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

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide. Advances in screening, diagnosis, and management have transformed clinical practice, particularly with the integration of immunotherapy and target therapies. Methods: A systematic literature search was carried out for the period between October 2016 to September 2024. Phase II and III randomized trials evaluating ICI monotherapy, ICI–chemotherapy combinations, and dual ICI regimens in patients with advanced NSCLC were included. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). Results: PD-1-targeted therapies demonstrated superior OS compared to PD-L1-based regimens, with cemiplimab monotherapyranking highest for OS benefit (posterior probability: 90%), followed by sintilimab plus platinum-based chemotherapy (PBC) and pemetrexed—PBC. PFS atezolizumab plus bevacizumab and PBC, and camrelizumab plus PBC were the most effective regimens. ICI–chemotherapy combinations achieved higher ORRs but were associated with greater toxicity. The most favorable safety profiles were observed with cemiplimab, nivolumab, and avelumab monotherapy, while atezolizumab plus PBC and sugemalimab plus PBC carried the highest toxicity burdens. Conclusions: In PD-L1-unselected advanced NSCLC, PD-1 blockade—particularly cemiplimab monotherapy—and rationally designed ICI–chemotherapy combinations represent the most efficacious treatment strategies. Balancing efficacy with safety remains critical, especially in the absence of predictive biomarkers. These findings support a patient-tailored approach to immunotherapy and highlight the need for further biomarker-driven and real-world investigations to optimize treatment selection.

Background: Lung cancer metastasis results from local invasion, loss of adhesion, migration, and distant implantation. Some small tumors metastasize diffusely other tumors progress to local bulky disease without metastasis. Here we compare these biologically divergent courses of progression and present an analysis of clinical features related to early diffuse metastasis vs. bulky disease. Methods: We retrospectively collected data from pathologically confirmed not-metastatic “bulky” (cT3-T4cN0cM0) or “diffusely metastatic” (cT1-T2cN1-3cM1) patients with lung cancer treated at our center from 2013 to 2023. Clinical data including sex, age, histology, ECOG-PS, tumor stage, smoking status, presence, and site of metastases, LDH, CRP, NLR ratio were collected. Results: A total of 375 patents with “bulky” (n = 95) or diffusely metastatic lung cancer (n = 280) were included in the analysis. In the univariate analysis, the diffusely metastatic population was younger (p = 0.001), had a higher proportion of never smokers (p = 0.02), histologically adenocarcinoma (p < 0.0001), TTF1 positive (p < 0.00001) and elevated baseline LDH in serum (LDH > 250U/l, p < 0.0001) compared to “bulky” population. Patients with diffuse metastatic disease presented worse OS (HR = 2.34, p = 0.0001) and PFS (HR = 6.89, p < 0.0001) compared to patients with bulky disease. Conclusions: Younger age, never smokers, TTF1 positivity, poorly differentiated tumors, adenocarcinoma histology were independently associated with risk of distant metastasis.

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) show robust efficacy and has revolutionized the treatment of NSCLC patients harboring an ALK-rearrangement. Side effects, sometimes even serious such as pneumonitis, can occur with ALK TKIs.

Background: Docetaxel alone or in combination with ramucirumab or nintedanib is recommended as second-line treatment in metastatic non-small cell lung cancer (NSCLC) patients after progression on first-line platinum-base chemotherapy in combination with immune-checkpoint inhibitors (ICI). The purpose of our study was to compare the toxicity profile and efficacy of docetaxel after paclitaxel- or pemetrexed-platinum chemotherapy alone or in combination with ICI. Patients und Methods: Metastatic NSCLC patients treated with docetaxel after pemetrexed or paclitaxel-platinum with chemotherapy with or without ICI were included in our retrospective analysis. Results: We included in our analyses a total of 53 patients (median age 60.3 years (SD 9.35) in the paclitaxel-group, and 62 years (SD 12) in the pemetrexed-group) treated at our Institution with docetaxel following either paclitaxel or pemetrexed chemotherapy. No treatment-related deaths and no new safety signals were observed. Conclusion: Docetaxel alone or in combination with ramucirumab or nintedanib demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on previous paclitaxel-or pemetrexed platinum-based chemotherapy. The results of this analysis can be a helpful reference in conducting further trials of new second-line treatment options.

Baseline Patient Characteristics – Cohort A