Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non–small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. Significance: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501

Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations. See related commentary by Rosner and Spira, p. 1055

Utilizing targeted therapy against activating mutations has opened a new era of treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). For patients with epidermal growth factor (EGFR)-mutated cancers, EGFR inhibitors, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib, significantly prolong progression-free survival and overall survival, and are the current standard of care. However, progression after EGFR inhibition invariably occurs, and further study has helped elucidate mechanisms of resistance. Abnormalities in the mesenchymal-epithelial transition (MET) oncogenic pathway have been implicated as common alterations after progression, with MET amplification as one of the most frequent mechanisms. Multiple drugs with inhibitory activity against MET, including TKIs, antibodies, and antibody–drug conjugates, have been developed and studied in advanced NSCLC. Combining MET and EGFR is a promising treatment strategy for patients found to have a MET-driven resistance mechanism. Combination TKI therapy and EGFR-MET bispecific antibodies have shown promising anti-tumor activity in early clinical trials. Future study including ongoing large-scale trials of combination EGFR-MET inhibition will help clarify if targeting this mechanism behind EGFR resistance will have meaningful clinical benefit for patients with advanced EGFR-mutated NSCLC.

The MET pathway can be activated by MET exon 14 skipping mutations, gene amplification, or overexpression. Mutations within this pathway carry a poor prognosis for patients with non-small cell lung cancer (NSCLC). MET exon 14 skipping mutations occur in 3-4% of patients with NSCLC, while MET amplifications are found in 1-6% of patients. The most effective method for detection of MET amplification is fluorescent in situ hybridization (FISH) and of MET exon 14 skipping mutations is RNA-based next generation sequencing (NGS). Immunohistochemistry (IHC) is an alternative method of diagnosis but is not as reliable. Early studies of MET tyrosine kinase inhibitors (TKIs) demonstrated limited clinical benefit. However, newer selective MET TKIs, such as capmatinib and tepotinib, have improved efficacy. Both drugs have an acceptable safety profile with the most common treatment-related adverse event being peripheral edema. One of the most frequent resistance mechanisms to EGFR inhibition with osimertinib is MET amplification. There is interest in combining EGFR inhibition plus MET inhibition in an attempt to target this resistance mechanism. Additional ways of targeting MET alterations are currently under investigation, including the bi-specific antibody amivantamab. Additional research is needed to further understand resistance mechanisms to MET inhibition. There is limited research into the efficacy of immune checkpoint inhibition for MET-altered NSCLC, though some data suggests decreased efficacy compared with wild-type patients and increased toxicity associated with the combination of immunotherapy and MET TKIs. Future directions for research will include combination clinical trials and understanding rational combinations for MET alterations.

Background: First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (EGFR) mutation is a tyrosine kinase inhibitor (TKI). Despite higher response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, a subset of these patients do not receive prolonged benefit from these agents. We investigate if the neutrophil-to-lymphocyte ratio (NLR) and other markers of cachexia and chronic inflammation correlate with worse outcomes in these patients. Methods: This study is a retrospective review of 137 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medicine from August 2011 to July 2019, with outcomes followed through July 2020. The predictive value of NLR and body mass index (BMI) was assessed at the start of therapy, and after 6 and 12 weeks of treatment by univariable and multivariable analyses. Results: On univariable analysis, NLR ≥ 5 or higher NLR on a continuous scale were both associated with significantly worse PFS and overall survival (OS) at treatment initiation, and after 6 or 12 weeks of treatment. On multivariable analysis, NLR ≥ 5 was associated with increased risk of death at 12 weeks of therapy (HR 3.002, 95% CI 1.282–7.029, p = 0.011), as was higher NLR on a continuous scale (HR 1.231, 95% CI 1.063–1.425, p = 0.0054). There was no difference in PFS and OS and amongst BMI categories though number of disease sites and Eastern Cooperative Oncology Group (ECOG) performance status was associated with worse PFS and OS. Conclusions: Patients with NLR ≥ 5 have a worse median PFS and median OS than patients with NLR < 5. NLR may have value as a predictive biomarker and may be useful for selecting patients for therapy intensification in the front-line setting either at diagnosis or after 12 weeks on therapy. NLR needs to be validated prospectively.