Combination of chemotherapy and immune checkpoint inhibitors in non-small cell lung cancer with actionable gene alterations other than EGFR, ALK, and ROS1 mutations: a retrospective observational study.

BACKGROUND: Discoveries of actionable gene alterations (AGAs) have driven significant advances in targeted therapies, enhancing survival for non-small cell lung cancer (NSCLC) patients. In cases of AGAs other than common EGFR, ALK, and ROS1 mutations, target therapies have various strengths of the recommendation depending on their previous studies. Meanwhile, the immune checkpoint inhibitors (ICIs) combined with chemotherapy is still widely used as a first-line treatment for most of NSCLC with AGAs due to limited accessibility of target therapy. METHODS: This study included patients with NSCLC harboring AGAs who received chemotherapy plus ICIs (CT + IO) or chemotherapy alone (CT) as a first-line treatment between January 2019 and May 2023 at Samsung Medical Center. We assessed the objective response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) between treatment groups. Subgroup analyses were conducted in the CT + IO group according to the type of AGAs and PD-L1 expression. RESULTS: In total, 163 NSCLC patients with AGAs other than common EGFR, ALK, and ROS1 were included, with a median age of 62.4 years. 57 (35.0%) patients received CT + IO and 106 (65.0%) received CT. The proportions of patients with EGFR exon 20 insertion (E20I), HER2 mutation (mHER2), RET fusion (RET), and MET exon 14 skipping (METex14) were 28.8% (n = 47), 39.9% (n = 65), 16.6% (n = 27), and 14.7% (n = 24), respectively. With 32.0 months of median follow-up duration (range: 28.5-37.0), median PFS was 8.0 months (95% CI, 6.0-12.8) in CT + IO and 6.4 months (95% CI, 5.5-8.0) in CT (HR: 0.71, 95% CI, 0.49-1.03). In CT + IO group, median PFS by AGAs were 5.0 months (95% CI, 3.2-NA), 8.3 months (95% CI, 6.0-NA), 5.8 months (95% CI, 4.5-NA), and 17.1 months (95% CI, 10.7-NA) for E20I, mHER2, RET and METex14 respectively. Among these, 44.4% of METex14 patients had a PD-L1 TPS of 50% or higher. 24-month OS rate according to PD-L1 expression were 45.4%, 56.3%, and 81.5% in PD-L1 TPS < 1%, 1 to 49%, and ≥ 50%. CONCLUSIONS: The combination of chemotherapy with ICIs in NSCLC patients with AGAs other than common EGFR, ALK, and ROS1 mutations demonstrated similar clinical outcomes compared to conventional chemotherapy. Patients with METex14 were associated with higher response rate and longer PFS among patients with AGAs when treated with chemotherapy plus ICIs. Also, the efficacy of the chemotherapy plus ICIs is positively correlate to the PD-L1 expression.