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Introduction Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially. Methods We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models. Results We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0). Conclusion Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis.

Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.

PURPOSE Local consolidative therapy (LCT) for patients with synchronous oligometastatic non–small-cell lung cancer is an evolving treatment strategy, but outcomes following LCT stratified by genetic mutations have not been reported. We sought to identify genomic associations with overall survival (OS) and progression-free survival (PFS) for these patients. METHODS We identified all patients presenting between 2000 and 2017 with stage IV non–small-cell lung cancer and ≤ 3 synchronous metastatic sites. Patients were grouped according to mutational statuses. Primary outcomes included OS and PFS following initial diagnosis. RESULTS Of 194 included patients, 121 received comprehensive LCT to all sites of disease with either surgery or radiation. TP53 mutations were identified in 40 of 78 (55%), KRAS in 32 of 95 (34%), EGFR in 24 of 109 (22%), and STK11 in nine of 77 (12%). At median follow-up of 96 months, median OS and PFS were 26 (95% CI, 23 to 31) months and 11 (95% CI, 9 to 13) months, respectively. On multivariable analysis, patients with EGFR mutations had lower mortality risk (hazard ratio [HR], 0.53; 95% CI, 0.29 to 0.98; P = .044) compared with wild-type patients, and patients with STK11 mutations had higher risk of progression or mortality (HR, 2.32; 95% CI, 1.12 to 4.79; P = .023) compared with wild-type patients. TP53 and KRAS mutations were not associated with OS or PFS. Among 71 patients with known EGFR mutational status who received comprehensive LCT, EGFR mutations were associated with lower mortality compared with wild-type (HR, 0.45; 95% CI, 0.22 to 0.94; P = .032). CONCLUSION When compared with wild-type patients, those with EGFR and STK11 mutations had longer OS and shorter PFS, respectively. EGFR mutations were associated with longer OS among oligometastatic patients treated with comprehensive LCT in addition to systemic therapy.

Purpose: RET fusions drive oncogenesis in 1-2% of non-small cell lung cancer (NSCLC) and are sensitive to the selective RET inhibitors selpercatinib and pralsetinib. They have also emerged as mechanisms of acquired resistance to other targeted therapies. The genomic landscape of RET fusions and the impact of co-occurring genomic alterations on the efficacy of selective RET inhibitors is yet to be fully described. Methods: A total of 678 RET fusion-positive samples were analyzed from three cohorts: Guardant360® circulating tumor DNA (ctDNA) (n=467), tissue and/or plasma from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) non-squamous NSCLC cohort (n=161), and the MD Anderson Cancer Center (MDACC) cohort of patients treated with selpercatinib or pralsetinib (n=50). Molecular characteristics were compared across all three cohorts and to the entire non-RET non-squamous NSCLC AACR Project GENIE cohort (n=17770). Fisher’s exact test was used to evaluate the difference in response rate between patient groups, and Cox proportional hazard models were used to calculate hazard ratios for time-to-event endpoints for patients in the MDACC clinical cohort (n=51, 50 patients with RET fusion, 1 patient with RET point mutation). Results: The most common fusion partner in all cohorts was KIF5B (ctDNA: 73%; GENIE: 69%; MDACC: 71%), followed by CCDC6 (19%; 17%; 18%) and NCOA4 (5%; 1%; 7%). Across all cohorts, co-mutations in TP53 were most common (60%; 34%; 40%) and EGFR, CDKN2A/B, MET, and ATM consistently co-occurred across all cohorts. EGFR co-occurred more frequently with non-KIF5B fusion partners (chi-square p < 0.006). MYC and CCND1 amplifications were enriched in all three cohorts compared to the non-RET cohort. In the MDACC clinical cohort (n=51), the majority were female, never-smokers, with adenocarcinoma histology. The median follow-up time was 28.3 months (95% CI: 15.2 ~ 35 months). Overall response rate (ORR) was 74.4% (95% CI: 58.8 ~ 86.5%), where patients with TP53 mutation had numerically lower ORR compared to patients without TP53 mutation (58.5% vs. 87.5%; p = 0.0632). Median progression-free survival (PFS) time was 16.5 months (95% CI: 13.5 ~ 27.4 months) and KIF5B fusions trended towards worse PFS outcome compared to non-KIF5B fusions (HR: 2.24; 95% CI: 0.88 ~ 5.67; p = 0.0896). TP53 alterations were associated with a significantly worse overall survival (OS) (HR: 2.93; 95% CI: 1.08 ~ 7.95; p = 0.0346). Conclusion: In the largest RET fusion-positive NSCLC cohort to date, RET fusions frequently co-occurred with other genomic alterations, most commonly in TP53. TP53 alterations are associated with a significant reduction in overall survival in patients treated with the selective RET inhibitors. Additional analysis is underway. Citation Format: Tuqa Al Khalaf, Simon Heeke, Lei Feng, Leylah M. Drusbosky, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Jack Lee, Jianjun Zhang, Don Gibbons, Ara Vaporciyan, Vincent Lam, Vivek Subbiah, John Heymach, Yasir Elamin. The genomic landscape of RET fusions in non-small cell lung cancer and the impact of co-occurring genomic alterations on the efficacy of selective RET inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4264.

BackgroundWhile the clinical outcomes of immune checkpoint inhibitor (ICI) use in older adults with advanced-stage non-small cell lung cancer (NSCLC) have been described, the role of ICI use continued beyond disease progression (BDP) remains to be well defined for this population. This retrospective single-center study explored the clinical outcomes of continuing ICIs BDP among older adult patients with advanced NSCLC.MethodsUsing MD Anderson’s Gemini Lung Cancer database, we retrospectively reviewed the clinical outcomes of older adults (≥70 years) diagnosed with advanced-stage NSCLC treated with anti-PD-(L)1 monotherapy from March 2015 through April 2019 to correlate clinicopathologic features with clinical outcomes. Clinical therapy responses were evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Toxicities were assessed using Common Terminology Criteria for Adverse Events (CTCAE), version 5. Patients treated BDP were defined as individuals receiving ICIs for ≥8 weeks prior to documentation of progression who subsequently remained on ICIs for ≥6 weeks.ResultsOf the 159 older adults meeting the inclusion criteria, 33 (21%) received ICIs BDP (64% male, median age 74.9 years (70.1–82.0) at the start of ICI treatment, 3 received first-line ICI therapy). Most patients were former (85%) or current (6%) smokers. 79% had adenocarcinoma histology. The median duration of immunotherapy continued BDP was 7.1 months (95% CI: 3.0–8.2). After a follow-up of 30.1 months, the median overall survival (mOS) was 31.5 months (95% CI: 16.5-not reached). Eight (24%) received local consolidative radiotherapy with a median duration of ICI BDP of 8.2 months (95% CI: 1.9–13.3). Twenty-five (76%) did not receive local consolidative therapy and achieved a median duration of ICI BDP of 4.1 months (95% CI: 2.3–7.8). Six (18%) exhibited pseudo-progression (i.e. delayed response to immunotherapy with decreased tumor burden on subsequent radiologic studies), with 4 achieving ”stable disease” as best response and 2 achieving a partial response. The median duration of immunotherapy continued beyond pseudo-progression was 11.7 months (95% CI: 7.1–35.7), and the mOS was 26.2 months (95% CI: 16.5–40.0). Patients treated with ICI BDP most commonly experienced fatigue (18%), pneumonitis (12%), rash (9%), and hypothyroidism (9%). Three patients (9%) experienced grade 3 or higher toxicities (one grade 3 arthralgias and two grade 3 pneumonitis).ConclusionsICI-use BDP in older adults with advanced NSCLC may benefit a subset of patients. Additionally, local consolidative therapy with radiation may offer prolonged duration of ICI treatment.AcknowledgementsSupported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Moon Shot Program and the MD Anderson Cancer Center Support Grant P30 CA01667. Special acknowledgment to the GEMINI team.Ethics ApprovalThis study was approved and conducted in accordance with the institutional review board at the University of Texas MD Anderson Cancer Center; approval number (PA13-0589).

As a result of the approval of several immune checkpoint inhibitors (ICIs) for the treatment of non-small cell lung cancer (NSCLC), many older adults are being treated with ICIs. Older adults are underrepresented in most pharmaceutical clinical trials. Therapy outcomes in this population with ICIs is particularly important since, age related factors may have an influence on the immune system.We utilized the MD Anderson Cancer Center Gemini Team's Lung Cancer Database to retrospectively study patients ≥70 years of age with advanced NSCLC treated with anti-PD-(L)1 monotherapy to look at the clinical outcomes.179 patients met the inclusion criteria for this retrospective analysis. There were 106 men and 73 women. The median age of the cohort was 74.9 years, and overall survival was 20.6 months. 27.6% of all patients had an objective response to therapy. In 33 patients who had radiological progression, treatment continued beyond progression due to clinical benefit. In this group, 6 patients had subsequent improvement in radiologic assessment. Age groups were not significantly associated with differences in clinical outcomes.This study suggests that anti-PD-(L)1 monotherapy is effective and well tolerated among older adults with advanced NSCLC. While pseudoprogression is rare, treatment beyond progression may provide clinical benefit in a subset of patients and warrants further investigation.