Culturomics and 16 S rDNA sequencing were applied to identify lung tumor-resident microorganisms. In vitro characterization revealed potential functions of these cancer-associated microorganisms. Eighteen clinical lung cancer (LC) tissues samples were collected. All the samples were cultured by culturomics, and analyzed with 16 S rDNA sequencing. Four isolated isolates belonging to the genus Staphylococcus were detected to find out the possible functions in vitro. A549 cells were infected with supernatant of these bacteria, and cell index which reflected cell proliferation was determined by Real-Time Cell Analysis (RTCA). ELISA was employed to detect levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in THP-1 cells stimulated with bacterial culture supernatants. A total of 12 bacteria were cultured and identified, most of which belonged to the Staphylococcus genus. Bacillus was detected through both methods. In vitro experiment, the cultured strains promoted cellular proliferation, and enhanced the levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) as well. Bacteria from LC tissues was isolated and identified. Lung tumor-resident microbiota was described. LC tumor-resident bacteria cause tumor development mediated by enhancing tumor cell proliferation and proinflammatory cytokines releasing by macrophages in the tumor microenvironment.

BACKGROUND:Savolitinib combined with osimertinib is a potential novel therapy for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) harbouring MET amplification after progression on EGFR tyrosine kinase inhibitor (TKI) therapy. We aimed to evaluate the efficacy and safety of savolitinib-osimertinib versus standard of care platinum-based doublet chemotherapy in this patient population. METHODS:SACHI was a multicentre, randomised, active-controlled, open-label, phase 3 trial conducted across 68 Chinese hospitals. Eligible adults with locally advanced or metastatic EGFR mutation-positive NSCLC and MET amplification after EGFR TKI failure were randomly assigned (1:1) to once daily oral savolitinib-osimertinib or intravenous chemotherapy (pemetrexed plus either cisplatin or carboplatin), both in 21-day cycles. Central randomisation was implemented through an interactive web-response system with stratification based on the presence of brain metastases, previous exposure to third-generation EGFR TKIs, and EGFR mutation subtype, using a mixed block-size methodology. The primary endpoint, investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours version 1.1, was tested using a hierarchical procedure: first in the third-generation EGFR TKI-naive population, and if positive, the intention-to-treat (ITT) population. Safety analysis was performed in all patients who received at least one dose of the study treatment. Interim analysis data cutoff was Aug 30, 2024. This study is registered with ClinicalTrials.gov (NCT05015608) and is complete. FINDINGS:Between Oct 15, 2021, and Aug 30, 2024, 211 patients were enrolled, 106 were randomly assigned to savolitinib-osimertinib and 105 were randomly assigned to chemotherapy, including 137 (65%) of 211 who were third-generation EGFR TKI-naive (69 in the savolitinib-osimertinib group; 68 in the chemotherapy group). In 106 patients in the savolitinib-osimertinib group, the median age was 59·4 years (IQR 54·3-65·8), 62 (58%) were female, and 44 (42%) were male. In 105 patients in the chemotherapy group, the median age was 61·9 years (IQR 56·3-69·1), 55 (52%) were female, and 50 (48%) were male. All participants were Asian. Median PFS was significantly prolonged with savolitinib-osimertinib versus chemotherapy in the third-generation EGFR TKI-naive (9·8 months [95% CI 6·9-12·5] vs 5·4 months [4·2-6·0]; hazard ratio 0·34 [0·21-0·56]; p<0·0001) and ITT populations (8·2 months [6·9-11·2] vs 4·5 months [3·0-5·4]; 0·34 [0·23-0·49]; p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in the same proportion of patients in both groups who received the study drugs (60 [57%] of 106 patients in the savolitinib-osimertinib group and 55 [57%] of 96 patients in the chemotherapy group). INTERPRETATION:The savolitinib-osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile. This regimen offers a potential oral treatment option for this biomarker-selected population. FUNDING:HUTCHMED and AstraZeneca.

Background Pembrolizumab plus chemotherapy prolonged overall survival (OS) and progression-free survival (PFS) versus placebo plus chemotherapy with manageable toxicity among participants with metastatic squamous non‒small-cell lung cancer (mNSCLC) enrolled in China in KEYNOTE-407 global (NCT02775435) and China extension (NCT03875092) studies. We report outcomes after ⁓5 years of follow-up from KEYNOTE-407 China. Methods Eligible participants from China with previously untreated squamous mNSCLC were randomized 1:1 to pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel every 3 weeks for 4 cycles, followed by pembrolizumab/placebo for ≤35 total cycles. Primary endpoints were OS and PFS per RECIST v1.1 by blinded independent central review. Results Among 125 participants (pembrolizumab plus chemotherapy, n=65; placebo plus chemotherapy, n=60), median follow-up was 56.5 (range, 53.5‒69.3) months at database cutoff (February 10, 2023). Median (95% CI) OS was 29.6 (18.2‒50.4) months for pembrolizumab and 12.7 (9.4‒17.3) for placebo; OS hazard ratio (HR) was 0.43 (95% CI, 0.29‒0.65). Median (95% CI) PFS was 8.3 (6.2‒10.5) months versus 4.2 (4.0‒5.4), and HR was 0.35 (95% CI, 0.24‒0.52). Grade 3‒5 treatment-related adverse events occurred in 81.5% and 81.7% of participants, respectively. Among 20 participants who completed 35 cycles of pembrolizumab, objective response rate was 90.0%; 3-year OS rate after completion of 35 cycles (∼5 years after randomization) was 79.4%. Conclusion After 4.7 years of follow-up, first-line pembrolizumab plus chemotherapy maintained clinically meaningful improvements in OS and PFS versus chemotherapy alone in squamous mNSCLC regardless of PD-L1 expression, supporting this regimen as a standard-of-care for Chinese patients with squamous mNSCLC.

INTRODUCTION:Tiragolumab may synergize with other immunotherapies to enhance antitumor immune responses. We report efficacy, safety, and biomarker findings from SKYSCRAPER-02C (NCT04665856), comparing tiragolumab plus atezolizumab plus carboplatin and etoposide (CE; experimental arm) with atezolizumab plus CE (control arm) in patients with untreated extensive-stage SCLC (ES-SCLC) in China. METHODS:Patients were randomized (1:1) to tiragolumab 600 mg or placebo, plus atezolizumab 1200 mg and CE (four cycles), then maintenance tiragolumab or placebo plus atezolizumab. Primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in patients without history or presence of brain metastases at baseline (primary analysis set). RESULTS:The primary analysis set comprised 54 patients in the experimental arm and 56 in the control arm. Median PFS was 5.6 months (experimental) and 5.4 months (control; unstratified hazard ratio = 0.65, 95% confidence interval: 0.43‒0.97; median follow-up 26.7 months); median OS was 18.7 and 13.5 months, respectively (unstratified hazard ratio 0.89, 95% confidence interval: 0.56‒1.40). The biomarker-evaluable population comprised 69 patients with immunohistochemistry data and 66 with RNA sequencing data. RNA sequencing survival analysis found that patients with non-negative matrix factorization 3 (SCLC-inflamed-neuroendocrine) or non-negative matrix factorization 4 (SCLC-inflamed-non-neuroendocrine) molecular subtypes, and those with high T-effector and tumor-associated macrophage immune signatures, benefited from tiragolumab plus atezolizumab plus CE treatment. Tiragolumab was well tolerated, with no new safety signals. CONCLUSIONS:Although results from the global SKYSCRAPER-02 study were not statistically significant, numerical improvements in PFS and OS were observed with tiragolumab plus atezolizumab plus CE versus atezolizumab plus CE in Chinese patients with ES-SCLC. Biomarker analysis identified immune-inflamed signatures that may guide future tyrosine-based inhibitory motif domain-based strategies.

BACKGROUND:SMARCA4-deficient thoracic tumors (SDTT) represent a newly defined and highly aggressive subtype of lung cancer for which no standard therapy has been established. Although immune checkpoint inhibitors (ICIs) have demonstrated potential clinical benefit, responses in SDTT are limited and heterogeneous, and the underlying immunologic mechanisms remain poorly understood. This study aimed to characterize the clinicopathologic features, survival outcomes, tumor immune microenvironment (TIME), and treatment responses of SDTT, as well as to explore potential therapeutic strategies. METHODS:In this retrospective, two-center study, 121 patients with SDTT and a comparative cohort of 132 patients with non-SDTT were analyzed. Clinicopathologic variables, treatment patterns, and survival outcomes were compared between groups. Multiplex immunohistochemistry (mIHC) was used to evaluate the immune contexture of SDTT. The efficacy of ICIs and anti-angiogenic therapy, administered as monotherapy or in combination, was also assessed. RESULTS:SDTT patients had significantly inferior survival compared with non-SDTT. Although ICIs conferred clinical benefit in SDTT patients, this benefit was attenuated compared with non-SDTT (median progression-free survival [PFS] 6.0 vs. 13.5 months; p = 0.002; median overall survival [OS], 21.1 months vs. not reached; p = 0.030). mIHC analysis showed a TIME characterized by stromal exclusion of CD8 + T cells and enrichment of TIM3 + exhausted T-cell subsets. A high density of CD8 + TIM3 + T cells was associated with a trend toward worse overall survival in the SDTT cohort. In exploratory analyses, combination therapy with ICIs and antiangiogenic agents was associated with longer progression-free survival than ICI monotherapy, along with a trend toward improved overall survival. CONCLUSION:Although ICIs provide clinical benefit in SDTT patients, their efficacy is attenuated compared with non-SDTT. Spatial mIHC analysis showed a CD8 + T cell-excluded, exhaustion-dominant immunosuppressive microenvironment. Exploratory findings suggest that combining antiangiogenic therapy with ICIs is associated with improved PFS; however, prospective validation is warranted.

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.

Background:Micropapillary (MP) pattern has been identified as a negative prognostic factor in patients with lung adenocarcinoma, but it has not been recognized as a high-risk factor for patients with stage IB lung adenocarcinoma treated with adjuvant chemotherapy. This multicenter cohort study aimed to evaluate the prognostic value of histological subtypes for stage I lung adenocarcinoma and to determine the relative survival benefit of adjuvant chemotherapy for subgroups based on MP pattern. Methods:This retrospective study included 412 patients with stage I lung adenocarcinoma [according the eighth edition of the tumor-node-metastasis (TNM) classification] with MP pattern who underwent complete surgical resection between January 2010 and December 2019. Patients were classified into 3 groups based on the proportion of MP component (10% and 50% as the threshold): MP component >50% (n=8), 10-50% (n=273) and <10% (n=131). Results:Among the 412 patients, the median age was 63 years, and 73.4% (113/154) patients with MP component ≥10% and 63.8% (51/80) of those with MP component <10% had epidermal growth factor receptor (EGFR) mutations. Patients with MP component >50% had a shorter overall survival (OS) compared with those with MP components of 10-50% [10-50% vs. >50%: hazard ratio (HR) =0.293, 95% confidence interval (CI): 0.083-1.027; P=0.052] or <10% (<10% vs. >50%: HR =0.214, 95% CI: 0.056-0.816; P=0.02). Notably, in the univariate analysis, the factors associated with a worse recurrence-free survival (RFS) were spread-through-air-space (STAS) status (HR =2.131, 95% CI: 1.104-4.112; P=0.02), male sex (HR =1.693, 95% CI: 1.048-2.735; P=0.03), smoking history (HR =1.817, 95% CI: 1.126-2.931; P=0.01), and tumor size >2 cm (HR =1.832, 95% CI: 1.138-2.949; P=0.01). Conclusions:MP component and risk factors might be considered critical features for patients with stage I lung adenocarcinomas and may inform the selection of patients who may benefit from adjuvant chemotherapy although no randomized evidence is available.

BACKGROUND:GEMSTONE-302 was a phase 3 trial in patients with treatment-naive metastatic squamous or non-squamous non-small-cell lung cancer (NSCLC), showed significant improvement in progression-free survival and overall survival with sugemalimab, a PD-L1 inhibitor, plus chemotherapy versus placebo plus chemotherapy. We report the 4-year outcomes from this study. METHODS:This randomised, double-blind, phase 3 trial was conducted across 35 hospitals and academic research centres in China. Eligible patients were aged 18-75 years; had treatment-naive, histologically or cytologically confirmed stage IV NSCLC, irrespective of PD-L1 expression levels; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomised (2:1) by investigators using an interactive web response or voice response system via permuted blocks (block sizes of three or six, randomised within each stratum). Patients received histology-specific platinum-based chemotherapy combined with either sugemalimab (1200 mg; sugemalimab group) or placebo (placebo group) for up to four cycles, followed by for up to 35 cycles of maintenance therapy with sugemalimab alone for patients with squamous NSCLC and sugemalimab plus pemetrexed for patients with non-squamous NSCLC in the sugemalimab group, or placebo for patients with squamous NSCLC and placebo plus pemetrexed for patients with non-squamous NSCLC in the placebo group, administered intravenously. Treatment beyond 35 cycles was permitted at the investigator's discretion. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Here, we report post-hoc 4-year efficacy and safety outcomes from GEMSTONE-302. This study is registered with ClinicalTrials.gov (NCT03789604) and concluded on May 15, 2023, with all patients discontinued. FINDINGS:Between December 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility. 479 patients were randomly assigned into the sugemalimab group (n=320) and placebo group (n=159). 254 (79%) patients were men and 66 (21%) were women in the sugemalimab group and 129 (81%) were men and 30 (19%) were women in the placebo group. All patients were Asian. As of the data cutoff on May 15, 2023, median follow-up durations were 43·5 months (IQR 41·2-46·9) in the sugemalimab group and 43·0 months (40·7-44·8) in the placebo group; median treatment durations were 7·2 months (4·2-18·8) with sugemalimab and 4·6 months (2·8-6·9) with placebo. Median progression-free survival was 9·0 months (95% CI 7·4-10·9) in the sugemalimab group versus 4·9 months (4·8-5·2) in the placebo group (hazard ratio [HR] 0·49 [95% CI 0·39-0·60]). Median overall survival was 25·2 months (20·1-30·2) in the sugemalimab group versus 16·9 months (12·8-20·7) in the placebo group (HR 0·68 [0·54-0·85]). The 4-year overall survival rates were 32·1% (95% CI 26·7-37·6) in the sugemalimab group versus 17·3% (11·1-24·7) in the placebo group. The most common grade 3-4 treatment related adverse events were decreased neutrophil count (105 [33%] with sugemalimab vs 52 [33%] with placebo), decreased white blood cell count (48 [15%] vs 27 [17%]), anaemia (44 [14%] vs 18 [11%]), and decreased platelet count (35 [11%] vs 15 [9%]). Treatment-related serious adverse events occurred in 82 (26%) patients with sugemalimab and 31 (20%) with placebo. No additional treatment-related deaths occurred since the previous overall survival interim analysis. No new safety signals were identified. INTERPRETATION:Sugemalimab with chemotherapy showed a superior long-term overall survival benefit compared with placebo with chemotherapy, as a first-line treatment for patients with NSCLC with no known sensitising EGFR, ALK, ROS1, or RET genomic alterations. These results underscore the efficacy of sugemalimab plus platinum-based chemotherapy as a standard first-line treatment option for both squamous and non-squamous metastatic NSCLC while maintaining a manageable safety profile. FUNDING:CStone Pharmaceuticals. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

8511 Background: Malignant mesothelioma is a rare neoplasm with a high unmet medical need. BNT327 is an investigational bispecific antibody, targeting both PD-L1 and VEGF-A in the tumor and tumor microenvironment (TME). By binding to PD-L1 on tumor cells it is designed to restore effector T-cell function and by binding to VEGF-A within the TME it also reverses the negative impact of VEGF signaling on immune cell infiltration and activation. In addition, via VEGF-A neutralization, it normalizes tumor vasculature. This dual targeting of PD-L1 and VEGF-A aims to deliver better efficacy and safety. BNT327 has shown encouraging preliminary activity in thoracic malignancies incl. SCLC (ESMO 2023) and NSCLC (ASCO & ESMO 2024). Methods: After a safety run-in (n=6), this ongoing, multicenter, single-arm phase 2 clinical trial recruited chemo naive pts (pts) aged ≥18 yrs with unresectable malignant mesothelioma (pleural (MPM) or peritoneal (MPeM)) to evaluate BNT327 30 mg/kg Q3W IV combined with 4-6 cycles pemetrexed and platinum, followed by BNT327 maintenance. Primary endpoints were efficacy (ORR per RECIST 1.1 for MPeM, mRECIST 1.1 for MPM) and safety (CTCAE V5.0). Results: As of 25 Oct 2023, 31 pts, median age 58 yrs (range 43-71), 80.6% ECOG PS 1 and 83.9% with metastatic disease had been enrolled, of which 23 had MPM and 8 MPeM. At the cutoff date of 20 Dec 2024, the median exposure duration was 16.0 mo (95% CI 8.1, 19.5) and median follow-up time 19.3 mo (95% CI 17.3, 20.9). In 23 pts with MPM, 1 pt had a CR and 9 had PRs as BOR, resulting in a confirmed ORR (cORR) of 43.5%. 10 pts had SD and 1 non-CR/non-PD, giving a DCR of 87.0%. Median PFS (mPFS) was 11.8 mo, and median DOR was 11.8 mo. The 12 mo OS rate was 82.6% (95% CI 60.1, 93.1), with median OS not yet reached. Among 13 pts with MPM of epithelioid histology, cORR was 30.8%, DCR was 84.6% and mPFS was 16.6 mo. Among 8 pts with MPeM, 6 had PR as BOR, leading to a cORR of 75.0%. 2 pts had SD, resulting in a DCR of 100%; median DOR was 16.3 mo. Median PFS and OS were not yet reached, with an OS rate of 62.5% (95% CI 22.9, 86.1) at 12 mo. 6 pts with MPeM of epithelioid histology displayed a cORR of 83.3%, DCR of 100% and mPFS of 19.5 mo. All pts experienced TRAEs, 93.5% of pts (29/31) of Grade (G) 3-4. 5 pts (16.1%) had G 3-4 treatment-related SAEs. 5 pts (16.1%) experienced an irAE, 1 (3.2%) of G 3-4. The most common TRAEs were decreased neutrophil count (27 pts, 87.1%), decreased white blood cell count (26 pts, 83.9%), proteinuria (24 pts, 77.4%), anemia (23 pts, 74.2%), decreased platelet count (19 pts, 61.3%), and nausea (16 pts, 51.6%). 6 pts discontinued treatment due to TRAEs; no treatment-related deaths occurred. 9 pts remain on treatment. Conclusions: BNT327 plus chemo as a 1L regimen for mesothelioma showed encouraging efficacy, including in tumors of epithelioid histology. AEs were consistent with those expected for the treatment regimen. Clinical trial information: NCT05918107 .

The role of the lung microbiota in cancer remains unclear. Here, we reveal that Staphylococcus is selectively enriched in metastatic tumor lesions and is associated with tumor recurrence in lung cancer patients. Using patient-derived bacterial strains, we employ a combination of cell line, organoid, mouse allograft, and xenograft models to demonstrate that S. nepalensis and S. capitis promote the metastatic potential of lung cancer cells. Mechanistically, lactate secreted by S. nepalensis and S. capitis upregulates MCT1 expression in tumor cells, facilitating lactate uptake and activating pseudohypoxia signaling. These effects can be eliminated by knocking out the lactate-producing genes (D-lactate dehydrogenase [ddh]/L-lactate dehydrogenase [ldh]) in the bacterial strains. Furthermore, we show that inhibiting MCT1 attenuates Staphylococcus-induced tumor metastasis both in vitro and in vivo. Collectively, our results demonstrate that tumor-resident Staphylococcus species promote lung cancer metastasis by activating host pseudohypoxia signaling and further identify key regulators as potential targets for therapeutic development.

BACKGROUND:Due to the low incidence of BRAF mutations, limited data is available about their prevalence and clinical characteristics. Moreover, comparative real-world efficacy of dabrafenib combined with trametinib versus other treatment regimens, especially in Chinese patients, is also lacking. METHODS:Patients who had BRAF genetic testing from the Lung Cancer Big Data Precise Treatment Collaboration Group (LANDSCAPE) database were included as Cohort I. The LANDSCAPE database comprises next-generation sequencing (NGS) data of 175,336 patients with lung cancer, originating from 6 Chinese genetic testing institutions. Cohort II included patients with unresectable locally advanced or metastatic NSCLC with a primary BRAF mutation from 19 centres in China from December 2015 to September 2022. FINDINGS:In Cohort I, of patients with NSCLC, 6249 (3.56%, 95% CI: 3.48%-3.65%) were confirmed to harbour a BRAF mutation. BRAF V600E accounted for 24.6% (1539/6249) of all patients with BRAF-mutated NSCLC. In Cohort II, a total of 129 patients with locally advanced or metastatic BRAF-mutated NSCLC were included. Of 112 patients who received NGS testing, 80 (71.4%) patients had concomitant mutations. The median first-line real-world progression-free survival (rwPFS) of dabrafenib plus trametinib for patients with BRAF V600 mutations was 25.0 months (N = 37), which was numerically longer than first-line immunotherapy-based therapy (N = 12, 15.7 months), and chemotherapy (N = 17, 9.2 months). INTERPRETATION:This study indicates that dabrafenib plus trametinib could be considered as the optimal treatment option for Chinese patients with NSCLC harbouring BRAF V600 mutations. FUNDING:National Natural Science Foundation of China (82072583); Beijing Municipal Administration of Hospitals Incubating Program (PX2020044); Beijing Hospitals Authority Youth Programme (QML20231113); Science Foundation of Peking University Cancer Hospital (2022-17); Peking University Cancer Hospital Inner Mongolia Hospital Public Hospital Reform and High-Quality Development Demonstration Project (Gastrointestinal Cancer + Thoracic Cancer) Research Fund (2024YNYB006).

BACKGROUND:This prospective, observational study evaluated the real-world safety of osimertinib in a broad Chinese population with non-small cell lung cancer (NSCLC). METHODS:Chinese NSCLC patients who received osimertinib were enrolled and followed up for 12 months. The primary endpoint was the incidence of adverse drug reactions (ADRs). RESULTS:From 20 April 2020 to 1 August 2022, 1,700 patients were enrolled from 30 centers, with 706 (41.5%) patients ≥65 years old. Osimertinib was administered as first-line, second-line, third/later-line and adjuvant therapy in 44.9%, 34.2%, 14.3% and 4.5% of the patients, respectively. ADRs, adverse events (AEs), Grade ≥3 AEs, and serious AEs were reported in 627 (36.9%), 959 (56.4%), 165 (9.7%), and 102 (6.0%) patients, respectively. AEs of special interests occurred in 59 (3.5%) patients, with 41 (2.4%) and 19 (1.1%) reporting QTc prolongation and interstitial lung disease/pneumonitis-like events, respectively. The safety profiles in patients ≥65 years old and those usually not included in randomized clinical trials were similar to that in the total population. CONCLUSION:This largest real-world safety study of osimertinib in China demonstrated that osimertinib was well-tolerated in a broad NSCLC population, including patients usually not included in randomized clinical trials, without new safety signals identified. CLINICAL TRIAL REGISTRATION:NCT03485326 (www.clinicaltrials.gov).

Aumolertinib, a third generation selective EGFR-TKI, is standard of care for the first-line treatment in advanced or metastatic NSCLC with sensitizing EGFR mutations in China. Evidence has shown that combining EGFR-TKIs with chemotherapy can improve outcomes compared to EGFR-TKIs monotherapy. AENEAS2 (NCT04923906) is a randomized, open-label, multicenter, phase 3 study assessing the efficacy and safety of aumolertinib plus chemotherapy versus aumolertinib alone as first-line treatment in locally advanced or metastatic NSCLC with sensitizing EGFR mutations. Patients who were naïve to treatment with locally advanced or metastatic NSCLC harboring EGFR mutations (exon 19 deletion or L858R mutation) were randomly assigned in a 1:1 ratio to receive aumolertinib 110 mg QD in combination with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC5), versus to receive aumolertinib 110 mg QD monotherapy. The primary endpoint is progression free survival (PFS) assessed by IRC (Independent Review Committee) per RECIST v1.1. Data cutoff date: 2024/06/18. A total of 624 patients were randomized to aumolertinib plus chemotherapy (n=310) or aumolertinib monotherapy (n=314) and stratified according to EGFR mutation status (Ex19del verse L858R) and CNS metastases at baseline (yes versus no). Baseline characteristics were balanced between treatment arms (aumolertinib plus chemotherapy versus aumolertinib): median age (range), 58.0 (30-84)/59.0 (31-81) years; 55.5/52.5 % female; 49.0/49.0% Ex19del; 51.0/51.0% L858R; 30.0/30.9% CNS metastases. Median follow-up was 23.4 months. Median PFS assessed by IRC was 28.9 months (95% CI, 26.3 to NA) in combination arm versus 18.9 months (95% CI, 17.8 to 21.1) in monotherapy arm; hazard ratio (HR) 0.471 (95% CI, 0.371 to 0.598; p<0.0001). The PFS benefit was consistent across pre-defined subgroups. The overall survival (OS) was immature with event-patient rate 21.6%; HR 0.442 (95% CI, 0.308 to 0.636; p<0.0001). Median cycles of pemetrexed exposure (range) were 20.0 (1-42) cycles, 88.8% of patients completed 4∼6 cycles of platinum therapy. All causality grade ≥3 AEs (aumolertinib plus chemotherapy versus aumolertinib): 75.7%/23.7%; AEs leading to discontinuation of aumolertinib: 3.0%/1.3%. The safety profile of aumolertinib plus pemetrexed and platinum was consistent with the established profiles of the individual agent. Aumolertinib plus chemotherapy as a first-line treatment in advanced EGFR-mutant NSCLC demonstrated a statistically significant and clinically meaningful PFS improvement over aumoletinib monotherapy, with a manageable safety profile. Shun Lu, Jie Hu, Jianhua Chen, Yan Yu, Xiangjiao Meng, Xiaorong Dong, Yanping Hu, Yinghua Ji, Ying Cheng, Weibo Wang, Fangling Ning, Zhihong Zhang, Zhiye Zhang, Chunling Liu, Qiming Wang, Wei Zheng, Xiujuan Qu, Honghai Wang, Runxiang Yang, Renhua Guo, Jianhua Shi, Feng Wu, Dongqing Lv, Jian Fang, Zhi Xu, Huaqiu Shi, Haichuan Su, Yongxing Chen, Cheng zhi Zhou, Junhong Zhang, Xuewen Liu, Zhaoxia Dai, Wen Li, Zili Meng, Guojun Zhang, Biyong Ren, Lin Wu, Yalun Li, Xinmin Yu, Ziping Wang, Jian Feng, Yueyin Pan, Juan Li, Xiangdong Zhou, Suxian Hu, Tongmei Zhang, Laiyu Liu, Jiming Shen, Shaonan Fan, Zhenming Chen. Aumolertinib with or without chemotherapy as first line treatment in locally advanced or metastatic NSCLC with sensitizing EGFR mutations (AENEAS2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT053.

INTRODUCTION:Although circulating tumor DNA (ctDNA) dynamics have been widely explored for therapeutic response assessment, standardized methodologies remain elusive. Here, we developed MinerVa-Delta, a novel approach to quantify ctDNA dynamics by calculating weighted mutation changes in samples with multiple tracked variants. METHODS:MinerVa-Delta was developed and analytically validated using serially diluted reference samples. The optimal cutoff was determined in a discovery cohort of 227 patients with advanced lung squamous cell carcinoma (LUSC) receiving programmed cell death protein 1 blockade plus chemotherapy or chemotherapy alone and further validated in an independent cohort of 97 patients with LUSC treated with chemotherapy alone. Variants were de novo called in pretreatment samples using a 769-gene next-generation sequencing panel, serving as a basis for personalized variant tracking in posttreatment plasma after two cycles of treatment. We applied MinerVa-Delta to evaluate prognosis and therapeutic response in advanced LUSC. RESULTS:Patients classified as molecular responders (MinerVa-Delta <30%) exhibited significantly improved outcomes compared with nonresponders (MinerVa-Delta ≥30%), with superior progression-free survival (hazard ratio = 0.19, p < 0.001) and overall survival (hazard ratio = 0.24, p < 0.001). MinerVa-Delta displayed consistent prediction performance in the validation cohort. Furthermore, MinerVa-Delta accurately identified radiologic stable disease patients, a clinically heterogeneous population, who could benefit from initial treatment. CONCLUSIONS:Our findings suggest MinerVa-Delta is feasible for evaluating treatment response in patients with advanced LUSC. Integrating ctDNA profiling with conventional imaging could enhance response assessment, particularly in radiologic stable disease patients, enabling more precise therapeutic decision-making.

Background:Early-stage lung adenocarcinoma has the potential to achieve long-term survival through radical surgery and appropriate adjuvant therapy. Despite rapid advancements in perioperative treatment strategies, postoperative adjuvant chemotherapy remains critically valuable. However, the optimal adjuvant chemotherapy regimen is yet to be established. Therefore, we initiated this study to evaluate the efficacy and safety of pemetrexed (PEM) plus platinum versus other platinum-based regimes as postoperative adjuvant chemotherapy in patients with stage II-IIIA lung adenocarcinoma after radical surgery to provide further clinical practice evidence. Methods:We performed a non-randomized, open-label, historical-control study. Seventy-one patients with pathologic stage II-IIIA lung adenocarcinoma who had undergone complete resection were prospectively enrolled, all of whom received pemetrexed combined with platinum adjuvant chemotherapy every 3 weeks for 4 cycles. In addition, we retrospectively collected the data from 209 patients recorded between January 2003 and December 2021 with pathologic stage II-IIIA lung adenocarcinoma who received radical surgery followed by adjuvant non-PEM (paclitaxel, gemcitabine and vinorelbine) plus platinum as historical control. The primary end point was disease-free survival (DFS). Univariable and multivariable Cox proportional hazards regression analyses were performed to identify independent prognostic factors for DFS. Propensity score matching (PSM) was applied to generate best-matched pairs for the two categories. All adverse events (AEs) were collected and compared. Results:In the prospective group, the median follow-up was 45.6 months (interquartile range, 40.3-55.7 months). Thirty-five of the 71 prospective patients developed disease progression, and 2-year DFS was 67.61%. The median DFS was not reached in the PEM group, compared with 18.9 months [95% confidence interval (CI): 15.6-22.0] in the non-PEM group. In the overall unmatched population, Kaplan-Meier analysis demonstrated a significant improvement in DFS with PEM (median DFS not reached vs. 18.9 months; P<0.001, hazard ratio =0.499, 95% CI: 0.345-0.72). In the PSM-matched cohort, the DFS benefit with PEM remained statistically significant (P=0.01). Besides, AEs of all grades were reported more frequently in the non-PEM plus platinum group than in PEM based group, such as neutropenia (76.1% vs. 25.4%), anemia (48.3% vs. 8.5%) and thrombocytopenia (23.4% vs. 5.6%). Conclusions:This study showed that PEM plus platinum outperforms non-PEM plus platinum as an adjuvant chemotherapy regimen for resected stage II-IIIA lung adenocarcinoma and with better tolerability.

INTRODUCTION:PEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic NSCLC (mNSCLC [EGFR/ALK wild type]) with programmed cell death ligand 1 (PD-L1) tumor cell (TC) membrane expression status of 25% or higher. We report the final analysis of PEARL. METHODS:Adults (N = 669) with previously untreated stage IV mNSCLC were randomized (1:1) to durvalumab 20 mg/kg every four weeks or chemotherapy every three weeks for four to six cycles. The dual primary endpoints were overall survival (OS) in the population with PD-L1 TC of 25% or higher and OS in the population at low risk of early mortality (LREM) with PD-L1 TC of 25% or higher. RESULTS:Durvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the 25% and higher PD-L1 TC population (OS hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.71-0.99, p = 0.037; median OS 14.6 months, 95% CI: 12.2-16.9 versus 12.8 months, 95% CI: 10.1-14.7, respectively). In the 25% and higher PD-L1 TC low risk of early mortality population the OS hazard ratio for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79-1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6-17.2) versus 15.0 months (95% CI: 13.1-16.8), respectively. In the safety population, the incidence of grade 3 or 4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy). CONCLUSIONS:Durvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and 25% and higher PD-L1 TC. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC.

BackgroundImmune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies has demonstrated efficacy in multiple tumor types. Nofazinlimab is a humanized rat antibody targeting PD-1. A first-in-human study of nofazinlimab conducted in Australia found no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) was not reached in the range of 1-10 mg/kg.ObjectiveWe evaluated nofazinlimab for multiple advanced malignancies in Chinese patients.Patients and methodsThis was a phase 1a/1b, open-label, multicenter, dose-escalation/expansion trial. In phase 1a, patients received an abbreviated dose escalation of nofazinlimab at 60 mg and 200 mg every 3 weeks (Q3W) to determine DLTs and the recommended phase 2 dose (RP2D). In phase 1b, patients received the RP2D (monotherapy/combination) in six arms by tumor type; DLTs were evaluated for nofazinlimab plus lenvatinib in the unresectable hepatocellular carcinoma (uHCC) arm. Safety (continuously monitored in patients who received nofazinlimab) and efficacy (patients with measurable baseline disease) were assessed.ResultsOverall, 107 patients were eligible and received nofazinlimab. In phase 1a, no DLTs were observed; the RP2D was 200mg Q3W. In phase 1b, no DLTs were observed with nofazinlimab plus lenvatinib. The safety profile was consistent with that observed in the first-in-human study (NCT03475251). In phase 1b, 21/88 (23.9%) patients achieved confirmed objective responses, 26 (29.5%) had stable disease, and 9/20 (45.0%) patients with uHCC achieved confirmed objective responses to nofazinlimab plus lenvatinib.ConclusionsNofazinlimab was well tolerated in Chinese patients. Preliminary efficacy was encouraging, particularly for nofazinlimab plus lenvatinib in uHCC, which is being studied in an ongoing phase 3 trial.Clinical Trial RegistrationNCT03809767; registered 18 January 2019.

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.