First Cycle Toxicity and Survival in Patients with Rare Cancers Treated with Checkpoint Inhibitors.

Abstract

Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally-funded basket trial ((NCT02834013) for patients with rare cancers (N = 684) to evaluate associations between irAEs and overall survival and progression-free survival. Patients were treated with nivolumab and ipilimumab; the trial was opened at > 1000 sites. Landmark Cox regression models were used to assess first cycle irAE associations with progression-free and overall survival. We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer overall survival (OS) (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p < .001) compared to no treatment-related irAE, while grade 3-4 irAEs were associated with shorter OS (HR = 1.41, 95% CI = 1.04-1.90, p = .025). Similar, but weaker, associations were observed with progression-free survival (PFS) and grade 1-2 treatment-related irAEs: HR = 0.83, 95% CI = 0.67-1.01, p = .067 and grade 3-4: HR = 1.35, 95% CI = 1.02-1.78, p = .037 compared to no treatment-related irAEs. Grade 1-2 dermatologic toxicity was associated with improved OS compared to other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52-0.85, p = .002). There was no significant OS difference between patients with Grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other Grade 1-2 toxicities. In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of irAE in the first cycle was predictive for survival.