*4.2. Combination of ICIs*

Combination therapy with different ICIs is currently being assessed, and the promising regimens include nivolmab+ipilimumab and durvalumab+tremelimumab. These studies have attempted to enhance the antitumor efficacy of immune cells by combining the inhibitors of PD-1/PD-L1 in the effector phase, using inhibitors of CTLA-4 in the priming phase.

In the CheckMate227 trial, a controlled trial involving combination therapy with nivolumab+ipilimumab and chemotherapy was conducted in 2019, and nivolumab+ipilimumab resulted in a significantly better OS among patientswith PD-L1≥1% (17.1mo vs. 14.9mo, HR 0.79) [21]. Accordingly, combination therapy with an anti PD-1 antibody and anti CTLA-4 antibody can be clinically introduced for the first time. The POSEIDON trial (NCT03164616; durvalumab+tremelimumab+platinum-based chemotherapy) examining is also ongoing.

Alternatively, higher rates of immune-related adverse events (irAE) have been reported upon ICIs combination therapy. In studies including other carcinomas, anti CTLA-4 antibodies are reportedly associated with a higher incidence of grade-III or higher irAE (31% vs. 10%) compared to anti PD-1 antibodies [22]. In particular, colitis (odds ratio (OR) 8.7) and hypophysitis (OR 6.5) were primarily observed with anti-CTLA-4 antibody preparations, pneumonitis (OR 6.4) and thyroiditis (OR 4.3) observed with anti-PD-1 antibody preparation [22]. In the CheckMate227 study, AEs were more prevalent in the nivolumab+ipilimumab group than in the nivolumab monotherapy group in groups with both all grades/grade-III and above (all grades 75.2% vs. 64.2%, grade-III and above 31.2% vs. 18.9%), and AEs for which treatment could not be continued were also reported in the combination group (12% vs. 6.9%) [23]. Other study has reported that the concomitant use of nivolumab+ipilimumab results in an earlier onset of irAE (particularly within 12 weeks) in comparison with nivolumab alone [24]. Thus, on using ICIs, more prudent measures for irAE are required than those used before.
