Showing papers by "Joao Victor Machado Alessi published in 2022"

Association of High Tumor Mutation Burden in Non–Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels

Abstract: Key Points Question Is tumor mutation burden (TMB) associated with improved outcomes of programmed cell death–1 (PD-1)/programmed death ligand–1 (PD-L1) inhibition across PD-L1 expression levels in non–small cell lung cancer (NSCLC)? Findings In this cohort study of 1552 patients with NSCLC, the group with high TMB had improved response rates and survival after receiving PD-1/PD-L1 inhibition therapy across PD-L1 expression subgroups compared with the group with low TMB. High TMB levels were associated with increased CD8-positive T-cell infiltration and distinct immune response gene expression signatures. Meaning These findings suggest that in NSCLC, a high number of nonsynonymous tumor mutations is associated with immune cell infiltration and inflammatory T-cell expression signatures, leading to increased sensitivity to PD-1/PD-L1 inhibition across PD-L1 expression subgroups.

Association of Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC.

Abstract: Importance Currently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy. Objective To develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC). Design, Setting, and Participants This multicenter retrospective discovery-validation cohort study included 685 ICI-treated patients with NSCLC with median follow-up of 38.1 and 43.3 months for the discovery (n = 446) and validation (n = 239) cohorts, respectively. Patients were treated between February 2014 and September 2021. We developed an ML automated method to count tumor, stroma, and TIL cells in whole-slide hematoxylin-eosin-stained images of NSCLC tumors. Tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression were assessed separately, and clinical response to ICI therapy was determined by medical record review. Data analysis was performed from June 2021 to April 2022. Exposures All patients received anti-PD-(L)1 monotherapy. Main Outcomes and Measures Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were determined by blinded medical record review. The area under curve (AUC) of TIL levels, TMB, and PD-L1 in predicting ICI response were calculated using ORR. Results Overall, there were 248 (56%) women in the discovery cohort and 97 (41%) in the validation cohort. In a multivariable analysis, high TIL level (≥250 cells/mm2) was independently associated with ICI response in both the discovery (PFS: HR, 0.71; P = .006; OS: HR, 0.74; P = .03) and validation (PFS: HR = 0.80; P = .01; OS: HR = 0.75; P = .001) cohorts. Survival benefit was seen in both first- and subsequent-line ICI treatments in patients with NSCLC. In the discovery cohort, the combined models of TILs/PD-L1 or TMB/PD-L1 had additional specificity in differentiating ICI responders compared with PD-L1 alone. In the PD-L1 negative (<1%) subgroup, TIL levels had superior classification accuracy for ICI response (AUC = 0.77) compared with TMB (AUC = 0.65). Conclusions and Relevance In these cohorts, TIL levels were robustly and independently associated with response to ICI treatment. Patient TIL assessment is relatively easily incorporated into the workflow of pathology laboratories at minimal additional cost, and may enhance precision therapy.

Comparative analysis and isoform-specific therapeutic vulnerabilities of KRAS mutations in non-small cell lung cancer.

Abstract: PURPOSE Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking. EXPERIMENTAL DESIGN We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3560 patients with non-small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations. RESULTS In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological and oncogenic properties both in vitro and in vivo These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared to other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs which underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared to KRAS wild-type tumors. CONCLUSIONS This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.

Prognostic effect of body mass index in patients with advanced NSCLC treated with chemoimmunotherapy combinations

Abstract: Introduction It has been recognized that increasing body mass index (BMI) is associated with improved outcome from immune checkpoint inhibitors (ICIs) in patients with various malignancies including non-small cell lung cancer (NSCLC). However, it is unclear whether baseline BMI may influence outcomes from first-line chemoimmunotherapy combinations. Methods In this international multicenter study, we evaluated the association between baseline BMI, progression-free survival (PFS) and overall survival (OS) in a cohort of patients with stage IV NSCLC consecutively treated with first-line chemoimmunotherapy combinations. BMI was categorized according to WHO criteria. Results Among the 853 included patients, 5.3% were underweight; 46.4% were of normal weight; 33.8% were overweight; and 14.5% were obese. Overweight and obese patients were more likely aged ≥70 years (p=0.00085), never smokers (p<0.0001), with better baseline Eastern Cooperative Oncology Group—Performance Status (p=0.0127), and had lower prevalence of central nervous system (p=0.0002) and liver metastases (p=0.0395). Univariable analyses showed a significant difference in the median OS across underweight (15.5 months), normal weight (14.6 months), overweight (20.9 months), and obese (16.8 months) patients (log-rank: p=0.045, log rank test for trend: p=0.131), while no difference was found with respect to the median PFS (log-rank for trend: p=0.510). Neither OS nor PFS was significantly associated with baseline BMI on multivariable analysis. Conclusions In contrast to what was observed in the context of chemotherapy-free ICI-based regimens, baseline BMI does not affect clinical outcomes from chemoimmunotherapy combinations in patients with advanced NSCLC.

Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors

Abstract: Abstract The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.

Three-year outcomes and correlative analyses in patients with non–small cell lung cancer (NSCLC) and a very high PD-L1 tumor proportion score (TPS) ≥ 90% treated with first-line pembrolizumab.

Abstract: 9043 Background: Although 1st-line PD-1 monotherapy has improved survival in advanced NSCLC with a PD-L1 TPS ≥50%, responses occur in ̃45% of patients (pts). We previously showed that among pts treated with 1st-line pembrolizumab, clinical outcomes were significantly improved in those with a PD-L1 TPS of ≥90% compared to a TPS of 50-89%. Here, we report the 3-year survival analysis to 1st-line pembrolizumab in pts with a PD-L1 TPS ≥90% vs 50-89%, and characterize genomic and immunophenotypic differences between these PD-L1 expression groups. Methods: Pts with stage IV EGFR/ALK wild-type NSCLC and PD-L1 TPS ≥50% who received 1st-line pembrolizumab at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC), with a minimum follow-up of 3 years were included. Comprehensive tumor genomic profiling and multiplexed immunofluorescence (mIF) were performed to examine genomic and immunophenotypic correlates of very high PD-L1 expression on separate cohorts of NSCLC at the DFCI. Results: Among 396 pts, median age was 69, 53.3% were women, 90.1% had a history of tobacco use, 83.6% had a ECOG performance status of 0-1, and 28.8% had a KRAS mutation. At a median follow-up of 42.6 months, median progression-free (mPFS) and overall survival (mOS) in the entire cohort were 5.1 months, and 19.0 months, respectively. When compared to pts with a PD-L1 TPS of 50-89% (N = 252), those with PD-L1 TPS ≥90% (N = 144) had a significantly longer mPFS (6.0 vs 4.5 months, HR 0.67, p < 0.001), and longer mOS (30.2 vs 16.9 months, HR 0.66, p < 0.01). Kaplan-Meier estimates of the 3-year PFS and OS were 24.9% and 47.0% in the PD-L1 TPS ≥90% groups, and 9.4% and 27.7% in the PD-L1 TPS 50-89% group, respectively. A PD-L1 TPS ≥90% was confirmed to be an independent predictor of improved PFS (HR 0.68, p < 0.01) and OS (HR 0.67, p < 0.01) in multivariable analysis. Tumor genomic profiling from a separate cohort of 500 NSCLC samples revealed that mutations in STK11, KEAP1, FBXW7, and CTNNB1 were significantly more frequent in tumors with a PD-L1 TPS of 50-89% compared to those with a PD-L1 TPS ≥90% (q < 0.05). mIF on 91 NSCLCs identified significantly higher CD8+PD1+ T cells and PD-L1+ immune cells in tumors with PD-L1 TPS ≥90% vs 50-89% (p < 0.05). Conclusions: Pembrolizumab monotherapy continues to demonstrate a meaningful long-term survival benefit in pts with advanced NSCLC and a PD-L1 TPS ≥90%. NSCLCs with very high PD-L1 TPS may have a more favorable genomic and immunophenotypic profile. These findings have implications for treatment selection and clinical trial interpretation and design.

Distinct genomic and immunophenotypic features of solid-predominant versus nonsolid-predominant stage I lung adenocarcinomas and association with disease recurrence after surgical resection.

Abstract: 8514 Background: Compared to lung adenocarcinomas (LUAD) with nonsolid-predominant histology (lepidic, acinar, papillary, micropapillary), those with predominantly solid features have a higher risk of disease recurrence after surgical resection. However, little is known about the genomic landscape and immunophenotype of solid vs nonsolid stage I LUAD. Methods: We collected clinicopathologic data from patients with resected stage I NSCLC (AJCC 8th Edition), which underwent next-generation sequencing to identify genomic alterations and tumor mutational burden (TMB). A subset of these samples also had multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 to determine differences in tumor immune cells subsets according to histologic subtype. Disease free-survival (DFS) was compared in patients based on their predominant histologic subtype (solid vs nonsolid). Results: Among 658 LUADs, 11.4% (N = 75) had solid-predominant and 88.6% (N = 583) nonsolid-predominant histology. After a median follow-up of 50 months from the time of surgery, 145 patients (22.0%) experienced recurrence. Compared to nonsolid-predominant LUAD, those with solid predominance had a significantly lower prevalence of activating EGFR, BRAFV600E, and METex14 mutations as well as ALK/ RET/ ROS1 rearrangements (9.3% versus 31.6%, P < 0.001), no difference in KRASG12C frequency (24% versus 16.8%, P = 0.14), a higher TMB (median 12.2 versus 7.2 mutations/megabase; P < 0.001), and a shorter median DFS from the time of surgical resection (43.2 months versus not reached, HR: 3.3 [95% CI: 2.2-4.9], P < 0.001). The detrimental effect of solid-predominant LUAD in DFS remained significant after adjusting for other factors such as tumor stage, surgery type, smoking status, and TMB (HR: 2.66 [95% CI: 1.71-4.11], P < 0.001]. Among LUADs profiled by multiplex immunofluorescence, compared to tumors with nonsolid-predominant subtype (N = 197), those with solid predominance (N = 23) had significantly higher numbers of CD8+, FOXP3+, PD-1+ immune cells, and PD-1+ CD8+ T cells, both intratumorally (P < 0.001) and at the tumor-stroma interface (P < 0.001). Solid-predominant subtype was also associated with a higher median PD-L1 expression level on tumor (5% versus 1%; P = 0.01) and immune cells (16% versus 7%, P = 0.02). Conclusions: Among patients with surgically-resected stage I LUAD, solid-predominant histology was associated with distinct genotypic and immunologic characteristics. These findings may aid in identifying patients at greater risk of recurrence after surgery.

Digital quantification of lymphocytic infiltration on routine H&E images and immunotherapy response in non–small cell lung cancer.

Abstract: 9066 Background: Current biomarker(s) for immuno-oncology (IO) therapy response prediction in lung cancer are limited. Additional predictive biomarkers are useful to help refine patient selection and guide precision therapy. Methods: Biopsy and surgical specimens stained with hematoxylin-eosin (H&E) were subjected to whole-slide scanning for 446 advanced stage non-small cell lung cancer (NSCLC) treated with single agent immune check point inhibitors (ICI). A machine learning model was trained on H&E images for classification of tumor infiltrating lymphocytes (TILs), tumor cells, and stromal cells in specific tissue types. Results: TIL levels were found to be highly variable, with a range of 12 to 4270 cells/mm2, and median of 319 (Q1 = 159, Q3 = 681). TIL levels were assessed on tissue samples from multiple organs which had shown primary or metastatic NSCLC, and were similar across all specimen sites except the liver, for which median TIL levels were significantly lower, at 90 cells/mm2. There was no correlation between tumor mutational burden (TMB) and TIL levels, while high TIL levels were correlated with high PD-L1 (≥ 50%) expression. Patients who experienced a partial/complete response to ICI therapy had a trend to higher median TILs compared to those who had progressive/stable disease (350 versus 310 cells/mm2, P = 0.09). In a multivariable analysis after controlling for covariates (incl. sex, age, cigarette smoking, ECOG, PD-L1, TMB & treatment line), a higher TIL level (≥ 250 cells/mm2) was an independent predictor of IO response for both progression-free survival (PFS; HRadj 0.70; 95% CI, 0.55 - 0.89; P = 0.003) and overall survival (HRadj 0.73; 95% CI, 0.56 - 0.95; P = 0.02). In a ROC analysis considering single biomarkers, PD-L1 had the highest AUC (0.68, P < 0.001), while TIL (AUC = 0.53, P = 0.08) and TMB (AUC = 0.55, P = 0.05) had similar AUC values for classifying responders from non-responders based on objective response rate. Using weighted linear regression approach to combine the biomarkers, paired PD-L1/TMB had the greatest AUC (0.70, P < 0.001) compared to PD-L1 single assay. In the PD-L1 negative (< 1%, N = 50) subgroup, TIL levels had superior predictive performance for classification of IO responders (AUC = 0.77, P = 0.02) compared to TMB (AUC = 0.57, P = 0.3), such that patients with a high TIL level (≥ 250 cells/mm2) had an improved PFS (median PFS: 2.7 vs 2.2 months; HR = 0.48; 95% CI, 0.26 - 0.87; P = 0.02). Conclusions: Digital TIL quantification with use of machine learning is feasible. TIL levels appear to be a robust and independent biomarker of likelihood of response to IO treatment in NSCLC, especially in the PD-L1 negative subgroup. The findings of this study are under validation in additional lung cancer cohorts.

Genomic correlates of acquired resistance to PD-(L)1 blockade in patients with advanced non-small cell lung cancer (NSCLC).

Abstract: 9021 Background: Despite improvements in survival with immune checkpoint inhibition (ICI), the majority of patients develop acquired resistance to ICI after an initial benefit. However, the mechanisms underlying acquired resistance to ICI in NSCLC are largely unknown. Methods: Patients with advanced NSCLC treated with ICI at the Dana-Farber Cancer Institute (DFCI), and whose tumors underwent genomic profiling before and after ICI, with no intervening therapies, were included. Mutations, tumor mutational burden (TMB), copy number variations (CNVs), and PD-L1 tumor proportion score (TPS) were compared between pre- and post-ICI samples. Acquired resistance was defined as the development of disease progression after an initial objective response, or stable disease ≥3 months with PD-(L)1 blockade. Results: Among 1763 patients with advanced NSCLC who received ICI, 45 had matched pre- and post-ICI tissue samples available for genomic profiling. Putative mechanisms of resistance were identified in 55% of cases (N = 25). Five patients (20%) acquired an STK11 mutation, one patient (4%) acquired a KEAP1 mutation, and another patient (4%) developed concurrent KEAP1 and SMARCA4 mutations. A patient (4%) with KRAS G12C-mutant NSCLC developed concurrent STK11 and KEAP1 mutations at resistance. In 3 cases (12%) with pre-existing STK11 or KEAP1 mutations prior to ICI administration, we identified acquired copy losses of STK11 and KEAP1, respectively, resulting in bi-allelic inactivation of these genes. Acquired beta-2-microglobulin ( B2M) mutations were detected in 3 patients (12%), one of whom developed concurrent B2M copy loss, indicating bi-allelic inactivation. Eight additional patients (32%) developed B2M gene deletions. Other acquired alterations that have been implicated in ICI resistance included CDKN2A/B loss (N = 10, 40%), including 5 with bi-allelic deletion, acquired PTEN deletions (N = 5, 20%), and MDM2 amplification (N = 2, 8%). When we examined alterations in immune checkpoint genes, we identified acquired CD274 (PD-L1) and PDCD1LG2 (PD-L2) loss in 8% of cases (N = 2), and bi-allelic deletion in one case (4%). Intervening ICI did not affect TMB (median TMB: 8.7 [pre-ICI] vs 9.1 [post-ICI] mut/Mb, P = 0.6), PD-L1 expression (median PD-L1 TPS: 3% [pre-ICI] vs 5.0% [post-ICI] mut/Mb, P = 0.5), or aneuploidy levels (as fraction of genome altered [FGA]) (median FGA: 18.4% [pre-ICI] vs 21.1% [post-ICI], P = 0.2), indicating that acquired gene level CNVs were not a reflection of increased cancer aneuploidy. In a control cohort of 30 patients with pre- and post-chemotherapy matched samples which underwent genomic profiling, no acquired mutations in STK11, KEAP1, SMARCA4, or B2M were detected. Conclusions: Mechanisms of acquired resistance to PD-(L)1 blockade are heterogenous, and new therapeutic strategies are required to delay and overcome ICI resistance in patients with NSCLC.

Activating MET kinase domain mutations define a novel molecular subtype of non–small cell lung cancer that is clinically targetable with the MET inhibitor elzovantinib (TPX-0022).

Abstract: 9124 Background: In non-small cell lung cancer (NSCLC), MET exon 14 skipping (METex14) mutations and MET amplification can be targeted with MET inhibitors. Here, we describe a novel, actionable molecular subtype of NSCLC characterized by activating MET-tyrosine kinase domain (MET-TKD) mutations in the absence of METex14 mutations. Methods: Clinicopathologic and genomic data were abstracted from NSCLC cases included in a multi-institutional cohort of tumors that underwent genomic profiling in the GENIE v10, China PanCancer, and the International Cancer Genome Consortium/ The Cancer Genome Atlas (ICGC/TCGA) datasets. External validation of the prevalence of MET-TKD mutations was performed on an independent cohort of NSCLC tissue and liquid samples from the Foundation Medicine genomic database. Results: Among 14,099 NSCLC samples in the multi-institutional cohort, 71 (0.5%) harbored MET-TKD mutations without concurrent METex14 mutations: 55 of these had uncertain pathogenic significance and 16 had known oncogenic potential, including MET H1094Y/R, D1228H/N/V, N1100S, H1106D, V1188I, and M1250T, in order of decreasing prevalence. In a separate cohort of 91,515 NSCLC samples from the Foundation Medicine database, MET-TKD mutations lacking concurrent METex14 mutations were identified in 799 (0.9%) samples, including H1094Y, L1195V, D1228H/N, M1250T and others. Among 60 NSCLC samples harboring MET-TKD mutations without concurrent METex14 mutations with complete genomic data in the multi-institutional cohort, 36 (60%) had concurrent driver alterations in KRAS, EGFR, ROS1, BRAF, HER2, or RET, while 24 (40%) had no concurrent oncogenic drivers. Among patients with available demographic data in the multi-institutional cohort, those with MET-TKD-mutant NSCLC (N = 70) were significantly younger than patients with METex14-mutant NSCLC (N = 353) (median age 63 [range 30-86] vs 73 [range 44-88], p < 0.0001), and there was no significant difference in sex or self-reported race. Confirmed partial responses to the MET tyrosine kinase inhibitor elzovantinib (TPX-0022) were observed in two patients with MET-TKD-mutant NSCLC and no other detectable driver mutations: a 64-year-old man with MET H1094Y-mutant NSCLC, and an 80-year-old man with MET F1200I-mutant NSCLC. Conclusions: Potentially actionable MET-TKD mutations lacking concurrent METex14 mutations represent a novel genomic subtype in 0.5-0.9% of NSCLC, and occur in the absence of other known drivers in a subset of cases.

Unique SLC12A2-ROS1 fusion is associated with marked response to crizotinib in lung adenocarcinoma

Abstract: Chromosomal rearrangements involving the c-ros oncogene 1 (ROS1) gene define a subset of non-small cell lung cancers highly sensitive to small-molecule tyrosine kinase inhibitors. However, little is known about the impact of different fusion partners on tyrosine kinase inhibitor efficacy. We herein describe a case of a 26-year-old never-smoker patient from southern Africa with metastatic lung adenocarcinoma driven by SLC12A2-ROS1 fusion, who had a pronounced and durable response to crizotinib. The present case underscores the importance of pursuing actionable alterations in patients with similar clinical and epidemiological characteristics. In addition, provides the second report of crizotinib activity against lung malignancies harboring the unique SLC12A2-ROS1 fusion and highlights the importance of a deeper understanding of molecular alterations in underrepresented subgroups of patients to tailor the decision-making in daily practice.

Outcomes of single-agent PD-(L)-1 versus combination with chemotherapy in patients with PD-L1-high (≥ 50%) lung cancer.

Abstract: 9052 Background: Single agent PD-(L)-1 blockade (IO) and PD-(L)-1 blockade combined with chemotherapy (ChemoIO) are both standard first-line treatments for patients with PD-L1-high (≥ 50%) metastatic non-small cell lung cancer (NSCLC). These regimens have not been compared prospectively, so comparative effectiveness is unclear. It is also unknown if clinical and molecular tumor characteristics differentially associate with benefit to IO vs ChemoIO in patients with NSCLC with high PD-L1 tumor expression. Methods: All patients with metastatic NSCLC treated with IO or ChemoIO at two institutions (Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute) were reviewed. Patients with EGFR or ALK alterations, PD-L1 expression < 50%, treated with IO or ChemoIO in > 1st line setting were excluded. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between the IO vs ChemoIO groups and association with clinical, pathologic, and molecular features was examined. To account for NGS panel differences, tumor mutational burden (TMB) values were harmonized using a z-score conversion as previously described (Vokes et al, 2019). Results: Of 639 patients with stage IV EGFR/ ALK wild-type NSCLC and PD-L1 ≥50% treated in the 1st line setting, 504 received IO and 135 received ChemoIO. Baseline ECOG performance status (p = 0.3), median PD-L1 % (p > 0.9) and TMB (p = 0.2) were similar between the IO and ChemoIO groups. For patients receiving IO vs ChemoIO, there was no significant difference in OS (HR 0.8, 95% CI 0.6 to 1.08; p = 0.2). Median PFS was shorter (HR 0.7, 95% CI 0.6 to 0.9; p = 0.004) and ORR was lower (40% IO vs 55% ChemoIO, p = 0.002) in the IO group. Among patients with durable responses (> 6 months), never smokers were less common in the IO group (6% vs 18%, p < 0.001), but there was no difference in PD-L1 expression, TMB, or mutational ( KRAS, STK11, or KEAP1) profile to suggest differential predictors of benefit to IO or ChemoIO. Conclusions: In patients with PD-L1 high NSCLC, there was no survival benefit associated with the addition of chemotherapy to IO. There were also no clear differences in PD-L1 expression or molecular features associated with durable response to IO vs ChemoIO. These findings have implications for treatment selection in this population.

Impact of STK11 copy loss on clinical outcomes to PD-(L)1 blockade in non–small cell lung cancer.

Abstract: 9059 Background: STK11 is among the most commonly altered genes in non-squamous lung cancers. While STK11 mutation is associated with diminished efficacy of immune checkpoint inhibition (ICI), particularly in KRAS mutated tumors, it is not known whether STK11 copy deletion influences outcomes to ICI. Methods: Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with ICI whose tumors underwent genomic profiling were included. Clinical outcomes to ICI were analyzed according to KRAS mutation and STK11 deletions. STK11 copy number variations (CNVs) were determined using an internal informatic pipeline. Kaplan-Meier methodology was used to estimate event-time distributions. Results: Of 559 patients with non-squamous NSCLCs (Nsq-NSCLC), 40.4% (N = 226) had a KRAS mutation ( KRASmut), 18.4% (N = 103) had an oncogenic STK11 mutation ( STK11mut), and 22.5% had either single (N = 123), or bi-allelic (N = 3) deletion ( STK11del). Given that 32.5% of STK11del cases had a concurrent oncogenic STK11 mutation in our cohort, to isolate the impact of STK11del on ICI outcomes we excluded samples with STK11mut from this analysis. In all comers with NSCLC, STK11del had no impact on objective response rate (22.2% versus 23.8%, P = 0.8), progression-free (PFS, HR 0.90, P = 0.30), and overall survival (OS, HR 0.96, P = 0.79) to ICI. When we examined the impact of STK11del on clinical outcomes to PD-(L)1 blockade among KRASmut cases we found that STK11del was associated with a numerically lower ORR (13.3% versus 30.0%, P = 0.12), and a significantly shorter PFS (HR 0.57, P = 0.018) compared to cases without STK11del. No difference in OS were observed between these groups (HR 0.77, P = 0.39). Among KRASwt NSCLCs, STK11del cases had a similar ORR (22.6% versus 22.9%, P = 0.99), PFS (HR 0.92, P = 0.63), and OS (HR 1.18, P = 0.32) to PD-(L)1 inhibition compared to cases without STK11del. Among KRASmut but not KRASwt NSCLCs, cases with STK11del had significantly lower PD-L1 expression compared to those without STK11 deletions (27.5% versus 70%, P = 0.01). Conclusions: STK11 deletion is associated with low response rate and short progression-free survival among KRAS mutant NSCLCs. Future analyses will incorporate additional cases to increase sample size and immunopathologic findings to assess impact of mono and bi-allelic deletion on protein expression.

528 Acquired resistance to PD-(L)1 blockade in patients with non-small cell lung cancer (NSCLC)

Abstract:

Background

Although immune checkpoint inhibition (ICI) has improved survival in patients with non-small cell lung cancer (NSCLC), the majority of patients develop acquired resistance (AR) to ICI after an initial benefit.^1-2 However, the mechanisms underlying AR to ICI in NSCLC are largely unknown.

Methods

Comprehensive genomic profiling and HLA-I immunohistochemistry (IHC, by blinded pathology assessment) were performed on samples from patients with NSCLC treated with PD-(L)1 blockade at the Dana-Farber Cancer Institute and matched pre and post ICI tumor biopsies (figure 1). Acquired resistance was defined as the development of disease progression after an initial objective response, or stable disease ≥3 months with PD-(L)1 blockade.

Results

Among 1823 patients with advanced NSCLC who received ICI, 60 developed acquired resistance to treatment and had matched pre- and post-ICI tissue samples. Putative mechanisms of AR to PD-(L)1 blockade were identified in 56.7% (34/60) of cases (figure 2). Acquired mutations in STK11 were identified in 8.3% of cases (N=5) resulting in homozygous loss in 2, due to acquired copy deletion. Acquired mutations in KEAP1 and SMARCA4 were noted in one (1.7%) and 3 patients (5%), respectively. Four patients (6.7%) developed acquired deleterious mutations in the beta 2-microglobulin (B2M) gene. Of these, one exhibited bi-allelic loss due to concurrent B2M copy deletion. Other acquired alterations implicated in resistance to ICI included homozygous loss in JAK1 (N=1, 1.7%) and APC (N=1, 1.7%), and acquired activating PI3KCA mutation (N=1, 1.7%). In examining acquired copy number variations (CNVs), we found bi-allelic deletions in CDKN2A/CDKN2B in four cases (6.7%), and acquired heterozygous deletion in CD274 (PD-L1) and PDCD1LG2 (PD-L2) genes in four cases (6.7%), while high level MDM2 and MYC amplifications were identified in 3 (5%) and 1 (1.7%) case, respectively. PD-L1 expression, tumor mutational burden, and total aneuploidy levels were not impacted by intervening ICI (figure 3). Among patients with tissue available for HLA-I IHC, we found a significant decrease in HLA-I expression by H-score at the moment of acquired resistance to ICI (median H-score decrease -10 [range: 0 to -220], P=0.03. figure 4). In 2 independent control cohorts of patients with pre- and post-chemotherapy (N=41) or EGFR inhibitors (N=90) tumor genomic profiling, no acquired mutations in STK11 or B2M were detected. Intervening chemotherapy and EGFR inhibition had no impact on HLA-I expression (figure 4).

Conclusions

Mechanisms of AR to PD-(L)1 blockade are heterogenous, and new therapeutic strategies are required to delay and overcome ICI resistance in patients with NSCLC.

References

Schoenfeld AJ, Antonia SJ, Awad MM, Felip E, Gainor J, Gettinger SN, Hodi FS, Johnson ML, Leighl NB, Lovly CM, Mok T, Perol M, Reck M, Solomon B, Soria JC, Tan DSW, Peters S, Hellmann MD. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer. Ann Oncol. 2021 Dec;32(12):1597-1607 Passaro A, Brahmer J, Antonia S, Mok T, Peters S. Managing resistance to immune checkpoint inhibitors in lung cancer: treatment and novel strategies. J Clin Oncol. 2022 Feb 20;40(6):598–610

Ethics Approval

Patients at the Dana-Farber Cancer Institute who consented to institutional review board-approved protocols DF/HCC 02-180, 11-104, 13-364, and/or 17-000 which allowed for conducting translational research and tumor next-generation sequencing, respectively, were included.

Consent

Not applicable

451 Serum albumin predicts outcome in patients with extensive stage small-cell lung cancer (ES-SCLC) receiving first-line combination of PD-(L)1 inhibitors and platinum-etoposide chemotherapy

Abstract: Background The combination of platinum-etoposide chemotherapy with PD-L1 inhibitors (chemoimmunotherapy) has become the new standard for first-line treatment of patients with extensive stage small-cell lung cancer (ES-SCLC). Never-theless, factors associated with outcomes in this setting are lacking. We sought to identify clinicopathological and genomic factors associated with outcome to first-line chemoimmunotherapy in patients with ES-SCLC. Methods Among patients at the Dana-Farber Cancer Institute with ES-SCLC who received a combination of platinum (car-boplatin or cisplatin), etoposide, and a PD-(L)1 inhibitor (ate-zolizumab, durvalumab, or pembrolizumab), baseline clinicopathological and genomic features were correlated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). For serum biomarkers (hemoglobin, sodium, albumin, lactate dehydrogenase [LDH], and derived neutrophile-to-lymphocyte ratio [dNLR]) a blood draw per-formed within 10 days from treatment start was considered. the time of blood draw not assessed dNLR.

Abstract 506: Dissecting the genomic and tumor immune microenvironment factors associated with disease recurrence in resected stage I NSCLC

Abstract: Background: Patients with early-stage non-small cell lung cancer (NSCLC) are at substantial risk for disease recurrence after surgical resection, and the discovery of biomarkers that predict disease recurrence has been challenging. We sought to identify genomic and immunologic factors associated with recurrence after surgery in stage I NSCLC. Methods: We collected clinicopathologic data from patients with resected stage I NSCLC (AJCC 8th Edition) which underwent multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1. A subset of these samples also had next-generation sequencing performed to identify genomic alterations and tumor mutational burden (TMB). A bidirectional stepwise elimination was applied on variables with a univariable disease-free survival (DFS) p-value <0.25. The final multivariable Cox model was validated with internal bootstrapping (B=300). Results: A total of 252 cases were included. After a median follow-up of 25.6 months from the time of surgery, 47 cases (18.7%) experienced recurrence, with a 2-year DFS rate of 82.9%, and a 2-year overall survival (OS) rate of 97.9%. Shorter DFS was associated with higher TMB, increased PD-L1 expression, and greater numbers of intratumoral (IT) CD8+, PD-1+, and PD-1+CD8+ immune cells, as well as increased CD8+ and FOXP3+ T cells at the tumor stroma interface (TSI) in univariable analyses (p<0.05). Multivariable analysis showed that shorter DFS was associated with increasing TMB and higher PD-L1 tumor cell expression. We observed a difference by immune cell localization and risk of recurrence: shorter DFS was associated with higher IT but lower TSI PD-1+ immune cells, and higher IT but lower TSI FOXP3+ T cells (Table). Internal bootstrap validation showed good model performance (C-index = 0.74). Conclusion: Genomic analysis and immunophenotyping of stage I NSCLCs can identify cases at greatest risk of disease recurrence after surgical resection. Table. Univariable and multivariable analysis Disease-free survival Univariable HR [95%CI] p-value Multivariable HR [95%CI] p-value Stage at diagnosis - 0.10 – – IA1 1.52 [0.58, 3.97] IA2 2.61 [0.95, 7.20] IA3 2.61 [1.03, 6.63] IB Histology - 0.42 Adenocarcinoma 1.38 [0.65, 2.97] Squamous Age* 1.02 [0.99, 1.06] 0.19 – – TMB* 1.09 [1.05, 1.12] <0.001 1.09 [1.05, 1.13] <0.001 Smoking* (pack-years) 1.01 [1.00, 1.02] 0.008 – – Smoking history - 0.012 – – Never 5.24 [1.27, 21.7] Former Current 4.92 [0.82, 29.5] Surgical treatment - 0.084 - 0.074 Lobectomy 1.80 [0.89, 3.62] 2.18 [0.93, 5.14] Sublobar Intratumoral** 1.09 [1.03, 1.16] 0.015 - – CD8+ 1.22 [1.10, 1.36] 0.002 1.80 [1.13, 2.87] 0.014 PD-1+ 1.51 [1.20, 1.90] 0.004 - – 0.004 PD-1+ CD8+ 1.22 [1.04, 1.44] 0.053 0.15 [0.04, 0.55] FOXP3+ Tumor-Stroma Interface** 1.06 [1.01, 1.11] 0.033 - - CD8+ 1.10 [1.01,1.20] 0.056 0.71 [0.56, 0.91] 0.007 PD-1+ 1.21 [0.99, 1.48] 0.100 - - PD-1+ CD8+ 1.28 [1.03, 1.59] 0.037 2.42 [1.49, 3.95] <0.001 FOXP3+ PD-L1 expression* 1.02 [1.01, 1.03] <0.001 1.03 [1.01, 1.04] <0.001 Tumor Proportion Score (TPS) 1.02 [1.01, 1.04] - - Immune cells 0.011 *Per unit increase. ** Per 100 units increase. Intratumoral, is defined as the region of the slide consisting of tumor beyond the tumor-stroma interface. Tumor-Stroma Interface is defined as the region within 40 microns to either side of the defined border between tumor and stroma. Citation Format: Joao Victor Alessi, Zihan Wei, Biagio Ricciuti, James Lindsay, Victor R. Vaz, Adriana Barrichello, Bijaya Sharma, Kristen D. Felt, Fangxin Hong, Lynette M. Sholl, Scott J. Rodig, Mark M. Awad. Dissecting the genomic and tumor immune microenvironment factors associated with disease recurrence in resected stage I NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 506.

Germline variants associated with immunotherapy-related adverse events

Abstract: Immune checkpoint inhibitors (ICIs) have yielded remarkable responses in patients across multiple cancer types, but often lead to immune related adverse events (irAEs). Although a germline cause for irAEs has been hypothesized, no systematic genome wide association study (GWAS) has been performed and no individual variants associated with the overall likelihood of developing irAEs have yet been identified. We carried out a Genome-Wide Association Study (GWAS) of 1,751 patients on ICIs across 12 cancer types, with replication in an independent cohort of 196 patients and independent clinical trial data from 2275 patients. We investigated two irAE phenotypes: (i) high-grade (3-5) events defined through manual curation and (ii) all detectable events (including high-grade) defined through electronic health record (EHR) diagnosis followed by manual confirmation. We identified three genome-wide significant associations (p<5x10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined p=1.6x10-11; hazard ratio (HR)=2.1), rs75824728 near IL22RA1 (combined p=6.6x10-9; HR=1.9), and rs113861051 on 4p15 (combined p=1.3x10-8, HR=2.0); with rs16906115 replicating in two independent studies. The association near IL7 colocalized with the gain of a novel cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation than non-carriers, and this stability was predictive of downstream irAEs and improved survival.

Immunophenotypic correlates and response to first-line pembrolizumab among elderly patients with PD-L1-high (≥ 50%) non–small cell lung cancer.

Abstract: 9054 Background: Older age is associated with increased levels of systemic inflammation and altered immunosurveillance in cancer. Whether aging correlates with a distinct immunophenotype or impacts clinical outcomes to first-line pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of ≥50% is unclear. Methods: We performed a retrospective analysis of patients with NSCLC. Multiplexed immunofluorescence (mIF) for CD8+, PD-1+, PD-1+CD8+ and FOXP3+ was performed to explore tumor immunophenotype. Clinical outcomes were analyzed on a separate cohort of patients with PD-L1-high (TPS of ≥50%) NSCLC (negative for sensitizing genomic alterations in EGFR and ALK) who received treatment with first-line pembrolizumab. Variables demonstrating a univariate signal of association of p < 0.1 were included in the multivariate model. The results were compared in patients < 80 vs ≥80 years old. Results: Among 541 patients with NSCLCs profiled by mIF, the median age was 67 (28-90). When comparing patients < 80y (n = 497) to ≥80y (n = 44), there was no difference in median CD8+ T cells/mm2 (171 vs 148; p = 0.69), PD-1+ immune cells/mm2 (81.1 vs 87.2; p = 0.95), or PD-1+CD8+ T cells/mm2 (18.0 vs 13.1; p = 0.56). NSCLCs from patients ≥80y had a higher median of intratumoral-associated FOXP3+ T cells/mm2 (63.6 vs 91.1; p = 0.03). In a cohort of 271 patients with PD-L1 ≥50% who received first-line pembrolizumab, baseline clinicopathological characteristics were balanced in the < 80y (n = 225) vs ≥80y (n = 46) groups in terms of sex, tobacco use, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), histology, presence of potentially targetable driver mutations (KRAS, MET, BRAF, HER2, RET), and PD-L1 TPS distribution (50-89% vs ≥90%). Compared to patients < 80y, patients ≥80y had no difference in objective response rate (ORR 39.1% vs 28.2%; p = 0.22) or median progression-free survival (mPFS 6.0 vs 3.0 months; p = 0.16). However, patients ≥80y had a shorter median overall survival (mOS 25.7 vs 7.6 months; p = 0.02), and this result remained significant after adjusting for ECOG-PS. Among those who experienced disease progression on pembrolizumab, patients ≥80y were significantly less likely to receive any second-line systemic therapy compared to patients < 80y (55.6% vs 30.8%; p = 0.008). Conclusions: In patients with NSCLC and PD-L1 ≥50%, the ORR and mPFS to first-line pembrolizumab were similar between patients < vs ≥80 years old. OS was shorter among patients ≥80y, potentially reflecting lower use of second-line therapy in elderly patients after progression on pembrolizumab. The immunophenotypic correlates of NSCLC in older patients need further investigation.

Acquired resistance to pd-(l)1 blockade in patients with non-small cell lung cancer

Abstract: 528 Figure 1 (A) Study schema. Patients with NSCLC and matched pre and post PD-(L)1 blockade, chemotherapy (control cohort #1) and targeted therapy (EGFR inhibitors, control cohort #2) tumor biopsies were included in this study. (B) Distribution of immunotherapy regimens received by the 60 patients who developed acquired resistance to PD-(L)1 based therapies. Abstract 528 Figure 2 Summary of the putative mechanisms of acquired resistance to PD-(L)1 blockade identified in this study. Abstracts528 Figure 2 Summary of the putative mechanisms of acquired resistance to PD-(L)1 blockade identified in this study. Abstracts J Immunother Cancer 2022;10(Suppl 2):A1–A1595 A553 PR EP RI NT Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract 4117: Clinicopathologic and molecular characterization of KRASG12D lung cancers

Abstract: Introduction: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRASmut non-small cell lung cancers (NSCLCs) exhibit heterogenous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never smoking status and has not been characterized in depth. Methods: We examined characteristics of patients with advanced KRASmut NSCLC seen at a single center. RECISTv1.1 and Cox-proportional hazards models adjusting for line of therapy and performance status were used to compare outcomes to immunotherapy. Benjamini-Hochberg corrected q-values were used for genomic comparisons. Results: Of 1,823 patients with KRASmut NSCLC, 16% (n=283) harbored KRASG12D which was mutually exclusive from other targetable alterations. Among these, the median age was 66 (range 20-92), 0.7% had squamous histology, 30% had a never/light smoking history (<10 pack-years, KRASG12D,light-sm) and 43% had a high pack-year smoking history (≥30 pack-years, KRASG12D,high-sm). Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year smoking history (median 22 vs 30, p<0.0001), more commonly had NKX2-1 and CDKN2A co-mutations (q<0.05), and less commonly had STK11 co-mutations (q<0.05). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% vs 10%, p=0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.3 v 9.9 mt/Mb, p<0.0001). Compared with KRASG12D,high-sm, KRASG12D,light-sm had lower PD-L1 TPS (median 0% vs 10%, p=0.005) and TMB (median 6.1 vs 9.9 mt/Mb, p<0.0001).As compared to patients with KRASnon-G12D (n=120) NSCLC and adequate baseline tissue for multiplex-immunofluorescence, KRASG12D (n=25) had fewer CD8+PD1+ T cells (median 13 vs 32 cells/mm2, p=0.04), PD1+ T cells (median 90 vs 135 cells/mm2, p=0.03), and lower proportion of PD-L1+ tumor and immune cells (median 1.2% vs 3.3%, p=0.06 and median 3.4% vs 7.5%, p=0.01, respectively).Among the subset of patients with advanced KRASmut NSCLC who received immunotherapy (n=57 with KRASG12D, n=411 with KRASnon-G12D), there was no difference in clinical outcomes to anti-PD-(L)1 monotherapy between KRASG12D and KRASnon-G12D (ORR: 18% vs 26%, p=0.3; mPFS: 2.8 vs 3.9 months, aHR 0.86 95% CI 0.60-1.25; mOS: 7.4 vs 15.1 months, aHR 0.77 95% CI 0.51-1.16). Similarly, there was no difference in clinical outcomes to chemo-immunotherapy between KRASG12D and KRASnon-G12D (ORR: 18% vs 39%, p=0.10; mPFS: 6.3 vs 7.0 months, aHR 0.79 95% CI 0.43-1.43; mOS: 14.0 vs 20.8 months, aHR 0.72 95% CI 0.38-1.35). Conclusions: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS mutated lung cancers and numerically worse outcomes to PD-(L)1 blockade-based therapies. Drug development for KRASG12D lung cancers will have to take these differences into account. Citation Format: Jia Luo, Biagio Ricciuti, Joao V. Alessi, Xinan Wang, Victor Vaz, Federica Pecci, Tom Nguyen, James Lindsay, Bijaya Sharma, Kristen D. Felt, Scott J. Rodig, Mizuki H. Nishino, Lynette M. Sholl, David A. Barbie, Pasi A. Jänne, Mark M. Awad. Clinicopathologic and molecular characterization of KRASG12D lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4117.

512 Time-of-day of pembrolizumab infusion and clinical outcomes of patients with NSCLC: too soon to promote morning infusions

Abstract: Background Circadian oscillations in T-cell function may influ-ence outcome from cancer immunotherapy. 1 Evidence for an association between time-of-day of immune checkpoint inhibi-tors (ICI) infusion on outcomes in patients with non-small cell lung cancer (NSCLC) is scanty. Methods In this multicenter study, we retrospectively evaluated the association between time-of-day patterns of pembrolizumab infusion and outcomes in a cohort of patients with treatment-naïve metastatic NSCLC with PD-L1 expression (cid:1) 50% treated from June 2016 to September 2021. Receipt of (cid:1) 20% vs <20% of infusions after the 16.30h cut off time ( “ late infusions ” ) was set as threshold for analysis. In addition, we explored increasing thresholds for late infusions based on centre-specific distribution of cut-off times. Results Overall 180/262 patients received (cid:1) 4 cycles and were eligible, 136 (75.5%) and 44 (24.5%) patients respectively received <20% and (cid:1) 20% of evening infusions. Evening infusions were associated with a lower number of cycles (median: 14 vs 8, p=0.0002). Following a propensity score matching (PSM)

Abstract 2143: Clinicopathologic, genomic and immunophenotypic landscape of ATM mutations in non-small cell lung cancer

Abstract: Introduction: Defective DNA damage repair machinery is a hallmark of cancer, resulting in increased mutation rates and genomic instability. In non-small cell lung cancer (NSCLC), ATM is mutated in ~10% of cases, representing the most commonly mutated DNA damage and repair gene. However, the clinicopathologic, genomic, and immunophenotypic correlates of ATM mutations in NSCLC are unknown. The impact of ATM mutation on clinical outcomes to PD-(L)1 blockade is also unclear. Methods: Clinicopathologic and genomic data were collected from 3592 patients (pts) with NSCLC who had consented to correlative studies at the Dana-Farber Cancer Institute (DFCI), and whose tumors underwent genomic profiling (OncoPanel). Multiplexed immunofluorescence (mIF) for CD8, PD1, PD-L1, FOXP3, and CK AE1/AE3 was performed on a subset of 416 NSCLC samples to examine tumor-infiltrating immune cells. ATM immunohistochemistry (IHC) was also performed on 184 ATM mutated NSCLCs with available tissue. ATM mutated (ATMMUT) tumors were defined as harboring loss-of-function mutations (nonsense, frameshift, splice site, known deleterious missense mutations). Missense mutation of unknown significance were excluded, unless deemed to affect protein function in silico. Tumors lacking ATM mutations or harboring benign ATM alterations were defined as ATM wild type (ATMWT). Results: A total of 399 deleterious ATM mutations were identified in 10.2% (365/3592) of samples; 138 (34.6%) mutations were truncating (nonsense, frameshift, and splice site mutations); the remaining 261 (65.4%) were missense mutations. Truncating mutations were significantly more likely to result in ATM loss by IHC compared to missense mutations (71.4% vs 28.9%, P<0.01) When we examined the genomic profiles of tumors with versus without deleterious ATM mutations, we found that ATMMUT NSCLCs were significantly enriched with KRAS, STK11, RBM10, and KDM5C co-mutations (P<0.01), while co-mutations in EGFR, CDKN2A and TP53 were nearly mutually exclusive (P<0.01). Among ATMMUT NSCLCs, those with ATM loss by IHC were significantly enriched with KRAS and STK11 co-mutations, while those with retained ATM expression were enriched with TP53 co-mutations (P<0.01). Pts with ATMMUT NSCLCs had similar outcomes to PD-(L)1 inhibition +/- chemotherapy, compared to ATMWT cases, and similar immune cell subsets infiltration (P>0.05). Pts with deleterious mutations in ATM and TP53 (ATMMUT/TP53MUT) had increased response rates to chemo-immunotherapy compared to those with ATMMUT/TP53WT, ATMWT/TP53MUT, or ATMWT/TP53WT genotypes (70% vs 56.2% vs 35.7% vs 27.4%, respectively, P=0.01), as well as increased tumor-stroma interface CD8+ T cells (P<0.01) and higher PD-L1 expression by mIF on tumor (P<0.01) and immune cells (P<0.01). Conclusion: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Citation Format: Biagio Ricciuti, Joao Victor Alessi, Xinan Wang, Arrien A. Bertram, Victor R. Vaz, Mizuki Nishino, James Lindsay, Kristen D. Felt, Bijaya Sharma, Lynette M. Sholl, Rodig Scott, Mark M. Awad, Michael L. Cheng. Clinicopathologic, genomic and immunophenotypic landscape of ATM mutations in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2143.