Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types

Abstract

Immune checkpoint inhibitors have demonstrated significant survival benefits in treating many types of cancers. However, their immune-related adverse events (irAEs) have not been systematically evaluated across cancer types in large-scale real-world populations. To address this gap, we conducted real-world data analyses using nationwide insurance claims data with 85.97 million enrollees across 8 years. We identified a significantly increased risk of developing irAEs among patients receiving immunotherapy agents in all seven cancer types commonly treated with immune checkpoint inhibitors. By six months after treatment initialization, those receiving immunotherapy were 1.50-4.00 times (95% CI, lower bound from 1.15 to 2.16, upper bound from 1.69 to 20.36) more likely to develop irAEs in the first 6 months of treatment, compared to matched chemotherapy or targeted therapy groups, with a total of 92,858 patients. The risk of developing irAEs among patients using nivolumab is higher compared to those using pembrolizumab. These results confirmed the need for clinicians to assess irAEs among cancer patients undergoing immunotherapy as part of management. Our methods are extensible to characterizing the effectiveness and adverse effects of novel treatments in large populations in an efficient and economical fashion.

Fig. 1. A summary of the patient cohorts in our study.

The numbers of patients at each stage of cohort derivation were shown. The detailed inclusion and exclusion criteria can be found in the Methods section.

Fig. 2. The immunotherapy group has a higher risk of developing subsequent irAEs across all cancer types under study.

A Melanoma. B Renal cancer. C Head and neck cancer. D Squamous cell carcinoma. E Basal cell carcinoma. F Brain cancer. G Lung cancer. The point estimates of the hazard ratios comparing the immunotherapy group with either chemotherapy (red curves) or targeted therapy (cyan curves) in 3, 6, 9, 12, and 15 months after treatment initiation are shown. Their corresponding 95% confidence intervals are displayed by the shaded areas. Chemotherapy agents include carboplatin, cisplatin, doxorubicin, fluorouracil, gemcitabine, and paclitaxel. Targeted therapy agents include bevacizumab, temsirolimus, axitinib, cabozantinib, erlotinib, everolimus, pazopanib, sorafenib, and sunitinib. The detailed list of CPT/HCPCS procedure codes and national drug codes can be found in Tables S3–S6. The number on the top right indicates the number of matched patients in the treatment group. With the exception of renal cancer, the hazard ratios did not differ significantly when using the chemotherapy group or the targeted therapy group as the comparison group. With the exception of comparing immunotherapy with targeted therapy among patients with squamous cell carcinoma of the skin and brain cancer, the 95% confidence intervals in all other comparisons involving all immunotherapy drugs do not include 1.

Fig. 3. Time-to-event plot showing the time between treatment initiation and the development of irAEs in seven cancer types.

A Melanoma. B Renal cancer. C Head and neck cancer. D Squamous cell carcinoma. E Basal cell carcinoma. F Brain cancer. G Lung cancer. The comparisons between chemotherapy with pembrolizumab, nivolumab, and all immune checkpoint inhibitors combined are shown in the three columns respectively. The top panel is the time-to-event plot for all irAEs, with a log-rank test p-value reported on the top right corner for both matched and unmatched samples. Each tick represents 50 censored patients. The curves are truncated in the 15th month after treatment initiation for better visualization.

Fig. 4. Time-to-event plot showing the time between treatment initiation and the development of specific irAEs.

The comparisons between renal cancer patients receiving chemotherapy with A pembrolizumab, B nivolumab, and C all immune checkpoint inhibitors are shown in three separate columns. We examined 56 irAEs separately, with p-values corrected by the Benjamini–Hochberg procedure. Adjusted p-values < 0.05 were highlighted in red. Renal cancer patients receiving nivolumab have higher risks of developing hypothyroidism and thyrotoxicosis, but those receiving pembrolizumab did not have a significantly increased risk. Each tick represents 50 censored patients. The curves are truncated in the 15th month after treatment initiation for better visualization. The numbers at the bottom panel indicate the number of remaining patients at 0, 3, 6, 9, 12, and 15 months after treatment initiation. Plots for all other cancer types can be found in Supplementary Fig. 2; plots for a longer time horizon can be found in Supplementary Fig. 4.

Fig. 5. Time-to-event plot showing the time between treatment initiation and the development of irAE groups.

A Pembrolizumab. B Nivolumab. C All immune checkpoint inhibitors.