Faculty Bibliography

INTRODUCTION/BACKGROUND:This randomized, double-blind, phase 3 study evaluated niraparib-plus-pembrolizumab as maintenance therapy for patients with advanced/metastatic non-small cell lung cancer (NSCLC; ZEAL-1L, ClinicalTrials.gov identifier: NCT04475939). METHODS:Adults with advanced/metastatic squamous/nonsquamous NSCLC without known targetable driver alteration were randomly assigned (1:1) to receive niraparib-plus-pembrolizumab or placebo-plus-pembrolizumab as maintenance therapy. Niraparib was given as a daily oral dose of 300 mg, and intravenous pembrolizumab was administered at 200 mg every 3 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in patients with complete or partial response (CR/PR) to front-line chemotherapy combined with pembrolizumab. Hierarchical testing was performed on the primary and key secondary endpoints in a prespecified sequential order; formal testing was stopped if any endpoint failed to reach statistical significance. RESULTS:Patients comprising the intent-to-treat (ITT) population (n=666) were randomly assigned to niraparib-plus-pembrolizumab (n=331) or placebo-plus-pembrolizumab (n=335) therapy. The median PFS for the CR/PR population (n=200 receiving niraparib-plus-pembrolizumab; n=201 receiving placebo-plus-pembrolizumab) was 5.55 months for both treatment arms (hazard ratio [HR], 1.00; 95% CI, 0.79-1.27; 1-sided p=0.502). Key secondary endpoints of PFS by BICR in the ITT population, overall survival in CR/PR and ITT populations, and time to progression in the central nervous system were not formally tested. The most common grade ≥3 treatment-related adverse events for the niraparib-plus-pembrolizumab arm were hematologic (anemia, thrombocytopenia, and neutropenia). CONCLUSION/CONCLUSIONS:The addition of niraparib to pembrolizumab for maintenance therapy in patients with advanced/metastatic NSCLC did not result in improved efficacy; no new safety signals were detected. CLINICAL TRIAL INFORMATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT04475939.

Immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) have improved survival for patients with early-stage NSCLC who are candidates for surgical resection. ICIs enhance antitumor responses and improve a variety of perioperative outcomes when used in the neoadjuvant, adjuvant, or perioperative setting. This review summarizes immunotherapies currently approved for neoadjuvant, adjuvant, and perioperative treatment of resectable NSCLC and the supporting evidence for approval. Gaps in data and future areas of clinical interest of using immunotherapies to maximize survival outcomes are also discussed.

The role of radiotherapy (RT) in stage IV NSCLC has traditionally been palliative; however, with advancements in systemic therapies and insights into the evolutionary processes underpinning advanced disease, the rationale for aggressive primary-tumor control has received renewed interest. This International Association for the Study of Lung Cancer (IASLC) consensus statement evaluates the current evidence for the role, timing, dosing, target volumes, and safety of primary-tumor RT in both actionable genomic alterations (AGA) and non-AGA metastatic NSCLC populations. The IASLC Advanced Radiation Technology subcommittee convened a multidisciplinary, international expert panel including radiation oncologists and medical oncologists from the IASLC Multidisciplinary Clinical Sciences Committee. Randomized studies published from 2010 to 2025 evaluating RT to the primary lung tumor in metastatic NSCLC populations (AGA and non-AGA) were identified through PubMed, and relevant published and presented abstracts were included. Evidence was synthesized and discussed to achieve consensus recommendations. In EGFR-mutant oligometastatic NSCLC, randomized phase III evidence supports early delivery of RT, conveyed as consolidation after induction systemic therapy, as a promising life-prolonging approach. In non-AGA populations, direct randomized evidence isolating the impact of primary irradiation remains limited. Emerging randomized data suggest dose escalation of definitive thoracic RT regimens may improve locoregional control compared with lower-dose approaches. Fractionation should be individualized to the primary tumor location to mitigate cardiopulmonary adverse events. Optimal target volumes remain uncertain, and the benefit of excluding involved thoracic lymph nodes has not yet been formally investigated in large, randomized trials. Safety data indicate toxicity is generally additive when RT is integrated with systemic agents; however, careful monitoring and recording of adverse events are important to ensure the addition of RT does not affect systemic therapy discontinuation rates. Definitive-dose RT to the primary lung tumor in metastatic NSCLC is supported by a growing biologic rationale and emerging trial data, with the strongest evidence in EGFR mutant populations. For patients without AGAs, preliminary findings are encouraging but insufficient for definitive treatment recommendations. The paucity of data necessitates prospective trials that isolate the contribution of primary-tumor RT, confirm its safety, and define the optimal RT sequencing, dose, and target volumes.

INTRODUCTION/UNASSIGNED:+ metastatic NSCLC (mNSCLC) remains unclear. As we consider intensification strategies, it is critical to identify factors that predict high-risk disease. METHODS/UNASSIGNED:+ mNSCLC. Baseline characteristics and the cumulative incidence (CI) of brain and liver metastases were compared (≥2-year survivors versus <2-year; pre-2017 versus post-2017). Multivariable Cox proportional hazard models were used to evaluate the association between factors and overall survival, and multivariable logistic regression models were used for the odds of death within 2 years. RESULTS/UNASSIGNED:= 0.201). CONCLUSIONS/UNASSIGNED:+ mNSCLC, the presence of liver metastases at baseline and on-treatment was associated with worse survival. In the ALK+ population, the cumulative incidence of brain but not liver metastases is improving, highlighting a need for therapies effective at the treatment and prevention of liver metastases.

The optimal treatment sequence in non-small cell lung cancer harboring class I BRAF mutations and atypical BRAF variants remains unclear. To better characterize therapeutic strategy, we retrospectively evaluated a multi-institutional cohort of BRAF-mutant NSCLC patients (n = 97) and an independent clinico-genomic database (n = 342), performed structural modeling, and conducted chemical screens of BRAF-mutant cell lines. Patients with class I BRAF mutation treated with BRAF-MEK inhibitors at any line of therapy had significantly greater median overall survival compared to those who did not receive BRAF-MEK inhibitors (40 vs 10 months, Log-rank p = 0.043). There, however, was no significant survival difference between patients treated with immune checkpoint inhibitors versus those not treated. Tumors with class II or III BRAF variants were significantly more likely to harbor concurrent MAPK pathway alterations relative to class I (Chi-Square p < 10^-4). Cell line studies identified genetic dependency on BRAF in class II cell lines without sensitivity to BRAF inhibitors, and dependency on EGFR in class III cell lines.

BACKGROUND/UNASSIGNED:First-line pembrolizumab plus chemotherapy has demonstrated durable, clinically meaningful survival benefits over 5 years, compared with chemotherapy alone, in pivotal clinical trials for patients with metastatic NSCLC. This retrospective study aimed to evaluate 5-year real-world outcomes with pembrolizumab plus chemotherapy at US oncology practices. METHODS/UNASSIGNED:-wild-type nonsquamous NSCLC) or pembrolizumab plus carboplatin/(nab)-paclitaxel from 1 November 2018 through 30 September 2020 (squamous NSCLC). Overall survival (OS) from first-line initiation, by histology and PD-L1 expression, was estimated using the Kaplan-Meier method. Data cutoff was 30 September 2024. RESULTS/UNASSIGNED:Median study follow-up was 60 months. Median (95% CI) OS was 15.0 months (13.4-16.0) and 12.9 months (10.3-17.1) among 1960 patients with nonsquamous and 433 with squamous NSCLC, respectively. At 5 years, OS rates were 21.6% and 18.2%, respectively, with 5-year OS rates by tumor PD-L1 < 1%/1-49%/≥50% expression of 15.8%/19.8%/32.6% in nonsquamous and 15.2%/14.1%/32.6% in squamous cohorts. CONCLUSIONS/UNASSIGNED:First-line pembrolizumab plus chemotherapy demonstrates long-term effectiveness for nonsquamous and squamous advanced/metastatic NSCLC, with 5-year OS rates in real-world settings that are consistent across PD-L1 expression strata with 5-year outcomes from the pivotal clinical trials.

IMPORTANCE/UNASSIGNED:Effective treatments for advanced or metastatic non-small cell lung cancer (NSCLC) are limited. Understanding clinical treatment patterns is critical for understanding unmet medical needs. OBJECTIVE/UNASSIGNED:To describe clinical treatment patterns and outcomes, including time to treatment discontinuation, progression-free survival, and overall survival, in patients who received platinum-based chemotherapy and anti-programmed cell death 1 protein or programmed cell death ligand 1 (PD-[L]1) regimens. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study used data from 2018 to 2023 from a US nationwide, electronic health record-derived, deidentified database with median duration of follow-up of 7.8 (range, 0-65.0) months. Patients 18 years or older with advanced or metastatic NSCLC in second- and third-line treatment settings were included. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, received platinum-based chemotherapy and anti-PD-(L)1 therapy in 1 (combination) or 2 (sequential) lines, and initiated at least 1 subsequent treatment between January 1, 2018, and June 30, 2023. Exclusion criteria included disease progression within 8 weeks after anti-PD-(L)1 treatment initiation. Follow-up was until death or last available data through June 30, 2023. EXPOSURES/UNASSIGNED:Antineoplastic drugs following platinum-based chemotherapy and anti-PD-(L)1 treatment. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Time to treatment discontinuation, progression-free survival, and overall survival were analyzed overall and by initial treatment. Exploratory subgroup analyses were stratified by patient characteristics and index treatment without adjustment for group differences. RESULTS/UNASSIGNED:In the 1793 patients (974 [54.3%] male) included in the analysis, mean (SD) age at index treatment was 67.4 (9.4) years and median time from advanced diagnosis to index treatment was 10.5 (range, 1.1-103.8) months. The most common index treatments were docetaxel plus ramucirumab (314 [17.5%]), docetaxel monotherapy (158 [8.8%]), and carboplatin plus paclitaxel (136 [7.6%]). Overall, median time from index treatment to treatment discontinuation was 3.71 (95% CI, 3.48-3.94) months; median progression-free survival, 5.29 (95% CI, 5.03-5.52) months; and median overall survival, 11.20 (95% CI, 10.48-11.93) months. In exploratory analyses, these outcomes were numerically shorter in patients who received chemotherapy monotherapy as index treatment vs the overall group; medians were numerically longer in patients who received index treatments of immuno-oncology monotherapy or chemotherapy plus immuno-oncology combination therapy. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this retrospective cohort study of patients with advanced or metastatic NSCLC, results underscored a significant need for novel treatments, including immuno-oncology combinations.

Lung cancer, the leading cause of cancer-related deaths globally, includes non-small cell lung cancer (NSCLC) (85% of cases) and small cell lung cancer (SCLC) (13-15%). While accurate diagnosis and treatment selection are critical, the absence of reliable predictive or prognostic biomarkers remains a significant challenge. This study explored the combined use of radiomics from CT scans and pathomics from H&E slides in three contexts: (1) predicting disease recurrence in early-stage NSCLC, (2) predicting immunotherapy response in advanced-stage NSCLC, and (3) predicting chemotherapy response in SCLC. The integrated radio-pathomic model significantly outperformed individual models. In early-stage NSCLC (N = 194), it achieved an HR of 8.35 (C-index: 0.71, p = 0.0043). In advanced-stage NSCLC (N = 35), the combined model improved predictive performance (AUC: 0.75, p = 0.042). In SCLC (N = 50), the integrated model showed an AUC of 0.78, surpassing both radiomic and pathomic models. These findings highlight the potential of combining radiomics and pathomics for improved lung cancer risk stratification and treatment prediction.

Molecular determinants of KRAS(G12C)inhibitor efficacy in KRAS^G12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRAS^G12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-treatment clearance of KRAS^G12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRAS^G12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.