-PD-1-associated grade ≥3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival. The Oncologist 2020;25:438-446 Implications for Practice: Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population-based real-world study in advanced melanoma reports an association with anti-programmed cell death protein 1 (PD-1)-induced grade ≥3 immune-related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD-1-directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes.

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

“…115 It has been reported quite recently that patients who experienced severe irAEs (grade > − 3) may even have an improved overall response rate and longer median time to progression compared to those without grade > − 3 irAEs, despite the use of corticosteroids. 116 The development of irAEs was associated with a clinical benefit in patients with gastric cancer, 117 non-small cell lung cancer 118 and melanoma 119 who were receiving nivolumab as monotherapy, but corticosteroids had no impact, although their use was not an end-point in these studies. Meanwhile, poor outcomes have been reported in patients receiving steroids (equivalent of > − 10 mg/day of prednisone) during nivolumab treatment for non-small cell lung cancer.…”

Immune Checkpoint Inhibitor-Related Pneumonitis

“…It is generally believed that the occurrence of irAEs in patients with cancer treated with immunotherapy indicates an active immune status suggestive of potential enhanced efficacy of the treatment and favorable outcome for the patient [61]. Several cohorts have reported better efficacy of immunotherapy in patients who experienced irAEs, while the effect on survival is more controversial, although most studies report no effect on survival or even more prolonged survival in patients with irAEs [62-66]. However, those cohorts included all types of irAEs and the percentage of pneumonitis was low in most of them.…”

Autoimmunity in Segmental Vitiligo

“…programmed death ligand-1 (PD-L1), indoleamine 2,3-dioxygenase (IDO)] have been found to regulate the immune privilege of the hair follicle. Inhibition of these factors by immunotherapy for melanoma results often in the development of vitiligo-like lesions very similar to NSV (30,31). It is therefore plausible to speculate that SV is less dependent on changes in factors regulating immune privilege compared to NSV (32).…”