8001 Background: The ALCHEMIST clinical trial platform, launched by the National Clinical Trials Network (NCTN) in 2014, screened patients with resected non-small cell lung cancer (NSCLC) for molecular markers and tailored post-operative adjuvant therapy trials. A081105 evaluated whether adjuvant erlotinib improved overall survival (OS) following complete resection in patients with early stage EGFR mutated lung adenocarcinoma. Methods: A081105 was a randomized phase III trial enrolling patients with completely resected stage IB (≥4 cm), II, or IIIA non-squamous NSCLC (per the 7 th TNM staging classification) harboring EGFR exon 19 deletion or L858R mutations. Patients were randomized 1:1 to erlotinib 150 mg daily for up to 2 years or placebo/observation, stratified by stage, prior chemotherapy, EGFR mutation subtype, and ECOG performance status. The primary endpoint was OS in the per-protocol (PP) population with centrally confirmed EGFR mutations, designed to detect a hazard ratio (HR) of 0.67 in favor of erlotinib with a power of 86% and one sided type I error rate of 5%. Secondary endpoints included OS and disease free survival (DFS) in a modified intent-to-treat (mITT) population with local or centrally confirmed EGFR mutations, and safety. A prespecified backstop analysis was conducted after a minimum of 5 years of follow-up on all patients. Results: Trial enrollment was discontinued when 390 of the intended 450 patients had been enrolled due to the proven benefit of adjuvant osimertinib. Among 390 enrolled patients, the arms were balanced for age (median: 67.0 years), sex (70% female), race (70% white), stage (II: 51%, IIIA: 37%), prior chemotherapy (82%), ECOG PS 0 (60%), and exon 19 deletion (57%). Adjuvant erlotinib did not significantly improve OS compared with placebo/observation in the overall PP population (364 patients, 108 events, HR 0.89; 95% CI, 0.59–1.34; 1-sided P = 0.29) or within exon 19 deletion (HR: 0.94) or L858R mutation (HR: 0.82) subgroups. Five-year OS rates were 78.6% versus 77.9%, respectively. Results were consistent in the mITT analysis (379 patients, 113 events, HR 0.86; 95% CI, 0.58–1.28). Erlotinib improved DFS (mITT: 181 events, median: 68 vs 50 months, HR 0.74; 95% CI, 0.55–1.01). Across both arms, 11% of patients started non-protocol treatment (Osimertinib: 9%) prior to disease progression, and 9% withdrew consent for all follow-up prior to recurrence. In the erlotinib arm, 3 deaths on study were reported; grade 3 or higher adverse events were reported on 39% of patients. Median duration of treatment on Erlotinib arm was 16 months; only 37% of patients completed the planned treatment. Conclusions: In resected EGFR -mutant NSCLC, adjuvant erlotinib did not improve overall survival but improved DFS. Additional studies are exploring efficacy in selected subsets of patients using genomics and proteomic analyses. Clinical trial information: NCT02193282 .

TPS8669 Background: Integration of immunotherapy into first line systemic therapy for patients with metastatic NSCLC has led to improvement in survival, but most patients experience disease progression. Blockade of PD-1 and VEGFR2 synergistically inhibits tumor growth by reducing tumor neovascularization and leads to upregulation of proinflammatory cytokines. We hypothesize that continuing second line anti-PD-1 therapy using cemiplimab in combination with docetaxel and ramucirumab may reverse immunotherapy resistance, and lead to improved overall survival (OS) compared to docetaxel and ramucirumab. Methods: Lung-MAP is a master protocol for patients with previously treated advanced NSCLC. S1800E is a phase II/III non-match Lung-MAP substudy, in which patients are randomized 1:1 to receive either standard of care treatment with intravenous docetaxel and ramucirumab (arm A) or investigational treatment with intravenous docetaxel and ramucirumab in combination with cemiplimab (arm B). The primary objective is to compare OS between patients assigned to arm A and arm B who have acquired resistance to platinum-based chemotherapy and immunotherapy for Stage IV or recurrent NSCLC. The total enrollment goal is 378 patients based on a design with 90% power to rule out an HR = 1 at the 1-sided 2.5% level, if the true HR = 0.66. The design includes 3 interim analyses, with a safety run-in for the first 10 patients on arm B. The main inclusion criteria are patients who experienced disease progression 84 days or more following initiation of anti-PD-(L)1 immunotherapy, with complete response, partial response or stable disease as their best response, in addition to progression on or following platinum-based chemotherapy. If a known sensitizing molecular alteration for which an FDA-approved targeted therapy for NSCLC exists (e.g., EGFR, ALK, ROS1, BRAF, RET, NTRK, KRAS, HER2 , and MET sensitizing mutations), patients must have previously received at least one line of targeted therapy. Prior docetaxel is not permitted, and there is a washout of 14 days from palliative radiation (shortened to 7 days for bone radiation) and 28 days from major surgery, with no plans for concurrent systemic therapy while on the clinical trial. Patients must have adequate organ and marrow function and ECOG performance status of 0-1. S1800E was activated on 4/28/2025, with first patient registered on 5/22/2025. As of 1/6/2026, 49 of the planned 378 patients have been enrolled. Clinical trial information: NCT06616584 .

8000 Background: The NCI’s ALCHEMIST program has screened thousands of patients with resected lung adenocarcinoma for mutations in EGFR and ALK. EA5142 studied the efficacy of adjuvant nivolumab after standard of care adjuvant therapy in patients with resected lung adenocarcinoma without sensitizing EGFR and ALK alterations and squamous cell carcinoma. Methods: Patients enrolled in the ALCHEMIST screening trial (A151216) with resected NSCLC tumors at least 4 cm and/or lymph node positive (N1/2) (for lung adenocarcinoma, without sensitizing EGFR and ALK alterations), were centrally tested for tumor cell PD-L1 expression using the DAKO 28-8 clone. After completion of all planned adjuvant therapy (chemotherapy and/or post-operative radiation) patients were randomized 1:1 to adjuvant nivolumab 480 mg IV every 4 weeks for up to 1 year or best supportive care. Patients were stratified by tumor histology, stage (AJCC 7 th edition IB/IIA vs IIB/IIIA), prior adjuvant treatment, and PD-L1 status (<1% vs ≥1%). The primary study endpoints were disease free survival (DFS) in all patients and in patients with high tumor PD-L1 expression (≥50%). Overall survival was powered to be tested hierarchically, if DFS was positive. Results: Between July 2016 and October 2019, 935 patients were randomized across 378 sites. The treatment arms were balanced for age (median 66 years), sex (52% male), smoking status (10% never smoked), histology (29% squamous), stage and PD-L1 expression (29% PD-L1 high). With a median follow-up of 72.6 months, nivolumab did not improve DFS in the intention to treat population (median DFS 71.3 months vs. 68.8 months in observation arm), hazard ratio (HR) 0.97 (95% CI 0.81-1.17, p=0.78) or the PD-L1 ≥50% subset (median DFS 89.8 months vs. 78.5 months in observation arm), HR 0.86 (95% CI 0.59-1.25, p=0.43). In multivariate analysis, adjusting for age, gender, and smoking history, the DFS HR was 0.99 (95% CI 0.82-1.19, p=0.89) in all randomized patients and 0.82 (95% CI 0.56-1.2, p=0.31) in the PD-L1 ≥50% subset. As the primary recurrence endpoint included any lung cancer, including new primaries, a sensitivity analysis was performed excluding new primary lung cancers, DFS HR 0.97 (95% CI 0.80-1.18, p=0.76) in all patients and HR 0.88 (95% CI 0.60-1.30, p=0.52 in the ≥50% subset. The median duration of treatment with adjuvant nivolumab was 9.4 months (range 0-12.7 months). The most common reasons for nivolumab discontinuation were adverse event (29%), patient withdrawal (11%), and disease progression while on treatment (10%). Treatment related grade 3-5 toxicities were reported in 25% of patients: Grade 3: 23%, Grade 4: 2%, Grade 5: <1%. Conclusions: In patients with resected NSCLC (≥4cm or LN+, EGFR/ALK -) adjuvant nivolumab did not improve DFS, irrespective of tumor PD-L1 expression. Clinical trial information: NCT02595944 .

BACKGROUND:Patient-reported outcomes (PROs) for cemiplimab monotherapy versus chemotherapy from the EMPOWER-Lung 1 phase 3 clinical trial (ClinicalTrials.gov identifier NCT03088540) in patients who had advanced non-small cell lung cancer with programmed cell death-ligand 1 expression ≥50% were previously reported. METHODS:This review article characterizes PRO findings for cemiplimab monotherapy versus chemotherapy overall and in prespecified subgroups of patients from the EMPOWER-Lung 1 clinical trial. Patients were randomly assigned 1:1 to receive either cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy, and multiple PROs, including the European Organization for Research and Treatment of Cancer Quality of Life-Core 30 questionnaire, were administered in the EMPOWER-Lung 1 trial. PRO analyses using mixed model for repeated measures analysis to estimate least-squares mean changes in PRO scores from baseline and Cox proportional hazards models for the time to deterioration using a 10-point threshold have been reported and are summarized herein. RESULTS:Generally, the mixed model for repeated measures analysis of global health status/quality of life (GHS/QoL) significantly favored cemiplimab versus chemotherapy in the overall study population and in prespecified subgroup populations. Statistically significant differences in the overall change from baseline in GHS/QoL favoring cemiplimab versus chemotherapy were observed overall and in multiple subgroups, including patients who had brain metastasis (p = .0110), an Eastern Cooperative Oncology Group performance status of 1 (p = .0017), squamous (p = .0247) and nonsquamous (p = .0073) histology, and patients aged 65 years and older (p = .0069). Statistically significant delays in the time to deterioration favoring cemiplimab were observed in GHS/QoL for the subgroup with programmed cell death-ligand 1 expression ≥90% (p = .0152) and the subgroup younger than 65 years (p = .0195). CONCLUSIONS:Collectively, the current data support the GHS/QoL benefit of first-line cemiplimab monotherapy versus chemotherapy overall and in multiple subpopulations of patients with programmed cell death-ligand 1 expression ≥50% advanced non-small cell lung cancer.

BACKGROUND:The management of non-metastatic non-small-cell lung cancer (NSCLC) has become increasingly complex with the integration of multimodality strategies and biomarker-driven approaches. Several clinically relevant areas remain insufficiently defined by current evidence and international guidelines. We conducted an international multidisciplinary consensus to address major areas of uncertainty in real-world practice. METHODS:A modified Delphi process was conducted during a 3-day in-person meeting in Barcelona, Spain (3-5 September 2025). Eighty-nine thoracic oncology experts independently rated predefined clinical statements developed by working groups and refined by a steering committee. Agreement was assessed using a 9-point Likert scale. Consensus was predefined as ≥75% of ratings in the 7-9 range; rejection as ≥75% in the 1-3 range. RESULTS:Ninety-six statements were evaluated. Consensus was achieved for 62 statements (64%), 31 (32%) remained without consensus, and 3 (3%) were rejected. Consensus supported routine FDG PET-CT for staging, histologic confirmation of suspicious mediastinal nodes, reflex PD-L1 testing and DNA-based next-generation sequencing at diagnosis, standardized post-neoadjuvant pathologic assessment, and sublobar resection with systematic nodal evaluation for selected peripheral node-negative tumors ≤2 cm. Consolidation durvalumab after definitive chemoradiotherapy was supported irrespective of PD-L1 expression in unresectable stage II-III disease. Persistent areas of controversy included brain MRI in stage I disease, mediastinal restaging after induction therapy, routine RNA-based testing, and the use of circulating tumor DNA/minimal residual disease to guide perioperative decisions. CONCLUSIONS:This international consensus provides structured expert guidance in areas of uncertainty in non-metastatic NSCLC and highlights priorities for future prospective research.

Background/Objectives: Research on the association between change from baseline in patient-reported outcomes (PROs) and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) exists. This study evaluated the association between post-baseline PROs and OS in patients with advanced NSCLC who received first-line cemiplimab-based therapy. Methods: We evaluated PRO data from two phase III studies (EMPOWER-Lung 1 [NCT03088540] and EMPOWER-Lung 3 [NCT03409614]) using a Cox proportional hazards model. Twelve pre-specified PRO scales from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Quality of Life Questionnaire Lung Cancer 13 module were evaluated. Landmark analyses were conducted at 3, 6, 9, and 12 months. Time-dependent analyses using change from baseline PROs as a time-dependent covariate were conducted to evaluate the association of post-baseline PRO improvement with OS. Results: At the 3-month landmark, we observed a 56% reduction in the risk of death (HR = 0.44; 95% CI: 0.32-0.62; nominal p < 0.0001) among stable/improved vs. worsened/unobserved PROs for global health status (GHS)/quality of life (QoL). Results at the 6-, 9-, and 12-month landmarks of GHS/QoL were consistent with those at the 3-month landmark. Time-dependent analyses showed that every 10-point improvement in GHS/QoL was associated with a 31% reduction in the risk of death (HR = 0.69; 95% CI: 0.64-0.75; nominal p < 0.0001). Conclusions: In patients with advanced NSCLC who received first-line cemiplimab-based therapy, improvements in post-baseline PROs are associated with improved OS. These results may inform endpoint selection and interpretation of future clinical trials.

8572 Background: Immune checkpoint inhibitors (ICIs) have advanced the treatment paradigm for non-small cell lung cancer (NSCLC), but ICIs are associated with risk of immune-related adverse events (irAEs). There is an unmet need to better understand how the severity of irAE impacts the clinical outcome of NSCLC treated with ICIs. We hypothesized that participants (pts) with lower grade irAEs would have better outcomes than those with higher grade irAEs and those without irAEs. Methods: We evaluated outcomes in Lung-MAP pts with advanced NSCLC treated with ICIs in the 2L setting (S1400A [durvalumab vs docetaxel], S1400I [nivolumab +/- ipilimumab], S1400F [durvalumab + tremelimumab], and S1800A [pembrolizumab + ramucirumab vs standard-of-care]), using 6-, 12-, and 24-week landmark analyses of the relationship between irAE severity (Grade(G) 1 or 2 vs G3 or 4 and vs no irAE) and overall survival (OS) from the landmark timepoint. OS was compared between groups using Cox Proportional hazards model with separate analyses for ICI-naïve (S1400A and S1400I) and ICI-exposed (S1400F and S1800A). Results: Analyses included 315 ICI-naïve and 127 ICI-refractory pts. In the ICI- naïve cohort, no irAEs and G 3-4 irAEs were associated with inferior OS compared with G1-2 irAEs by 12 wks of treatment (no irAEs: HR 1.68, CI 1.28 – 2.22, p < 0.0005 G3-4: HR 2.28, CI 1.47 – 3.53; p < 0.0005). This difference in OS between the irAE groups was consistent at the 6 wk (p = 0.006) and 24 wk (p = 0.03) landmark timepoints. See table for outcomes in the ICI naïve cohort. In the ICI-exposed cohort, there was no difference in OS between the irAE groups at any landmark timepoint (6 weeks: p = 0.39; 24 weeks: p = 0.98). Conclusions: In the ICI-naïve cohort, G1-2 irAEs in were associated with better OS compared to no irAEs and G3-4 irAEs for all landmark times. This association was not observed in the ICI-exposed cohort. Additional analyses will incorporate molecular and immune features evaluating risk and severity of irAEs. Outcomes for ICI naïve cohort. Landmark Time irAE Group N mOS (95% CI) 6 weeks No irAE 160 9.0 (7.9-10.9) G 1-2 124 14.6 (10.1-19.0) G 3-4 20 5.9 (3.5-10.8) 12 weeks No irAE 124 8.2 (6.5-9.8) G 1-2 130 15.4 (11.5-9.8) G 3-4 29 5.3 (2.9 - 8.0) 24 weeks No irAE 77 7.0 (5.8-9.8) G 1-2 121 14.9 (10.9-18.5) G 3-4 34 5.9 (3.1-13.9)

TPS8680 Background: MET amplification is a known oncogenic driver in non-small cell lung cancer (NSCLC), estimated to occur in approximately 3-4% of non-squamous (nsq) and squamous (sq) cases. While targeted therapies such as tyrosine kinase inhibitors (TKIs) have demonstrated activity in this population, with objective response rates (ORR) approximating 30%, there is a need for novel therapeutic approaches, particularly for patients who have progressed on standard systemic therapies. Amivantamab hyaluronidase is a fully human bispecific antibody targeting EGFR and MET co-formulated with recombinant human hyaluronidase (rHuPH20) for subcutaneous administration. The mechanism of action involves the inhibition of EGFR and MET signaling, receptor degradation, and the induction of antibody-dependent cellular cytotoxicity. S1900J is evaluating the efficacy of this subcutaneous formulation in specific histological cohorts. Methods: S1900J is a 2-stage, single arm phase II biomarker-driven Lung-MAP sub-study. The study includes 2 cohorts of Stage IV or recurrent NSCLC, based on histology (non-squamous and squamous NSCLC). Biomarker eligibility requires documentation of MET amplification as primary driver via tissue or ctDNA NGS. Participants must have received at least one prior line of systemic therapy; notably, patients who have received prior MET TKI therapy (e.g., crizotinib, capmatinib) or harboring other actionable alterations are excluded. Participants receive amivantamab hyaluronidase via subcutaneous injection weekly during Cycle 1 (Days 1, 8, 15, 22) and every 2 weeks thereafter (Days 1, 15). Dosing is weight-based: 1,600 mg amivantamab/20,000 units hyaluronidase for participants < 80 kg, and 2,240 mg amivantamab/28,000 units hyaluronidase for patients ≥80 kg. The primary endpoint is response. with a goal of 40 evaluable participants per cohort. The study design has 90% power to rule out a 15% ORR at the 1-sided 5% level, if the true ORR is 35%. Secondary objectives include progression-free survival, duration of response, and response rates in the subset with MET amplification by FoundationOne CDx assays. Correlative studies of interest include the evaluation of concordance between tissue-based and liquid biopsy (ctDNA) next-generation sequencing for the detection of MET amplification. S1900J opened to accrual on 9/27/2024 and is actively enrolling patients. Clinical trial information: NCT06116682 .

Histologic transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of resistance in anaplastic lymphoma kinase (ALK)-rearranged disease. Diagnosis is traditionally dependent on tissue biopsy, which may be limited by lesion accessibility and low disease burden. We report a case of ALK-rearranged lung adenocarcinoma that underwent small cell transformation, in which methylation-based circulating cell-free DNA (cfDNA) analysis detected a small cell lung cancer signature 5 months prior to tissue confirmation. Serial liquid biopsies demonstrated dynamic changes in tumor fraction and histologic composition that correlated with response to chemoradiation and continuation of ALK-directed therapy. This case highlights the potential utility of methylation-based liquid biopsy for early detection and longitudinal monitoring of histologic transformation in oncogene-driven NSCLC.

MEK inhibition (MEKi) combined with programmed death ligand 1 inhibition (immune checkpoint inhibitor [ICI]) modulates the tumor immune microenvironment. This phase 1 study evaluated sequencing schemes of MEKi and ICI with trametinib and pembrolizumab in NSCLC. In this 3+3 dose escalation study, patients with advanced NSCLC were treated with lead-in trametinib (arm A) or lead-in pembrolizumab (arm B) for cycle 1, followed by a 1.5 to 2 mg oral daily dose of trametinib (d 1-10) with pembrolizumab 200 mg intravenously every 21 days. Eligible patients with progressive disease on or after platinum-based chemotherapy were enrolled. Prior ICI was allowed. Tumor tissue was analyzed with quantitative immunofluorescence. High-parameter flow cytometry was performed on blood. Adverse events were graded using the Common Terminology Criteria for Adverse Events version 4 and efficacy was evaluated by Response Evaluation Criteria in Solid Tumors version 1.1. Fifteen patients enrolled (nine arm A and six arm B) with 13 (86%) harboring KRAS mutations and 10 (66%) receiving prior ICI. Five patients (33%) experienced at least one grade greater than or equal to 3 treatment-related adverse event including one dose-limiting toxicity (grade 3 esophagitis). Two patients had a partial response (ORR = 14%). Trametinib lead-in was associated with decreased T-regulatory cells and myeloid-derived suppressor cells (p = 0.002 and p = 0.05, respectively). The activity of trametinib and pembrolizumab is modest in NSCLC with increased toxicity compared with programmed death ligand 1 blockade alone. The recommended phase 2 dose for the combination is 2 mg of oral trametinib (d 1-10) and 200 mg of intravenous pembrolizumab every 21 days, with lead-in trametinib. Adverse events were comparable with other MEKi and ICI combination studies. Though limited clinical activity was observed, lead-in MEKi may induce favorable immune cell alterations.

e22585 Background: Epidermal Growth Factor Receptor (EGFR) mutation analysis in non-small cell lung cancer (NSCLC) is crucial for navigating treatment decision-making and improving survival outcomes. EGFR mutations are more prevalent among Asian Americans at 38.8% as compared to 17.4% in whites (REF). Hawaii has the highest proportion of Asian Americans and Native Hawaiian/Pacific Islanders (NH/PI) in the USA. Among this diverse population of Asian Americans, Native Hawaiians, and Pacific Islanders, the . Here, we present an analysis of EGFR-mutated NSCLC across diverse patient populations in Hawaii. Methods: This study included patients aged 18 years and older diagnosed with NSCLC at Hawaii Pacific Health between January 1, 2021, and December 31, 2023, and at Queen’s Medical Center between July 1, 2016, and December 31, 2022, in Hawaii (n = 281). Clinical data, including sex, race and ethnicity (whites, Filipino, Japanese American, other Asian American, NH/PI, and Other ethnicities), smoking status, and histological subtypes were also collected. Fisher’s exact test was used to analyze associations between EGFR mutations and patient characteristics. Results: Among 1028 NSCLC patients screened, 281 patients were appropriate for EGFR testing based on stage, histology, and clinical characteristics, of which 126 patients (44.8%) were positive. Female, Never-smokers, and adenocarcinoma histology were significantly associated with a higher prevalence of EGFR mutations (54.2%, 68.5%, and 54.3%, respectively; p < 0.05). As compared to whites, EGFR mutations were significantly more prevalent among Filipinos (OR 3.45; 95% CI: 1.52–8.10; p = 0.01), Japanese Americans (OR 2.42; 95% CI: 1.02–5.90; p = 0.03), and other Asian (OR 2.70; 95% CI: 1.13–6.68; p = 0.01). The prevalence of EGFR mutations among NH/PI was 42.3 %. No significant differences in EGFR mutation prevalence were observed among NH/PI patients with unknown/other races as compared to whites. Conclusions: To our knowledge, this is the first study to investigate the prevalence of EGFR mutations among various race and ethnic groups in Hawaii. Novel findings include: Filipino NSCLC cases having the highest prevalence of EGFR mutations and defining the prevalence of EGFR mutations in the NH/PI population (42.3%). Additional studies will explore the association between EGFR-mutant NSCLC and survival outcomes in this unique Hawaiian population.

Background There is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).Methods Patients with advanced-stage cancers from 24 cancer types treated with single-agent anti-PD(L)1 therapy in standard-of-care settings were included. Deidentified data from electronic health records from approximately 280 cancer treatment facilities were captured into a clinico-genomic database. This study used the TMB algorithm from the FDA-approved test supporting solid tumor CDx and composite mortality variable validated against the national death index: real-world overall survival (rwOS). Following a prespecified analysis plan, rwOS by TMB level was assessed using Cox PH models adjusted for Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, and socioeconomic assessment.Results 8440 patients met inclusion criteria. Adjusting for aforementioned factors, increasing TMB was significantly associated with rwOS across tumor types; HRs (95% CIs) relative to TMB<5: TMB 5 to <10: 0.95 (0.89 to 1.02), TMB 10 to <20: 0.79 (0.73 to 0.85), TMB≥20: 0.52 (0.47 to 0.58). For individual cancer types with prespecified statistical power, adjusted rwOS comparing TMB≥10 vs TMB<10 significantly favored TMB≥10 in 9 of 10 cancer types. In microsatellite stable subcohorts (except colorectal cancer), TMB≥10 remained associated with enriched ICI benefit. Exploratory assessments of patients receiving ICI+chemotherapy (n=4369) observed more favorable rwOS only in TMB≥20.Conclusions Across >8000 patients treated with single-agent ICI, and within individual cancer types with sufficient power, elevated TMB based on the FDA-approved CDx was associated with more favorable rwOS compared with similar patients with lower TMB levels. This biomarker deserves further clinical investigation to potentially guide the use of immunotherapy in expanded clinical contexts.

Background Immune checkpoint inhibitors (ICIs) have shown substantial benefit for patients with advanced non-small cell lung cancer (NSCLC). However, resistance to ICIs remains a major clinical challenge. Here, we perform a comprehensive bioinformatic analysis of plasma proteomic profiles to explore the underlying biology of treatment resistance in NSCLC.Methods The analysis was performed on 388 “resistance-associated proteins” (RAPs) that were previously described as pretreatment plasma proteomic predictors within the PROphet computational model designed to predict ICI clinical benefit in NSCLC. Putative tissue origins of the RAPs were explored using publicly available datasets. Enrichment analyses were performed to investigate RAP-related biological processes. Plasma proteomic data from 50 healthy subjects and 272 patients with NSCLC were compared, where patients were classified as displaying clinical benefit (CB; n=76) or no CB (NCB; n=196). Therapeutic agents targeting RAPs were identified in drug and clinical trial databases.Results The RAP set was significantly enriched with proteins associated with lung cancer, liver tissue, cell proliferation, extracellular matrix, invasion, and metastasis. Comparison of RAP expression in healthy subjects and patients with NSCLC revealed five distinct RAP subsets that provide mechanistic insights. The RAP subset displaying a pattern of high expression in the healthy population relative to the NSCLC population included multiple proteins associated with antitumor activities, while the subset displaying a pattern of highest expression in the NCB population included proteins associated with various hallmarks of treatment resistance. Analysis of patient-specific RAP profiles revealed inter-patient diversity of potential resistance mechanisms, suggesting that RAPs may aid in developing personalized therapeutic strategies. Furthermore, examination of drug and clinical trial databases revealed that 17.5% of the RAPs are drug targets, highlighting the RAP set as a valuable resource for drug development.Conclusions The study provides insight into the underlying biology of ICI resistance in NSCLC and highlights the potential clinical value of RAP profiles for developing personalized therapies.

Supplementary Table 3. Patient Characteristics for those with and without assay results

Supplementary Table 2. Representativeness of Study Participants

Supplementary Figure 1. Progression-Free Survival and Overall Survival in patients with cancers with TP53 co-mutations, and STK11 co-mutations.