The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer.

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Background: Chemoimmunotherapy has become a standard treatment option for patients with untreated advanced non-small-cell lung cancer (NSCLC). However, numerous patients with advanced NSCLC develop disease progression. Therefore, the selection of second-line treatment after chemoimmunotherapy is crucial for improving clinical outcomes. Methods: Of 88 enrolled patients with advanced NSCLC who received chemoimmunotherapy, we retrospectively evaluated 33 who received second-line chemotherapy after progression of chemoimmunotherapy at six centers in Japan. Among them, 18 patients received docetaxel plus ramucirumab and 15 patients received single-agent chemotherapy.Results: The objective response rate in patients treated with docetaxel plus ramucirumab was significantly higher than that in patients treated with a single-agent chemotherapy regimen (55.6% vs. 0%, p < 0.001). The median progression-free survival (PFS) of patients who received docetaxel plus ramucirumab and single-agent chemotherapy was 5.8 months and 5.0 months, respectively (log-rank test p = 0.17). In the docetaxel plus ramucirumab regimen group, patients who responded to chemoimmunotherapy for ≥8.8 months had a significantly longer response to docetaxel plus ramucirumab than those who responded for <8.8 months (not reached vs. 4.1 months, log-rank test p = 0.003). In contrast, in the single-agent chemotherapy group, there was no significant difference in PFS between the ≥8.8and <8.8-month PFS groups with chemoimmunotherapy (5.0 vs. 1.6 months, log-rank test p = 0.66). Conclusion: Our retrospective observations suggest that the group with longer PFS with chemoimmunotherapy might be expected to benefit from docetaxel plus ramucirumab treatment in second-line settings for patients with advanced NSCLC.

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.