Impact of the combined timing of PD-1/PD-L1 inhibitors and chemotherapy on the outcomes in patients with refractory lung cancer

BACKGROUND: PD-1/PD-L1 inhibitors in combination with chemotherapy are widely used in clinical practice. However, the ideal combined timing of them has not been fully explored. METHODS: In this study, simulation experiments to explore the impacts of the combination of anti-PD-1 antibody (anti-PD-1 Ab) on the cytotoxic effects of chemotherapeutic drugs in peripheral blood mononuclear cells were performed. In addition, the effects of the combined timing of PD-1/PD-L1 inhibitors and chemotherapy on efficacy and safety were retrospectively analysed in patients with refractory lung cancer. RESULTS: Experiments in vitro showed that administering the anti-PD-1 Ab 3 days after chemotherapy (represented by dicycloplatin) resulted in significantly weaker cytotoxic effects on lymphocytes, compared with administering the anti-PD-1 Ab before or concurrent with chemotherapy. Moreover, data from 64 lung cancer patients treated with PD-1/PD-L1 inhibitors plus chemotherapy as a second- or higher-line therapy were retrospectively analysed. The results showed that administering PD-1/PD-L1 inhibitors 1-10 days (especially 3-5 days) after chemotherapy was associated with longer overall survival [17.3 months versus 12.7 months; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.28-1.19, P = 0.137 in univariate analysis; HR = 0.36, 95% CI 0.16-0.80, P = 0.012 in multivariate analysis] and a trend of improved progression-free survival (5.1 months versus 4.2 months; HR = 0.81, 95% CI 0.42-1.54, P = 0.512) compared with administering PD-1/PD-L1 inhibitors before or concurrent with chemotherapy. CONCLUSION: Our findings suggest that administering PD-1/PD-L1 inhibitors 1-10 days (especially 3-5 days) after chemotherapy is superior to administering PD-1/PD-L1 inhibitors before or concurrent with chemotherapy in patients with refractory lung cancer, but this result needs to be further explored by prospective studies.