Search

GT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a "3 + 3" schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103. Secondary objectives included describing objective response rate, progression-free survival and overall survival. Dose escalation cohorts included GT103 given intravenously at 0.3, 1, 3, 10, and 15 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. Thirty one patients were enrolled across 3 institutions. Two dose-limiting adverse events were reported: grade 3 acute kidney injury (0.3 mg/kg) and grade 2 colitis (1 mg/kg). No dose-limiting toxicities were noted at the highest dose levels and the MTD was not reached. No objective responses were seen. Stable disease occurred in 9 patients (29%) and the median overall survival was 25.7 weeks (95% confidence interval [CI], 19.1-30.6). Pharmacokinetic analysis confirmed an estimated half life of 6.5 days. The recommended phase 2 dose of GT103 was 10 mg/kg every 3 weeks, however further dose optimization is needed given the absence of an MTD. The study achieved its primary objective of demonstrating safety and tolerability of GT103 in refractory NSCLC., Competing Interests: Competing interests: This research was supported by Grid Therapeutics. Drs. Patz, Campa, and Gottlin have affiliation with both Grid Therapeutics and Duke University. JMC reports trial funding from Bristol-Myers Squibb, Genentech, Spectrum, Adaptimmune, AbbVie, Moderna, GlaxoSmithKline, Array, AstraZeneca, Grid Therapeutics, Abel Zeta, Pfizer; advisory/consulting from AstraZeneca, Merck, Pfizer, Spectrum, Genentech, Novartis, Turning Point, G1 Therapeutics, Vivacitas, Omega, Amgen, Corbus, Sanofi; speaking and travel from Merck and Amgen; DSMB from BioThera and G1 Therapeutics. GS reports speaking for Astra-Zeneca, consulting for Daiichi Sankyo, board member for Florida chapter of ASCO, and stock Options and consulting compensation for Onc.AI. HM reports advisory board for AstraZeneca, Genentech, and Daiichi Sankyo; and research funding from AstraZeneca. TS reports clinical trial funding from AstraZeneca, Seagen, Mirati Therapeutics, Genentech/Roche, Nuvalent, Inc.; consulting from Takeda, G1 Therapeutics, Spectrum Pharmaceuticals, Gilead Sciences, AstraZeneca, Coherus Biosciences, Blueprint Medicines, Boehringer Ingelheim, Pfizer, Abbvie; travel funding from Pfizer; DSMB participation from Genentech. NR reports advisory compensation from BMS, Merck, Jazz, Genentech, Daiichi, Regeneron, ABBVIE, research funding Merck, Regeneron, and speaking from Jazz. JC reports Scientific Advisor from Actimed, Enzychem, Gen Sci, Pfizer, Tensegrity; DSMB Member of BioAtla, G1 Therapeutics; PI/Institutional Research Funding for AstraZeneca, Helsinn, Pfizer, NCI/NCTN; Publications Committee of Amgen, Frensenius-Kabi, G1, Pfizer. GS reports advisory board from EMD Serono, BMS, Merck, Seattle Genetics, Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly, Loxo Oncology, Vial, Aktis, Daiichi-Sankyo; Consultant/Scientific Advisory Board (SAB)/trial steering committee: Syapse, Merck, Servier, Syncorp, Ellipses; Research Support to institution from EMD Serono, Jazz Therapeutics, Bayer, Sumitomo Pharma, Blue Earth Diagnostics; Speaker from Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Pfizer, Merck; Data safety monitoring committee (honorarium) from Mereo; Employment: Spouse employed by Myriad, Exact Sciences; and Travel: BMS, Astellas. SB receives support from the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance (CARRA), serves on an NIH DSMB, and consults for UCB (Morrisville, NC, USA), CARRA, and Rutgers University. Stephen Balevic is a member of the American College of Rheumatology, the Childhood Arthritis and Rheumatology Research Alliance (CARRA), Alpha Omega Alpha, the American Society of Clinical Investigators, and the Society for Pediatric Research, and served as the Assistant Scientific Director for CARRAAN reports funding from Genentech, Genmab, MedImmune/AstraZeneca, Seattle Genetics; consulting from Sanofi, Promega; SAB from Leap Therapeutics; NCI Chair, Core Correlatives Sciences Committee (NCTN-CCSC); and patents of No 925592 and No. 62/337,633. MC is a founder of Grid Therapeutics, LLC and is on the advisory board. EBG is a founder of Grid Therapeutics, LLC. SA reports being member of scientific advisory boards for Cellepus Therapeutics (and Co-founder), Leap Therapeutics, Guardian Bio, Immutep, Shoreline Therapeutics, Tubulis, Xilis, Glympse Bio, Achilles Therapeutics, Memgen, RAPT Biotherapeutics. EFP is a founder, CEO and on the BOD of Grid Therapeutics, LLC. All other authors report no competing interests., (© 2024. The Author(s).)

Background: CALGB 30610 trial demonstrated that once daily thoracic radiotherapy (TRT) was not superior compared to standard twice daily TRT, in patients with limited stage small cell lung cancer. Quality of life outcomes may help oncologists decide the best treatment approach., Methods: A total of 417 patients on CALGB 30610 participated in the quality-of-life substudy (CALGB 70702), which included the FACT Trial Outcome Index-Lung Cancer (FACT-L TOI), FACT-Esophageal Cancer (FACT-E) Eating and Swallowing Indices, ECOG Acute Esophagitis Scale, Hospital Anxiety and Depression Scale (HADS), difficulty swallowing, EQ-5D, and treatment convenience assessment at baseline, 3, 5, 7, 12, 26, and 52 weeks after starting TRT. Primary end points included FACT-L TOI and FACT-E at 12 weeks. Mean changes from baseline were compared between arms using general linear mixed models., Results: FACT-L worsening was more in the twice daily arm at week 3 (-1.0 vs. -7.0). FACT-L TOI worsening was less at week 3 (-2.9 vs. -7.6) and greater at week 12 (-7.6 vs. -2.8) in the once daily arm. The once daily arm had a lower EQ-5D index worsening at 3 weeks (0.01 vs. -0.02). Increase in acute esophagitis score (1.06 vs. 2.89; p < .001) and difficulty swallowing (0.39 vs. 1.14) were greater in the twice daily arm at week 3. A total of 74.5% of patients on the once daily arm felt that treatment was convenient, compared to 67% of patients in the twice daily arm (p = .03)., Conclusions: The once daily arm had better quality-of-life scores earlier during treatment and was perceived to be more convenient., (© 2024 American Cancer Society.)

Introduction: Stage IIIA non-small cell lung cancers (NSCLC) are treated with surgery-based multimodality approach or definitive chemoradiation therapy plus durvalumab consolidation. It is not clear whether surgery-based multimodality therapy has any survival advantage over definitive chemoradiation plus immunotherapy consolidation., Method: National Cancer Database (NCDB) was used to identify NSCLC patients at stage IIIA (AJCC8, T3N1/T4N0-1 or T1N2/T2N2) who are treated with surgery-based multimodality approach or definitive chemoradiation plus durvalumab. Survival between groups were compared using inverse probability treatment weighting (IPTW)-adjusted Kaplan Meier curves and Cox proportional hazards regression analysis. Results were independently confirmed by Landmark Inverse and Clone Censor Weight analyses to address immortal time bias., Results: From 2017 to 2019, 24,170 patients are identified as potentially resectable stage IIIA (T3N1, T4N0-1, T1N2/T2N2). Among them, 2,615 (10.8%) received surgery-based multimodality therapy and 2,985 (12.4%) received definitive chemoradiation plus durvalumab. Surgery based multimodality approach had significant survival advantage over definitive chemoradiation plus durvalumab (HR 0.74; 95% CI 0.69-0.79, P < .001). The median overall survival (mOS) for the definitive chemoradiation plus durvalumab group was 48.59 m whereas mOS was not reached for surgery-based multimodality group. This trend persisted in both N2 negative and positive tumors. Neoadjuvant chemotherapy was just as effective as adjuvant chemotherapy and delay of immunotherapy consolidation to 12 weeks after initiation of chemoradiation did not negatively affect survival outcome., Conclusion: For stage IIIA NSCLC patients, surgery-based multimodality treatment outperformed chemoradiation plus durvalumab in survival., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: The impact of patient-specific, disease-related, and social factors on outcomes in limited-stage small cell lung cancer (LS-SCLC) is not well defined. A post hoc secondary analysis of such factors from the Cancer and Leukemia Group B (CALGB) 30610-Radiation Therapy Oncology Group (RTOG) 0538 trial may impact future trial design., Objective: To assess the comprehensive demographic, disease-related, treatment-related, and social factors for potential associations with survival outcomes and understand whether specific subpopulations may benefit from radiotherapy (RT) dose escalation in LS-SCLC., Design, Setting, and Participants: This post hoc secondary analysis of a randomized clinical trial included 638 adults with LS-SCLC treated at 186 unique treatment sites with at least 1 accrual for all patients from March 15, 2008, to December 1, 2019; 313 patients were randomized to receive RT twice daily to a dosage of 45 Gy for 3 weeks and 325 to receive RT once daily to a dosage of 70 Gy for 7 weeks. Data were locked February 28, 2022, and analyzed from November 28, 2022, to June 4, 2024., Interventions: Twice-daily RT or once-daily RT., Main Outcomes and Measures: Multivariable Cox proportional hazards models evaluated the association of treatment groups and other risk factors with progression-free survival (PFS) and overall survival (OS). Patient-specific factors included age, sex, and Eastern Cooperative Oncology Group performance status. Disease-related factors included tumor, nodal, and overall cancer stages. Treatment-related factors included type of chemotherapy, timing of concurrent RT, RT technique, and prophylactic cranial irradiation. Social factors included marital status and treatment center accrual volume., Results: Among 507 patients (260 [51.3%] female and 247 [48.7%] male; mean [SD] age, 62.6 [7.9] years) included in the multivariate survival analysis, with a median follow-up of 4.7 (IQR, 3.7-7.1) years, female sex was associated with improved OS (hazard ratio [HR], 0.73 [95% CI, 0.58-0.91]; P = .006), while being 70 years or older was associated with decreased OS (HR, 1.50 [95% CI, 1.14-1.98]; P = .004). Neither age nor sex was associated with PFS. When compared with those with N1 disease, OS and PFS were worse in patients with N2 (HRs, 1.64 [95% CI, 1.19-2.26]; P = .002 and 1.36 [95% CI, 1.02-1.81]; P = .04, respectively) and N3 (HRs, 2.03 [95% CI, 1.40-2.93]; P < .001 and 1.63 [95% CI, 1.17-2.26]; P = .004) disease. Compared with stage II cancer, OS was worse for stage IIIA (HR, 1.65 [95% CI, 1.17-2.31]; P = .004) and stage IIIB (HR, 1.94 [95% CI, 1.34-2.83]; P < .001). Compared with high-volume accrual centers, treatment at low- or middle-volume accrual centers was associated with worse PFS (HRs, 1.94 [95% CI, 1.33-2.82; P < .001] and 1.44 [95% CI, 1.15-1.82; P = .002], respectively) and worse OS (HRs, 1.55 [95% CI, 1.03-2.32; P = .03] and 1.33 [95% CI, 1.04-1.70; P = .02], respectively)., Conclusions and Relevance: This secondary analysis of the CALGB 30610-RTOG 0538 randomized clinical trial of patients with LS-SCLC found associations between female sex or being younger than 70 years and improved overall survival and between advanced nodal stage or treatment at low- or middle-volume accrual centers and worse outcomes. These findings suggest that stratification by nodal stage, clinical stage, and age should be considered in future randomized trials., Trial Registration: ClinicalTrials.gov Identifier: NCT00632853.

Importance: Outcomes for patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiation therapy (CRT) have improved with adjuvant immune checkpoint inhibitors, with a reported 5-year overall survival benefit of approximately 10% for adjuvant durvalumab vs placebo after completion of CRT without progression and with preserved performance status. Starting atezolizumab prior to CRT may allow more patients to benefit from immunotherapy., Objective: To evaluate clinical outcomes of patients treated with atezolizumab before and after CRT for unresectable stage III NSCLC., Design, Setting, and Participants: This single-cohort, phase II, nonrandomized controlled trial was conducted at 11 US sites. Patients with pathologically confirmed, unresectable stage III NSCLC who were treatment naive and had good performance status were enrolled between January 3, 2018, and July 24, 2019. Data were locked on March 21, 2023., Interventions: Patients received four 21-day cycles of atezolizumab, 1200 mg intravenously, with therapy administered on day 1 of each cycle. Patients not experiencing tumor progression continued to CRT (60 Gy to involved fields) concurrent with weekly carboplatin area under the curve of 2 and paclitaxel, 50 mg/m2, followed by planned consolidation carboplatin area under the curve of 6 and paclitaxel, 200 mg/m2, for two 21-day cycles. Patients not experiencing progression continued atezolizumab, 1200 mg, every 21 days to complete 1 year of therapy., Main Outcomes and Measures: The primary end point was the disease control rate at 12 weeks. Secondary end points were progression-free survival, overall survival, overall response rate, safety, and translational science end points., Results: A total of 62 patients (median [range] age, 63.9 [38.1-86.5] years; 32 female [51.6%]) were enrolled and received at least 1 dose of atezolizumab. The disease control rate at 12 weeks was 74.2% (80% CI, 65.7%-81.4%). Median progression-free survival was 30.0 months (95% CI, 15.8 to not evaluable), and the median overall survival was not reached. The overall survival rate at 24 months was 73.7% (95% CI, 63.4%-85.7%), and the overall response rate was 66.2%. Seventeen patients (27.4%) experienced grade 3 or higher immune-related adverse events, including 1 with grade 5 pneumonitis and 1 with grade 4 Guillain-Barré syndrome. Thirty patients (48.4%) experienced grade 3 or higher treatment-related adverse events., Conclusions and Relevance: These findings suggest that neoadjuvant atezolizumab merits further study based on safety and encouraging outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT03102242.

Importance: The randomized clinical trial Cancer and Leukemia Group B (CALGB) 140503 showed that for patients with clinically staged T1N0 non-small cell lung cancer (NSCLC; ≤2 cm), sublobar resections were associated with similar oncological outcomes to those after lobar resection. The association of the extent of parenchymal resection with recurrence and survival in patients with tumors pathologically upstaged to T2 based on visceral pleural invasion (VPI) is controversial., Objective: To determine survival and recurrence rates in patients with small peripheral pT2 NSCLC (≤2 cm) that was treated by either lobar or sublobar resection in CALGB 140503., Design, Participants, and Setting: CALGB 140503, a randomized multicenter noninferiority trial, included 697 patients with small peripheral NSCLC that was clinically staged as T1N0. Enrollment was from June 2007 through March 2017 at 83 participating institutions, and after a median follow-up of 7 years, the primary outcome of disease-free survival after sublobar resection was noninferior to that after lobar resection., Intervention: Lobar or sublobar resection., Main Outcomes and Measures: Survival end points were estimated by the Kaplan-Meier estimator. Hazard ratios and 95% CIs were estimated using stratified Cox proportional hazard models., Results: Of 679 participants, 390 (57.4%) were female, and the median (range) age was 67.8 (37.8-89.7) years. Among 697 patients randomized, 566 (81.2%) had pT1 tumors (no VPI) and 113 (16.2%) had pT2 tumors (VPI). Five-year disease-free survival was 65.9% (95% CI, 61.9%-70.2%) in patients with pT1 compared with 53.3% (95% CI, 44.3%-64.1%) in patients with pT2 tumors (stratified log-rank: P = .02). Disease recurrence developed in 27.6% of patients with pT1 (locoregional only: 60 [10.8%]; distant only: 81 [14.6%]) and 41.6% of those with pT2 (locoregional only: 17 [15.0%]; distant only: 27 [23.9%]). Five-year recurrence-free survival was 73.1% (95% CI, 69.2%-77.1%) for pT1 tumors and 58.2% (95% CI, 49.2%-68.8%) for pT2 tumors (stratified log-rank: P = .01). There were no intergroup differences in disease-free or recurrence-free survival based on the extent of parenchymal resection., Conclusions and Relevance: The results of this secondary analysis suggest that compared with patients with tumors without VPI, patients who had tumors with VPI had worse disease-free and recurrence-free survival and a higher rate of local and distant disease recurrence. These high rates of recurrence were independent of the extent of parenchymal resection, and these data support the inclusion of these patients in adjuvant therapy trials., Trial Registration: ClinicalTrials.gov Identifier: NCT0049933.

Background: Despite surgical resection, long-term survival of patients with resectable non-small cell lung cancer (NSCLC) remains poor. Adjuvant chemotherapy, the standard of care for locally advanced NSCLC, provides a marginal 5.4% benefit in survival. Immune checkpoint inhibitors (ICIs) have shown a significant survival benefit in some patients with advanced NSCLC and are being evaluated for perioperative use in resectable NSCLC., Methods: We conducted a literature search using the PubMed online database to identify clinical trials of immunotherapy in resectable NSCLC and studies analyzing biomarkers and immune priming strategies., Results: Building on previous phase I and II trials, randomized phase III trials have shown efficacy of neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant atezolizumab, and adjuvant pembrolizumab in the treatment of NSCLC with improvement of event-free/disease-free survival of 24% to 42%, leading to United States Food and Drug Administration approval of these drugs in the treatment of resectable NSCLC. Three additional phase III trials have also recently reported the use of immunotherapy both before and after surgery, with pathologic complete response rates of 17% to 25%, significantly better than chemotherapy alone. Perioperative ICI therapy has comparable perioperative morbidity to chemotherapy alone and does not impair surgical outcomes., Conclusions: Perioperative immunotherapy, in combination with chemotherapy, is safe and improves outcomes in patients with resectable NSCLC. Questions regarding patient selection, the need for adjuvant ICI therapy after neoadjuvant chemoimmunotherapy, and the duration of perioperative immunotherapy remain to be answered by future trials., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Patients with early-stage non-small-cell lung cancer (NSCLC) who undergo curative surgical resection are at risk for developing second primary lung cancer (SPLC). Cancer and Leukemia Group B 140503 (Alliance) was a multicenter, international, randomized, phase III trial in patients with stage T1aN0 NSCLC (using the TNM staging system seventh edition) and demonstrated the noninferiority for disease-free survival between sublobar resection (SLR) and lobar resection (LR). After surgery, patients underwent computed tomography surveillance as defined by the protocol. The determination of a SPLC was done by the treating physician and recorded in the study database. We performed an analysis of the rate of SPLC (per patient per year) and the 5-year cumulative incidence in the study population and within the SLR and LR arms. Median follow-up was 7 years. The rate per patient per year in the study population, in the SLR arm, and in the LR arm was 3.4% (95% CI, 2.9 to 4.1), 3.8% (95% CI, 2.9 to 4.9), and 3.1% (95% CI, 2.4 to 4.1), respectively. The estimated 5-year cumulative incidence of SPLC in the study population, SLR arm, and LR arm was 15.9% (95% CI, 12.9 to 18.9), 17.2% (95% CI, 12.7 to 21.5), and 14.7% (95% CI, 10.6 to 18.7), respectively.

Background: We have recently reported the primary results of CALGB 140503 (Alliance), a randomized trial in patients with peripheral cT1aN0 non-small cell lung cancer (American Joint Committee on Cancer seventh) treated with either lobar resection (LR) or sublobar resection (SLR). Here we report differences in disease-free survival (DFS), overall survival (OS) and lung cancer-specific survival (LCSS) between LR, segmental resection (SR), and wedge resection (WR). We also report differences between WR and SR in terms of surgical margins, rate of locoregional recurrence (LRR), and expiratory flow rate at 6 months postoperatively., Methods: Between June 2007 and March 2017, a total of 697 patients were randomized to LR (n = 357) or SLR (n = 340) stratified by clinical tumor size, histology, and smoking history. Ten patients were converted from SLR to LR, and 5 patients were converted from LR to SLR. Survival endpoints were estimated using the Kaplan-Maier estimator and tested by the stratified log-rank test. The Kruskal-Wallis test was used to compare margins and changes in forced expiratory volume in 1 second (FEV1) between groups, and the χ 2 test was used to test the associations between recurrence and groups., Results: A total of 362 patients had LR, 131 had SR, and 204 had WR. Basic demographic and clinical and pathologic characteristics were similar in the 3 groups. Five-year DFS was 64.7% after LR (95% confidence interval [CI], 59.6%-70.1%), 63.8% after SR (95% CI, 55.6%-73.2%), and 62.5% after WR (95% CI, 55.8%-69.9%) (P = .888, log-rank test). Five-year OS was 78.7% after LR, 81.9% after SR, and 79.7% after WR (P = .873, log-rank test). Five-year LCSS was 86.8% after LR, 89.2% after SR, and 89.7% after WR (P = .903, log-rank test). LRR occurred in 12% after SR and in 14% after WR (P = .295). At 6 months postoperatively, the median reduction in % FEV1 was 5% after WR and 3% after SR (P = .930)., Conclusions: In this large randomized trial, LR, SR, and WR were associated with similar survival outcomes. Although LRR was numerically higher after WR compared to SR, the difference was not statistically significant. There was no significant difference in the reduction of FEV1 between the SR and WR groups., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Although level 1 evidence supports 45-Gy twice-daily radiotherapy as standard for limited-stage small-cell lung cancer, most patients receive higher-dose once-daily regimens in clinical practice. Whether increasing radiotherapy dose improves outcomes remains to be prospectively demonstrated., Methods: This phase III trial, CALGB 30610/RTOG 0538 (ClinicalTrials.gov identifier: NCT00632853), was conducted in two stages. In the first stage, patients with limited-stage disease were randomly assigned to receive 45-Gy twice-daily, 70-Gy once-daily, or 61.2-Gy concomitant-boost radiotherapy, starting with either the first or second (of four total) chemotherapy cycles. In the second stage, allocation to the 61.2-Gy arm was discontinued following planned interim toxicity analysis, and the study continued with two remaining arms. The primary end point was overall survival (OS) in the intention-to-treat population., Results: Trial accrual opened on March 15, 2008, and closed on December 1, 2019. All patients randomly assigned to 45-Gy twice-daily (n = 313) or 70-Gy once-daily radiotherapy (n = 325) are included in this analysis. After a median follow-up of 4.7 years, OS was not improved on the once-daily arm (hazard ratio for death, 0.94; 95% CI, 0.76 to 1.17; P = .594). Median survival is 28.5 months for twice-daily treatment, and 30.1 months for once-daily treatment, with 5-year OS of 29% and 32%, respectively. Treatment was tolerable, and the frequency of severe adverse events, including esophageal and pulmonary toxicity, was similar on both arms., Conclusion: Although 45-Gy twice-daily radiotherapy remains the standard of care, this study provides the most robust information available to help guide the choice of thoracic radiotherapy regimen for patients with limited-stage small-cell lung cancer.

Background: The increased detection of small-sized peripheral non-small-cell lung cancer (NSCLC) has renewed interest in sublobar resection in lieu of lobectomy., Methods: We conducted a multicenter, noninferiority, phase 3 trial in which patients with NSCLC clinically staged as T1aN0 (tumor size, ≤2 cm) were randomly assigned to undergo sublobar resection or lobar resection after intraoperative confirmation of node-negative disease. The primary end point was disease-free survival, defined as the time between randomization and disease recurrence or death from any cause. Secondary end points were overall survival, locoregional and systemic recurrence, and pulmonary functions., Results: From June 2007 through March 2017, a total of 697 patients were assigned to undergo sublobar resection (340 patients) or lobar resection (357 patients). After a median follow-up of 7 years, sublobar resection was noninferior to lobar resection for disease-free survival (hazard ratio for disease recurrence or death, 1.01; 90% confidence interval [CI], 0.83 to 1.24). In addition, overall survival after sublobar resection was similar to that after lobar resection (hazard ratio for death, 0.95; 95% CI, 0.72 to 1.26). The 5-year disease-free survival was 63.6% (95% CI, 57.9 to 68.8) after sublobar resection and 64.1% (95% CI, 58.5 to 69.0) after lobar resection. The 5-year overall survival was 80.3% (95% CI, 75.5 to 84.3) after sublobar resection and 78.9% (95% CI, 74.1 to 82.9) after lobar resection. No substantial difference was seen between the two groups in the incidence of locoregional or distant recurrence. At 6 months postoperatively, a between-group difference of 2 percentage points was measured in the median percentage of predicted forced expiratory volume in 1 second, favoring the sublobar-resection group., Conclusions: In patients with peripheral NSCLC with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, sublobar resection was not inferior to lobectomy with respect to disease-free survival. Overall survival was similar with the two procedures. (Funded by the National Cancer Institute and others; CALGB 140503 ClinicalTrials.gov number, NCT00499330.)., (Copyright © 2023 Massachusetts Medical Society.)

Objectives: There are limited real-world data about patient-reported outcomes with immunotherapies (IO) in metastatic non-small cell lung cancer (mNSCLC). We describe patient-reported distress and clinical outcomes with IO-based treatments or cytotoxic chemotherapies (Chemo)., Methods: We conducted a single-institution retrospective chart review of adults with mNSCLC treated at Duke from 03/2015 to 06/2020. At each visit, patients self-reported their distress level and sources of distress using the NCCN Distress Thermometer (DT) and its 39-item Problem List. We abstracted demographic, clinical, distress, and investigator assessed-clinical response data, then analyzed these using descriptive statistics and generalized estimating equations., Results: Data from 152 patients were analyzed in four groups: Chemo alone, IO + Chemo, single agent IO, dual agent IO. Distress was worse before treatment start in all groups, and the odds of actionable distress (DT score > 4) decreased by 10 % per month. The most frequent sources of distress were physical symptoms (e.g., fatigue, pain), which remained high longitudinally. Patients receiving IO had higher clinical response rates and a lower rate of unplanned healthcare encounters compared to patients treated with Chemo alone. Only one-third of all patients were seen by palliative care., Conclusions: This single-center, real-world evidence study demonstrates that patients with mNSCLC experience significant distress prior to starting first-line treatment. IO treatment was associated with higher clinical benefit rates and lower healthcare utilization compared to chemotherapy. Symptom distress persists over time, highlighting potential unmet palliative and supportive care needs in mNSCLC care in the IO treatment era., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Treatment of advanced stage non-small cell lung cancer (NSCLC) has changed dramatically due to immunotherapy. However, patients without Programmed Death-Ligand 1 (PD-L1) protein expression often benefit less from immunotherapy. This trial is designed to test if stereotactic body radiation therapy (SBRT) to a single tumor site can significantly enhance the outcome of patients with advanced stage PD-L1(-) NSCLC when added to systemic therapy including immunotherapy., Materials and Methods: Alliance A082002 is based on subgroup analysis from the randomized phase II PEMBRO-RT trial., PEMBRO-RT compared pembrolizumab alone or with SBRT and revealed improved progression-free and overall survival (PFS and OS, respectively) in PD-L1(-) patients when adding SBRT (8 Gy x 3 fractions). In A082002, patients without PD-L1 expression will be randomized to SBRT (8 Gy x3) plus systemic therapy vs. systemic therapy alone. The primary endpoint of the phase II portion of the trial is PFS and will require 100 patients. The primary endpoint of the phase III portion of the trial is OS and will require an additional 284 patients. This trial will clarify whether adding SBRT to systemic therapy can improve PFS and OS in a larger multi-institutional cohort. Several systemic treatment options are allowed including either immunotherapy alone or chemo-immunotherapy., Conclusions: This phase II/III Alliance trial A082002 will test whether the addition of SBRT to a single tumor site will enhance the anti-tumor activity of systemic immunotherapy or chemo-immunotherapy in patients with stage IV PD-L1(-) NSCLC. It is now open in the National Clinical Trials Network (NCTN)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Approximately a third of patients with non-small-cell lung cancer (NSCLC) present with surgically resectable disease. Patients who undergo surgical resection are at a high risk of relapse, and neoadjuvant and adjuvant chemotherapy improves disease-free survival (DFS) and overall survival (OS). The outcomes with neoadjuvant and adjuvant chemotherapy are similar, and both are used in clinical practice. Recent trials investigated the role of immunotherapy and targeted therapy in patients with early-stage disease. A phase III trial of adjuvant atezolizumab compared with standard of care (SOC) in patients with resected stage II or III disease and PD-L1 expression of 1% or greater, and a second trial of adjuvant pembrolizumab compared with placebo in patients with stage IB-III (regardless of tumor proportion score PD-L1 expression), both demonstrated an improvement in DFS. In the neoadjuvant setting, results of a phase III trial of chemotherapy and nivolumab compared with chemotherapy alone revealed an improvement in pathological complete response rate and event-free survival in patients with stage IB-IIIA disease. Finally, for epidermal growth factor receptor (EGFR) mutant NSCLC, a phase III trial of osimertinib compared with SOC revealed an improvement in DFS. The results of these and ongoing trials illustrate the integration of immunotherapy and targeted therapies into the treatment paradigm of patients with surgically resected NSCLC and have led to FDA and EMA approvals in selected populations. Neoadjuvant trials have investigated novel endpoints such as major and complete pathological response, which have the potential to serve as surrogate endpoints for future trials., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Importance: Standard treatment for resectable non-small cell lung cancer (NSCLC) includes anatomic resection with adequate lymph node dissection and adjuvant chemotherapy for appropriate patients. Historically, many patients with early-stage NSCLC have not received such treatment, which may affect the interpretation of the results of adjuvant therapy trials., Objective: To ascertain patterns of guideline-concordant treatment among patients enrolled in a US-wide screening protocol for adjuvant treatment trials for resected NSCLC., Design, Setting, and Participants: This retrospective cohort study included 2833 patients with stage IB to IIIA NSCLC (per American Joint Committee on Cancer 7th edition criteria) who enrolled in the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) screening study (Alliance for Clinical Trials in Oncology A151216) from August 18, 2014, to April 1, 2019, and who did not enroll in a therapeutic adjuvant clinical trial; patients had tumors of at least 4 cm and/or with positive lymph nodes. Statistical analysis was conducted from June 1, 2020, through October 1, 2021., Exposures: Care patterns were ascertained overall and by sociodemographic and clinical factors, including age, sex, race and ethnicity, educational level, marital status, geography, histologic characteristics, stage, genomic variant status, smoking history, and comorbidities., Main Outcomes and Measures: Five outcomes are reported: whether patients (1) had anatomic surgical resection, (2) had adequate lymph node dissection (≥1 N1 nodal station plus ≥3 N2 nodal stations), (3) received any adjuvant chemotherapy, (4) received any cisplatin-based adjuvant chemotherapy, and (5) received at least 4 cycles of adjuvant chemotherapy., Results: Of the 2833 patients (1505 women [53%]; mean [SD] age, 66.5 [9.2] years) included in this analysis, 2697 (95%) had anatomic surgical resection, 1513 (53%) had adequate lymph node dissection, 1617 (57%) received any adjuvant chemotherapy, 1237 (44%) received at least 4 cycles of adjuvant platinum-based chemotherapy, and 965 (34%) received any cisplatin-based adjuvant chemotherapy. Rates were similar across race and ethnicity., Conclusions and Relevance: This cohort study found that among participants in a screening protocol for adjuvant clinical trials for resected early-stage NSCLC, just 53% underwent adequate lymph node dissection, and 57% received adjuvant chemotherapy, despite indications for such treatment. These results may affect the interpretation of adjuvant trials. Efforts are needed to optimize the use of proven therapies for early-stage NSCLC., Trial Registration: ClinicalTrials.gov Identifier: NCT02194738.

Competing Interests: Thomas E. StinchcombeThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Genentech/Roche, Foundation Medicine, EMD Serono, Novartis, Daiichi Sankyo, Lilly, Medtronic, Puma Biotechnology, Janssen Oncology, Regeneron, Turning Point Therapeutics, Sanofi/Aventis, GlaxoSmithKlineResearch Funding: AstraZeneca (Inst), Takeda (Inst), Advaxis (Inst), Regeneron (Inst), Seattle Genetics (Inst), Mirati Therapeutics (Inst) Jeffrey BradleyHonoraria: AstraZeneca/MedImmune, Mevion Medical SystemsConsulting or Advisory Role: Varian Medical Systems, GenentechNo other potential conflicts of interest were reported.

Background: Proportional hazards (PH) assumption is often violated in cancer immunotherapy studies. Restricted mean survival time (RMST) ratio is a valid metric to quantify the size of treatment effect when non-proportional hazard (NPH) is present. This study investigated the use of RMST ratio and hazard ratio (HR) in studying progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in non-small cell lung cancer immunotherapy trials., Methods: Trial level data were collected from 14 phase III trials published between 2012 and 2018. A weighted least-square regression (WLSR) was performed to evaluate the trial-level surrogacy. Surrogacy was evaluated via the association between RMST ratios for PFS and OS and between HRs for PFS and OS., Results: Using data extracted from published articles, low to moderate correlation (0.49) between PFS and OS was observed for HR while low correlation (0.35) was observed for RMST ratio. When trials violating PH in PFS were included, more consistent correlations for both HR (0.43) and RMST ratio (0.44) were observed., Conclusions: In summary, the strength of PFS surrogacy for OS depends on whether HR or RMST ratio are chosen. RMST ratio and additional sensitivity analysis should be considered in addition to HR.

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor-1 (PD-1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD-1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non-small cell lung cancer (NSCLC)., Methods: Patients whose tumors had programmed cell death ligand 1 (PD-L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%-49% (cohort 2) received first-line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics., Results: Thirty-eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%-80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%-43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9-22.1 months) and 4.2 months (95% CI, 2.0-6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0-12.5 months), respectively. Grade ≥3 treatment-emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single-agent niraparib and pembrolizumab., Conclusions: Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC., Lay Summary: The JASPER clinical trial studied a new combination treatment for advanced or metastatic non-small cell lung cancer (NSCLC). Pembrolizumab, a drug approved for NSCLC, was given with niraparib. Previous research showed that these 2 drugs together might work better than either drug alone. This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one-fifth of patients with lower levels of the marker responded. The types of side effects from the combination were similar to side effects from both drugs alone. These results support more research on this combination., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Heart dose and heart disease increase the risk for cardiac toxicity associated with radiation therapy. We hypothesized that computed tomography (CT) coronary calcifications are associated with cardiac toxicity and may help ascertain baseline heart disease., Methods and Materials: We analyzed the cumulative incidence of cardiac events in patients with stage III non-small cell lung cancer receiving median 74 Gy on prospective dose-escalation trials. Events were defined as symptomatic effusion, pericarditis, unstable angina, infarction, significant arrhythmia, and/or heart failure. Coronary calcifications were delineated on simulation CTs using radiation software program (130 HU threshold). Calcifications were defined as "none," "low," and "high," with median volume dividing low and high., Results: Of 109 patients, 26 had cardiac events at median 26 months (range, 1-84 months) after radiation therapy. Median follow-up in surviving patients was 8.8 years (range, 2.3-17.3). On simulation CTs, 64 patients (59%) had coronary calcifications with median volume 0.2 cm 3 (range, 0.01-8.3). Only 16 patients (15%) had baseline coronary artery disease. Cardiac events occurred in 7% (3 of 45), 29% (9 of 31), and 42% (14 of 33) of patients with no, low, and high calcifications, respectively. Calcification burden was associated with cardiac toxicity on univariate (low vs none: hazard ratio [HR] 5.0, P = .015; high vs none: HR 8.1, P < .001) and multivariate analyses (low vs none: HR 7.0, P = .005, high vs none: HR 10.6, P < .001, heart mean dose: HR 1.1/Gy, P < .001). Four-year competing risk-adjusted event rates for no, low, and high calcifications were 4%, 23%, and 34%, respectively., Conclusions: The presence of coronary calcifications is a cardiac risk factor that can identify high-risk patients for medical referral and help guide clinicians before potentially cardiotoxic cancer treatments., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients., Methods: We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis., Results: Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10 -7 ], 0.86 (0.80-0.93, P = 9.4 × 10 -5 ) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (P trend  < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes., Conclusion: These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objectives: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC)., Materials and Methods: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m 2 ), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m 2 , Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy., Results: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached)., Conclusions: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Nivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC., Objective: To determine whether the addition of ipilimumab to nivolumab improves survival in patients with advanced, pretreated, immunotherapy-naive squamous (Sq) NSCLC., Design, Setting, and Participants: The Lung Cancer Master Protocol (Lung-MAP) S1400I phase 3, open-label randomized clinical trial was conducted from December 18, 2015, to April 23, 2018, randomizing patients in a 1:1 ratio to nivolumab alone or combined with ipilimumab. The median follow-up in surviving patients was 29.5 months. The trial was conducted through the National Clinical Trials Network and included patients with advanced immunotherapy-naive SqNSCLC and a Zubrod score of 0 (asymptomatic) to 1 (symptomatic but completely ambulatory) with disease progression after standard platinum-based chemotherapy. Randomization was stratified by sex and number of prior therapies (1 vs 2 or more). Data were analyzed from May 3, 2018, to February 1, 2021., Interventions: Nivolumab, 3 mg/kg intravenously every 2 weeks, with or without ipilimumab, 1 mg/kg intravenously every 6 weeks, until disease progression or intolerable toxic effects., Main Outcomes and Measures: The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (IA-PFS) and response per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1., Results: Of 275 enrolled patients, 252 (mean age, 67.5 years [range 41.8-90.3 years]; 169 men [67%]; 206 White patients [82%]) were deemed eligible (125 randomized to nivolumab/ipilimumab and 127 to nivolumab). The study was closed for futility at a planned interim analysis. Overall survival was not significantly different between the groups (hazard ratio [HR], 0.87; 95% CI, 0.66-1.16; P = .34). Median survival was 10 months (95% CI, 8.0-14.4 months) in the nivolumab/ipilimumab group and 11 months (95% CI, 8.6-13.7 months) in the nivolumab group. The IA-PFS HR was 0.80 (95% CI, 0.61-1.03; P = .09); median IA-PFS was 3.8 months (95% CI, 2.7-4.4 months) in the nivolumab/ipilimumab group and 2.9 months (95% CI, 1.8-4.0 months) in the nivolumab alone group. Response rates were 18% (95% CI, 12%-25%) with nivolumab/ipilimumab and 17% (95% CI, 10%-23%) with nivolumab. Median response duration was 28.4 months (95% CI, 4.9 months to not reached) with nivolumab/ipilimumab and 9.7 months with nivolumab (95% CI, 4.2-23.1 months). Grade 3 or higher treatment-related adverse events occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 (33.3%) who received nivolumab alone. Toxic effects led to discontinuation in 31 of 124 patients (25%) on nivolumab/ipilimumab and in 19 of 123 (15%) on nivolumab., Conclusions and Relevance: In this phase 3 randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor-naive SqNSCLC., Trial Registration: ClinicalTrials.gov Identifier: NCT02785952.

Introduction: S1400F is a non-match substudy of Lung Cancer Master Protocol (Lung-MAP) evaluating the immunotherapy combination of durvalumab and tremelimumab to overcome resistance to anti-programmed death ligand 1 (PD-(L)1) therapy in patients with advanced squamous lung carcinoma (sq non-small-cell lung cancer (NSCLC))., Methods: Patients with previously treated sqNSCLC with disease progression after anti-PD-(L)1 monotherapy, who did not qualify for any active molecularly targeted Lung-MAP substudies, were eligible. Patients received tremelimumab 75 mg plus durvalumab 1500 mg once every 28 days for four cycles then durvalumab alone every 28 days until disease progression. The primary endpoint was the objective response rate (RECIST V.1.1). Primary and acquired resistance cohorts, defined as disease progression within 24 weeks versus ≥24 weeks of starting prior anti-PD-(L)1 therapy, were analyzed separately and an interim analysis for futility was planned after 20 patients in each cohort were evaluable for response., Results: A total of 58 eligible patients received drug, 28 with primary resistance and 30 with acquired resistance to anti-PD-(L)1 monotherapy. Grade ≥3 adverse events at least possibly related to treatment were seen in 20 (34%) patients. The response rate in the primary resistance cohort was 7% (95% CI 0% to 17%), with one complete and one partial response. No responses were seen in the acquired resistance cohort. In the primary and resistance cohorts the median progression-free survival was 2.0 months (95% CI 1.6 to 3.0) and 2.1 months (95% CI 1.6 to 3.2), respectively, and overall survival was 7.7 months (95% CI 4.0 to 12.0) and 7.6 months (95% CI 5.3 to 10.2), respectively., Conclusion: Durvalumab plus tremelimumab had minimal activity in patients with advanced sqNSCLC progressing on prior anti-PD-1 therapy. Trial registration number NCT03373760., Competing Interests: Competing interests: The authors’ financial disclosures include: NBL received travel support and institutional research funding from Astra Zeneca and personal fees (CME lectures) from MSD and BMS, unrelated to the study. MR salary support from Hope Foundation, participation on DMSB for AstraZeneca, unrelated to study. NR received personal fees from Abbvie, Apricity, AstraZeneca, Boehringer Ingelheim, Calithera, Dracen, Editas, Eli Lilly, EMD Serono, G1 Therapeutics, Genentech, Gilead, GlaxoSmith Kline, Illumina, Merck, Neogenomics, Novartis and Takeda, and personal fees and stock options from Arcus, Belicum, Brooklyn ImmunoTherapeutics, and Gritstone; royalties for patent filed by MSKCC identifying determinants of cancer response to immunotherapy (PCT/US2015/062208 licensed to Personal Genome Diagnostics; PM reports personal fees from Guardant Health. LHS research support from Merck, Bristol-Myers-Squibb, and Boehringer, participating in DSMB for Regeneron, patent with Varian. SCR fees for expert testimony. JC reports consulting fees from Amgen, AstraZeneca, Coherus, Merck, NCCN, Pfizer and travel support from AstraZeneca, GI Therapeutics, participating on DSMB or Ad Board for Beyond Spring, Celegene, G1 Therapeutics, Janssen, Merrimack, Mylan, Roche. JDB is principal investigator of AstraZeneca sponsored trial (PACIFIC 2), research support and consulting fees from Varian. TS institutional grants from Genentech/Roche, Blueprint Medicines, AstraZeneca, Takeda, Advaxis, Regeneron, participation on DSMB or ad board for Takeda, AstraZeneca, Genentech/Roche, Foundation Medicine, Pfizer, EMD Serono, Novartis, Daiichi Sankyo, Lilly, Puma Biotechnology, Janssen Oncology, Regeneron. SR grants from Tesaro, Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK, consult fees from Amgen, BMS, Genentech/Roche, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, Sanofi, GSK, Lilly. RSH reports membership in board of directors for Immunocore Holdings Ltd, Junshi Pharmaceuticals, consulting including travel support from AstraZeneca, Genentech/Roche, Merck, Ventana Medical Systems, Inc., consulting with ARMO Biosciences, Bayer Healthcare Pharmaceuticals, Bolt Biotherapeutics, Bristol-Myers Squibb, Candel Therapeutics, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly and Company, EMD Serono, Foundation Medicine, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Oncternal Therapeutics, Pfizer, Ribbon Therapeutics, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, Ventana Medical Systems, WindMIL Therapeutics, Xencor. Research support from AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck. VP research funding from AstraZeneca, BMS, Eli Lilly, Novartis, Merck, F. Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers-Squibb, Checkmate, Incyte, consulting fees from AbbVie, Araxes, Arrys Therapeutics, Bolt Therapeutics, Clovis Oncology, Exelixis, G2 Innovation, Gritstone, Ideaya, Leeds Biolabs, Loxo Oncology, Takeda, Tesaro, TRM Oncology, AstraZeneca, BMS, Eli Lilly, Novartis, Merck, F. Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers-Squibb, personal fees from F. Hoffman-La Roche, employee of Pfizer. KK travel and consultant fees from AstraZeneca.DRG consultant and participation on advisory boards for AstraZeneca (institutional), Roche-Genentech (institutional), Guardant Health (institutional), IO Biotech (institutional) and Oncocyte (institutional) fees paid to institution, research funding from Amgen, AstraZeneca, Genentech and Merck, personal fees from Inivata, Lilly, Merck and Novartis.The following investigators have no financial disclosures to report: FH, JW, WjI, KM, JM., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The gonadotropin-releasing hormone (GnRH) signaling pathway controls reproductive functions and cancer growth and progression. However, few studies investigated roles of genetic variants of GnRH pathway genes in survival of patients with non-small cell lung cancer (NSCLC). Therefore, we first evaluated associations between 22,528 single-nucleotide polymorphisms (SNPs) in 101 GnRH pathway genes and survival of 1185 NSCLC patients using a dataset from Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We found 572 SNPs to be significantly associated with overall survival (OS) of NSCLC (P ≤ 0.05, Bayesian false discovery probability ≤0.80). We then validated these SNPs in another dataset with 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. Finally, two independent SNPs (HBEGF rs4150236G>A and ITPR3 rs116454384C>T) remained significantly associated with NSCLC OS in the combined analysis with hazards ratios of 0.84 (95% confidence interval = 0.76-0.92, P = 0.0003) and 0.85 (0.78-0.94, 0.0012), respectively; their genetic score (the number of protective genotypes) was associated with a better OS and disease-specific survival (P trend  = 0.0002 and 0.0001, respectively). Further expression quantitative trail loci analysis showed a significant correlation between ITPR3 rs116454384 T allele and an increased mRNA expression level in both whole blood and normal lung tissue, and high ITPR3 mRNA expression levels in tumors were associated with a better survival of NSCLC patients. Because ITPR3 mutations were rare in tumors, ITPR3 rs116454384C>T likely had an effect on cancer progression by regulating the gene expression. Therefore, genetic variants of HBEGF rs4150236G>A and ITPR3 rs116454384C>T may be predictors for NSCLC survival, but HBEGF rs4150236G>A functional relevance remains to be determined., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Non-small-cell lung cancer (NSCLC) causes significant mortality each year. After successful resection of disease stage IB (>4 cm) to IIIA (per AJCC 7), adjuvant platinum-based chemotherapy improves median overall survival and is the standard of care, but many patients still experience recurrence of disease. An adjuvant regimen with greater efficacy could substantially improve outcomes. Pembrolizumab, a programmed cell death-1 inhibitor, has become an important option in the treatment of metastatic NSCLC. ALCHEMIST is a clinical trial platform of the National Cancer Institute that includes biomarker analysis for resected NSCLC and supports therapeutic trials including A081801 (ACCIO), a three-arm study that will evaluate both concurrent chemotherapy plus pembrolizumab and sequential chemotherapy followed by pembrolizumab to standard of care adjuvant platinum-based chemotherapy. Clinical trial registration: NCT04267848 (ClinicalTrials.gov).

Introduction: The CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study., Methods: Patients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms., Results: The final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board., Conclusion: A randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: This signal finding study (S1400G) was designed to evaluate the efficacy of talazoparib in advanced stage squamous cell lung cancer harboring homologous recombination repair deficiency., Patients and Methods: The full eligible population (FEP) had tumors with a deleterious mutation in any of the study-defined homologous recombination repair genes and without prior exposure to a PARP inhibitor. The primary analysis population (PAP) is a subset of FEP with alteration in ATM, ATR, BRCA1, BRCA2, or PALB2. Treatment consisted of talazoparib 1 mg daily continuously in 21-day cycles. A 2-stage design with exact 93% power and 1-sided 0.07 type I error required enrollment of 40 patients in the PAP in order to rule out an overall response rate (ORR) of 15% or less if the true ORR is ≥ 35%., Results: The study enrolled 47 patients in the FEP, of whom 24 were in the PAP. The median age for the FEP was 66.7 years; 83% were male and 85% white. ORR in the PAP was 4% (95% confidence interval [CI], 0, 21) with disease control rate of 54% (95% CI, 33, 74). Median progression-free survival and overall survival were 2.4 months (95% CI, 1.5-2.8) and 5.2 months (95% CI, 4.0-10), respectively. In the FEP, ORR was 11% (95% CI, 3.6, 23), the disease control rate was 51% (95% CI, 36, 66), and the median duration of response was 1.8 months (95% CI, 1.3, 4.2). Median progression-free and overall survival were 2.5 months and 5.7 months, respectively., Conclusions: S1400G failed to show sufficient level of efficacy for single agent talazoparib in a biomarker defined subset of squamous lung cancer with homologous recombination repair deficiency., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Lung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET-positive squamous cell carcinoma (SCC)., Patients and Methods: Patients with previously treated SCC with c-MET-positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment., Results: Forty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1)., Conclusion: Telisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Osimertinib is an effective therapy in EGFR -mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of EGFR -mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance., Patients and Methods: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced EGFR -mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily., Results: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia., Conclusions: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted., (©2020 American Association for Cancer Research.)

Background: Prior comparisons of chemotherapy adverse events (AEs) by age and performance status (PS) are limited by the traditional maximum grade approach, which ignores low-grade AEs and longitudinal changes., Materials and Methods: To compare fatigue and neuropathy longitudinally by age (<65, ≥65 years) and PS (0-1, 2), we analyzed data from a large phase III trial of carboplatin and paclitaxel versus paclitaxel for advanced non-small cell lung cancer (CALGB 9730, n = 529). We performed multivariable (a) linear mixed models to estimate mean AE grade over time, (b) linear regression to estimate area under the curve (AUC), and (c) proportional hazards models to estimate the hazard ratio of developing grade ≥2 AE, as well as traditional maximum grade analyses., Results: Older patients had on average a 0.17-point (95% confidence interval [CI], 0.00-0.34; p = .049) higher mean fatigue grade longitudinally compared with younger patients. PS 2 was associated with earlier development of grade ≥2 fatigue (hazard ratio [HR], 1.56; 95% CI, 1.07-2.27; p = .02). For neuropathy, older age was associated with earlier development of grade ≥2 neuropathy (HR, 1.41; 95% CI, 1.00-1.97; p = .049). Patients with PS 2 had a 1.30 point lower neuropathy AUC (95% CI, -2.36 to -0.25; p = .02) compared with PS 0-1. In contrast, maximum grade analyses only detected a higher percentage of older adults with grade ≥3 fatigue and neuropathy at some point during treatment., Conclusion: Our comparison of complementary but distinct aspects of chemotherapy toxicity identified important longitudinal differences in fatigue and neuropathy by age and PS that are missed by the traditional maximum grade approach. Clinical trial identification number: NCT00003117 (CALGB 9730) IMPLICATIONS FOR PRACTICE: The traditional maximum grade approach ignores persistent low-grade adverse events (AEs) and changes over time. This toxicity over time analysis of fatigue and neuropathy during chemotherapy for advanced non-small cell lung cancer demonstrates how to use longitudinal methods to comprehensively characterize AEs over time by age and performance status (PS). We identified important longitudinal differences in fatigue and neuropathy that are missed by the maximum grade approach. This new information about how older adults and patients with PS 2 experience these toxicities longitudinally may be used clinically to improve discussions about treatment options and what to expect to inform shared decision making and symptom management., (© AlphaMed Press 2020.)

Introduction: Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor (TKI) with activity against ALK resistance mutations and central nervous system activity. We prospectively studied the activity and safety of brigatinib in patients with disease progression after other next-generation ALK TKIs., Methods: Patients with stage IIIB or IV ALK+ NSCLC and progressive disease after next-generation ALK TKIs were eligible. Patients were required to undergo tumor biopsy less than or equal to 60 days before enrollment, and circulating tumor DNA was collected at baseline. Brigatinib treatment was 90 mg daily for 7 days and then escalated to 180 mg daily. Primary end point was objective response rate, and two-stage design was used., Results: Between March 2017 and November 2018, a total of 20 patients were treated in stage 1; median age was 55 years (range: 32-71), median number of previous therapies was three (range: 1-6), median number of previous ALK TKIs was two (range: 1-4), and 11 had central nervous system disease at baseline. The objective response rate was 40% (95% confidence interval [CI]: 19%-62%), and the duration of response was 5.3 months (95% CI: 3.6-nonassessable). With follow-up of 22 months, the median progression-free survival was 7.0 months (95% CI: 4.6-10.1). Grade 3 or 4 adverse events were consistent with those of previous studies., Conclusions: Brigatinib has activity in ALK+ NSCLC after previous next-generation ALK TKIs. Further study in patients with disease progression on next-generation ALK TKI is warranted. National Clinical Trials #: NCT02706626., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive EGFR -mutant non-small-cell lung cancer (NSCLC) by preventing or delaying resistance., Methods: Patients with EGFR -mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m 2 intravenously every 2 weeks or afatinib alone. The primary end point was PFS., Results: Between March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; P = .94; median, 11.9 months v 13.4 months). Similarly, there was no difference in response rate (67% v 74%; P = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; P = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed., Conclusions: The addition of cetuximab to afatinib did not improve outcomes in previously untreated EGFR -mutant NSCLC, despite recognized activity in the acquired resistance setting., Competing Interests: The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. Boehringer Ingelheim Pharmaceuticals (BIPI) had no role in the design, analysis or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances, as well as intellectual property considerations. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: Clinical trials of anti-programmed cell death ligand 1 (PD-L1) inhibitor to treat advanced non-small-cell lung cancer (aNSCLC) have permitted treatment beyond progression (TBP). However, the outcomes of patients receiving TBP in routine clinical care are unknown., Materials and Methods: The present retrospective, observational, multicenter analysis evaluated de-identified electronic health record-derived data from community-based clinics in the United States. The patients had confirmed aNSCLC, had started anti-PD-L1 inhibitor therapy (nivolumab, pembrolizumab, or atezolizumab) before October 1, 2018, and had experienced a real-world progression (rwP) event. The study period ended March 31, 2019. The primary objective was to compare the overall survival (OS) of patients who had discontinued immunotherapy ≤ 30 days (non-TBP) compared with > 30 days after rwP (TBP). Descriptive analyses were performed. The Kaplan-Meier method and log-rank test were conducted for OS. An adjusted multivariable Cox proportional hazards regression model was also used., Results: Overall, the data from 4223 patients were analyzed; 2555 (60.5%) and 1668 (39.5%) in the non-TBP and TBP cohorts, respectively. The median treatment duration for the non-TBP and TBP patients was 2.8 and 9.1 months (log-rank test, P < .001), respectively. The TBP group experienced longer unadjusted OS compared with the non-TBP group (11.5 vs. 5.1 months; log-rank test, P < .001). After adjusting for clinically relevant patient characteristics, the TBP OS benefit persisted (adjusted hazard ratio, 0.69; P < .001)., Conclusions: TBP with PD-L1 inhibitor therapy is common in aNSCLC routine care and is potentially effective. These results support clinical trial observations likely to affect practice patterns., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: IFNγ is a pleiotropic cytokine that plays critical immunomodulatory roles in intercellular communication in innate and adaptive immune responses. Despite recognition of IFNγ signaling effects on host defense against viral infection and its utility in immunotherapy and tumor progression, the roles of genetic variants of the IFNγ signaling pathway genes in survival of patients with cancer remain unknown., Methods: We used a discovery genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial ( n = 1,185) and a replication genotyping dataset from the Harvard Lung Cancer Susceptibility Study ( n = 984) to evaluate associations between 14,553 genetic variants in 150 IFNγ pathway genes and survival of non-small cell lung cancer (NSCLC)., Results: The combined analysis identified two independent potentially functional SNPs, ELP2 rs7242481G>A and PIAS1 rs1049493T>C, to be significantly associated with NSCLC survival, with a combined HR of 0.85 (95% confidence interval, 0.78-0.92; P < 0.0001) and 0.87 (0.81-0.93; P < 0.0001), respectively. Expression quantitative trait loci analyses showed that the survival-associated ELP2 rs7242481A allele was significantly associated with increased mRNA expression levels of elongator acetyltransferase complex subunit 2 ( ELP2 ) in 373 lymphoblastoid cell lines and 369 whole-blood samples. The PIAS1 rs1049493C allele was significantly associated with decreased mRNA expression levels of PIAS1 in 383 normal lung tissues and 369 whole-blood samples., Conclusions: Genetic variants of IFNγ signaling genes are potential prognostic markers for NSCLC survival, likely through modulating the expression of key genes involved in host immune response., Impact: Once validated, these variants could be useful predictors of NSCLC survival., (©2020 American Association for Cancer Research.)

The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79-0.94, p = 0.0007), 1.31 (1.16-1.47, p = 6.0 × 10 -5 ) and 1.27 (1.12-1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (p trend < 0.0001 for OS and p trend < 0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes., (© 2019 UICC.)

Background: High out-of-pocket costs may impact anticancer treatment uptake. The Low-Income Subsidy (LIS) program can reduce patient out-of-pocket cost for Medicare Part D-covered treatments. We examined whether the LIS increased uptake and reduced time to initiate orally administered anticancer drugs in patients with advanced non-small cell lung cancer (NSCLC)., Methods: Using Surveillance, Epidemiology and End Results (SEER)-Medicare data, we identified older adults (aged 65 years and older) diagnosed with advanced NSCLC from 2007 through 2013 and categorized them as full LIS, partial LIS, or non-LIS. We used propensity-score weighted (IPTW) Cox proportional hazards regression to assess the likelihood of and time to initiate Part D treatments. Part B medication uptake was our negative control because supplemental insurance reduces out-of-pocket costs for those drugs. All statistical tests were two-sided., Results: Among 19 746 advanced NSCLC patients, approximately 10% initiated Part D treatments. Patients with partial or no LIS were less likely to initiate Part D treatments than were those with full subsidies (partial LIS vs full LIS HRIPTW = 0.77, 95% confidence interval = 0.62 to 0.97; non-LIS vs full LIS HRIPTW = 0.87, 95% confidence interval  = 0.79 to 0.95). Time to initiate Part D treatments was also slightly shorter among full-LIS patients (full LIS mean [SD] = 10.8 [0.04] months; partial LIS mean [SD] = 11.3 [0.08] months; and non-LIS mean [SD] = 11.1 [0.03] months, P < .001). Conversely, patients with partial or no LIS had shorter time to initiation of Part B drugs., Conclusions: Patients receiving the full LIS had higher orally administered anticancer treatment uptake than patients without LIS. Notably, patients with partial LIS had the lowest treatment uptake, likely because of their low incomes combined with high expected out-of-pocket spending. High out-of-pocket costs for Part D medications may be a barrier to treatment use for patients without full LIS., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lung cancer is the leading cause of cancer-related death in the United States. Approximately 20% of these patients present with brain metastases (BMs). Surgical resection, stereotactic radiosurgery, and whole-brain radiation therapy have historically been the primary treatment modalities for patients with non-small-cell lung cancer (NSCLC) and BMs. The treatments for BMs have become complex with the discovery of targetable molecular drivers and the development of an astonishing number of tyrosine kinase inhibitors. Many of these tyrosine kinase inhibitors have robust and durable efficacy against CNS metastases. In many circumstances, these drugs can defer local therapy and even reduce the risk of CNS progression. More recently, immune checkpoint inhibitors have changed the treatment landscape for many patients with NSCLC; however, the role of immunotherapy in patients with BMs is the subject of ongoing investigations. This article will review the current data and our approach to patients with NSCLC and BMs.

Purpose: Pemetrexed or bevacizumab is used for maintenance therapy of advanced nonsquamous non-small-cell lung cancer (NSCLC). The combination of bevacizumab and pemetrexed has also demonstrated efficacy. We conducted a randomized study to determine the optimal maintenance therapy., Patients and Methods: Patients with advanced nonsquamous NSCLC and no prior systemic therapy received carboplatin (area under the curve, 6), paclitaxel (200 mg/m 2 ), and bevacizumab (15 mg/kg) for up to four cycles. Patients without progression after four cycles were randomly assigned to maintenance therapy with bevacizumab (15 mg/kg), pemetrexed (500 mg/m 2 ), or a combination of the two agents. The primary end point was overall survival, with bevacizumab serving as the control group., Results: Of the 1,516 patients enrolled, 874 (57%) were randomly assigned after induction therapy to one of the three maintenance therapy groups. With a median follow-up of 50.6 months, median survival with pemetrexed was 15.9 months, compared with 14.4 months with bevacizumab (hazard ratio [HR], 0.86; P = .12); median survival with pemetrexed and bevacizumab was 16.4 months (HR, 0.9; P = .28); median progression-free survival was 4.2, 5.1 (HR, 0.85; P = .06), and 7.5 months (HR, 0.67; P < .001) for the three groups, respectively. Incidence of worst grade 3 to 4 toxicity was 29%, 37%, and 51%, respectively, for bevacizumab, pemetrexed, and the combination regimen., Conclusion: Single-agent bevacizumab or pemetrexed is efficacious as maintenance therapy for advanced nonsquamous NSCLC. Because of a lack of survival benefit and higher toxicity, the combination of bevacizumab and pemetrexed cannot be recommended.

Background: Older patients with non-small cell lung cancer (NSCLC) are often not prescribed standard therapy. It is important to know which older patients would be candidates for aggressive therapy based on their prognosis, and to develop a model that can help determine prognosis., Methods: Data on older patients (≥70 years) enrolled on 38 NCI cooperative group trials of advanced NSCLC from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise selection. We derived a prognostic score using the estimated Cox PH regression coefficient. We then calculated the area under receiver operating characteristic (ROC) curve of survival in the testing set., Results: The final analysis included 1467 patients, who were randomly divided into a training (n = 963) and a testing set (n = 504). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS = 1) + 8 (if PS = 2) + 11 (if initial stage = IV) + 4 (if weight loss). Patients were classified into two prognostic groups: good (0-8) and poor (≥9). The median survival in the two groups in the testing set were 13.15 (95% CI, 10.82-15.91) and 8.52 months (95% CI, 7.5-9.63), respectively. The model had area under the 1-year and 2-year ROCs (0.6 and 0.65, respectively) that were higher than existing models., Conclusions: Male gender, poor performance status, distant metastases and recent weight loss predict for poor overall survival (OS) in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Platinum and etoposide with thoracic radiation followed by prophylactic cranial irradiation constitute the standard treatment for limited-stage small cell lung cancer (LS-SCLC). Many patients with LS-SCLC are elderly with comorbidities., Methods: Individual patient data were collected from 11 phase 2 or 3 trials for LS-SCLC conducted by the National Clinical Trials Network and activated from 1990 to 2010. The primary endpoint was overall survival (OS); the secondary endpoints were progression-free survival (PFS), the rate of severe adverse events, and off-treatment reasons. The outcomes were compared for patients 70 years old or older (elderly patients) and patients younger than 70 years (younger patients)., Results: Individual patient data from 1049 younger patients (81%) and 254 elderly patients (19%) were analyzed. In the multivariate model, elderly patients, in comparison with younger patients, had worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18-1.63; median OS for elderly patients, 17.8 months; OS for younger patients, 23.5 months) and worse PFS (HR, 1.19; 95% CI, 1.03-1.39; median PFS for elderly patients, 10.6 months; median PFS for younger patients, 12.3 months). Elderly patients, in comparison with younger patients, experienced more grade 5 adverse events (8% vs 3%; P < .01) and more grade 3 or higher dyspnea (11% vs 7%; P = .03) but less grade 3 or higher esophagitis/dysphagia (14% vs 19%; P = .04) and less grade 3 or higher vomiting (11% vs 17%; P = .01). Elderly patients completed treatment less often, discontinued treatment because of adverse events and patient refusal more frequently, and died during treatment more frequently., Conclusions: Elderly patients with LS-SCLC have worse PFS and OS and more difficulty in tolerating therapy. Future trials should incorporate assessments of elderly patients, novel monitoring of adverse events, and more tolerable radiation and systemic therapies., (© 2018 American Cancer Society.)

Objective: Concurrent chemoradiotherapy (CRT) was the standard treatment for locally advanced NSCLC (LA-NSCLC). This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on adverse events (AEs)., Methods: We collected individual patient data from 3600 patients with LA-NSCLC who participated in 16 cooperative group trials of concurrent CRT. The TRT parameters examined included field design strategy (elective nodal irradiation [ENI] versus involved-field [IF] TRT [IF-TRT]) and TRT dose (60 Gy versus ≥60 Gy). The primary end point of this analysis was the occurrence of AEs. ORs for AEs were calculated with univariable and multivariable logistic models., Results: TRT doses ranged from 60 to 74 Gy. ENI was not associated with more grade 3 or higher AEs than IF-TRT was (multivariable OR = 0.77, 95% confidence interval [CI]: 0.543-1.102, p = 0.1545). Doses higher than 60 Gy (high-dose TRT) were associated with significantly more grade 3 or higher AEs (multivariable OR = 1.82, 95% CI: 1.501-2.203, p < 0.0001). In contrast, ENI was associated with significantly more grade 4 or higher AEs (multivariable OR = 1.33, 95% CI: 1.035-1.709, p = 0.0258). Doses higher than 60 Gy were also associated with more grade 4 or higher AEs (multivariate OR = 1.42, 95% CI: 1.191-1.700, p = 0.0001). Grade 5 AEs plus treatment-related deaths were more frequent with higher-dose TRT (p = 0.0012) but not ENI (p = 0.099)., Conclusions: For patients with LA-NSCLC treated with concurrent CRT, IF-TRT was not associated with the overall risk of grade 3 or higher AEs but was associated with significantly fewer grade 4 or higher AEs than ENI TRT. This is likely the result of irradiation of a lesser amount of adjacent critical normal tissue. Higher TRT doses were associated significantly with grade 3 or higher and grade 4 or higher AEs. On the basis of these findings and our prior report on survival, CRT using IF-TRT and 60 Gy (conventionally fractionated) were associated with more favorable patient survival and less toxicity than was the use of ENI or higher radiotherapy doses., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)