Efficacy of chemotherapy plus immune checkpoint inhibitors in patients with non-small cell lung cancer who have rare oncogenic driver mutations: a retrospective analysis.

Targeted therapy is now the standard of care in driver-oncogene-positive non-small cell lung cancer (NSCLC). Its initial clinical effects are remarkable. However, almost all patients experience treatment resistance to targeted therapy. Hence, chemotherapy is considered a subsequent treatment option. In patients with driver-oncogene-negative NSCLC, combined immune checkpoint inhibitors (ICIs) and chemotherapy as the first-line therapy has been found to be beneficial. However, the efficacy of ICI plus chemotherapy against driver-oncogene-positive NSCLC other than epidermal growth factor receptor mutation and anaplastic lymphoma kinase fusion is unclear. Using the hospital medical records, we retrospectively reviewed advanced or recurrent NSCLC patients who were treated with chemotherapy with or without ICIs at Aichi Cancer Center Hospital between January 2014 and January 2023. Patients with druggable rare mutations such as KRAS-G12C, MET exon 14 skipping, HER2 20 insertion, BRAF-V600E mutations, and ROS1 and RET rearrangements were analyzed. In total, 61 patients were included in this analysis. ICI plus chemotherapy was administered in 36 patients (the ICI-chemo group) and chemotherapy in 25 patients (the chemo group). The median progression-free survival (PFS) rates were 14.0 months in the ICI-chemo group and 4.8 months in the chemo group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.28-1.01). The median overall survival rates were 31.3 and 21.7 months in the ICI-chemo and chemo groups, respectively (HR = 0.70, 95% CI = 0.33-1.50). Multivariate Cox regression analysis of PFS revealed that HER2 exon 20 insertion mutation was significantly associated with a poorer PFS (HR: 2.39, 95% CI: 1.19-4.77, P = 0.014). Further, ICI-chemo treatment was significantly associated with a better PFS (HR: 0.48, 95% CI: 0.25-0.91, P = 0.025). ICI plus chemotherapy improves treatment efficacy in rare driver-oncogene-positive NSCLC.

Yamaguchi T ，Shimizu J ，Matsuzawa R ，Watanabe N ，Horio Y ，Fujiwara Y ... -  《BMC CANCER》

Clinical outcomes for immune checkpoint inhibitors plus chemotherapy in non-small-cell lung cancer patients with uncommon driver gene alterations.

Qin H ，Yan H ，Chen Y ，Xu Q ，Huang Z ，Jiang W ，Wang Z ，Deng L ，Zhang X ，Zhang L ，Yang N ，Zeng L ，Zhang Y ... -  《BMC CANCER》

Efficacy of first-line immune checkpoint inhibitors in patients with advanced NSCLC with KRAS, MET, FGFR, RET, BRAF, and HER2 alterations.

In patients with non-small cell lung cancer (NSCLC) harboring driver alterations, the efficacy of immune checkpoint inhibitors (ICIs) remains uncertain. Our study aimed to examine the first-line ICI efficacy in patients with NSCLC harboring KRAS, MET, FGFR, RET, BRAF, and HER2 alterations in a real-world setting. This single-center, retrospective cohort study included patients with advanced NSCLC harboring KRAS, MET, FGFR, RET, BRAF, HER2 alterations or driver-negative, and were treated with first-line ICI therapy. Best overall response, progression-free survival (PFS), and overall survival (OS) were evaluated. Seventy-eight patients with NSCLC were included (median age, 72 years): 67% were men, 15% were never-smokers, and 83% had adenocarcinoma. The driver alterations involved KRAS (n = 21), MET (n = 6), FGFR (n = 3), RET (n = 2), BRAF (n = 2), HER2 (n = 1), and driver-negative (n = 43). The partial responses for KRAS, MET, FGFR, RET, BRAF, HER2, and driver-negative were 57%, 50%, 100%, 50%, 100%, 0%, and 47%, respectively. The median PFS (months) was 16.2 (95% confidence interval [CI]: 6.3- not reached [NR]) for KRAS, 2.8 (95% CI: 2.7-NR) for MET, 11.7 (95% CI: 5.9-NR) for other alterations (FGFR, RET, BRAF, and HER2), and 10.0 (95% CI: 3.7-14.3) for driver-negative, respectively. The median OS (months) was 31.3 (95% CI: 9.0-NR) for KRAS, not reached for MET, 23.5 (95% CI: 18.3-NR) for other alterations, and 21.1 (95% CI: 15.2-NR) for driver-negative, respectively. The benefit of the first-line ICI was similar in advanced NSCLC regardless of the driver alterations, except for MET alterations.

Uehara Y ，Watanabe K ，Hakozaki T ，Yomota M ，Hosomi Y ... -  《-》

Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.

This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1). Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PD-L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007). We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC. Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.

Shi Y ，Lei Y ，Liu L ，Zhang S ，Wang W ，Zhao J ，Zhao S ，Dong X ，Yao M ，Wang K ，Zhou Q ... -  《Cancer Medicine》

Efficacy of first-line immune checkpoint inhibitor and anti-angiogenic agent combination therapy for Kirsten rat sarcoma viral antigen-mutant advanced non-small-cell lung cancer: a systematic review and network meta-analysis.

Tsukada A ，Morita C ，Shimizu Y ，Uemura Y ，Naka G ，Takasaki J ，Nokihara H ，Izumi S ，Hojo M ... -  《-》