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Introduction: Patients with oligometastatic NSCLC benefit from locally ablative therapies (LAT); the role of adjuvant systemic therapies, however, remains less clear. In a single-arm, phase II clinical trial, we found that patients with oligometastatic NSCLC treated with a year of pembrolizumab after LAT had superior progression-free survival (PFS) compared with a historical control cohort. Herein, we present long-term follow-up on PFS and overall survival (OS)., Methods: From February 1, 2015, to September 30, 2017, 45 patients with synchronous or metachronous oligometastatic (≤4 metastatic sites) NSCLC treated with LAT to all sites received adjuvant pembrolizumab every 21 days for up to 16 cycles. The primary efficacy end point was PFS from the start of pembrolizumab. Secondary end points included OS and safety. Median duration of follow-up was 66 months, and data cutoff was December 1, 2022., Results: A total of 45 patients were enrolled and treated with pembrolizumab after LAT (median age, 64 y [range, 46-82]; 21 women [47%]; 31 with a solitary oligometastatic site [69%]). At the data cutoff, 32 patients had progressive disease, 19 patients had died, and 13 patients had no evidence of relapse. Median PFS was 19.7 months (95% confidence interval: 7.6-31.7 mo); median OS was not reached (95% confidence interval: 37.7 mo-not reached). OS at 5 years was 60.0% (SE, 7.4%). Metachronous oligometastatic disease was associated with improved OS and PFS through Cox proportional hazard models., Conclusions: Pembrolizumab after LAT for oligometastatic NSCLC results in promising PFS and OS with a tolerable safety profile., Competing Interests: Dr. Cantor reports receiving honoraria from HMP. Dr. Aggarwal reports receiving institutional research funding from 10.13039/100004325AstraZeneca, 10.13039/100004328Genentech, 10.13039/100017655Incyte, 10.13039/100019794Macrogenics, 10.13039/501100004628Medimmune, and 10.13039/100009947Merck Sharp and Dohme, and receiving consultation fees from Genentech, Lilly, Celgene Merck, AstraZeneca, Blueprint Genetics, Shionogi, Daiichi Sankyo, Regeneron, Sanofi, Eisai, BeiGene, Turning Point, Pfizer, Janssen, and Boehringer Ingelheim. Dr. Evans reports receiving honoraria from Merck. Dr. Cohen reports receiving institutional research funding from F-Star Biotechnology, Innate Biopharma, and Cantargia. Dr. Bauml is currently employed by Janssen Research and Development but all work for this study was done as an employee at the University of Pennsylvania, and reports owning stock in Johnson & Johnson. Dr. Langer reports receiving institutional research funding from AstraZeneca, Eli Lilly, 10.13039/501100002424Fujifilm, 10.13039/100008897Janssen Pharmaceuticals, 10.13039/100016255Inovio, 10.13039/100004334Merck, Oncocyte, Takeda, and Trizell; receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Roche, Gilead, GlaxoSmithKline, Merck, Mirati, Novocure, Pfizer, Regeneron, Sanofi-Aventis, and Takeda; and having participation on a safety monitoring board or advisory board for Amgen, OncocyteDX, the Radiation Therapy Oncology Group Foundation, and the Veterans Administration. The remaining authors declare no conflict of interest., (© 2024 by the International Association for the Study of Lung Cancer.)

Background: In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC)., Methods: Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon's 2-stage phase II clinical trial design was used, with an α error of 5% and a power β of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion., Results: Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met., Conclusion: The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068)., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare variant of malignant mesothelioma, representing 10-15% of malignant mesothelioma cases. The preferred therapeutic approach is cytoreductive surgery (CRS) accompanied by hyperthermic intraperitoneal chemotherapy (HIPEC); the role of systemic chemotherapy is not well established. While some limited retrospective studies report worse outcomes with neoadjuvant chemotherapy, our institution has favored the use of neoadjuvant chemotherapy for symptom relief and surgical optimization. The aim of our study was to assess the outcomes of patients receiving neoadjuvant chemotherapy, compared to those receiving adjuvant or no perioperative chemotherapy., Patients and Methods: We conducted a single-center retrospective cohort study of treatment-naïve, non-papillary DMPM patients seen at our institution between 1/1/2009 and 9/1/2019. We explored the effect of type of systemic therapy on clinical outcomes and estimated median overall survival (mOS) using Kaplan-Meier curves. Hazard ratios (HR) calculated by Cox proportional hazard model were used to estimate effect of the exposures on overall survival., Results: 47 patients were identified with DMPM (median age at diagnosis 61.2 years, 76.6% epithelioid histology, 74.5% white race, 55.3% known asbestos exposure). CRS was performed in 53.2% of patients (25/47); 76.0% of surgical patients received HIPEC (19/25). The majority received systemic chemotherapy (37/47, 78.7%); among patients receiving both CRS and chemotherapy, neoadjuvant chemotherapy was more common than adjuvant chemotherapy (12 neoadjuvant, 8 adjuvant). Overall mOS was 84.1 months. Among neoadjuvant patients, 10/12 underwent surgery, and 2 were lost to follow-up; the majority (9/10) had clinically stable or improved disease during the pre-operative period. There were numerical more issues with chemotherapy with the adjuvant patients (4/8: 2 switches in platinum agent, 2 patients stopped therapy) than with the neoadjuvant patients (2/10: 1 switch in platinum agent, 1 delay due to peri-procedural symptoms). Neoadjuvant chemotherapy was not associated with worse mOS compared to adjuvant chemotherapy (mOS NR vs 95.1 mo, HR 0.89, 95% CI 0.18-4.5, p = 0.89)., Conclusions: When used preferentially, the use of neoadjuvant chemotherapy in DMPM patients was not associated with worse outcomes compared to adjuvant chemotherapy. It was well-tolerated and did not prevent surgical intervention., Competing Interests: Melina E. Marmarelis reports researching funding from Eli Lilly (Inst), Trizell (Inst), AstraZeneca (Inst); consulting role with Novocure, Boehringer Ingelheim; stock in Gilead Sciences, Portola Pharmaceuticals, Merck, Bluebird Bio, Johnson & Johnson, Pfizer; and previous medical writing support from Novartis. Christine A. Ciunci reports research funding from Celgene (Inst), Merck (Inst), Bristol-Myers Squibb (Inst), MacroGenics (Inst); and honoraria from Imedex. Corey J. Langer reports research funding from Merck (Inst), Advantagene (Inst), Clovis Oncology (Inst), Celgene (Inst), Inovio Pharmaceuticals (Inst), ARIAD (Inst), GlaxoSmithKline (Inst), Genentech/Roche (Inst), Stem CentRx (Inst), Lilly, Trizell (Inst); honoraria from Bristol-Myers Squibb, Genentech/Roche, Lilly/ImClone, AstraZeneca, Takeda Science Foundation; consulting roles with Genentech/Roche, Lilly/ImClone, Merck, Abbott Biotherapeutics, Bayer/Onyx, Clarient, Clovis Oncology, Celgene, Cancer Support Community, Bristol-Myers Squibb, ARIAD, Takeda, AstraZeneca, Pfizer, Novocure, Gilead Sciences; and other relationships with Lilly, Amgen, Peregrine Pharmaceuticals, Synta. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Immunotherapy has prolonged the time that NSCLC patients are off platinum-based (PB) chemotherapy. However, the significance of the platinum-free-interval (PFI) is unclear. We evaluated whether an optimal PFI exists in NSCLC for PB re-exposure in contemporary treatment settings., Methods: We conducted a retrospective cohort study of patients with metastatic NSCLC treated with 1st-line PB chemotherapy with or without immunotherapy. Using multivariable Cox models stratified by treatment strategies, we evaluated whether salvage PB vs. nonPB chemotherapy resulted in superior outcomes and whether this was modulated by the PFI., Results: A total of 751 patients treated with salvage chemotherapy after PB chemoimmunotherapy were identified in 2 treatment strategy cohorts: 3rd-line after sequential chemotherapy and immunotherapy (Sequential Chemo IO, n = 604); 2ndline after chemoimmunotherapy (Concurrent ChemoIO, n = 147). An optimal PFI of 5 and 6 months was identified in the Sequential Chemo IO and Concurrent ChemoIO cohorts, respectively, but there was no overall survival or progression free survival advantage for PB vs. nonPB chemotherapy in long or short PFI groups., Conclusion: An optimal PFI was identified in this contemporary NSCLC cohort treated with two common immunotherapy-containing treatment approaches, but PFI threshold did not predict benefit from platinum re-exposure as it has in other malignancies., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: There are no established imaging biomarkers that predict response during chemoradiation for patients with locally advanced non-small cell lung carcinoma. At our institution, proton therapy (PT) patients undergo repeat computed tomography (CT) simulations twice during radiation. We hypothesized that tumor regression measured on these scans would separate early and late responders and that early response would translate into better outcomes., Methods and Materials: Patients underwent CT simulations before starting PT (CT0) and between weeks 1 to 3 (CT1) and weeks 4 to 7 (CT2) of PT. Primary tumor volume (TVR) and nodal volume (NVR) reduction were calculated at CT1 and CT2. Based on recursive partitioning analysis, early response at CT1 and CT2 was defined as ≥20% and ≥40%, respectively. Locoregional and overall progression-free survival (PFS), distant metastasis-free survival, and overall survival by response status were measured using Kaplan-Meier analysis., Results: Ninety-seven patients with locally advanced non-small cell lung carcinoma underwent definitive PT to a median dose of 66.6 Gy with concurrent chemotherapy. Median TVR and NVR at CT1 were 19% (0-79%) and 19% (0-75%), respectively. At CT2, they were 33% (2-98%) and 35% (0-89%), respectively. With a median follow-up of 25 months, the median overall survival and PFS for the entire cohort was 24.9 and 13.2 months, respectively. Compared with patients with TVR and NVR <20% at T1 and <40% at T2, patients with TVR and NVR ≥20% at CT1 and ≥40% at CT2 had improved median locoregional PFS (27.15 vs 12.97 months for TVR ≥40% vs <40%, P < .01, and 25.67 vs 12.09 months for NVR ≥40% vs <40%, P < .01) and median PFS (22.7 vs 9.2 months, P < .01, and 20.3 vs 7.9 months, P < .01), confirmed on multivariate Cox regression analysis., Conclusions: Significantly improved outcomes in patients with early responses to therapy, as measured by TVR and NVR, were seen. Further study is warranted to determine whether treatment intensification will improve outcomes in slow-responding patients., (Copyright © 2019. Published by Elsevier Inc.)

Importance: Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from locally ablative therapy (LAT) such as surgery or stereotactic radiotherapy. Prior studies were conducted before the advent of immunotherapy, and a strong biological rationale for the use of immunotherapy exists in a minimal residual disease state., Objective: To evaluate whether the addition of pembrolizumab after LAT improves outcomes for patients with oligometastatic NSCLC., Design, Setting, and Participants: This single-arm phase 2 trial of pembrolizumab therapy was performed from February 1, 2015, through September 30, 2017, at an academic referral cancer center. The 51 eligible patients enrolled had oligometastatic NSCLC (≤4 metastatic sites) and had completed LAT to all known sites of disease. Data were analyzed from February 1, 2015, to August 23, 2018., Interventions: Within 4 to 12 weeks of completing LAT, patients began intravenous pembrolizumab therapy, 200 mg every 21 days, for 8 cycles, with provision to continue to 16 cycles in the absence of progressive disease or untoward toxic effects., Main Outcomes and Measures: The 2 primary efficacy end points were progression-free survival (PFS) from the start of LAT (PFS-L), which preceded enrollment in the trial, and PFS from the start of pembrolizumab therapy (PFS-P). The study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included overall survival, safety, and quality of life as measured by the Functional Assessment of Cancer Therapy-Lung instrument., Results: Of 51 patients enrolled, 45 (24 men [53%]; median age, 64 years [range, 46-82 years]) received pembrolizumab. At the time of analysis, 24 patients had progressive disease or had died. Median PFS-L was 19.1 months (95% CI, 9.4-28.7 months), significantly greater than the historical median of 6.6 months (P = .005). Median PFS-P was 18.7 months (95% CI, 10.1-27.1 months). Eleven patients died. Overall mean (SE) survival rate at 12 months was 90.9% (4.3%); at 24 months, 77.5% (6.7%). Neither programmed death ligand 1 expression nor CD8 T-cell tumor infiltration was associated with PFS-L. Pembrolizumab after LAT yielded no new safety signals and no reduction in quality of life., Conclusions and Relevance: Pembrolizumab after LAT for oligometastatic NSCLC appears to improve PFS with no reduction in quality of life., Trial Registration: ClinicalTrials.gov identifier: NCT02316002.

Background: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches., Methods: We examined outcomes of patients with stage III-IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression., Results: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss., Conclusion: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS., (Published by Oxford University Press 2018.)

Purpose: The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non-small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations., Methods: We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS)., Results: From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/KRAS, 18 had STK11/TP53, and seven had STK11/KRAS/TP53. Patients with STK11/KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/TP53 (4.3 months; log-rank P = .043), and STK11/KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/TP53 (28.3 months; log-rank P < .001), and STK11/KRAS/TP53 (22 months; log-rank P = .025)., Conclusion: Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Purpose: TP53 mutation (MT) in epidermal growth factor receptor ( EGFR ) -MT non-small cell lung cancer (NSCLC) is associated with poor response to targeted therapy; however, its impact on survival is not clearly established., Patients and Methods: We performed an analysis of patients with stage IV EGFR MT NSCLC with available gene sequencing data. Associations between baseline characteristics; molecular profile, including TP53 MT; and survival outcomes were assessed., Results: We identified 131 consecutive patients with EGFR MT; 81 (62%) had a TP53 MT, and 55 (42%) had other coexisting oncogenic MTs. Emergent EGFR T790M MT was observed in 42 patients (32%). Overall survival (OS) was longer for younger patients ( P = .003), never smokers ( P = .002), those with Eastern Cooperative Oncology Group performance status 0 to 1 ( P = .004), and emergent T790M MT ( P = .018). TP53 MT ( P = .021) and other coexisting oncogenic MTs ( P = 0.011) were associated with inferior OS. In a multivariable regression analysis adjusted for age, smoking, Eastern Cooperative Oncology Group performance status, and the presence of TP53 MT ( P = .063) and other coexisting MTs ( P = .064) did not achieve statistical significance. Patients with EGFR T790M /TP53 double MT had worse OS compared with patients with T790M MT alone (46.4 months v 82.9 months). In our series, five patients transformed to small-cell lung cancer (5.6%). All had TP53 MT. In four patients, allelic fraction of TP53 MT increased at the time of transformation., Conclusion: The presence of TP53 and other coexisting MTs in EGFR MT NSCLC were associated with inferior OS, including patients with emergent T790M MT. An increase in TP53 mutation allelic fraction may potentially be a useful clinical predictor of small-cell transformation., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC). However, thus far, its use has only been established in patients with advanced disease either as first-line therapy in selected patients or following chemotherapy. What is not yet known is how best to incorporate radiation with immunotherapy agents. Many patients with advanced disease can benefit from palliative radiation, but the combination of radiation with immunotherapy has the potential to increase the toxicity of both modalities. Intriguingly, the combination also has the potential to enhance the efficacy of both modalities. For this reason, combining immunotherapy and radiation may help salvage patients with recurrent localized disease who are candidates for re-irradiation. We review the current data evaluating immunotherapy with both palliative radiation as well as definitive re-irradiation in NSCLC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objectives: The management of recurrent NSCLC in the setting of prior radiation therapy is challenging. Proton radiotherapy (PRT) is ideally suited to minimize toxicity to previously irradiated organs. We report the safety/feasibility of PRT for NSCLC reirradiation in a prospective multi-institutional study., Materials and Methods: Between October 2010 and December 2015, 57 patients with recurrent NSCLC in or near their prior radiation field were treated at three proton centers. Patients were classified by tumor volume, location, and clinical characteristics. Toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Survival outcomes were estimated by using Kaplan-Meier analysis., Results: Fifty-two patients (93%) completed the reirradiation course. Their median age was 65 years (41-86). Patients with high tumor volume (clinical target volume-to-internal target volume ratio ≥250 cm 3 ) were closed to enrollment owing to infeasibility in August 2012. Concurrent systemic therapy was delivered to 67% of patients. Fourteen patients (25%) had evidence of local (n = 9) or regional (n = 5) recurrence. Distant metastases after reirradiation developed in six patients (11%). The 1-year rates of overall and progression-free survival were 59% and 58%, respectively. In total, grade 3 or higher acute and/or late toxicity developed in 24 patients (42%), acute toxicity developed in 22 (39%), and late toxicity developed in seven (12%). Six grade 5 toxicities were observed. Increased overlap with the central airway region, mean esophagus and heart doses, and concurrent chemotherapy were associated with significantly higher rates of grade 3 or higher toxicity. Decreased overall survival was seen with increased mean esophagus dose (p = 0.007)., Conclusions: In this prospective study, PRT for recurrent NSCLC is feasible but can be associated with significant toxicity. Providers should remain cautious in reirradiating NSCLC, paying close consideration to tumor volume, location, and relevant dosimetric parameters. Further research is needed for optimal patient selection to improve overall outcomes., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: The expanding number of targeted therapeutics for non-small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS., Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible., Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible., Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772-82. ©2016 AACR., (©2016 American Association for Cancer Research.)