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 (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.

The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Meanwhile, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associated with baseline PLR (hazard ratio (HR): 2.49, p = 0.0473), systemic immune-inflammation index (SII; HR: 2.65, p = 0.0337), prognostic nutrition index (PNI; HR: 4.15, p = 0.00185), and the 3-week values for SII (HR: 2.85, p = 0.0473) and PNI (HR: 3.04, p = 0.0125). Immunological and nutritional markers could be useful in predicting the outcomes of first-line treatment with alectinib. Since PLR and SII consist of platelet counts, platelet count could be an important constituent of these markers.

ImportanceImmune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non–small cell lung cancer (NSCLC) for patients with a programmed cell death ligand–1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is unclear.ObjectiveTo clarify the association of a history of concurrent medication use with treatment outcomes for ICIs with or without chemotherapy in patients with NSCLC with a high PD-L1 TPS and to determine whether these clinical histories are biomarkers for appropriate treatment selection.Design, Setting, and ParticipantsThis retrospective, multicenter cohort study at 13 hospitals in Japan included patients with advanced NSCLC with a PD-L1 TPS of 50% or more who had received pembrolizumab ICI monotherapy or ICI plus chemotherapy as the initial treatment between March 2017 and December 2020. The median (IQR) follow-up duration was 18.5 (9.2-31.2) months. Data were analyzed from April 2022 through May 2023.ExposureICI monotherapy with pembrolizumab or ICI plus chemotherapy as first-line treatment.Main Outcomes and MeasuresThe primary analysis was the association of treatment outcomes with baseline patient characteristics, including concomitant drug history, after propensity score matching. Cox proportional hazard models were used to determine the associations of patient characteristics with survival outcomes. Logistic regression analysis was used to determine the association of concomitant medication history with treatment outcomes and other patient characteristics.ResultsA total of 425 patients with NSCLC were enrolled in the study including 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) who were treated with pembrolizumab monotherapy as the first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) who were treated with ICI plus chemotherapy as the first-line treatment. In multivariable analysis, a history of proton pump inhibitor (PPI) use was independently associated with shorter progression-free survival (PFS) in the pembrolizumab monotherapy group (hazard ratio [HR], 1.38; 95% CI, 1.00-1.91; P = .048), but not in the ICI plus chemotherapy group. In patients with a PPI history, both the median (IQR) PFS (19.3 [9.0 to not reached] months vs 5.7 [2.4 to 15.2] months; HR, 0.38; 95% CI, 0.20-0.72; P = .002) and the median (IQR) overall survival (not reached [9.0 months to not reached) vs 18.4 [10.5 to 50.0] months; HR, 0.43; 95% CI, 0.20-0.92; P = .03) were significantly longer in the ICI plus chemotherapy group than in the pembrolizumab monotherapy group. In patients without a history of PPI use, both the median (IQR) PFS (18.8 months [6.6 months to not reached] vs 10.6 months [2.7 months to not reached]; HR, 0.81; 95% CI, 0.56-1.17; P = .26) and the median (IQR) overall survival (not reached [12.6 months to not reached] vs 29.9 [13.3 to 54.3] months, HR, 0.75; 95% CI, 0.48-1.18; P = .21) did not differ between groups.Conclusions and RelevanceThis cohort study found that a history of PPI use could be an important clinical factor in treatment decision-making for patients with NSCLC with a PD-L1 TPS of 50% or more.

BackgroundPatients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer have received immunochemotherapy as one of the treatment options after tyrosine kinase inhibitor (TKI) failure. We examined the efficacy of immunochemotherapy in actual clinical practice and investigated subgroups of EGFR-mutant patients suitable for immunochemotherapy.MethodsWe conducted a multicenter retrospective cohort study of EGFR-mutant patients treated with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) therapy versus platinum-based chemotherapy (Chemo) and immune checkpoint inhibitor (ICI) monotherapy after EGFR-TKI therapy. Progression-free survival (PFS), according to underlying factors, including programmed death-ligand 1 (PD-L1) status, was also analyzed between the ABCP and Chemo groups.ResultsOf the 65 patients, 20, 37, and 8 received ABCP therapy, chemotherapy, and ICI monotherapy, respectively. The median PFS and overall survival periods in the ABCP, Chemo and ICI groups were 5.6 and 20.9 months, 5.4 and 22.1 months, and 1.2 and 9.2 months, respectively (PFS, P = 0.63; OS, P = 0.11). The median PFS periods of PD-L1-positive patients in the ABCP and Chemo groups were 6.9 and 4.7 months, respectively (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.41–2.17, P = 0.89). The median PFS of PD-L1-negative patients in the Chemo group (8.7 months) was significantly longer than that in the ABCP group (4.6 months) (HR, 0.34; 95% CI, 0.12–0.97, P = 0.04).ConclusionsThe effect of ABCP therapy was similar to chemotherapy in EGFR-mutant patients in a real-world setting. Particularly, for PD-L1-negative patients, platinum-based chemotherapy may be recommended over ABCP therapy.