*4.1. Combination with Chemotherapy*

To enhance the efficacy of immunotherapy, the combination of platinum-based chemotherapy and ICIs has already been validated and introduced into actual clinical practice (Figure 1). As one of them, a comparative study of CDDP or CBDCA+Pemetrexed (PEM) plus pembrolizumab vs. CDDP or CBDCA+PEM was conducted in the KEYNOTE-189 trial, and the PFS was significantly higher in the ICI-combined group than in the chemotherapy group in PFS (8.8 mo vs. 4.9 mo, HR 0.52) and OS (NR vs. 11.3 mo, HR 0.49) [16], and this regimen was approved as first-line treatment for advanced-stage NSCLC. This study included a platinum-combination therapy, which has not been directly compared with ICI alone, and it thus remains controversial whether pembrolizumab alone or ICI plus chemotherapy is beneficial for patients with high PD-L1 expression levels. Upon ICI monotherapy, cases presenting

with cancer progression at an early stage pose a problem, whereas during combination therapy, it is advantageous to reduce progressive disease at early stages in combination treatment with cytotoxic anticancer drugs.

The therapeutic efficacy of atezolizumab as first-line therapy for NSCLC was reported in an IMpower150 trial (NCT02366143) in combination with CBDCA+paclitaxel (PTX)+bevacizumab (BEV) [19]. In this study, subgroup analyses confirmed the efficacy of ICIs among patients with hepatic metastases and driver mutations, which were previously poor responders to ICIs, suggesting the potential effects of the concomitant use of angiogenesis inhibitors. Combination therapy with angiogenesis inhibitors is expected in this regimen in cases with complications including cerebral edema and pleural effusion caused by brain metastasis.

Subsequently, the efficacy of CBDCA+nabPTX in combination with pembrolizumab was also reported in squamous cell carcinoma in a KEYNOTE-407 trial (NCT02775435) [17]; furthermore, the combination treatment with CBDCA+nabPTX and atezolizumab [20] yielded better outcomes than chemotherapy during first-line treatment of squamous cell lung cancer in the IMpower130 trial (NCT02367781). Clinical trials are currently underway for numerous combinations of ICIs and chemotherapy, including the IMpower132 trial (NCT02657434; CBDCA+PEM+ atezolizumab versus CBDCA+PEM in non-squamous lung cancer), TORG1630 trial (UMIN000021813; DTX+nivolumab versus DTX alone in NSCLC), KEYNOTE-604 trial (NCT03066778; pembrolizumab+ etoposide+carboplatin/cisplatin (EP) versus placebo+EP in SCLC), and CASPIAN trial (NCT03043872; durvalumab+tremelimumab+EP versus durvalumab+EP in SCLC).

Based on these results, various combinations of ICI plus platinum-based chemotherapy, ICI alone, and chemotherapy alone seemed appropriate as first-line treatment of advanced-stage NSCLC at present. It is thus important to examine the optimum treatment for each case on the basis of the factors including the performance status, PD-L1 expression rate, presence of driver gene mutations, and medical history.
