Abstract
Therapies that targeted PD-1 have shown remarkable rates of durable clinical responses in patients with various tumor types. However, the extent and knowledge of pulmonary toxicities associated with PD-1 blockade, mainly manifested as pneumonitis, remains obscure. In this study, a total of 6360 subjects from 16 phase II/III clinical trials were pooled for meta-analysis to evaluate the overall incidence and risk of PD-1 inhibitors-related pneumonitis in cancer patients. The incidence of pneumonitis during anti-PD-1 immunotherapy was 2.92% (95%CI: 2.18–3.90%) for all-grade and 1.53% (95%CI: 1.15–2.04%) for high-grade pneumonitis. Compared with routine chemotherapy, PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Moreover, among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Furthermore, no significant differences were detected in the incidences of all- and high-grade pneumonitis between high-dose and low-dose groups of PD-1 inhibitors. In conclusion, PD-1 inhibitors were probably associated with an increased risk of pneumonitis in a dose-independent manner, compared with routine chemotherapeutic agents. The frequency and severity of treatment-mediated pneumonitis was quite different in patients with various tumor types.
Highlights
These results indicated that the risk of pneumonitis induced by PD-1 inhibitors was much higher than that of routine chemotherapeutic agents in cancer patients
Our results indicated that: 1. Anti-PD-1 immunotherapy would significantly increase the incidence and severity of pneumonitis compared with routine chemotherapy in cancer patients; 2
The data of our meta-analysis demonstrated that PD-1 inhibitors dramatically increased the risk of immune-associated pneumonitis in cancer patients compared with routine chemotherapy
Summary
PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the nonsmall cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Blockade of the PD-1 pathway with antibodies could augment the function of tumor-specific CD4+T-cells and restore the anti-tumor immunity[5,6,7]. IgG4-κmonoclonal antibodies (mAbs) for PD-1 inhibition, pembrolizumab (humanised; Keytruda , Merck) and nivolumab (fully human; Opdivo , Bristol-Myers Squibb), for the treatment of patients with unresectable or metastatic melanoma and metastatic squamous non-small-cell lung cancer (NSCLC)[8]. Anti-PD-1 immune checkpoint mAbs have demonstrated antineoplastic activity across multiple malignancies, the toxicities associated with PD-1/PD-L1 blockade cannot be ignored. Among irAEs noted during trials of PD-1 inhibitors, pneumonitis has been considered to be an “event of special interest”, occurring at a rate of around 3% and resulting in three treatment-related deaths in a phase I trial of nivolumab for NSCLC13
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