Cancer cachexia (CCx) is a complex, multifactorial syndrome associated with poor outcomes, yet its clinical identification is often hindered by unreliable recall of historical body weight. We developed an interpretable machine learning (ML) framework to detect CCx by integrating routinely collected metabolic and inflammatory hematological features from the nationwide multicenter INSCOC cohort in China (N = 16,858). Using a systematic, data-driven strategies, we identified a stable and biologically coherent set of features that collectively characterize a cachexia-associated phenotype. The final model demonstrates consistent predictive discrimination for CCx in both test cohort (AUC: 0.758, 95% CI: 0.742-0.775) and validation cohort (AUC: 0.748, 95% CI: 0.730-0.766). Importantly, this phenotype-based model generalizes under strict temporal validation and enables objective identification of CCx in real-world clinical settings without reliance on recalled body weight. Together, our findings support a conceptual shift from a purely weight-based syndrome of CCx toward an integrative metabolic-inflammatory phenotype.

PURPOSE:The ongoing OCEAN II study (ClinicalTrials.gov identifier: NCT05195632) evaluates encorafenib in combination with binimetinib (E+B) in Chinese participants with BRAFV600E-mutated metastatic non-small cell lung cancer (NSCLC). METHODS:Participants with metastatic unresectable stage IV BRAFV600E-mutated NSCLC (treatment-naïve or with prior systemic therapy excluding BRAF/MEK-inhibitors), were enrolled in a phase 2 study with two parts: safety lead-in (SLI) and pivotal part (PP). Participants received daily oral encorafenib (450mg) and twice daily oral binimetinib (90mg total). Primary endpoints were dose-limiting toxicities (DLT) during SLI and confirmed objective response rate by independent central review (cORR-ICR) during PP. Secondary endpoints were other measures of efficacy, safety, and pharmacokinetics. RESULTS:In total, 63 participants were enrolled. One DLT (non-serious Grade 3 lipase increased) during SLI considered possibly related to E+B resolved without intervention, supporting initiation of PP. Pre-defined statistical efficacy criteria on the first 50 participants were met. In the main analysis, cORR-ICRwas59% (95%CI 45-72). At a later ad hoc analysis, cORR-ICR was 61% (95%CI 47-74), disease control rate 87% (95%CI 75-95). Medians (95%CI) were, time-to-response 1.8 months, duration of response 17.5 months, progression-free survival 13.8 months (7.5-not estimable), overall survival 27.9 months (14.7-30.0). 98.4% of participants experienced ≥1 treatment-related TEAE, and 55.6% had any Grade ≥3 TEAE. Nine (14.3%) participants discontinued any drug due to adverse events. CONCLUSION:These data confirm the clinical benefit of E+B in Chinese participants with BRAFV600E-mNSCLC, a population with distinct genomic and disease characteristics. No new safety concerns were identified in Chinese participants.

Background In the global phase 3 randomized LEAP-006 study (NCT03829319), addition of lenvatinib to pembrolizumab plus chemotherapy did not significantly improve efficacy outcomes in metastatic nonsquamous non-small–cell lung cancer (NSCLC). We present findings from an extension study of LEAP-006 (NCT04716933) including participants from China. Methods Adults (≥18 years) from mainland China with untreated metastatic nonsquamous NSCLC without targetable genetic alterations were randomized 1:1 to lenvatinib 8mg once daily or placebo, plus pembrolizumab 200mg plus cisplatin or carboplatin plus pemetrexed for 4 cycles, followed by lenvatinib or placebo plus pembrolizumab plus pemetrexed for ≤35 cycles. PFS and OS were dual primary endpoints. No alpha was assigned to these analyses. Results Of 201 enrolled participants from China, 101 received lenvatinib plus pembrolizumab and chemotherapy (lenvatinib arm) and 100 to placebo plus pembrolizumab and chemotherapy (placebo arm). Median follow-up was 32.7 months (data cutoff August 11, 2023). Median PFS (95% CI) was 15.3 (12.2‒19.6) and 9.2 (8.2‒12.5) in the lenvatinib and placebo arms, respectively (HR, 0.68; 95% CI, 0.48‒0.97); median OS (95% CI) was 26.6 (22.2‒35.0) months and 22.0 (16.6‒24.8) months (HR, 0.78; 95% CI, 0.54‒1.12). Grade ≥3 treatment-related adverse events occurred in 83.2% and 62.0% of participants in the lenvatinib and placebo arms, respectively; treatment-related AEs that led to death were reported in 7.9% and 3.0% of participants. Conclusions In the China extension of LEAP-006, addition of lenvatinib to pembrolizumab plus chemotherapy was associated with numerical improvements in PFS and OS with manageable safety in previously untreated metastatic nonsquamous NSCLC.

8640 Background: Lung cancer is the most common cause of cancer and cancer death in China. Patients (pts) with BRAF V600E mutant metastatic non-small cell lung cancer (mNSCLC) can benefit from targeted treatments such as encorafenib + binimetinib (E+B). E+B is approved in Western countries (PHAROS: NCT03915951); however, evidence of efficacy and safety in Chinese pts is lacking. OCEAN II (NCT05195632) is the 1st study to specifically evaluate the efficacy, safety and pharmacokinetic of this targeted combination in Chinese pts with BRAF V600E mutant mNSCLC. Methods: OCEAN II is an ongoing multicenter, open-label, phase 2 (P2) study with a Safety Lead-in (SLI). Eligible pts had unresectable stage IV BRAF V600E mutant NSCLC, were treatment-naive or had received systemic therapy, excluding BRAF/MEK inhibitors. Pts received E 450 mg once daily + B 45 mg twice daily. Primary endpoints were dose-limiting toxicities (DLT) during the 1st 28 days (SLI) and confirmed objective response rate (cORR) by independent central review (ICR) (P2). Secondary endpoints (P2) were disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between June 2022 and October 2023, 63 pts were enrolled (SLI = 15, P2 = 48): median age 65 yrs (range 52–82), 49% female, 75% with ECOG score = 1. There was only 1 DLT (non-serious grade 3 lipase increased) during SLI, supporting P2 initiation. At the primary analysis cut-off date (27 May 2024), the primary endpoint was met; cORR by ICR was 59.3% (95% confidence interval [CI] 45.0–72.4) in the Efficacy set, with pre-defined statistical significance criteria met. An ad hoc analysis (cut-off 27 March 2025) was conducted when all pts had ≥12 months (mo) follow up. cORR by ICR was 61.1% (95% CI 46.9–74.1), with 6 (11%) complete and 27 (50%) partial responses, and DCR of 87.0% (95% CI 75.1–94.6). Median time to response was 1.8 mo (range 1.7–13.7), median DoR 17.5 mo (95% CI 12.9–NR), median PFS 13.8 mo (95% CI 7.5–NR) and median OS 27.9 mo (95% CI 14.7–30.0). DoR and OS are not yet mature (median follow-up for OS: 21 months). Median treatment duration was 32.3 weeks, with 7 (11%) pts receiving treatment for > 2 years, and 10 (15.9%) remaining on treatment. Treatment-emergent adverse events (TEAEs) ≥ grade 3 occurred in 56% of pts. Related TEAEs in ≥25% were anemia (36%), increased aspartate aminotransferase (33%), increased alanine aminotransferase (30%), increased creatine kinase (29%), vomiting (27%), increased creatinine (25%). Nine (14%) pts discontinued any drug due to AEs. Conclusions: The data confirm the clinical benefit of E+B in Chinese pts with BRAF V600E mutant mNSCLC, a population with distinct genomic and disease characteristics. No new safety concern was identified in the Chinese population. These data can support regulatory decisions and clinical practice guidelines in China. Clinical trial information: NCT03915951 .

Importance The ASTRUM-005 phase 3 randomized clinical trial showed substantial survival benefit from adding serplulimab to chemotherapy for previously untreated extensive-stage small cell lung cancer (ES-SCLC). However, the long-term outcomes are unclear. Objective To investigate the efficacy, safety, patient-reported outcomes (PROs), and exploratory biomarker findings from ASTRUM-005 at an extended follow-up. Design, Setting, and Participants This international, double-blind, phase 3 randomized clinical trial enrolled patients from September 12, 2019, to April 27, 2021 in China, Russia, Ukraine, Poland, Turkey, and Georgia. Eligible patients had histologically or cytologically confirmed ES-SCLC with no prior systemic therapy. Patients were followed up through May 7, 2024, and the data analysis of this prespecified, secondary analysis lasted from August to September 2024. The median follow-up duration was 42.4 months (range, 0.2-55.2). Exposures Patients were randomized in a 2:1 ratio to receive intravenous serplulimab (4.5 mg/kg; serplulimab group) or placebo (placebo group), which was combined with up to 4 cycles of carboplatin and etoposide every 3 weeks. Main outcomes and measures The primary end point was overall survival (OS). Secondary end points included other efficacy end points, safety, and PROs. Results A total of 585 patients (median [range] age was 63 [28-76] years in the serplulimab group and 62 [31-83] years in the placebo group) with previously untreated ES-SCLC, and 389 (66.5%) were randomly assigned to the serplulimab group and 196 (33.5%) to the placebo group. Baseline characteristics were balanced across treatment groups. At data cutoff, 280 OS events (72.0%) in the serplulimab group and 166 (84.7%) in the placebo group were observed. Compared with the placebo group, the serplulimab group showed more favorable efficacy (median OS, 15.8 [95% CI, 13.9-17.4] vs 11.1 [95% CI, 10.0-12.4] months; hazard ratio, 0.60; 95% CI, 0.49-0.73; P < .001). The serplulimab group showed improved OS rates at 4 years compared with the placebo group (21.9% vs 7.2%). Grade 3 or higher serplulimab-related or placebo-related treatment-emergent adverse events occurred for 136 (35.0%) and 57 patients (29.1%) in the respective groups. A PRO analysis revealed consistent trends of improved overall health, dyspnea, and pain in both groups and faster recovery from alopecia in the serplulimab group. Conclusions and Relevance This secondary analysis of a randomized clinical trial demonstrated long-term benefit from adding serplulimab to chemotherapy for previously untreated patients with ES-SCLC, supporting this therapy as a first-line standard of care for this patient population. Trial Registration ClinicalTrials.gov Identifier: NCT04063163

After the global approval of atezolizumab plus bevacizumab and chemotherapy as first-line metastatic nonsquamous non-small-cell lung cancer (nsqNSCLC) treatment, the IMpower151 ( NCT04194203 ) trial was conducted in China to address regional differences. Chemotherapy-naive patients with metastatic nsqNSCLC (N = 305) were randomized 1:1 to receive either atezolizumab, bevacizumab, carboplatin and paclitaxel or pemetrexed (ABCPem/Pac; n = 152) or placebo plus bevacizumab, carboplatin and pemetrexed or paclitaxel (BCPem/Pac; n = 153). The primary endpoint was investigator-assessed progression-free survival (INV-PFS); secondary endpoints included subgroup analyses of INV-PFS, independent review facility-assessed PFS, overall survival, and investigator-assessed objective response rate and duration of response per RECIST v.1.1. Most patients (97%) received pemetrexed, and 53% had EGFR+ tumors. Median INV-PFS for ABCPem/Pac versus BCPem/Pac was 9.5 versus 7.1 months (stratified hazard ratio: 0.84; 95% confidence interval: 0.65, 1.09; P = 0.184). INV-PFS across subgroups and independent review facility-assessed PFS were consistent with INV-PFS in the intention-to-treat population. Median overall survival was 20.7 versus 18.7 months in the ABCPem/Pac versus BCPem/Pac arms, respectively (stratified hazard ratio: 0.93; 95% confidence interval: 0.67, 1.28). Confirmed objective response rate with ABCPem/Pac versus BCPem/Pac was 48% versus 50%, respectively; median duration of response was 11.3 versus 8.3 months. Adverse events of special interest for atezolizumab were observed in 68% (grades 3 and 4: 11%) and 71% (grades 3 and 4: 7%) of patients receiving ABCPem/Pac and BCPem/Pac, respectively. The most common adverse events of special interest for atezolizumab in the ABCPem/Pac and BCPem/Pac arms were hepatitis (driven by laboratory abnormalities; mostly low grade), hypothyroidism and rash. Overall, IMpower151 did not meet its primary endpoint (INV-PFS) in metastatic nsqNSCLC. ABCPem/Pac was generally well tolerated, with no new safety signals. Trial registration number: ClinicalTrials.gov, NCT02366143.

Importance:Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. Objective:To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. Design, Setting, and Participants:This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Interventions:Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. Main Outcomes and Measures:The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Results:Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). Conclusions and Relevance:In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. Trial Registration:ClinicalTrials.gov Identifier: NCT04012606.

Background: In the phase 3 ORIENT-11 study, sintilimab plus pemetrexed-platinum provided statistically significant longer overall survival and progression-free survival versus placebo plus pemetrexed-platinum as first- line treatment in patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Here, we report the patient-reported outcomes (PRO) analysis findings in ORIENT-11. Methods: PROs were measured using the European Organization for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire Core 30 items (EORTC QLQ-C30) and the Lung Cancer Symptom Scale (LCSS) questionnaire. PRO endpoints included evaluation of least square (LS) mean changes from baseline to week 12 (platinum-containing treatment) and week 21 (maintenance treatment), time to true deterioration (TTD), and overall improvement or stability rate for QLQ-C30 and LCSS scales. PRO scores in two groups were compared using the Mann-Whitney test. Least squares (LS) mean changes from baseline to week 12, week 21, and other time points were assessed with mixed-effect model repeated measures analysis. TTD was calculated using the Kaplan-Meier method and compared with the Cox proportional hazards model between groups. Results: 252 (94.7 %) patients in the sintilimab-combination group and 123 (93.9 %) patients in the placebo- combination group had a baseline and at least one postbaseline PRO assessment. Change from baseline to week 12 or 21 favored the sintilimab-combination group on QLQ-C30 global health status/quality of life (GHS/ QoL), most function and symptoms scales, and most LCSS scales. Notably, the QLQ-C30 pain score change gradually deteriorated in the placebo-combination group with increased treatment. At the same time, it improved in the sintilimab-combination group significantly from 6 weeks later, with the improvement sustained in subsequent courses of treatment. Sintilimab plus chemotherapy significantly delayed the TTD in most QLQ C30 and LCSS scales compared with placebo plus chemotherapy, and the overall improvement or stability rates were higher in the former. Conclusions: The addition of sintilimab to chemotherapy maintained or improved health-related quality of life and symptoms compared with chemotherapy. Along with the previous efficacy and safety results, these data support the addition of sintilimab to standard chemotherapy as first-line therapy in locally advanced or metastatic non-squamous NSCLC. Clinical trial registration: NCT03607539.

BACKGROUND:Limertinib is a new third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This study aimed to prospectively assess the efficacy and safety of limertinib versus gefitinib as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR-sensitising mutation. METHODS:This multicentre, randomised, double-blind, double-dummy, phase 3 trial was done at 56 hospitals in China. Eligible patients were aged ≥18 years with locally advanced or metastatic NSCLC with EGFR-sensitising mutation (exon 19 deletion or exon 21 L858R mutation) detected in tumour tissue samples using the Cobas EGFR Mutation Test at a central laboratory. Patients were randomly assigned (1:1) to receive oral limertinib 80 mg twice a day and gefitinib-matching placebo 250 mg once a day or oral gefitinib 250 mg once a day plus limertinib-matching placebo 80 mg twice a day in 21-day cycles, until disease progression or other discontinuation criteria was met. Random assignment was stratified according to EGFR mutation type (exon 19 deletion or exon 21 L858R mutation) and CNS metastasis (yes or no) using permuted blocks (block size four) through an interactive web-based response system. The primary endpoint was independent central review (ICR)-assessed progression-free survival. All enrolled patients who received at least one dose of study treatment were included in the full analysis set for efficacy analysis. All enrolled patients who received at least one dose of study treatment and one safety assessment were included in the safety set. This study is registered with ClinicalTrials.gov, NCT04143607, and follow-up is ongoing. FINDINGS:Between June 30, 2021, and Sept 22, 2022, 337 patients were enrolled and 168 were randomly assigned to the limertinib group and 169 to the gefitinib group. Patients' median age was 63 years (34-82). 214 (64%) of 337 patients were female and 123 (36%) were male. The median masked ICR-assessed progression-free survival was 20·7 months (95% CI 15·2-22·1) in the limertinib group and 9·7 months (95% CI 8·3-11·1) in the gefitinib group (hazard ratio [HR] 0·44 [95% CI 0·34-0·58]; p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 42 (25%) of 168 patients in the limertinib group and 42 (25%) of 169 patients in the gefitinib group. Treatment-related serious adverse events occurred in nine (5%) patients and 17 (10%) patients in each group, respectively. Six (4%) patients in the limertinib group died due to adverse events, all of which were considered possibly unrelated to the study drug by investigators. In the gefitinib group, seven (4%) patients died due to adverse events, with three (2%) of those deaths judged as possibly related to the study drug by investigators. Three treatment-related deaths in the gefitinib group were recorded (one case related to pneumonia and two with cause of death unknown). INTERPRETATION:Limertinib showed superior efficacy compared with gefitinib and a manageable safety profile for locally advanced or metastatic NSCLC patients with EGFR-sensitising mutation and should be considered as another first-line treatment option for this patient population. FUNDING:Jiangsu Aosaikang Pharmaceutical. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

In the phase 3 KEYNOTE-042 China study of participants enrolled in China in the global KEYNOTE-042 (NCT02220894) and China extension (NCT03850444) studies, pembrolizumab improved overall survival (OS) versus chemotherapy in locally advanced or metastatic non-small-cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% (hazard ratio [HR], 0.63; 95% CI, 0.43-0.94), ≥20% (0.66; 0.47-0.92), and ≥1% (0.67; 0.50-0.89). We present outcomes from this study after 5 years of follow-up. Chinese participants with previously untreated locally advanced or metastatic NSCLC with PD-L1 TPS ≥1% without EGFR or ALK alterations were eligible. Participants were randomized 1:1 to pembrolizumab 200 mg every 3 weeks for up to 35 cycles or carboplatin plus paclitaxel or pemetrexed with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in the PD-L1 TPS ≥50%, ≥20%, and ≥1% subgroups. Median follow-up was 63.7 (range, 56.3-72.6) months among 262 participants (pembrolizumab, n = 128; chemotherapy, n = 134) included in this study. Pembrolizumab prolonged OS versus chemotherapy in participants with PD-L1 TPS ≥50% (HR, 0.65; 95% CI, 0.45-0.93), ≥20% (0.67; 0.49-0.91), and ≥1% (0.66; 0.51-0.87). Grade 3 to 5 treatment-related AEs occurred in 19.5% and 68.8% of participants in the pembrolizumab and chemotherapy groups, respectively. In conclusion, after 5 years of follow-up, pembrolizumab continued to demonstrate improved OS versus chemotherapy with manageable safety in Chinese participants with previously untreated locally advanced or metastatic NSCLC that expressed PD-L1. These data further support pembrolizumab monotherapy as a standard of care for these patients.

Background: Chemotherapy remains the standard-of-care for many patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC), but acquired resistance presents challenges. The aim of this open-label, multicenter phase 2 clinical trial was to determine the efficacy and safety of utidelone, a novel genetically engineered epothilone analog and microtubule-stabilizing agent, as a third- or later-line treatment for locally advanced or metastatic NSCLC. Methods: Patients who had failed standard second-line treatment (including platinum-containing chemotherapy or targeted therapy) received utidelone (40 mg/m2 2 via intravenous injection daily, day 1-5) every 21 days. The primary endpoint was the objective response rate (ORR). Secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: From March 12, 2019 to January 18, 2021, 26 pretreated patients with locally advanced or metastatic NSCLC (100% of patients had received prior platinum and 65.4% patients had received prior taxane treatment) were enrolled (80.8% of patients had adenocarcinoma). At baseline, nine (34.6%) patients had received second- line treatment, 10 (38.5%) patients had received third-line treatment, and seven (26.9%) patients had received fourth- or later-line treatment. By the data cut-off date of August 10, 2021, the median follow-up was 7.49 months (range, 1.4-26.7 months). The ORR was 15.4% (95% confidence interval [CI], 4.4%-34.9%) in the intention-to- treat (ITT) cohort (N N = 26) and 19.0% (95% CI, 5.4%-41.9%) in the per-protocol (PP) cohort (N N = 21). The disease control rate was 69.2% (95% CI, 48.2%-85.7%) and 81.0% (95% CI, 58.1%-94.6%) in the ITT and PP cohorts, respectively. The median DoR was 4.1 months (95% CI, 3.1-5.1 months) in the ITT cohort. The median PFS was 4.37 months (95% CI, 2.50-5.29 months) in the ITT cohort and 4.37 months (95% CI, 2.50-9.76 months) in the PP cohort. The median OS was not reached, and the 12-month OS rate was 69% (95% CI, 45.1%-84.1%). Grade 3/4 treatment-emergent adverse events occurred in 38.5% of patients, and the most common was peripheral neuropathy (23.1%, all Grade 3), which was manageable with dose modifications. Conclusions: In this clinical trial, utidelone showed promising efficacy and had a manageable safety profile. Further clinical studies are warranted to confirm its role in NSCLC treatment. Trial registration: No.NCT03693547; https://classic.clinicaltrials.gov.

Background Furmonertinib showed superior ef fi cacy compared with ge fi tinib as fi rst -line therapy in patients with epidermal growth factor receptor ( EGFR ) mutation -positive non -small cell lung cancer (NSCLC) in the FURLONG study. Here we present prespeci fi ed secondary endpoints of patient -reported outcomes (PRO). Methods In this multicentre, double-blind, double -dummy, randomised phase 3 study, patients were 1:1 randomly assigned to receive furmonertinib 80 mg once daily or ge fi tinib 250 mg once daily. PROs assessed by the European Organization for Research and Treatment of Cancer Quality -of -Life Questionnaire Core 30 and Quality -ofLife Questionnaire Lung Cancer 13 were analysed using a mixed model for repeated measures and time -to -event analyses. A difference in score of 10 points or more was deemed clinically relevant. Findings Three hundred and fi fty-seven patients (furmonertinib group, n = 178; ge fi tinib group, n = 179) received at least one dose of the study drug, all of whom completed at least one PRO assessment. Statistically signi fi cant difference of overall score changes from baseline favoured furmonertinib in physical functioning (between -group difference 2.14 [95% CI 0.25 - 4.04], p = 0.027), nausea/vomiting ( - 1.56 [95% CI - 2.62 to - 0.49], p = 0.004), appetite loss ( - 2.24 [95% CI - 4.26 to - 0.23], p = 0.029), diarrhoea ( - 3.36 [95% CI - 5.19 to - 1.54], p < 0.001), alopecia ( - 2.62 [95% CI - 4.54 to - 0.71], p = 0.007), and pain in other parts ( - 4.55 [95% CI - 7.37 to - 1.74], p = 0.002), but not reached clinical relevance. Time to deterioration in physical functioning (hazard ratio 0.63 [95% CI 0.42 - 0.94], p = 0.021), cognitive functioning (0.73 [95% CI 0.54 - 0.98 ], p = 0.034), nausea/vomiting (0.64 [95% CI 0.41 - 0.99], p = 0.042), appetite loss (0.63 [95% CI 0.43 - 0.92], p = 0.016), diarrhoea (0.63 [95% CI 0.46 - 0.85], p = 0.002), dyspnoea (0.72 [95% CI 0.53 - 0.98], p = 0.034), cough (0.67 [95% CI 0.44 - 1.00], p = 0.049), dysphagia (0.54 [95% CI 0.35 - 0.83], p = 0.004), and alopecia (0.62 [95% CI 0.42 - 0.90], p = 0.012) was longer with furmonertinib versus ge fi tinib. Interpretation In patients with locally advanced or metastatic EGFR mutation -positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to ge fi tinib.

Importance Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. Objective To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. Design, Setting, and Participants This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Interventions Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. Main Outcomes and Measures The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Results Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). Conclusions and Relevance In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. Trial Registration ClinicalTrials.gov Identifier: NCT04012606

BACKGROUND:The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS:Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS:These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION:ClinicalTrials.gov number, NCT03849768.

BackgroundPenpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer.MethodsThis multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18–75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1–49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993).FindingsBetween Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0–41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8–-9·6 vs 4·2 months, 95% CI 4·2–4·3; HR 0·43, 95% CI 0·33–0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7–9·7 vs 4·2 months, 4·1–4·3; HR 0·37, 0·27–0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group.InterpretationPenpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease.FundingThe National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

Objective: IMpower210（NCT02813785） explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer（NSCLC） in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system（7th edition）; Eastern Cooperative Oncology Group performance status of 0 or 1; and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab（1,200 mg） or docetaxel（75 mg/m~2）. The primary study endpoint was overall survival（OS） in the intention-to-treat（ITT） population with wild-type epidermal growth factor receptor expression（ITT EGFR-WT） and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population（n=467） was 12.3 [95% confidence interval（95% CI）,10.3-13.8] months in the atezolizumab arm（n=312） and 9.9（95% CI, 7.8-13.9） months in the docetaxel arm[n=155; stratified hazard ratio（HR）, 0.82; 95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5（95% CI, 10.8-13.8） months with atezolizumab treatment and 11.1（95% CI, 8.4-14.2） months（n=377） with docetaxel treatment（n=188; stratified HR, 0.87; 95% CI, 0.71-1.08）. Grade 3/4 treatment-related adverse events（TRAEs） occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Abstract Introduction IMpower151 (NCT04194203) was a phase 3 study to evaluate the efficacy and safety of atezolizumab, bevacizumab, carboplatin, plus paclitaxel or pemetrexed (ABCP) vs BCP, as 1L treatment for metastatic nsqNSCLC. IMpower151 did not meet its primary endpoint of INV-PFS. The objectives of this biomarker analysis were to characterize the molecular subtypes of metastatic nsqNSCLC and to explore the relationship between molecular subtype, predefined gene expression signatures, PD-L1 status and clinical outcomes with ABCP and BCP. Methods RNA sequencing of 250 nsqNSCLC tumor samples from IMpower151 was analyzed in the ACBP (n=123) and BCP (n=127) treatment arms. Non-negative matrix factorization (NMF) was applied to variably expressed genes to define molecular subtypes. Gene expression signatures were defined based on previously published associations with their respective biology. Tumor PD-L1 levels were determined by SP263 immunohistochemistry (Ventana). Results No PD-L1 dependent difference of survival benefit of ABCP compared to BCP was observed at the cutoff of TC 1% or TC 50%. Four molecular subtypes (NMF1-NMF4) were identified based on RNA sequencing. NMF1 (n=78) were immune-depleted and had low tumor proliferation. NMF2 (n=73) were characterized by low level of anti-tumor immune cells, increased expression of stromal signatures and high tumor proliferation. NMF3 (n=65) had the most inflamed transcriptomic profile with high enrichment of immune cells, and increased expression of stromal signatures as well. NMF4 (n=34) had the enrichment of granulocytes, a less inflamed immunophenotype and decreased expression of stromal signatures. The positive rate of PD-L1 expression with TC>=1% was significantly lower in NMF1 compared to other subtypes. None of patients with the four NMF subtypes showed significantly longer PFS or OS with ABCP than BCP. Overall, patients with NMF2 showed numerically shorter PFS and patients with NMF3 showed numerically longer PFS than other subtypes. Gene expression signatures of antitumor cytokines are correlated with survival benefit of ABCP compared to BCP. Patients with high expression level of antitumor cytokines showed substantially improved PFS and OS benefit from ABCP than BCP in both ITT population and EGFR mutation population. Conclusion Four molecular subtypes of nsqNSCLC with different immune-cell and tumor microenvironmental features were characterized. NMF2 may identify a fibrotic and immune-depleted subgroup correlated with worse prognosis. NMF3 may identify an immune-inflamed subgroup correlated with better prognosis. Neither NMF subtypes nor PD-L1 IHC level showed a correlation with survival benefit of ABCP controlled by BCP. The gene expression signature of antitumor cytokines could serve as a potential predictive biomarker for survival benefit of ABCP in metastatic nsqNSCLC including EGFR mutant patients. This finding is based on the exploratory analysis of a single clinical trial with limited sample size. It needs further investigation in other cohorts of tumor tissues and with larger clinical potential in blood samples as well. Citation Format: Caicun Zhou, Charlie Sun, Stacey Huang, Xiaorong Dong, Gongyan Chen, Zhehai Wang, Xianghua Wu, Yu Yao, Yiping Zhang, Ying Cheng, Hongming Pan, Xiaodong Zhang, Jiuwei Cui, Lifeng Wang, Xi Chen, Xiaoling Li, Ziping Wang, Qiming Wang, Jianxing He, Mengzhao Wang, Li Qian, Habib Hamidi, Shanshan Li, Marcus Ballinger, David S. Shames, Minu Srivastava. RNA-seq molecular subtypes and gene expression signatures in the phase 3 IMpower151 study of 1L bevacizumab + pemetrexed/paclitaxel ± atezolizumab in metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT235.

BACKGROUND:Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS:This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS:Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION:Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING:Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

BACKGROUND:In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS:Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS:A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION:Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.