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Objective The extent of lymphadenectomy in patients with c-stage I non-small cell lung cancer is controversial. Cancer and Leukemia Group B 140503 (Alliance; NCT00499330) randomized patients with peripheral clinical stage 1A non-small cell lung cancer 2 cm or less to lobar or sublobar resection after frozen-section examination of 2 mediastinal nodes and 1 major hilar node (simple sampling) confirmed the absence of nodal metastases. Additional node dissection was performed at the surgeon's discretion and included simple sampling, systematic sampling, or complete lymph node dissection. We report the impact of the extent of lymphadenectomy on disease- and recurrence-free survival in this trial. Methods Between June 2007 and March 2017, 697 patients were randomized to lobar resection (357) or sublobar resection (340). Data on the extent of lymphadenectomy were available on 689 patients: A total of 182 patients had complete lymph node dissection, 349 patients had systematic sampling, and 158 patients had simple sampling. Disease-free survival was defined as the time to lung cancer recurrence or all-cause mortality. Recurrence-free survival was defined as the time to lung cancer recurrence or death from lung cancer. Survival end points were estimated using the Kaplan-Meier method. Stratified Cox proportional hazards models estimated hazard ratios and their CIs. Results Baseline characteristics were generally similar between groups. Five-year disease-free survival was 62.3% (95% CI, 55.2-70.4) after complete lymph node dissection, 65.7% (95% CI, 60.7-71.2) after systematic sampling, and 61.2% (95% CI, 53.7-69.7) after simple sampling. Disease-free survival was not statistically significantly different between lobar resection and sublobar resection based on the extent of node dissection. Five-year disease-free survival among patients who had complete lymph node dissection was 65.7% (95% CI, 56.4-76.6) after lobar resection and 58.5% (95% CI, 48.2-71.1) after sublobar resection (P = .530). Five-year disease-free survival in patients who had simple sampling/systematic sampling was 63.5% (95% CI, 57.6-70.0) after lobar resection and 65.1% (95% CI, 59.2-71.6) after sublobar resection. Five-year recurrence-free survival for patients who had complete lymph node dissection was 72.5% (95% CI, 63.5-82.9) after lobar resection and 68.9% (95% CI, 59.0-80.5) after sublobar resection (P = .526). Five-year recurrence-free survival in patients who had simple sampling/systematic sampling was 70.8% (95% CI, 65.0-77.0) after lobar resection and 70.2% (95% CI, 64.4-76.5) after sublobar resection (P = .604). There was no difference between groups in the incidence of systemic recurrence or isolated hilar, mediastinal, or supraclavicular nodal recurrence. Conclusions In patients with peripheral c-stage IA non-small cell lung cancer 2 cm or less in size who have no nodal metastases to at least 2 mediastinal nodes and 1 major hilar lymph node, there is no difference in disease-free survival or recurrence-free survival based on the extent of lymph node dissection regardless of the magnitude of parenchymal resection. Our findings apply to a highly selected cohort of patients deemed node negative by meticulous radiographic and intraoperative nodal staging

Purpose: Investigator-initiated trials (IIT) may address important biological and clinical questions that may not be prioritized by pharmaceutical sponsors. However, little is known about the process by which IIT proposals are evaluated and activated.Experimental Design: We performed a retrospective study of IIT concepts submitted through the Academic Thoracic Oncology Medical Investigators Consortium, which comprises 13 institutions in the United States and Canada, from consortium inception in 2014 to 2024. We compared approved and disapproved concepts using chi 2 tests, Fisher exact tests, and Wilcoxon rank-sum tests.Results: Among 68 presented IIT concepts, 60 (88%) received consortium approval a median of 30 days (IQR, 31-59 days) after submission. Concepts submitted by junior faculty were more likely to be approved than those from full professors (P = 0.003). Of the 60 concepts subsequently submitted to pharmaceutical sponsors, 15 (25%) were approved, 43 (72%) were disapproved, and 2 (3%) remain under review. The median time between concept submission to a sponsor and the sponsor's decision was 61 days (IQR, 31-183 days). Concepts with shorter projected durations were more likely to be approved by the pharmaceutical sponsor (P = 0.05). For sponsor-approved IIT concepts, the median overall time from initial submission to trial activation was 18 months.Conclusions: Only a small proportion of proposed investigator-initiated cancer clinical trials are successfully activated following a prolonged development process. Given the importance of IITs in addressing real-world, practical questions and the growing professional challenges facing clinical research physician faculty, further attention to IIT development facilitators and barriers is warranted.

Introduction: Although lobectomy has long been the standard of surgical treatment for early-stage NSCLC, segmental and wedge resections have become another option often used over the past two decades. Methods: To examine the trends over time in the utilization, quality, and overall survival (OS) differences of lobectomy, segmentectomy, and wedge resection, we performed an observational, population-level study of 76,466 patients with T1 or T2 N0M0 NSCLC tumors 2 cm or less in size in the National Cancer Database, from 2004 to 2020. To compare the OS of the three treatments, we used inverse probability of treatment weighting to analyze a subgroup of cases with nodal examination and minimal comorbidity burden. Results: From 2004 to 2020, the use of lobectomy decreased from 75.2% to 67.6% of resections, wedge remained relatively stable (20.5%-22.8%), and segmentectomy increased from 4.3% to 9.7%. The likelihood of nodal assessments and negative margins has increased for all treatments. Younger patients, patients with low comorbidity burden, and patients with smaller tumors have become increasingly likely to receive segmental and wedge resections. Five-year OS of segmentectomy (80.6%, 95% confidence interval [CI]: 78.1%-83.2%) remained non- inferior to lobectomy (83.6%, 95% CI: 83.1%-84.1%]), whereas wedge resection was inferior until 2016 to 2019 (five-y OS 1/4 79.9%, 95% CI: 75.9%-83.8%). Conclusions: Sublobar resections, particularly segmentectomies, have increased in frequency and quality. The growing use of sublobar resections for younger and healthier patients highlights the need for additional clinical evidence demonstrating whether these trends do indeed lead to better outcomes. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

AbstractGT103 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.

PURPOSE:Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that degrades the tumor suppressor p53. In cancers, MDM2 amplification (MDM2amp) leads to overexpression of MDM2, inducing p53 degradation and a p53-null phenotype even in the absence of TP53 mutations. We report here the preclinical and clinical activities of milademetan, a potent and selective oral small-molecule inhibitor of the MDM2-p53 interaction, in MDM2amp, TP53 wild-type (WT) solid tumors. PATIENTS AND METHODS:Milademetan was tested against a variety of cell line and xenograft tumor models. This supported a phase II basket study (MANTRA-2) in patients with advanced MDM2amp, TP53-WT solid tumors. The primary endpoint was the objective response rate, and key secondary endpoints included progression-free survival and adverse events. RESULTS:Milademetan showed potent activity against MDM2amp, TP53-WT laboratory models. In the phase II trial, 40 patients received milademetan, 31 of whom had centrally confirmed molecular testing. The best overall response was 19.4% (6/31) with one confirmed response (3.2%) and five unconfirmed partial responses, including a patient with endometrial stromal sarcoma who achieved a 100% target lesion reduction. The median progression-free survival was 3.5 months (95% confidence interval, 1.8-3.7). Grade 3 or 4 adverse events observed included thrombocytopenia, neutropenia, anemia, leukopenia, and diarrhea. CONCLUSION:Milademetan had a manageable safety profile and achieved responses against a variety of refractory MDM2amp, TP53-WT solid tumors, but tumor reductions were short-lived. Subsequent efforts should focus on combination strategies, further biomarker refinement, or novel MDM2 targeting approaches to achieve more durable clinical benefit.

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.

Background Our study was designed to determine the safety, efficacy, and immunological effects of perioperative pembrolizumab in early-stage NSCLC.Methods This is a single-arm phase II study of perioperative pembrolizumab in patients with untreated, clinical stage IB to IIIA NSCLC. Patients received two doses of 200 mg pembrolizumab, surgery, standard adjuvant chemotherapy, followed by four doses adjuvant pembrolizumab. The primary objective of this study was to determine surgical feasibility rate, and secondary objectives are pathological response rate, treatment adverse events, efficacy data, and exploratory analysis of biomarkers.Results 30 patients initiated perioperative pembrolizumab, and 25 completed tumor resection. At median follow-up of 59 months after surgical resection, seven patients had disease progression, while six had died representing. A 5-year progression-free survival (PFS) from time of surgery was 72.0% (56.4%–91.9%) and overall survival (OS) from time of surgery was 75.8% (60.7%–94.7%). Major pathological response (MPR) was found in seven tumors (28%) including two complete responses (4%). Across all treated patients, four receiving neoadjuvant and four receiving adjuvant pembrolizumab experienced treatment-related adverse events of grade 3 or higher with no grade 5 events. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased across our patient cohort over time from baseline until postsurgery and remained elevated at the end of treatment. There was a significant difference between mean plasma PCSK9 levels for patients with MPR versus all other patients on study when checked postoperatively.Conclusions Perioperative pembrolizumab was safe and effective with promising MPR rate, PFS, and OS.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380.

BACKGROUND:Treatment options for patients with advanced non-small cell lung cancer (NSCLC) with disease progression following immune checkpoint inhibitor (ICI) and platinum-based chemotherapy are limited. GT103 is a fully human immunoglobulin G3 monoclonal antibody targeting complement factor H, which promotes antitumor immunity. In a Phase I study, GT103 was well tolerated and maximum tolerated dose was not reached. METHODS:A single arm, Simon two-stage, Phase II study was conducted that evaluated efficacy and safety of GT103 plus pembrolizumab in patients with advanced NSCLC who have had progression on up to two lines of therapy, including an ICI. Patients with actionable genomic drivers were eligible if they had received at least one targeted therapy. Patients received GT103 10 mg/kg and pembrolizumab 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were safety and objective response rate. Secondary objectives were overall survival and progression-free survival. RESULTS:Twenty-one patients were enrolled. Most common treatment-related adverse events occurring in ≥10% of patients were fatigue (24%, n = 5) and decreased lymphocyte count (24%, n = 5). One patient experienced grade 3 treatment-related adverse events, including pneumonitis and decreased lymphocyte count. Objective response rate was 10% (95% CI, 1-30) with two objective responses (1 complete response (CR), 1 partial response (PR)). Disease control rate (= CR + PR + stable disease (SD)) was 67% (n = 14). Four patients (19%) experienced disease control for over 9 months. Median progression-free survival was 2.6 months (95% CI, 1.4-4.0) and median overall survival was 10.3 months (95% CI, 6.6-NE). CONCLUSION:Combination of GT103 with pembrolizumab was well tolerated with no new safety signals. A subset of patients experienced durable responses and disease control despite prior exposure to ICI.

BackgroundDespite 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.MethodsWe 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.ResultsBuilding 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.ConclusionsPerioperative 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.

ImportanceOutcomes 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.ObjectiveTo evaluate clinical outcomes of patients treated with atezolizumab before and after CRT for unresectable stage III NSCLC.Design, Setting, and ParticipantsThis 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.InterventionsPatients 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 MeasuresThe 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.ResultsA 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 RelevanceThese findings suggest that neoadjuvant atezolizumab merits further study based on safety and encouraging outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT03102242

Background: We have recently reported the primary results of CALGB 140503 (Alli-ance), 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 lo-coregional recurrence (LRR), and expiratory flow rate at 6 months postoperatively.Methods: Between June 2007 and March 2017, a total of 697 patients were ran-domized 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 c2 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 demo-graphic 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 me-dian 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 differ-ence in the reduction of FEV1 between the SR and WR groups. (J Thorac Cardiovasc Surg 2024;167:338-47)

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.