Immunotherapy-related adverse events (irAEs) in melanoma patients are more common in autumn and winter while other season-specific patterns have also been observed.

The findings, from a retrospective study of 394 melanoma patients treated with combination anti-PD-1 and anti-CTLA-4 immunotherapy in Australia and in Switzerland, suggest that exposure to specific seasonal environmental factors influence the development of irAEs.

The study, published in the European Journal of Cancer [link here], found 87% of patients experienced toxicity events of any grade after a median 2.4 months of drug exposure and 22.1 months follow-up.

The most common irAEs of any grade were skin rash (35%), hepatitis (31%) and colitis (29%) with most patients experiencing more than one irAE. The most frequent grade 3–4 toxicities were colitis (19%) and hepatitis (18%).

Most (71%) irAEs occurred within the first 3 months from the start of checkpoint inhibitor therapy.

“Of the 19 categories of irAEs, 7 were numerically more frequent in winter (skin rash, colitis, pancreatitis, gastritis-duodenitis-enteritis, nephritis, neurotoxicity and “other”), 5 in autumn (hepatitis, thyroiditis, hypophysitis, myositis and cytokine release syndrome), 2 in summer (arthritis and pneumonitis) and 2 in spring (vitiligo-like depigmentation and diabetes),” the study said.

“Collectively, more irAEs were recorded in autumn and winter (210 and 221 respectively) than in spring and summer (158 and 175 respectively).”

The study noted the analysis is complicated by the fact that most treatments started in summer and autumn than in winter and spring.

After accounting for the seasonal variability in treatment initiation, it found the ratio of toxicity events per treatment initiated was the highest in winter (2.4) and lowest in summer (1.7).

“When evaluated per month, the highest ratio was observed in early autumn and the lowest in early spring (2.6 and 1.4 respectively),” the study said.

As well, the lag time between treatment initiation and development of irAEs, meant an irAE resulting from a treatment started in one particular season may spill over into the next season or beyond.

The study noted that pneumonitis developed faster in autumn, winter (and summer) in comparison with spring (p = 0.025), hepatitis manifested more rapidly in spring (p = 0.016) and the interval to the development of a sarcoid-like reaction seemed to be shorter in autumn (p = 0.041).

“For common toxicities like skin rash, colitis and thyroiditis, no obvious pattern was observed.”

“Collectively, these findings indicate that exposure to environmental factors associated with a particular season after starting treatment with immune checkpoint inhibitors may be associated with an accelerated (or delayed) rate at which specific irAEs develop.”

“In other words, starting immune checkpoint inhibition in a given season may confer an increased or decreased risk for the development of a particular irAE over time.”

The study, led by investigators from the Melanoma Institute Australia, said while it may be possible to expand the dataset beyond melanoma managed with combination immunotherapy, “the heterogeneity in the frequency and severity of the irAEs may dilute signal finding.”

“Further research into environmental factors contributing to irAEs may uncover factors that would support preventive and therapeutic strategies so that the safety of patients treated with immune checkpoint inhibition can be improved,” they concluded.

They noted that seasonality has been documented in cardiovascular conditions and notably in infectious diseases.