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Purpose: ATM is the most commonly mutated DNA damage and repair gene in non–small cell lung cancer (NSCLC); however, limited characterization has been pursued. Experimental Design: Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM–wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. Conclusions: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

Preferred first-line treatment for patients with metastatic EGFR-mutant lung cancer is osimertinib, yet it is not known if patient outcomes may be improved by identifying and intervening upon molecular markers associated with therapeutic resistance.All patients with metastatic EGFR-mutant lung cancer treated with first-line osimertinib at Memorial Sloan Kettering Cancer Center (n=327) were identified. Available pre-treatment and post-progression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free and overall survival were estimated using Kaplan Meier methods.Using multivariate analysis, baseline atypical EGFR (mPFS 5.8 mo, p0.001) and concurrent TP53/RB1 alterations (mPFS 10.5 mo, p=0.015) were associated with shorter progression-free survival on first-line osimertinib. Of 95 patients with post-progression biopsies, acquired resistance mechanisms were identified in 52% (off-target n=24, histological transformation n=14, on-target n=12), with MET amplification (n=9), small cell lung transformation (n=7) and acquired EGFR amplification (n=7) the most frequently identified mechanisms. While there was no difference in post-progression survival based on identified resistance (p=0.07), patients with subsequent second-line therapy tailored to post-progression biopsy results had improved post-progression survival (HR 0.09, p=0.006). Paired post-progression tumors had higher tumor mutational burden (p=0.008) and further dominant APOBEC mutational signatures (p=0.07) compared to pre-treatment samples.Patients with EGFR-mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation based on identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pre-treatment genomic alterations.

Purpose: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Experimental Design: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. Results: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6–40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment.

Dedifferentiated chondrosarcoma (DDCS) is a rare high-grade chondrosarcoma characterized by a well-differentiated chondrosarcoma (WDCS) component that abruptly transitions to a high-grade, noncartilaginous sarcomatous component. To date, the molecular pathogenesis of DDCS and its distinction from conventional chondrosarcoma remain poorly understood. By targeted sequencing, we examined the mutational and copy-number profiles of 18 DDCS, including macrodissected WDCS components, compared with 55 clinically sequenced conventional chondrosarcomas. In conjunction with publicly available external data, we analyzed the methylation and expression profiles of 34 DDCS and 94 conventional chondrosarcomas. Isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 (IDH1/IDH2) mutations were present in 36% conventional chondrosarcomas and 71% DDCS. Compared with conventional chondrosarcomas, DDCS had higher frequencies of TP53 and TERT promoter mutations and CDKN2A/B copy-number losses. Paired analysis of macrodissected WDCS and the high-grade components revealed TERT promoter mutations as early events. Despite phenotypic similarities, the percentage of genome with copy-number alterations in DDCS was significantly lower than that in other high-grade sarcomas. Differential methylation analysis revealed reduction of IDH1/IDH2-associated global hypermethylation characteristically seen in conventional chondrosarcoma and a distinct methylation profile in DDCS. The WDCS and high-grade components in DDCS showed similar methylation profiles. These CpG sites were associated with upregulated expression of genes involved in G2–M checkpoints and E2F targets. Genomic profiling revealed enrichment of TP53, TERT promoter, and CDKN2A/B alterations in DDCS. Integrated methylation and gene expression analysis revealed distinct IDH1/IDH2-associated methylation and transcriptional profiles as early events in DDCS, which may underlie the pathogenesis of dedifferentiation in chondrosarcomas.Significance:DDCS is a rare, high-grade chondrosarcoma with a dismal prognosis. About 50%–80% of DDCS harbor IDH1/IDH2 mutations. We uncover a significant alteration of IDH-associated methylation profile in DDCS, which we propose is key to the progression to dedifferentiation. In this context, the potential effect of the use of IDH inhibitors is unclear but important to address, as clinical trials of selective IDH1 inhibitors showed worse outcome in DDCS.

Purpose: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. Patients and Methods: We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. Results: Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%–88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%–58%). Conclusions: We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

Resting myocardial blood flow (MBF) and myocardial flow reserve (MFR) are reduced in heart failure (HF) patients supported by pulsatile left ventricular assist devices (LVADs). The effect of continuous-flow (CF) physiology on these parameters is underexplored in CF-LVAD patients. We investigated the impact of CF-LVADs on resting MBF and MFR under two left ventricular (LV) loading conditions. Nine HeartMate II patients (42 ± 12 years, 100% male) on support for 370 ± 281 days were enrolled. Results were compared with 9 HF patients (58 ± 13 years, 67% male, LV ejection fraction 27 ± 9%) and 10 healthy volunteers (56 ± 10 years, 20% male). CF-LVAD patients underwent transthoracic echocardiography with ramp study. MBF and MFR were measured utilizing positron emission/computed tomography imaging under two LV loading conditions: "high-speed" (HS), promoting aortic valve (AV) closure and LV unloading; "low-speed" (LS), promoting AV opening and LV loading. Global resting MBF was similar in HS, LS, HF, and healthy: 0.8 ± 0.3, 0.7 ± 0.3, 0.7 ± 0.1, 0.9 ± 0.2 ml/min/g, respectively; p = NS. HS global MFR was reduced compared with LS and HF: 1.6 ± 0.6 versus 1.9 ± 0.5, p = 0.004; 1.6 ± 0.6 versus 2.4 ± 0.5, p = 0.01, respectively. HS regional MFR was reduced compared with LS in the left anterior descending (1.7 ± 0.7 vs. 2.0 ± 0.6, p = 0.027) and left circumflex (1.8 ± 0.7 vs. 2.2 ± 0.9, p = 0.008), but not in right coronary artery (1.7 ± 0.7 vs. 1.7 ± 0.6, p = 0.76). Resting MBF is preserved among CF-LVAD patients and is similar to HF and healthy. Promoting LV ventricular unloading with higher speed was associated with lower global and regional left coronary MFR, while right coronary MFR did not change.

Advances in biomarkers, targeted therapies, and immuno-oncology have transformed the clinical management of patients with advanced NSCLC. For oncogene-driven tumors, there are highly effective targeted therapies against EGFR, ALK, ROS1, BRAF, TRK, RET, and MET. In addition, investigational therapies for KRAS, NRG1, and HER2 have shown promising results and may become standard-of-care in the near future. In parallel, immune-checkpoint therapy has emerged as an indispensable treatment modality, especially for patients lacking actionable oncogenic drivers. While PD-L1 expression has shown modest predictive utility, biomarkers for immune-checkpoint inhibition in NSCLC have remained elusive and represent an area of active investigation. Given the growing importance of biomarkers, optimal utilization of small tissue biopsies and alternative genotyping methods using circulating cell-free DNA have become increasingly integrated into clinical practice. In this review, we will summarize the current landscape and emerging trends in precision medicine for patients with advanced NSCLC with a special focus on predictive biomarker testing.

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions. Significance: We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483

Purpose: Clinical relevance thresholds and laboratory methods are poorly defined for MET amplification, a targetable biomarker across malignancies. Experimental Design: The utility of next-generation sequencing (NGS) in assessing MET copy number alterations was determined in >50,000 solid tumors. Using fluorescence in situ hybridization as reference, we validated and optimized NGS analysis. Results: Incorporating read-depth and focality analyses achieved 91% concordance, 97% sensitivity, and 89% specificity. Tumor heterogeneity, neoplastic cell proportions, and genomic focality affected MET amplification assessment. NGS methodology showed superiority in capturing overall amplification status in heterogeneous tumors and defining amplification focality among other genomic alterations. MET copy gains and amplifications were found in 408 samples across 23 malignancies. Total MET copy number inversely correlated with amplified segment size. High-level/focal amplification was enriched in certain genomic subgroups and associated with targeted therapy response. Conclusions: Leveraging our integrated bioinformatic approach, targeted therapy benefit was observed across diverse MET amplification contexts.

Background Fatigue is a common and often debilitating symptom experienced by many stroke survivors. Significant post stroke fatigue may predispose individuals to other health complications, such as falls, which can lead to fractures and soft tissue injuries. Only limited research has examined the association between fatigue and falls in stroke survivors. Methods Data were obtained from the Sax Institute’s 45 and Up Study, from a subset of individuals who had experienced a stroke. The Modified Fatigue Impact Scale—5-item version (MFIS-5) was used to measure the level of fatigue. A logistic regression model, adjusted for stroke characteristics and comorbidities, was used to determine the magnitude of association between change in fatigue score and odds of having had a fall. Results A total of 576 participants completed the questionnaire. A total of 214 (37.2%) participants reported having had a fall in the previous 12 months. There was a statistically significant association between fatigue scores and fall status (p p Conclusion This study revealed an association between an increasing risk of falls with increasing severity of post stroke fatigue. Accurate detection and management of fatigue may help reduce the risk of falls and should be the focus of future research.

Purpose: RB1 mutations and loss of retinoblastoma (Rb) expression represent consistent but not entirely invariable hallmarks of small cell lung cancer (SCLC). The prevalence and characteristics of SCLC retaining wild-type Rb are not well-established. Furthermore, the performance of targeted next-generation sequencing (NGS) versus immunohistochemistry for Rb assessment is not well-defined. Experimental Design: A total of 208 clinical SCLC samples were analyzed by comprehensive targeted NGS, covering all exons of RB1, and Rb IHC. On the basis of established coordination of Rb/p16/cyclinD1 expression, p16-high/cyclinD1-low profile was used as a marker of constitutive Rb deficiency. Results: Fourteen of 208 (6%) SCLC expressed wild-type Rb, accompanied by a unique p16-low/cyclinD1-high profile supporting Rb proficiency. Rb-proficient SCLC was associated with neuroendocrine-low phenotype, combined SCLC with non-SCLC (NSCLC) histology and aggressive behavior. These tumors exclusively harbored CCND1 amplification (29%), and were markedly enriched in CDKN2A mutations (50%) and NSCLC-type alterations (KEAP1, STK11, FGFR1). The remaining 194 of 208 SCLC were Rb-deficient (p16-high/cyclinD1-low), including 184 cases with Rb loss (of which 29% lacked detectable RB1 alterations by clinical NGS pipeline), and 10 cases with mutated but expressed Rb. Conclusions: This is the largest study to date to concurrently analyze Rb by NGS and IHC in SCLC, identifying a 6% rate of Rb proficiency. Pathologic-genomic data implicate NSCLC-related progenitors as a putative source of Rb-proficient SCLC. Consistent upstream Rb inactivation via CDKN2A/p16↓ and CCND1/cyclinD1↑ suggests the potential utility of CDK4/6 inhibitors in this aggressive SCLC subset. The study also clarifies technical aspects of Rb status determination in clinical practice, highlighting the limitations of exon-only sequencing for RB1 interrogation. See related commentary by Mahadevan and Sholl, p. 4603

Supplementary Figure 8. Oncoprint plot showing the distribution of the most commonly mutated genes in NSCLCs with complete ATM loss by IHC (ATMLOST), intact ATM expression (ATMINTACT), and ATM heterogeneous loss (ATMHET LOST) by IHC.

Supplementary Figure 25. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ PD1+ T cells according to ATM/TP53 co-mutation status. (D) Intratumoral, (E) tumor-stroma interface, and (F) total FOXP3+ immune cells according to ATM/TP53 co-mutation status.

Supplementary Table 6. Baseline clinicopathologic features of patients with ATM mutated NSCLC according ATM protein expression by immunohistochemistry.

Supplementary Figure 15. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to chemo-immunotherapy among patients with advanced/metastatic PD-L1 negative (

Supplementary Figure 16. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 inhibition monotherapy among patients with advanced/metastatic NSCLC, according to ATM/TP53 co-mutation status. (D) Objective response rate, (E) progression-free survival, and (F) overall survival to PD-(L)1 inhibition in combination with chemotherapy among patients with advanced NSCLC, according to ATM/TP53 co-mutation status.

Supplementary Figure 1. (A) ATM mutation classification schema (B) Lollipop plot of all 714 mutations in the ATM gene identified in the combined DFCI/MSK cohort. (C) Lollipop plot of all 152 benign mutations in the ATM gene identified in the combined DFCI/MSK cohort.

Supplementary Figure 11. Overall survival since the date of initial diagnosis among patients with stage IV NSCLC according to ATM mutation status.

Supplementary Figure 28. (A) Box-plot showing the distribution of tumor-infiltrating lymphocytes assessed using computational pathology algorithm in ATMMUT and ATMWT NSCLCs. (B) Box-plot showing the distribution of tumor-infiltrating lymphocytes assessed using computational pathology algorithm in according to ATM/TP53 co-mutation status in NSCLC.

Supplementary Figure 12. Disease-free survival and overall survival among patients with (A) stage I, (B) stage II, and (C) stage III NSCLC according to ATM expression by immunohistochemistry.

Purpose:ATM is the most commonly mutated DNA damage and repair gene in non–small cell lung cancer (NSCLC); however, limited characterization has been pursued.Experimental Design:Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets.Results:A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM–wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy.Conclusions:Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

Supplementary Table 1. Baseline clinicopathologic features of the 5172 patients with NSCLC which underwent comprehensive tumor genomic profiling at the Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center.

Supplementary Figure 6. (A) Tumor mutational burden and (B) PD-L1 tumor proportion score distributions according to ATM protein expression by IHC (lost versus intact).

Supplementary Figure 13. Overall survival since the date of initial diagnosis among patients with stage IV NSCLC according to ATM expression by immunohistochemistry.

Supplementary Figure 14. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 immune checkpoint blockade monotherapy among patients with advanced/metastatic PD-L1 negative (

Supplementary Figure 24. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ T cells according to ATM/TP53 co-mutation status. (D) Intratumoral, (E) tumor-stroma interface, and (F) total PD1+ immune cells according to ATM/TP53 co-mutation status.

Supplementary Figure 29. Box plot showing immune cell subsets significantly enriched among ATMMUT versus ATMWT NSCLC as assessed by deconvoluting bulky RNAseq data from the TCGA-NSCLC dataset. Non-significant results are not shown.

Supplementary Figure 9. (A) Disease free- and overall survival among patients with (A) stage I, and (B) stage II NSCLC according to ATM mutation status.

Supplementary Figure 18. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 immune checkpoint blockade monotherapy among patients with ATMMUT NSCLC, according to STK11 mutation. (D) Objective response rate, (E) progression-free survival, and (F) overall survival to PD-(L)1 immune checkpoint blockade in combination with platinum doublet chemotherapy among patients with ATMMUT NSCLC, according to STK11 mutation.

Supplementary Figure 27. Tumor mutational burden in NSCLC samples which underwent NGS at the DFCI and MSK according to ATM/TP53 co-mutation status.

Supplementary Figure 3. Co-mutation plot showing co-occurrent and mutual exclusive mutations among (A) ATMMUT and (B) ATMWT NSCLCs.

Supplementary Figure 23. Correlation of intratumoral, tumor-stroma interface, and total CD8+, PD1+, CD8+PD1+, FOXP3+ T cells and tumoral and non-tumoral PD-L1+ cells among ATMMUT NSCLCs.

Supplementary Figure 17. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 inhibition among patients with advanced/metastatic NSCLC, according to ATM expression by immunohistochemistry.

Supplementary Figure 7. (A) Histograms showing the distribution of deleterious class I and class II ATM mutations with lost or intact ATM protein expression by IHC. (B) Histograms showing the distribution of deleterious missense, nonsense, splice site, and insertion/deletion mutations with lost or intact ATM protein expression by IHC. (C) proportion of NSCLCs with predicted benign and predicted pathogenic ATM missense mutations with lost and intact ATM expression by IHC.

Supplementary Table 4. Baseline clinicopathologic features of patients with ATM mutated NSCLC according ATM protein expression by immunohistochemistry.

Supplementary Figure 20. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ T cells in ATMMUT and ATMWT NSCLCs. (D) Intratumoral, (E) tumor-stroma interface, and (F) total PD1+ immune cells in ATMMUT and ATMWT NSCLCs.

Supplementary Table 2. List of potential ATM germline variants identified among 3800 patients with NSCLC at the DFCI

Supplementary Table 5. List of ATM mutations with matched IHC

Supplementary Table 3. Baseline clinicopathologic features of patients with ATMMUT and ATMWT NSCLC at the Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center.

Supplementary Figure 10. (A) Progression-free and (B) overall survival among all patients with stage III NSCLC according to ATM mutation status. (C) Progression-free and (D) overall survival among patients with stage III NSCLC who received concurrent chemoradiotherapy followed by durvalumab maintenance according to ATM mutation status.

Supplementary Table 7. Baseline clinicopathologic features of patients with ATM mutated and ATM wild-type NSCLCs which underwent multiplexed immunofluorescence at the DFCI.

Supplementary Figure 19. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 immune checkpoint blockade monotherapy among patients with ATMMUT NSCLC, according to KEAP1 mutation. (D) Objective response rate, (E) progression-free survival, and (F) overall survival to PD-(L)1 immune checkpoint blockade in combination with platinum doublet chemotherapy among patients with ATMMUT NSCLC, according to KEAP1 mutation status

Supplementary Figure 26. Proportion of (A) tumor, (B) non-tumor, and (C) total PD-L1+ cells according to ATM/TP53 co-mutation status.

Supplementary Figure 21. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ PD1+ T cells in ATMMUT and ATMWT NSCLCs. (D) Intratumoral, (E) tumor-stroma interface, and (F) total FOXP3+ immune cells in ATMMUT and ATMWT NSCLCs.

Supplemental Figure 1. Dose modifications of Combination Osimertinib and Dacomitinib (initial therapy study).