Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab

Abstract

BackgroundRecent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. In this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab.MethodsThe subjects of this study were AGC patients received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups.ResultsOf the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3–407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that number of metastatic sites ≥2 (HR = 2.15; 95% CI, 1.02 to 4.54), high ALP level (HR = 2.50; 95% CI, 1.27 to 4.54), and absence of irAEs (HR = 9.54, 95% CI, 3.34 to 27.30 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). There were no grade 4 or 5 adverse events related to nivolumab.ConclusionsDevelopment of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.

Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

“…Previous studies have shown that immunerelated events occurring early in the course of immune checkpoint inhibitor treatment may correlate with clinical benefit in several malignancies. [14][15][16][17] No new safety signals were observed, and the overall incidence of treatment-related events with longer follow-up was similar to previous rates. 3 8 Looking at treatmentrelated AEs by 6-month interval, the overall incidence decreased over time in both arms, yet consistently higher rates of any-grade and grade 3-4 AEs occurred with SUN versus NIVO+IPI.…”

Immune-related Adverse Effects and Outcome of Patients With Cancer Treated With Immune Checkpoint Inhibitors

“…A retrospective study focusing on patients with advanced gastric cancer treated with nivolumab (n=65) conducted by Masuda et al found significantly longer PFS and OS in patients with irAEs compared to those without (p<0.001 and p<0.001, respectively) (45). Furthermore, the results of multivariable Cox model demonstrated that absence of irAEs represented an independent factor associated with a poor prognosis (HR=9.54, p<0.001) (45).…”

Glasgow Prognostic Score (GPS) and Tumor Response as Biomarkers of Nivolumab Monotherapy in Third- or Later-line Setting for Advanced Gastric Cancer

“…Second, although examinations for PD-L1 expression, MSI or Epstein-Barr virus positivity require technical expertise, GPS and DCBC do not. Finally, with the use of GPS and DCBC, prediction can be made prior to administration of nivolumab, unlike previously suggested biomarkers such as development of immune-related adverse events (25). On the other hand, the following disadvantages should be taken into account: GPS is intrinsically susceptible to transient inflammation including acute infection, and DCBC can be utilized only when the information of response to chemotherapy immediately prior to nivolumab is available.…”