BACKGROUND/AIM:Cancer cachexia, characterized by weight loss and systemic inflammation, has been associated with poor prognosis in non-small cell lung cancer (NSCLC). However, its impact on treatment outcomes in tumors with mutant epidermal growth factor receptor (EGFR) remains unclear. This multicenter retrospective cohort study evaluated the impact of cancer cachexia on treatment selection after the development of resistance to EGFR tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS:This study included 439 patients with advanced EGFR-mutant NSCLC who received chemotherapy (n=304) or immune checkpoint inhibitors (ICIs) combined with chemotherapy (n=135) after EGFR-TKI failure. Cancer cachexia was diagnosed based on specific weight loss criteria and laboratory data. Propensity score matching was performed to adjust for baseline differences, and survival outcomes were compared. RESULTS:Overall, significant differences in treatment outcomes were observed between the groups. In the chemotherapy group, cancer cachexia was an independent predictor of overall survival (hazard ratio=1.53; p=0.004), whereas it was not associated with survival in the ICIs/chemotherapy group. Among patients with cachexia, overall survival was significantly longer with ICIs/chemotherapy than with chemotherapy alone (13.8 vs. 11.2 months; p=0.049). CONCLUSION:Although no significant survival difference was found between chemotherapy and ICIs/chemotherapy in the overall population, ICIs/chemotherapy conferred a survival benefit to patients with cancer cachexia. These findings suggest that the presence of cachexia may serve as a potential biomarker for treatment selection in EGFR-TKI-resistant, EGFR-mutant NSCLC.

PURPOSE:To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer with driver alterations. METHODS:This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized controlled trials (RCTs), with the latest time frame spanning March-October 2025. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts was convened. The literature search included systematic reviews, meta-analyses, and RCTs. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS:This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Thirteen studies were identified in the latest search of literature to date. RECOMMENDATIONS:Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients with driver alterations.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

Abstract Background: In patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) has demonstrated encouraging efficacy following prior treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, real-world evidence comparing ABCP with standard platinum-based chemotherapy remains unclear. Methods: We conducted a multicenter retrospective study including 408 patients with advanced or recurrent EGFR-mutant NSCLC who received either platinum-based chemotherapy (with or without bevacizumab) or ABCP after EGFR-TKI treatment at 20 institutions in Japan. Clinical outcomes were evaluated using propensity score matching to adjust for baseline characteristics. Results: After propensity score matching, there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the Chemo/Chemo + BEV and ABCP groups (median PFS, p = 0.44; median OS, p = 0.84). In the subgroup of patients with programmed death-ligand 1 (PD-L1) expression ≥50%, the ABCP group exhibited significantly longer PFS compared with the Chemo/Chemo + BEV group (p = 0.02). Conclusions: Among patients with EGFR-mutant NSCLC previously treated with EGFR-TKIs, those with high PD-L1 expression may derive greater benefit from ABCP therapy compared with platinum-based chemotherapy, suggesting that ABCP could represent a more promising treatment option in this subgroup. Citation Format: Tadaaki Yamada, Kenji Morimoto, Naoki Furuya, Hisashi Tanaka, Akihiro Yoshimura, Tomohiro Oba, Makoto Hibino, Takahito Fukuda, Yasuhiro Goto, Akira Nakao, Shinsuke Ogusu, Yuta Okazaki, Taishi Harada, Takayo Ota, Ken Masubuchi, Tae Hata, Koji Mikami, Shoki Matsumoto, Ryoichi Honda, Koji Date, Yusuke Chihara, Koichi Takayama. Retrospective study for clinical biomarkers to guide post-EGFR-TKI treatment strategies in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5238.

Human epidermal growth factor receptor 2 (HER2)-tyrosine kinase inhibitors (TKIs) are being developed for the treatment of patients with HER2-aberrant lung and gastric cancers. However, achieving complete tumor remission remains challenging. Here, we investigated the molecular mechanisms underlying adaptive resistance to HER2-TKIs in HER2-aberrant tumor cells in order to devise strategies to prevent the emergence of drug-tolerant cells. Our findings showed that the AXL receptor was activated by HER2-TKIs and maintained cell survival by interacting with epidermal growth factor receptor, HER2, and HER3. This process, mediated by the SHC1BP-SHC1 axis, contributed to adaptive resistance to HER2-TKIs in a subset of HER2-aberrant lung and gastric cancers. AXL inhibition significantly delayed tumor regrowth of AXL-overexpressing cells by enhancing HER2-TKI-induced apoptosis in xenograft models. These results suggest that patients with HER2-aberrant lung and gastric cancers exhibiting high AXL expression may benefit from an initial combination therapy with an AXL inhibitor.

8559 Background: Pembrolizumab plus platinum-based chemotherapy is a standard first-line treatment for previously untreated advanced squamous non-small cell lung cancer (NSCLC) based on the KEYNOTE-407 trial. Ubenimex, an oral CD13/aminopeptidase inhibitor, has immunostimulatory and antitumor activity. We conducted a phase II trial to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. Methods: This study was a prospective, multicenter, single-arm phase II trial. Eligible patients with previously untreated advanced squamous NSCLC received ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex started at level 1 (30mg/day), which was increased to levels 2 (60 mg/day) and 3 (120 mg/day) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity (DLT) rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level were analyzed. The primary efficacy endpoint was objective response rate (ORR) by independent central review, estimated descriptively with a 90% confidence interval; the ORR in the KEYNOTE-407 (62.6%) served as a reference value for study design. Results: No DLTs were observed across dose levels 1–3. Therefore, level 3 was selected as the recommended dose. From January 2024 to January 2025, 28 patients were enrolled from 18 institutions, and all patients were evaluable for efficacy and safety. Baseline characteristics were male/female 25/3; median age 72 (range, 40-86); ECOG PS 0/1 12/16. The ORR was 71.4% (90% CI, 54.3-84.9). With a median follow-up of 12.8 months, median progression-free survival (PFS) was 16.8 months (95% CI, 5.6-not reached); median overall survival (OS) was not reached. Grade 3/4 adverse events included pneumonitis (3.6%), anemia (46.4%), febrile neutropenia (10.7%). There was no treatment-related death. Conclusions: Ubenimex with 120 mg/day (60 mg twice daily) combined with pembrolizumab, nab-paclitaxel, and carboplatin was feasible and showed encouraging antitumor activity with manageable safety in previously untreated advanced squamous NSCLC, supporting further randomized evaluation. Clinical trial information: jRCT2031210707.

Background The standard of care for patients with advanced Anaplastic lymphoma kinase (ALK)-positive NSCLC is ALK-tyrosine kinase inhibitors (TKIs). At initial diagnosis, 30-35% of patients have brain metastases, which are associated with a poor prognosis. The treatment for brain metastases is based on symptoms due to the brain metastases lesions and the general condition of the patient. ALTA-1L study showed that brigatinib is promising for ALK-positive NSCLC with brain metastases, however, the patients with symptomatic brain metastases were excluded. Thus, it remains unclear whether to treat brain metastases of ALK-positive NSCLC patients with ALK-TKI or local therapy such as surgery or radiotherapy. Methods We have designed a single-arm phase II trial of brigatinib for patients with ALK-TKI naïve ALK-positive NSCLC and at least one brain metastasis ≥5 mm in size that has not been previously treated. Patients will receive brigatinib until disease progression or unacceptable toxicities. Nineteen patients were enrolled by fifteen sites, and enrollment was terminated by September 2025. The primary endpoint is intracranial response rate. Results Intracranial response rate as a primary endpoint and intracranial progression free survival, extracranial response rate, extracranial progression free survival, systemic response rate, systemic progression free survival, overall survival and safety data will be shown. Conclusion If the study demonstrates intracranial efficacy for brigatinib in this patient population, then brigatinib could be a first-choice for ALK-positive NSCLC patients with brain metastases, and radiation therapy or surgery for the brain metastases might be avoided or postponed.

TPS8676 Background: While EGFR tyrosine kinase inhibitors (TKIs) such as afatinib are standard treatments for patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon or compound EGFR mutations (excluding exon 20 insertions and T790M), the duration of response is often limited, with a median progression-free survival (PFS) of approximately 8 to 10 months. Amivantamab is an EGFR mesenchymal–epithelial transition factor (MET) bispecific antibody with immune cell–directing activity that has multiple mechanisms of action as defined in preclinical models. For common EGFR mutated NSCLC, combination therapy with lazertinib has been approved in several countries based on its superiority in Phase III trial. Although a phase I study of amivantamab plus lazertinib combination therapy showed promising efficacy with a median PFS of 19.5 months in treatment-naïve patients with uncommon or compound EGFR mutations, this was a small-scale non-comparative study where efficacy was not the primary endpoint. The AGEHA study (WJOG17323L) is designed to prospectively evaluate whether amivantamab + lazertinib provides superior efficacy and acceptable safety compared to afatinib in patients with treatment-naïve, uncommon or compound EGFR mutated NSCLC. Methods: This multicenter, randomized, open-label, phase II trial is conducted by the West Japan Oncology Group (WJOG). Eligible patients are randomized in a 1:1 ratio to receive either combination therapy with amivantamab plus lazertinib in Arm A, or afatinib monotherapy in Arm B. The primary objective is to compare PFS between the two treatment arms. Secondary objectives include safety, overall response rate, and overall survival. Additionally, mandatory blood samples are collected at baseline and at the time of disease progression for comprehensive biomarker analysis using the Guardant Health platform to identify molecular predictors of response and resistance mechanisms, including approximately 740 gene alterations and methylation abnormalities. The target sample size is 70 patients (35 per arm). This study is designed with a one-sided alpha of 0.1 and a power of 80% to detect the superiority of amivantamab plus lazertinib over afatinib monotherapy. The primary analysis will compare PFS using a stratified log-rank test, and hazard ratios will be estimated using a Cox proportional hazards model. Key Eligibility Criteria: Patients must be histologically confirmed advanced or recurrent non-squamous NSCLC harboring uncommon or compound EGFR mutations, excluding exon 20 insertions and T790M. Participants must be treatment-naïve for advanced disease with an ECOG performance status of 0–1. Patient enrollment began in January 2026, with a recruitment period of two years and a total study duration of five years. Clinical trial information: jRCTs031250560 .

TPS8667 Background: The standard of care for stage IV non-small cell lung cancer (NSCLC) patients without actionable driver mutations is immune-checkpoint inhibitors (ICIs) with or without platinum-based chemotherapy. For patients with synchronous oligometastatic disease, local ablative therapy (LAT) to all lesions, including primary sites, may improve survival based on several randomized phase II trials. Furthermore, combining LAT with ICIs may enhance anti-tumor immune responses by reducing tumor burden. However, a recent large phase II/III study failed to demonstrate a survival benefit for adding LAT to systemic therapy in patients with synchronous or induced oligometastatic NSCLC. Consequently, it remains unclear whether LAT provides a survival benefit in synchronous oligometastatic NSCLC. Based on the promising results from our preceding phase II trial (TRAP-OLIGO; WJOG11118L), we initiated this phase III trial to definitively evaluate the benefit of adding LAT to pembrolizumab plus platinum-based chemotherapy specifically for synchronous oligometastatic NSCLC. Methods: J-OLIGO is a multicenter, open-label, randomized phase III intergroup trial. Eligible patients have untreated stage IV NSCLC, ECOG PS 0-1, 1–3 metastases, and no actionable driver mutations. During the induction phase, patients receive 4 cycles of pembrolizumab plus platinum-based chemotherapy. Patients who achieve disease control with induction therapy and remain eligible for LAT to all residual lesions are randomized (1:1) to either the LAT group (Intervention) or the standard group (Control). The feasibility and appropriateness of LAT for each patient are evaluated by a multidisciplinary tumor board, consisting of medical oncologists, radiation oncologists, and thoracic surgeons, to ensure definitive treatment of all viable lesions. The LAT group receives definitive surgery and/or definitive radiotherapy to all sites, followed by maintenance pembrolizumab (±pemetrexed). Stratification factors include number of metastases, PD-L1 TPS, histology, and induction response. The primary endpoint is overall survival (OS), defined as the time from randomization. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), and the safety. Based on results from previous studies, the study has 80% power to detect a hazard ratio of 0.55 for OS (median OS: 20 vs. 36 months) with a one-sided alpha of 0.05. The target sample size is 150 patients for primary registration and 100 for secondary registration. Accrual began in October 2025 and is planned for 4 years, followed by a 4-year follow-up period. This trial is supported by the Japan Agency for Medical Research and Development (AMED) under the Project for Innovative Cancer Research. Clinical trial information: jRCTs041250114.

8631 Background: Precision medicine based on multi-gene analysis improves prognosis and has established multigene analysis as the standard of care in lung adenocarcinoma.However, the clinical utility of multi-gene analysis in lung squamous cell carcinoma (LUSC) remains controversial due to the rarity of actionable driver alterations and the uncertain therapeutic benefits of targeted therapy. This study aimed to elucidate the prognostic value of driver alterations and the efficacy of targeted therapy in LUSC. Methods: We have prospectively analyzed patients with non-small cell lung cancer (NSCLC) enrolled in a nationwide genomic screening project in Japan (LC-SCRUM-Asia) using NGS (Oncomine Comprehensive/Precision Assay). We evaluated clinical outcomes in patients with LUSC, comparing overall survival (OS) according to the presence of actionable driver alterations and receipt of targeted therapy. Results: From March 2015 to October 2025, 19,357 patients were enrolled, of whom 2,917 had LUSC. Among these LUSC patients, actionable driver alterations were identified in 180 patients (6.2%) cases, including EGFR mutations (n = 78), KRAS G12C (n = 33), MET exon 14 skipping (n = 28), ALK fusions (n = 18), EGFR exon 20 insertions (n = 7), RET fusions (n = 6), ROS1 fusions (n = 5), BRAF V600E (n = 4), and HER2 exon 20 insertions (n = 1).In the survival analysis of 2,017 patients with advanced/recurrent disease, median OS was significantly longer in patients with actionable driver alterations compared to those without (18.2 vs. 15.0 months; HR 0.79, p = 0.02). However, among patients with actionable driver alterations, there was no significant difference in median OS between patients who received targeted therapies (n = 97) and those who did not (n = 45) (18.3 vs. 17.0 months, p = 0.94). The efficacy of targeted therapies was notably limited; median progression-free survival was 12.4 months for ALK tyrosine kinase inhibitors (TKIs) (n = 17), 8.4 months for EGFR TKIs (n = 46), 4.5 months for KRAS G12C inhibitors (n = 10), 3.6 months for MET TKIs (n = 15), and 3.4 months for ROS1 TKIs (n = 5). Collectively, these outcomes were consistently inferior to those reported in pivotal clinical trials. Conclusions: Although actionable driver alterations were identified in approximately 6% of LUSC and were associated with a favorable prognosis, targeted therapy demonstrated limited efficacy and failed to extend overall survival compared to non-targeted approaches. These findings indicate that the clinical utility of multi-gene analysis in LUSC is currently limited, highlighting the need for the development of novel therapeutic strategies specific to this histology.

[Box: see text]Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only). Updates are published regularly and can be found on the ASCO Publications website.

PURPOSE:Thyroid transcription factor 1 (TTF-1) expression is a useful predictor of treatment efficacy in advanced non-squamous non-small cell lung cancer (NSCLC). This study aimed to evaluate whether TTF-1 could predict the effectiveness of chemotherapy versus chemoimmunotherapy in patients with non-squamous NSCLC with programmed death ligand-1 (PD-L1) expression between 1% and 49%. MATERIALS AND METHODS:We conducted a retrospective study of patients with NSCLC who were treated with chemotherapy or chemoimmunotherapy between March 2016 and May 2023. The patients had histologically confirmed NSCLC, stage III-IV or postoperative recurrence, TTF-1 measurements, and PD-L1 expression levels between 1% and 49%. Clinical data were analyzed to evaluate the effect of TTF-1 expression on treatment efficacy. RESULTS:This study included 283 of 624 patients. TTF-1-positive patients showed longer progression-free survival (PFS) and overall survival (OS) (PFS: 6.4 months [95% confidence interval (CI), 5.0 to 9.4] vs. 4.1 months [95% CI, 2.7 to 6.1], p=0.03; OS: 17.9 months [95% CI, 15.2 to 28.1] vs. 9.4 months [95% CI, 6.3 to 17.0], p < 0.01) in the chemotherapy cohorts (n=93). In the chemoimmunotherapy cohort (n=190), there was no significant difference in PFS and OS between TTF-1-positive and -negative groups (PFS: 7.6 months [95% CI, 6.4 to 11.0] vs. 6.0 months [95% CI, 3.6 to 12.6], p=0.59; OS: 25.0 months [95% CI, 18.0 to 49.2] vs. 21.3 months [95% CI, 9.8 to 28.8], p=0.09). CONCLUSION:In patients with NSCLC with PD-L1 expression between 1% and 49%, TTF-1 expression was a predictor of chemotherapeutic, but not chemoimmunotherapeutic, efficacy.

8537 Background: Therapeutic strategies have been developed in patients with non-small cell lung cancer (NSCLC) harboring gene amplifications (amp) such as MET and HER2 . Although both plasma cell-free DNA (cfDNA) and tissue-based next-generation sequencing (NGS) are available for the detection of gene amp, the concordance between plasma cfDNA and tissue-based analysis for the detection of gene amp remains unclear. Methods: We investigated plasma cfDNA and tissue-based NGS concordance for detection of gene amp in NSCLC using a large-scale screening cohort (LC-SCRUM-Liquid). Paired blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC. Guardant360 panel or Oncomine Precision Assay panel was used for plasma cfDNA NGS. Oncomine Comprehensive Assay panel or Oncomine Precision Assay was used for tissue-based NGS. The concordance of EGFR , MET and HER2 gene amp were evaluated. Results: A total of 1,133 pairs of blood and tissue samples were successfully analyzed between December 2017 and December 2024. The median age of the patients was 69 years (range 25-91), 60% were male, 68% were ever smokers, and 79% had a histopathological diagnosis of adenocarcinoma. The positive percent agreement (PPA) and positive predictive value (PPV) of plasma cfDNA analysis relative to tissue-based analysis are shown in the table. For detecting MET amp, the PPA of plasma cfDNA analysis relative to tissue-based analysis tended to be lower in the patients with metastases involving fewer than two organs compared to those with metastases involving two or more organs (25% vs. 63%, P = 0.07). Among the patients with EGFR , MET , or HER2 amp detected by either tissue-based or plasma cfDNA analysis, the correlation of the copy number variants between tissue-based and plasma cfDNA analysis was very weak (r = 0.20). Conclusions: The concordance between plasma cfDNA and tissue-based analysis for detecting gene amp is markedly low, particularly in patients with a low tumor burden. Detection of gene amp using plasma cfDNA analysis may be insufficient for accurately evaluating the efficacy of targeted therapies for patients with lung cancer harboring gene amp. Concordance of gene amp between plasma cell-free DNA and tissue-based analysis. Tissue PPA PPV + - cfDNA EGFR amp + 9 37 13% 20% - 60 1027 MET amp + 9 7 38% 56% - 15 1102 HER2 amp + 0 4 0% 0% - 3 1126

Background: Neoadjuvant chemoimmunotherapy has emerged as a standard option for resectable stage II-III non-small cell lung cancer (NSCLC); however, its impact on surgical feasibility, operative complexity, and perioperative outcomes remains incompletely characterized. We compared surgical feasibility, complexity, and perioperative outcomes across different neoadjuvant strategies. Methods: This single-center retrospective study included patients with stage II-III NSCLC who underwent curative-intent resection following neoadjuvant chemoimmunotherapy (neo-CIT), chemotherapy alone (neo-CT), or chemoradiotherapy (neo-CRT) during the same period. Surgical complexity was assessed using a four-level empirical grading scale. Perioperative outcomes, pathological response, and complications were compared among treatment groups using appropriate nonparametric statistical methods. Results: Twenty-four patients were included in the analysis (neo-CIT, n = 8; neo-CT, n = 12; neo-CRT, n = 4). R0 resection was achieved in 100%, 66.7%, and 75% of patients in the neo-CIT, neo-CT, and neo-CRT groups, respectively. Operative time, estimated blood loss, length of hospital stay, and overall postoperative complication rates did not differ significantly among groups. Thirty-day mortality was 0% in all groups, and 90-day mortality was 12.5% in the neo-CIT group and 0% in the neo-CT and neo-CRT groups. Surgical complexity scores were high across all cohorts and, when analyzed across the entire cohort, were not significantly associated with longer operative time (p = 0.16), greater blood loss (p = 0.83), or pathological response (p = 0.55). Neo-CIT was not associated with increased objective perioperative risk compared with neoadjuvant chemotherapy or chemoradiotherapy. Conclusions: In this single-institution exploratory analysis, neoadjuvant chemoimmunotherapy appeared to be surgically feasible and did not result in an apparent increase in perioperative risk compared with other neoadjuvant strategies. Although surgeons perceived increased operative complexity, objective perioperative risk remained acceptable when procedures were performed by experienced thoracic surgeons. However, given the limited sample size and lack of statistical power, these findings should be interpreted with caution and should not be considered evidence of equivalence.

8531 Background: Although reduced efficacy of HER2-TKIs after trastuzumab deruxtecan (T-DXd) has been reported in HER2 exon 20 insertion–positive non–small cell lung cancer (NSCLC), the efficacy of T-DXd following prior HER2-TKI exposure remains unclear. Methods: We identified patients with HER2 exon 20 insertion–positive NSCLC treated with T-DXd from two cohorts: the National Cancer Center Hospital East (N = 26,971) and the LC-SCRUM-Asia (N = 20,902). Clinical outcomes (ORR, DCR, and PFS) were evaluated across three groups based on prior HER2-TKI therapy: (1) HER2-TKI-naïve patients (naïve cohort), (2) those treated with selective HER2-TKIs (zongertinib or severtinib) (selective TKI cohort), and (3) those treated with non-selective pan-HER2-TKIs (such as poziotinib, afatinib, and others) (non-selective TKI cohort). Results: Of 77 patients (0.2%) included, 60 in the naïve cohort, 7 in the selective TKI cohort, and 10 in the non-selective TKI cohort. Overall, the median age was 60 years (range, 44–76), and 56% of patients were female. By NGS analysis, all tumors harbored ERBB2 exon 20 insertions within the tyrosine kinase domain; the YVMA subtype was the most common (57%). T-DXd was administered as a median fourth-line therapy (range, 2–8). Baseline clinical and genomic characteristics were generally comparable across the three groups. According to prior HER2-TKI exposure, the ORR was 60% (36/60) in the naïve cohort, 29% (2/7) in the selective TKI cohort, and 60% (6/10) in the non-selective TKI cohort. The DCRs were 83% (50/60), 71% (5/7), and 80% (8/10), respectively. Median PFS with T-DXd was 9.9 months in the naïve cohort, compared with 6.5 months in the selective TKI cohort and 5.3 months in the non-selective TKI cohort. The 6-month PFS rate was 72%, 71%, and 50%, respectively. Among 10 patients who did not achieve an objective response to prior HER2-TKIs (best response of stable or progressive disease), 6 achieved a partial response with subsequent T-DXd. Conclusions: Although prior HER2-TKI exposure, particularly selective HER2-TKIs, may attenuate the efficacy of T-DXd in HER2 exon 20 insertion–positive NSCLC compared with HER2-TKI–naïve patients, T-DXd retained clinically meaningful activity in a subset of patients, including those who did not achieve objective responses to prior HER2-TKIs.

Background: Clinical trial eligible patients with advanced non-small cell lung cancer (aNSCLC) and low programmed cell death ligand 1 (PD-L1) expression achieve greater benefit from immune checkpoint inhibitor (ICI) combination chemotherapy (ICI-Chemo) compared with Chemo alone. We examined whether patients ineligible for clinical trials may benefit from ICI-Chemo. Methods: This multicenter retrospective cohort study enrolled patients with aNSCLC, including unresectable Stage III (IIIB/IIIC) and IV disease with a PD-L1 tumor proportion score of 1-49% treated with ICI-Chemo or Chemo as first-line therapy from 2018 to 2023 in Japan. Treatment outcome and safety of ICI-Chemo versus Chemo groups in trial-eligible and trial-ineligible patients was compared based on criteria from previous phase III clinical trials. Results: Overall, 728 patients were analyzed: 333 trial-eligible and 395 ineligible patients. The median overall survival was 25.1 months in the ICI-Chemo group and 18.5 months in the Chemo group for eligible patients (HR 0.73, 95 %CI: 0.54-0.97) and was 18.2 months in the ICI-Chemo group and 14.9 months in the Chemo group for ineligible patients (HR 0.75, 95 %CI: 0.59-0.95). Median progression-free survival was longer with ICI-Chemo in both groups. For ineligible patients, performance status (PS) >= 2 and squamous cell carcinoma (SqCC) were clinical factors associated with worse survival prognosis, and survival outcomes with ICI-Chemo and Chemo were comparable. The ineligible group had no increase in severe adverse events compared to the eligible group. Conclusions: This study suggests a possible clinical benefit of receiving ICI-Chemo for trial-ineligible patients with low PD-L1 expression, excluding those with PS >= 2 or SqCC.

This retrospective study conducted at 19 centers in Japan included 316 patients with advanced nonsquamous non-small cell lung cancer (NSCLC) with a programmed cell death ligand 1 (PD-L1) tumor percentage score (TPS) of 1% to 49% who received chemoimmunotherapy as first-line treatment. The median follow-up time was 39.2 months (7.9-68.9 months) and the results showed comparable survival outcome and all adverse events of grade >= 3 among the combination chemotherapy regimens with PD-1, PD-L1 and PD-1/CTLA-4 inhibitors. The incidence of hematologic and nonhematologic toxicities differed among the regimens, although the differences were not statistically significant. The incidence of grade >= 3 pneumonitis was significantly lower among patients who received anti-PD-L1 antibodies. Thus, clinicians could prioritize patient factors such as avoidable adverse events and pneumonitis when selecting a chemoimmunotherapy regimen for patients with advanced nonsquamous NSCLC with a PD-L1 TPS of 1% to 49%. Background: Although chemoimmunotherapy is recommended for advanced nonsquamous non-small cell lung cancer (NSCLC) with low programmed cell death ligand 1 (PD-L1) expression, no head-to-head comparisons of immune check point inhibitors (ICIs) have been performed. Therefore, we compared the effect and safety of regimens in these patients to guide evidence-based treatment. Methods: This retrospective study included patients with advanced nonsquamous NSCLC with a PD-L1 tumor proportion score of 1% to 49% administered ICI combination platinum-based chemotherapy between May 2018 and May 2023 at 19 institutions in Japan. The main analysis compared survival outcomes and the incidence of grade >= 3 adverse events among regimens. Results: Among 316 included patients (median [range] age, 69 [36-89] years; 242 males; 41 never smokers), 200 (63%), 68 (22%), and 48 (15%) received chemotherapy combined with anti-programmed cell death protein 1 (PD-1), anti-PD-L1, and anti-PD-1/cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies, respectively. The median overall survival times were 28.6, 23.1, and 24.4 months (P = .41), and the median progression-free survival times were 9.4, 7.2, and 8.7 months (P = .28) in the anti-PD-1/Chemo, antiPD-L1/Chemo and anti-PD-1/CTLA-4/Chemo groups, respectively. The anti-PD-1/CTLA-4/Chemo group had the lowest incidence of hematologic toxicity (P = .13) and the highest incidence of nonhematologic toxicity (P = .07). The incidence of grade >= 3 pneumonitis was significantly lower in the anti-PD-L1/Chemo group (P = .049). Conclusions: Despite comparable survival benefits, adverse events differed among three regimens in patients with low PD-L1 expression. Notably, anti-PD-L1 antibody combination chemotherapy may reduce the risk of severe pneumonitis. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.