Seasonal patterns in immunotherapy outcomes.
Authors: Kennedy Oliver , Ali Nadia , Lee Rebecca , Adam Safwaan , Blackhall Fiona Helen , Califano Raffaele , Cooksley Tim , Cove-Smith Laura , Foy Victoria , Gupta Avinash , Pillai Manon Rhys , Serra-Bellver Patricio , Summers Yvonne , Waddell Tom , Lorigan Paul 
Published: June 2024

e14684

Background: Immune checkpoint inhibitors (ICIs) allow the immune system to target cancer cells. The immune system is affected by seasonal factors e.g. viruses, allergens, vaccines and ultraviolet exposure. There is evidence that some immune-related adverse events are more common in winter and that higher vitamin D (VD) levels and VD supplementation are associated with longer overall survival (OS). This study aimed to determine if season of ICI initiation was associated with OS. Methods: We evaluated patients who received ICI treatment at The Christie Hospital, UK, between 2017 and 2022. Season of ICI initiation was categorised as: (i) Nov-Apr vs May-Oct and (ii) Dec-Feb vs Jun-Aug (i.e. winter vs summer). For each category, median OS (mOS) was estimated using the Kaplan-Meier method. Adjusted Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals for associations of season of ICI initiation with OS and to test for interactions with ICI and diagnosis. Where data were available, associations of baseline VD levels and VD supplements with OS were estimated along with the association between season of ICI initiation and OS in patients with normal VD and/or receiving VD supplements. Results: 3010 patients were included and 1804 OS events occurred during 36.4 months [m] median follow-up. ICI indications included pembrolizumab or atezolizumab for advanced non-small cell lung cancer (NSCLC, 1st line n 304, median OS [mOS] 17.0 m; 2nd line n 197, mOS 10.7 m), pembrolizumab plus chemotherapy for advanced NSCLC (n 288, mOS 16.3 m), pembrolizumab or nivolumab for melanoma (advanced n 211, mOS 25.2 m; adjuvant n 226, mOS not reached), and ipilimumab + nivolumab for melanoma (n 203, mOS 45.4 m) or renal cancer (n 129, mOS 38.6 m). Confounders were balanced across seasons of ICI initiation, including sex (48% Nov-Apr vs 52% May-Oct), age (median 66.7 vs 67.2 years), PS 0/1 (83% vs 84%), body mass index (median 26.0 vs 25.7 kg/m2) and setting (adjuvant 13.0% vs advanced 12.4%). Season of ICI initiation was not associated with OS (Nov to Apr vs May to Oct mOS 20.8 vs 20.5 m, HR 1.01, 0.92-1.11; Dec-Feb vs Jun-Aug mOS 20.0 vs 21.3 m, HR 0.97, 0.85-1.10). Interactions with ICI and diagnosis were not significant. 214 patients had baseline VD levels and 96 received VD supplements before ICI initiation. VD deficiency was highest in February (23.6%) and lowest in August (1.1%). Among 209 patients with normal VD levels or receiving VD supplements, season of initiation was not associated with OS (Nov to Apr vs May to Oct mOS 45.4 vs 43.4 m; HR 0.98, 0.63-1.53). However, VD deficiency (n 37) was associated with shorter OS (HR 2.06, 1.21-3.52) and VD supplementation with longer OS (HR 0.69, 0.52-0.92). Conclusions: While VD deficiency and VD supplementation were associated with OS, season of ICI initiation was not. These results provide reassurance the OS benefits of ICIs remain similar irrespective of time of year of initiation despite seasonal factors that may influence the immune system.