BACKGROUND:Although ALK-positive non-small cell lung cancer (NSCLC) derives limited benefit from immune checkpoint inhibitors, PD-L1 expression is frequently elevated at diagnosis. The clinical relevance of PD-L1 expression for the efficacy and durability of response to ALK tyrosine kinase inhibitors (TKIs) remains unclear. We investigated the association between tumor PD-L1 expression and outcomes with first-line ALK TKIs and used complementary preclinical models to explore potential biological mechanisms. METHODS:Clinical, pathologic, molecular, and treatment outcomes were evaluated among patients with ALK-rearranged NSCLC treated at the University of Colorado. PD-L1 expression was assessed by tumor proportion score (TPS). Murine EML4-ALK lung cancer cell lines were engineered to overexpress PD-L1, and effects on ALK TKI response were evaluated in vitro and in immune-competent mouse models. RESULTS:Among 130 TKI-naïve patients treated with first-line ALK TKIs, 57 (44%) had high PD-L1 expression (TPS ≥ 50%). After multivariable adjustment, high PD-L1 expression was associated with significantly shorter progression-free survival (PFS) compared with low PD-L1 expression (11 vs. 21 months; HR 2.29, 95% CI, 1.51-3.49; P ≤ .001), with no difference in overall survival (91 vs. 107 months; HR 1.16, 95% CI, 0.62-2.17). Objective response rates were similar between PD-L1-high and -low tumors (81.8% vs. 83.3%; Pearson r = -0.20, 95% CI, -0.40-0.07). In preclinical EML4-ALK models, tumor cell PD-L1 overexpression did not alter alectinib sensitivity, depth, or durability of response in vitro or in vivo CONCLUSIONS: High PD-L1 expression is associated with shorter PFS to first-line ALK TKIs without affecting the initial radiographic response. Preclinical findings suggest that PD-L1-intrinsic tumor cell signaling does not directly impair ALK TKI efficacy, implicating tumor microenvironment-mediated mechanisms in reduced response durability.

INTRODUCTION:Machine learning algorithms may improve the efficiency and accuracy of pathologic response (PR) assessment in surgically resected lung cancers after neoadjuvant therapy. The aim of this study was to develop digital models for quantifying tumor bed (TB) area and residual viable tumor (VT) and to compare these results to previously published assessments of PR by pathologists from the International Association for the Study of Lung Cancer reproducibility study. METHODS:Manual pathologist annotations (N = 15,564) of regions including TB and VT were used to train a convolutional neural network model (digital artificial intelligence [AI]) and a convex hull algorithm (CHA). PR was determined by the percentage of VT in the TB area. The pathologists determined the average PR (APR) across slides (unweighted), which was compared with the weighted average for digital AI and CHA. The concordance between pathologist APR, digital AI, and CHA was calculated and correlated with outcomes. RESULTS:There was a strong correlation between approaches: APR versus digital AI (0.97), APR versus CHA (0.97), and digital AI versus CHA (0.99). Digital AI and CHA demonstrated 100% agreement for MPR. The κ concordance for MPR was 0.82 (95% confidence interval [CI]: 0.69, 0.96) for APR versus digital AI/CHA with six discordant cases. The concordance was higher for squamous cell carcinoma (κ = 0.92, 95% CI: 0.76, 1.0) than for nonsquamous carcinoma (κ = 0.77, 95% CI: 0.59, 0.96). APR and digital AI demonstrated similar relapse-free survival and overall survival. CONCLUSION:The overall high level of agreement supports the utility of machine learning approaches for evaluation of PR in patients with NSCLC.

OBJECTIVES:To evaluate the impact of common pathologic features, single or in combination, in patients with early-stage lung adenocarcinoma, according to lung resection extent. METHODS:A retrospective, multicentric cohort study including patients with cT1a-bN0M0 lung adenocarcinoma and with at least visceral pleural invasion under the surface (PL1) or up to surface (PL2), lymphovascular invasion, spread through air spaces, necrosis, or neural invasion who underwent lobectomy or segmentectomy with systematic lymph nodal dissection from 2015 to 2021 in 10 European centers. Overall survival (OS), disease-free survival, and lung cancer-specific death between both groups were assessed before and after stabilized inverse probability of treatment-weighting matching. Risk factors for oncologic outcomes were analyzed using parsimonious model Cox proportional hazard regression in both entire and multiple-feature datasets. Kaplan-Meier and cumulative incidence function was used to assess outcome. Log-rank and Gray tests were used to compare the groups. Linearized risk assessed recurrences. RESULTS:Of 1703 patients with cT1a-bN0M0 lung adenocarcinoma, 530 had at least 1 poor pathologic feature and 130 had multiple features. For the 530 patients, 5-year OS: lobectomy was 83.0% and segmentectomy was 89.4%, P = .2; 5-year disease-free survivall obectomy was 78.1% segmentectomy was 83.8%, P = .06; and 5-year lung cancer-specific death lobectomy was 8.9% and segmentectomy was 7.2%, P = .6, which were similar. It was the same in the matched cohort. In multivariable analysis, no poor pathologic feature impacted outcome more than others. Multiple poor features were not associated with any clinical, pathologic trait, but they impacted OS (hazard ratio, 3.24; P = .002). Locoregional recurrence (linearized risk: lobectomy 0.083, segmentectomy 0.086) was similar in the matched entire dataset. CONCLUSIONS:Segmentectomy with systematic lymph nodal dissection can be indicated in patients with stage IA1-2 lung adenocarcinoma suspected to have poor pathologic features. Multiple factors were not predictable but impacted OS.

Abstract Introduction: Alterations of the HGF-cMET axis, often through MET gene amplification, can act as resistance mechanism to tyrosine kinase inhibitors (TKIs) in patients with ALK and RET rearranged non-small cell lung cancer (NSCLC). The efficacy of targeting the cMET pathway through use of MET tyrosine kinase inhibitors continues to evolve. An unresolved question is whether the HGF-cMET pathway is activated early in cancer cells after ALK and RET TKI exposure. Here, we evaluate novel pre-clinical models to better characterize the onset of MET pathway-mediated resistance using murine cell lines and orthotopic murine models. Methods: Murine Eml4-Alk (EA1 and EA3) and Trim24-Ret (TR.1) cell lines were cultured with increasing doses of alectinib (EA1 and EA3) or pralestinib or selpercatinib (TR.1) until resistance was acquired. A cell line was established from an orthotopic TR.1 tumor that progressed on selpercatinib (TR.1-1092). Passage control cells and the TKI-resistant cultures were submitted to clonogenic growth assays in targeting TKI or crizotinib (MET TKI). Control and TKI-resistant cell lines were submitted to HGF ELISA, MET immunoblotting and RNAseq. Orthotopic TR.1 tumors were established in C57BL/6 mice and after ~2 weeks, daily treatment with selpercatinib was performed for 21 days with weekly mCT to monitor tumor size. At 21 days when the tumors were beginning to progress, half the mice were treated with selpercatinib and crizotinib (a MET TKI) while the other half continued on selpercatinib alone. Results: HGF levels (pg/μg) were significantly higher in alectinib-resistant EA1 cells vs. EA3 cells and was associated with retained sensitivity to crizotinib in alectinib-resistant EA1, but not EA3 cells. MET mRNA (but not gene copy number) and HGF mRNA/protein levels in pralsetinib and selpercatinib resistant TR.1 lines were significantly higher than controls and accompanied by acquired sensitivity to crizotinib. In C57BL/6 mice bearing orthotopic TR.1 tumors, the progression on selpercatinib occurring after 2-3 weeks of treatment was reversed in a durable manner by co-treatment with crizotinib. Conclusions: The HGF-cMET axis is activated early in response to ALK and RET TKI exposure through transcriptional mechanisms without evidence of MET gene amplification. These findings unveil a potential therapeutic window to disrupt the MET bypass pathway in ALK and RET rearranged NSCLC prior to overt clinical progression. Citation Format: Tejas Patil, Trista Hinz, Sharon Pine, Hatim Saabawy, Paul Bunn, Erin L. Schenk, Ross Camidge, Lynn Heasley. Early activation of HGF-cMET serves as a bypass pathway to ALK and RET tyrosine kinase inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5867.

PURPOSE The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m2 every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m2 daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). RESULTS Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade ≥3 related treatment-emergent adverse events (TEAEs). The most common grade ≥3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan. CONCLUSION Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged.

Introduction:Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods:Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results:Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions:The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

8068 Background: Neoadjuvant chemotherapy and immunotherapy have become standard for patients with resectable non-small cell lung cancer with no targetable oncogenic driver. For patients with tumors driven by most actionable oncogenes, little benefit has been seen. The LEADER Screening Trial designed by the LCMC and supported by the Thoracic Surgical Oncology Group aims to determine the proportion of clinical Stage IA2-III lung adenocarcinomas and adenosquamous carcinomas with one of 12 actionable oncogenes, detected through tumor and blood genomics. This abstract presents data from the first 110 tumors, all tested at Foundation Medicine. Methods: This analysis includes eligible patients on the LEADER trial with recectable NSCLC (not purely squamous) tested centrally with FoundationOneCDx (F1CDx, tissue) and/or FoundationOneLiquidCDx (F1LCDx, liquid biopsy) prior to 15Dec2023. An actionable oncogene is defined as: EGFR sensitizing or exon 20; KRAS G12C; BRAFV600E; HER2 mutation or amplification, MET ex14 skipping mutation or amplification; or RET, ROS1, ALK,or NTRK1/2/3 fusion. Detectable ct DNA was defined as tumor fraction > 0. Results: Of the 110 patients, 95% (105/110) had a successful tissue and/or liquid profiling. Of samples received, 91% (64/70) yielded successful tissue profiling, and 86% (91/ 106) successful blood profiling. All unsuccessful tests were due to inadequate DNA extraction. Some ctDNA was present in 37% (34/91) of blood samples; 62% (56/91) had no detectable. We found an actionable oncogenic driver in 35% (38/110, 95% confidence interval 26-44%) of patients tested. If any ctDNA was detected in blood, there was a 100% agreement with tumor tissue whether a driver was present or absent. In blood samples without paired tumor, an actionable alteration was found in 19% of cases (8/42). Identified driver alterations included: 12 EGFR sensitizing, 12 KRAS G12C, 4 EGFRexon 20 insertions, 2 BRAFV600E, 2 RET fusions, 2 HER2 mutations, 1 ALK fusion, 1 HER2 amplification, 1 MET ex14 skipping, and 1 ROS1 fusion. Alterations detected on liquid biopsy included EGFRexon 20 insertion, EGFR sensitizing mutations, KRAS G12C, RETfusion, and HER2 mutation. Conclusions: In this national study using both tissue and blood NGS testing, actionable oncogenic drivers were found in 35% of patients with clinical stages IA2-III lung adenocarcinoma at diagnosis. Blood testing identified an actionable driver 19% of the time when tumor testing was not done. Comprehensive genomics testing on patients with early-stage lung cancer should be standard. It identifies relevant oncogenic drivers and provides important ‘negative selection’ to identify the patients appropriate for neoadjuvant chemoimmunotherapy. Accrual to the LEADER trial continues. Clinical trial information: NCT04712877 .

INTRODUCTION:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be spread by individuals unaware they are infected. Such dissemination has heightened ramifications in cancer patients, who may need to visit healthcare facilities frequently, be exposed to immune-compromising therapies, and face greater morbidity from coronavirus disease 2019 (COVID-19). We determined characteristics of (1) asymptomatic, clinically diagnosed, and (2) serologically documented but clinically undiagnosed SARS-CoV-2 infection among individuals with lung cancer. PATIENTS AND METHODS:In a multicenter registry, individuals with lung cancer (regardless of prior SARS-CoV-2 vaccination or documented infection) underwent collection of clinical data and serial blood samples, which were tested for antinucleocapsid protein antibody (anti-N Ab) or IgG (N) levels. We used multivariable logistic regression models to investigate clinical characteristics associated with the presence or absence of symptoms and the presence or absence of a clinical diagnosis among patients with their first SARS-CoV-2 infection. RESULTS:Among patients with serologic evidence or clinically documented SARS-CoV-2 infection, 80/142 (56%) had no reported symptoms at their first infection, and 61/149 (40%) were never diagnosed. Asymptomatic infection was more common among older individuals and earlier-stage lung cancer. In multivariable analysis, non-white individuals with SARS-CoV-2 serologic positivity were 70% less likely ever to be clinically diagnosed (P = .002). CONCLUSIONS:In a multicenter lung cancer population, a substantial proportion of SARS-CoV-2 infections had no associated symptoms or were never clinically diagnosed. Because such cases appear to occur more frequently in populations that may face greater COVID-19-associated morbidity, measures to limit disease spread and severity remain critical.

INTRODUCTION:For patients with EGFR mutant NSCLC who progress on osimertinib, the clinical benefit of continuing osimertinib with next line platinum pemetrexed chemotherapy remains unknown. METHODS:In this international, multi-center, retrospective cohort study, a total of 159 patients with EGFR mutant NSCLC who progressed on osimertinib and received platinum-pemetrexed therapy on progression from 2013 to 2023 were included. The data cutoff was December 31, 2023. Data analysis was conducted from January 2024 to June 2024. The primary endpoints were progression free survival (PFS) and overall survival (OS), analyzed using Kaplan-Meier methods. Multivariable Cox regression adjusting for patient-specific and cancer-specific factors was performed. RESULTS:421 patients with EGFR mutant NSCLC with progression on osimertinib were identified, of which159 patients who met pre-specified inclusion criteria were divided into two groups: Cohort 1 (osimertinib + platinum-pemetrexed) included 50 patients (median [IQR] age, 59 [30 - 83] years; 36 [72.0 %] female; 11 [22.4 %] Asian) and Cohort 2 (platinum-pemetrexed alone) included 109 patients (median [IQR] age, 54 [25 - 80] years; 62 [56.9 %] female; 74 [64.9 %] Asian). Most patients were never smokers (Cohort 1, 37 [74.0 %]; Cohort 2, 66 [60.6 %]). One third of patients had baseline brain metastases (Cohort 1, 19 [38.0 %]; Cohort 2, 36 [38.3 %]). Both cohorts had a median of two prior lines of anti-cancer therapy. The addition of bevacizumab or immune checkpoint inhibitors (ICI) to next-line platinum-pemetrexed chemotherapy was more common in Cohort 2 (bevacizumab use, 30.3 % vs 8.0 %, p = 0.002; ICI use, 33.0 % vs 2.0 %, p = 0.001). With a median duration of follow up of 30 months, there was a significant PFS benefit to continuing osimertinib with next line platinum pemetrexed chemotherapy (9.0 vs 4.5 months; HR 0.49, 95 % CI 0.32 - 0.74, p = 0.0032), also seen in subset analyses of patients who received first line osimertinib (n = 55, 11.0 vs 6.2 months; HR 0.41, 95 % CI 0.25 - 0.73, p = 0.002). Among patients with EGFR mutant NSCLC without brain metastases after progression on osimertinib, we found that continuing osimertinib with next line platinum pemetrexed significantly reduced the median time to CNS progression (n = 38; 7.0 vs 4.1 months; HR 0.47, 95 % CI 0.48 - 0.98, p = 0.01). After adjusted analysis, there was no significant OS difference between Cohorts 1 and 2 (19 months vs 13 months; HR 0.92, 95 % CI 0.60 - 1.39, p = 0.68). CONCLUSIONS AND RELEVANCE:For patients with EGFR mutant NSCLC who progress on osimertinib, there is a significant PFS, but not OS, benefit to continuing osimertinib with next line platinum pemetrexed chemotherapy. The continuation of osimertinib with next line platinum pemetrexed chemotherapy appears to reduce the risk of CNS progression.

8626 Background: Patients with ALK rearrangements are highly responsive to ALK tyrosine kinase inhibitors (TKIs). Negative prognostic markers to ALK TKIs include TP53 alterations and ALK Variants 3a/b. The prognostic role that PD-L1 expression plays in first line ALK TKI outcomes is less clear. Methods: Retrospective review of patients with metastatic ALK-rearranged NSCLC seen between 2015 - 2022 at the University of Colorado who received first line ALK TKIs was performed. PD-L1 expression was denoted as high (≥50%) or low (< 1% or 1-49%) based on pre-treatment biopsies. Clinicopathologic features, treatment outcomes, and genomic data were collected. Survival outcomes were assessed using Kaplan Meier methods. Multivariate modeling adjusted for brain metastases, TP53 mutations, ALK variant status, and ALK TKI. PD-L1 was overexpressed in EML4-ALK murine cell lines with lentiviruses. In vitro and in vivo response to ALK TKIs were compared to non-infected cell lines. Neutrophils and lymphocytes were quantified on pre-treatment H&E slides. Results: Baseline characteristics of 130 patients are shown. Median PFS was significantly (p < 0.001) longer in the PD-L1 low cohort than the PD-L1 high cohort (21 vs 11 mos, HR 0.44, 95% CI 0.29 – 0.66). There was no difference in OS between the PD-L1 low and PD-L1 high cohort (p = 0.4, 107 vs 91 mos, HR 0.86, 95% CI 0.46 – 1.61). In an alectinib sub-group analysis (n = 89), PD-L1 high expressers had a higher rate of CNS progression (93.0 vs 73.9%, p = 0.022). Forced overexpression of PD-L1 in murine EML4-ALK cell lines exerted no difference to in vitroor in vivo response to alectinib. Pre-treatment biopsies from the PD-L1 high cohort (n = 19) revealed significantly more neutrophils (p = 0.021), but not lymphocytes (p = 0.904). Conclusions: High PD-L1 expression (≥50%) is associated with worse PFS and higher intracranial progression rate among those receiving ALK TKIs. Induced PD-L1 expression in ALK cell lines did not alter in vitro or in vivo ALK TKI sensitivity. Higher neutrophil counts track with high PD-L1 expression (≥50%), suggesting that differences within the immune tumor microenvironment may be relevant. [Table: see text]

Lung cancer, the leading cause of cancer-related deaths globally, remains a pressing health issue despite significant medical advances. The New York Lung Cancer Foundation brought together experts from academia, the pharmaceutical and biotech industries as well as organizational leaders and patient advocates, to thoroughly examine the current state of lung cancer diagnosis, treatment, and research. The goal was to identify areas where our understanding is incomplete and to develop collaborative public health and scientific strategies to generate better patient outcomes, as highlighted in our “Calls to Action.” The consortium prioritized 8 different calls to action. These include (1) develop strategies to cure more patients with early-stage lung cancer, (2) investigate carcinogenesis leading to lung cancers in patients without a history of smoking, (3) harness precision medicine for disease interception and prevention, (4) implement solutions to deliver prevention measures and effective therapies to individuals in under-resourced countries, (5) facilitate collaborations with industry to collect and share data and samples, (6) create and maintain open access to big data repositories, (7) develop new immunotherapeutic agents for lung cancer treatment and prevention, and (8) invest in research in both the academic and community settings. These calls to action provide guidance to representatives from academia, the pharmaceutical and biotech industries, organizational and regulatory leaders, and patient advocates to guide ongoing and planned initiatives.

In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB–IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14–28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.