Cardiothoracic Related Complications of Anti-PD/PD-L1 Immunotherapy

Abstract

Background: Despite their high prevalence of cutaneous, gastrointestinal, and endocrine adverse effects, anti-PD/PD-L1-targeted immunotherapy is associated with astonishingly high rates of persistent clinical responses in patients across a range of tumour types. Pneumonitis and cardiotoxicity risks linked with checkpoint inhibitor therapy are not well addressed.

Methods: In cancer patients, a systematic review of the literature was undertaken on randomised clinical trials (RCTs) comparing anti-PD/PD-L1 mono-immunotherapy (IMM) to chemotherapy (CTH) procedures. The primary endpoint was the rate of pneumonitis in IMM compared CTH.

Secondary endpoints were (I) high-grade pneumonitis rate in IMM compared to CTH and (II) tumor response rate, progression-free survival (PFS), and overall survival (OS) between IMM and CTH (III) comparison of cardiotoxicity grades in IMM to others (IV) cardiotoxicity grade difference between IMM and other studies having lung cancer and other cancer subgroups and in IMM compared with chemotherapy (CTH) only studies (V) outcome of IMM compared with others (in all studies and in lung cancer/other cancers subgroups) as well as in IMMs compared with CTH only studies and (VI) difference in mortality in the same groups. Random model, leave-one-out- analysis and meta-regression were performed.

Results: Thirteen RCTs studying 7,246 patients for pneumonitis and 11 RCTs studying 6574 patients for cardiotoxicity were included; Both high-grade and all-grade pneumonitis were higher among patients in the IMM arm when compared to the CTH arm (OR =4.39, 95% CI =1.65–11.69, P=0.003 and OR =2.46, 95% CI =1.29–4.6, P=0.007). Tumor response rate was significantly better in the immunotherapy arm (OR =2.31, 95% CI =1.62–3.29, P<0.001). PFS and OS were longer in patients who received IMM compared to patients in the CTH arm (HR =0.75, 95% CI =0.65–0.85, P<0.001, and HR =0.71, 95% CI =0.66–0.77, P<0.001). There was no difference in all grade cardiotoxicity among all recruited studies (RR: 1.15; 95% CI: 0.73–1.80; p = 0.55) or in subgroups of lung cancer (RR: 0.68; 95% CI: 0.22–2.09; p = 0.50) or other cancers (RR = 1.27; 95% CI: 0.78–2.08; p = 0.34). Similarly, no difference was present in high grades cardiotoxicity among all recruited studies (RR: 1.47; 95% CI: 0.87–2.46; p = 0.15) or in subgroups of lung cancer (RR: 0.80; 95% CI: 0.25–2.50; p = 0.70) or other cancers (RR: 1.71, 95% CI: 0.96–3.06; p = 0.07).

Conclusions: When compared to traditional CTH regimens for NSCLC and melanoma, anti-PD-1 therapy caused more high-grade and all-grade pneumonitis, but not anti-PD-L1 therapy. Other than that, high-grade adverse events were more common in the CTH arm. Tumor response rate, PFS, and OS are all significantly improved with IMM over CTH. These findings can be utilised to help guide therapy selection and set treatment expectations for these patients. Cardiotoxicity was statistically insignificant regardless the treatment regimen either chemotherapy or dual immunotherapy. The use of anti-PD/PDL1 provided better response and survival rates when used in lung cancer subgroup.