Discussion
cancer, NIVO, death
CANCER, DISEASE
First-line NIVO + IPI and NIVO + Chemo treatments resulted in a substantial survival advantage over Chemo in Japanese patients with advanced ESCC. The efficacy and safety of NIVO + IPI and NIVO + Chemo were consistent between the CheckMate 648 Japanese subpopulation and the global population (including Japan) [Patients with better clinical condition are generally more likely to receive subsequent treatment. This may explain the higher rates of subsequent anticancer therapies in the current study across all arms in the Japanese subpopulation (63%–75%) versus the global population (51–63%), especially the rate of subsequent systemic anticancer therapies received [Also, the Japanese subpopulation had a relatively higher percentage of smokers than the global population (89% vs. 80%) [The HRs for death for NIVO + IPI or NIVO + Chemo versus Chemo were < 1, suggesting overall survival advantage irrespective of increasing tumor-cell PD-L1 cutoff values (≥ 1%, ≥ 5%, ≥ 10%; HRs 0.46, 0.45, 0.50 for NIVO + IPI and 0.54, 0.51, 0.54 for NIVO + Chemo, respectively). In contrast, HRs for death in NIVO + IPI or NIVO + Chemo arms versus Chemo were close to 1 for tumor-cell PD-L1 < 1% (HR 1.01 for NIVO + IPI and 0.99 for NIVO + Chemo, respectively). The relatively smaller efficacy of NIVO + IPI or NIVO + Chemo at tumor-cell PD-L1 < 1% suggests that tumor-cell PD-L1 expression might be one of the predictors of response; however, the magnitude of efficacy did not increase in patients with higher tumor-cell PD-L1 expression levels (≥ 1%, ≥ 5%, ≥ 10%). Therefore, there seems to be a limitation to performing response prediction with only PD-L1.In the four anti-PD-1 phase 3 studies, namely, KEYNOTE-590 (pembrolizumab), ESCORT-1st, (camrelizumab), JUPITER-06 (toripalimab), and ORIENT-15 (sintilimab), the anti-PD-1 antibody + chemotherapy combination significantly prolonged median OS compared with placebo + chemotherapy [In the NIVO + IPI arm, the incidence of serious TRAEs was higher than that in the NIVO + Chemo and Chemo arms, whereas the incidence of any TRAEs was lower. Similar trends were observed in the global population [The NIVO + IPI and NIVO + Chemo arms were not compared statistically as this study was not designed to compare these 2 arms. It was also not possible to speculate advantage of one or the other nivolumab combination treatment for specific study subgroups. In clinical practice, the choice of cancer treatment regimen is governed by several considerations including disease status, patients’ requirements and preferences, and capacity to tolerate specific immunotherapy or chemotherapy. Future studies and exploratory post hoc analyses are warranted to determine prognostic predictors for each of the nivolumab combination regimen.