Abstract The evolutionary trajectory of lung squamous cell carcinoma (LUSC) remains poorly defined, hindering the development of effective therapies. By integrating genomic and transcriptomic sequencing from human LUSC specimens, we delineated a polyclonal-to-monoclonal evolutionary trajectory during LUSC progression. This evolutionary pattern was corroborated by single-cell RNA sequencing, which revealed consistent tumor cell heterogeneity. Specifically, the SBS5 mutational signature was enriched and correlated with poor prognosis independent of tumor stage. By further utilizing the spontaneous LUSC mouse model to identify key genomic and genetic events in LUSC progression, we observed that the JNK pathway was inhibited and that cytoskeleton-related pathways were dysregulated during LUSC development, and identified the mutations in the JNK pathway (e.g., DACT1 ) and cytoskeletal regulators (e.g., KIF26A ). Collectively, these findings established a polyclonal–monoclonal evolution paradigm for LUSC, potentially regulated by JNK pathways, which could benefit LUSC precision therapeutics.

BACKGROUND:Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS:HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION:Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING:Summit Therapeutics.

Importance:Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies. Objective:To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population. Design, Setting, and Participants:Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025. Interventions:Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy. Main Outcomes and Measures:This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee). Results:The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively. Conclusions and Relevance:Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy. Trial Registration:ClinicalTrials.gov Identifier: NCT05184712.

8109 Background: Alveltamig (ZG006) is a trispecific T cell engager (Tri-TE) targeting Delta-like ligand 3 (DLL3) and CD3, designed to bridge tumor cells and T cells by binding to two distinct DLL3 epitopes on tumor cells and CD3 on T cells, thereby mediating T cell-specific killing of DLL3-expressing tumor cells such as small cell lung cancer (SCLC). Methods: This is a multicenter, randomized, open-label, phase 2 dose-optimization study. Patients with SCLC who have failed at least two prior lines of standard therapy are randomized 1:1 to receive ZG006 at either 10 mg or 30 mg Q2W (both with a 1 mg priming dose). Based on the prior data from dose optimization in this study with an objective response rate (ORR) at 53.3% and median progression-free survival (PFS) at 7.03 months in the 10 mg group, 10 mg Q2W was selected as the recommended dose schedule for ongoing pivotal studies in advanced SCLC. Here we present the updated efficacy data with longer follow up and key subgroup analyses from this study. Results: This analysis included 60 treated patients (30 each from 10 and 30 mg group). With a median follow-up of about 13.5 months, the median duration of response (DoR) was not mature with 9-month DoR rates reaching 61.6% and 58.4% for 10 mg and 30 mg respectively. Likewise, the median OS for both groups was not reached, however, 12-month OS rates for two groups have approached 65.9% and 59.2% respectively. Based on the IRC data as of Sept 30, 2025, for the 10 mg and 30 mg groups, patients with previously treated and stable brain metastases at baseline achieved a confirmed ORR of 50.0% (4/8) and 44.4% (4/9), respectively, while patients without baseline brain metastases had an ORR of 54.5% (12/22) and 61.9% (13/21). Patients presented with baseline liver metastases achieved an ORR of 58.3% (7/12) and 46.2% (6/13), compared with 50.0% (9/18) and 64.7% (11/17) in patients without liver metastases. While 27 patients in 10 mg and 24 patients in 30 mg had previously received immune checkpoint inhibitors, a notable ORR of 55.6% (15/27) and 58.3% (14/24) was observed. Among patients with exactly two prior lines of systemic therapy, the ORRs were 50.0% (8/16) and 64.7% (11/17), whereas those who had received three or more prior lines demonstrated an ORR of 57.1% (8/14) and 46.2% (6/13) in 10 and 30 mg groups. Conclusions: With longer follow up, both ZG006 10 mg Q2W and 30 mg Q2W continued to demonstrate robust antitumor activity with a trend of longer DoR and OS in patients with relapsed or refractory SCLC. Subgroup analyses demonstrated consistent antitumor activity across key prognostic subgroups including those with baseline treated brain metastases, those with baseline liver metastases, and those who received multiple lines of prior systemic treatment. These results also support further development of ZG006 in SCLC with ongoing pivotal studies. Clinical trial information: NCT06283719 .

Histone lysine methylation is a post-translational modification system that has a profound impact on gene expression. The methylation of H3K79 plays an important role in gene transcription, repair of DNA damage, and cell cycle. In recent years, it has been discovered that Disruptor of telomeric silencing 1-like (DOT1L) can methylate H3K79 and is the only known H3K79 methyltransferase. DOT1L activity in leukemia cells interacts with ubiquitinated H2B to promote nucleosome binding. AF family proteins bind DNA to ENL to recruit DOT1L to the promoters of KMT2A (formerly MLL1)-rearranged leukemia target genes, promoting HOXA9 overexpression, a key event in leukemia. Moreover, DOT1L O-GlcNAcylation promotes its protein stability and proliferation of MLL fusion leukemia cells. This review summarizes the structure, biological functions and upstream regulatory mechanisms of DOT1L-mediated H3K79 methylation. Relevant literature was searched in PubMed and Web of Science for studies published from 2000 to 2024 using keywords including "DOT1L," "H3K79 methylation" and "KMT2A leukemia."

QuestionDoes adding ivonescimab to chemotherapy improve overall survival in patients with epidermal growth factor receptor (EGFR) gene variant non-small cell lung cancer after disease progression with EGFR tyrosine kinase inhibitor (TKI) therapy?FindingsIn this phase 3, randomized, double-blind trial, ivonescimab plus chemotherapy significantly improved overall survival (median, 16.8 vs 14.1 months) and the 30-month survival rate (29.1% vs 18.4%) compared with chemotherapy alone.MeaningThis regimen provides an effective post-EGFR-TKI treatment option, with a statistically significant survival benefit, a modest absolute improvement in median overall survival, and a more pronounced separation in long-term survival rate. ImportancePatients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies.ObjectiveTo provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025.InterventionsPatients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy.Main Outcomes and MeasuresThis final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee).ResultsThe 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively.Conclusions and RelevanceIvonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy.Trial RegistrationClinicalTrials.gov Identifier: NCT05184712 This randomized trial assesses the effect of ivonescimab added to chemotherapy on overall survival among patients with EGFR-variant non-small cell lung cancer (NSCLC) who had disease progression with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy.

BACKGROUND Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. In cases of metastatic CRC (mCRC) that are resistant to conventional chemotherapy-based treatments, the efficacy of available therapeutic options is typically low. CRC exhibiting overexpression or amplification of the human epidermal growth factor receptor 2 (HER2) gene has shown responsiveness to HER2-targeted therapies. CASE SUMMARY We present the case of a 69-year-old woman diagnosed with mCRC with an NRAS p.G12V mutation and microsatellite stability, identified through tumor sequencing, along with HER2 overexpression detected by immunohistochemistry. She exhibited an excellent response to disitamab vedotin-containing therapy. To our knowledge, this is the first reported case of mCRC with HER2 overexpression and an NRAS p.G12V mutation achieving a remarkable clinical response to anti-HER2 therapy. CONCLUSION Disitamab vedotin demonstrates promising anti-tumor effects in HER2-overexpressing mCRC, offering patients an additional treatment option.

8007 Background: ZG006 is a trispecific T cell engager (Tri-TE) targeting Delta-like ligand 3 (DLL3) and CD3, designed to bridge tumor cells and T cells by binding to two distinct DLL3 epitopes on tumor cells and CD3 on T cells, thereby mediating T cell-specific killing of DLL3-expressing tumor cells such as small cell lung cancer (SCLC). Here, we report the results from the phase 2 dose expansion study of ZG006 for the treatment of patients (pts) with advanced SCLC. Methods: This is a randomization, multi-center, open-label phase 2 study of ZG006 as monotherapy in SCLC pts failed to at least 2 prior lines of standard systemic treatments. Based on ZG006 phase 1 study results, both 10 mg and 30 mg Q2W dose levels with a priming dose of 1 mg are being evaluated in this phase 2 dose optimization study, 60 pts are to be randomized at a ratio of 1:1 to receive ZG006. The primary endpoint was objective response rate (ORR) according to RECIST1.1. DLL3 expression was not required but retrospectively evaluated by IHC. Results: As of Dec. 31, 2024, a total of 40 SCLC pts were randomized (19 on 10 mg, 21 on 30 mg) and received≥1 dose of ZG006. Median age was 57.5 (range: 48-73) years. Of the 40 pts, 31 (77.5%) were males and 27 (67.5%) had smoking history; all had received ≥2 prior line treatments and 45.0% ≥3 lines; majority (72.5%) had prior anti-PD-(L)1 treatments. Baseline metastatic sites of liver and brain accounted 52.5% (21/40) and 20.0% (8/40), respectively. Among 27 (13 at 10 mg, 14 at 30 mg) efficacy-evaluable SCLC pts who had at least one post-baseline tumor scan, 18 (5 confirmed, others pending confirmed) achieved partial response (7 at 10 mg, 11 at 30 mg). Overall, the ORR was 66.7% and the DCR was 92.6%. For the 10 mg group, ORR was 53.8% and DCR was 84.6%; for the 30 mg group, ORR was 78.6% and DCR was 100.0%. DoR and PFS, not yet matured and will be updated with additional follow-up time. Among the all combined 27 pts, 21 (77.8%) pts had low (N = 17) or medium (N = 4) DLL3 expression at baseline, and they demonstrated reasonably great anti-tumor efficacy with 15 PRs and 71.4% ORR. Treatment-related adverse events (TRAEs) occurred in 35 pts (87.5%); most commonly (≥20%): pyrexia (57.5%), cytokine release syndrome (CRS, 47.5%), vomiting (27.5%), rash (25.0%), decreased appetite (25.0%), aspartate aminotransferase increased (22.5%), white blood cell count decreased (22.5%) and platelet count decreased (22.5%). Only five pts (12.5%) experienced grade 3/4 TRAEs including one grade 3 CRS, and no pts experienced TRAEs leading to treatment discontinuation or death. Five pts (12.5%) experienced serious TRAEs. No significant difference was observed in the safety profile between these two dose groups. Conclusions: ZG006 exhibited promising efficacy and acceptable safety in SCLC pts receiving ≥2 lines of prior treatment, even in pts with low DLL3 expression. The enrollment of ZG006-002 study is ongoing. Clinical trial information: NCT06283719 .

Antibody–drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8 mg kg−1, and the recommended expansion dose was selected as 2.0 mg kg−1 and 2.4 mg kg−1 every 3 weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: NCT05434234 and NCT06057922 . In a large-scale, international, multicenter, phase 1/1b trial, treatment of patients with advanced solid tumors with the B7H3-targeting antibody–drug conjugate YL201 was safe and showed preliminary clinical efficacy.

Background:SIBP04 is a biosimilar of bevacizumab (Avastin®, Roche, Basel, Switzerland). This study evaluated the equivalence of SIBP04 to Avastin® as first-line treatment for locally advanced or metastatic non-squamous non-small-cell lung cancer (nsqNSCLC). Methods:In this randomized, double-blind, multi-center, phase 3 trial, we recruited patients with locally advanced or metastatic nsqNSCLC from 58 hospitals at China. Patients were randomly allocated 1:1 to receive SIBP04 or Avastin® (15 mg/kg) combined with paclitaxel (175 mg/m2) and carboplatin (area under curve [AUC] = 5.0, no more than 800 mg) (PC) regimens intravenously (3-week cycles, up to six cycles) followed by SIBP04 maintenance therapy. The primary endpoint was objective response rate (ORR), defined as the best overall response from the first dose to the 18th week, assessed by the independent review committee (IRC) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Clinical equivalence of the primary endpoint was done by comparing the two-sided 90% confidence interval (CI) of the ORR ratio (SIBP04 plus PC vs. Avastin® plus PC) in the per-protocol set (PPS) populaiton with the prespecified equivalence margin of 0.75-1.33. Secondary endpoints included progression-free survival, overall survival, duration of response, disease control rate, safety, immunogenicity, and pharmacological bioequivalence of steady-state trough concentrations. Results:From April 17, 2020, to April 20, 2021, 517 patients were randomly assigned to receive SIBP04 plus PC (n = 259) or Avastin® plus PC (n = 258). The ORR of the SIBP04 plus PC group was 55.6% (95% CI, 49.3-61.8) and that of the Avastin® plus PC group was 59.3% (95% CI, 53.0-65.4) in the full analysis set (FAS) population (P = 0. 3944). The ORR of the SIBP04 plus PC group was 62.6% (95% CI, 55.8-69.0) and that of the Avastin® plus PC group was 64.7% (95% CI, 58.0-71.0) in the PPS population (P = 0.6448). The ORR ratio (SIBP04 plus PC vs. Avastin® plus PC) was 0.94 (90% CI, 0.8270-1.0621) in the FAS population and 0.97 (90% CI, 0.8578-1.0900) in the PPS population, respectively, both within the prespecified equivalence margin of 0.75-1.33. Other efficacy endpoints, safety, immunogenicity, and pharmacokinetics were all comparable across the groups. Conclusions:SIBP04 showed equivalent efficacy and safety profile to Avastin® in patients with locally advanced or metastatic nsqNSCLC. SIBP04 plus PC regimen will offer an alternative first-line treatment option for this patient population. Trial registration:Clinicaltrials.gov, identifier NCT05318443.

8077 Background: ARUKA has been implicated in the emergence of resistance to osimertinib. VIC-1911 is a highly selective ARUKA inhibitor that has minimal activity in EGFR-mutant (mt) cell lines as a monotherapy. Preclinical data show synergy of VIC-1911 with osimertinib across in vitro and in vivo osimertinib-resistant models. Sustained tumor control after drug withdrawal is observed in both osimertinib-naïve and -resistant xenograft models. This trial evaluated the safety and efficacy of VIC-1911 plus osimertinib in patients with TKI-resistant, EGFRmt NSCLC (NCT05489731). Methods: This is a phase I trial with a 3+3 dose escalation stage and a dose expansion stage. Eligible patients should have advanced NSCLC with EGFR 19del/L858R and failure after ≥1 lines of EGFR-TKIs. Patients enrolled into the dose escalation stage were treated with VIC-1911 150mg or 200mg BID intermittently (4 days on, 3 days off) plus osimertinib 80 mg QD consecutively. Patients enrolled into the dose expansion stage were treated with VIC-1911 at the recommended phase 2 dose (RP2D) plus osimertinib 80 mg QD. Toxicity was assessed by the NCI CTCAE V5. Efficacy was evaluated per RECIST v1.1. Results: As of 18 December 2023, a total of 24 patients were treated. Median lines of prior treatment were 3 (range,1-8). Seven patients were enrolled during the dose escalation stage (150mg = 4, 200mg = 3). No DLT was observed and 200mg was selected as the RP2D. The most common AEs related to VIC-1911 at RP2D were diarrhea (52.3%), leucopenia (38.1%), neutropenia (33.3%), and thrombocytopenia (28.6%). Efficacy was evaluable in 23 patients. Among them, 10 patients were osimertinib-naïve (T790M-negative = 8,T790M-positive = 2) and 13 were osimertinib-resistant. For osimertinib-naïve patients, confirmed objective response rate (ORR) was 50% (5PRs, T790M-negative = 4, T790M-positive = 1) and disease control rate (DCR) was 80% (3SDs). For osimertinib-resistant patients, ORR was 0% and DCR was 53.8% (7SDs). Among patients with disease control, 66.7% (10/15) stayed on treatment as of data cutoff. The median follow-up duration was 5.5 months. Median duration of response (DOR) was not reached. The 6-month (6m) DOR rate was 50%. Median progression-free survival (PFS) was not reached and 4.3months for osimertinib- naïve and -resistant patients, respectively. The 6m PFS rate was 70.0% and 38.5%, respectively. Updated DOR and PFS data will be presented. Conclusions: VIC-1911 in combination of osimertinib is well-tolerated in previously-treated EGFRmt NSCLC. The combination demonstrates sustained antitumor activity, which indicates the potential of AURKA blockade in delaying the emergence of resistance to osimertinib. Clinical trial information: NCT05489731 .

Importance:For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective:To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants:Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions:Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures:The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results:Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions:Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration:ClinicalTrials.gov Identifier: NCT05184712.

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.

8508 Background: Ivonescimab (AK112/SMT112) is a anti-PD-1/VEGF bispecific antibody. Previous phase I/II clinical studies have shown potential efficacy of ivonescimab in NSCLC patients with EGFR mutations who had failed prior EGFR-TKIs therapies. This phase 3 study aimed to evaluate and confirm the efficacy and safety of ivonescimab combined with chemotherapy versus chemotherapy alone in this population. Methods: Patients were randomized 1:1 to receive ivonescimab (20 mg/kg) plus pemetrexed (500 mg/m2) and carboplatin (AUC 5) or placebo plus chemotherapy once every 3 weeks for four cycles, with stratification according to the third-generation EGFR-TKI (received vs not received) and brain metastases (presence vs absence), followed by maintenance therapy of ivonescimab and pemetrexed or placebo and pemetrexed. The primary endpoint was progression-free survival (PFS) in intention-to-treat (ITT) population assessed by independent radiographic review committee (IRRC) per RECIST v1.1. Here we report the results of the first planned interim analysis. Results: Total 322 patients were randomized (161 to the ivonescimab plus chemotherapy arm, 161 to the placebo plus chemotherapy arm). 86.3% versus 85.1% of patients had received the third generation EGFR-TKIs treatment, 21.7% versus 23.0% of patients had brain metastases. As of March 10, 2023, median follow up time was 7.89 months. PFS was significantly improved in the ivonescimab plus chemotherapy arm (HR 0.46 [0.34, 0.62], P < 0.0001). Median PFS (95%CI) by IRRC were 7.06m (5.85, 8.74) in the ivonescimab arm versus 4.80m (4.21, 5.55) in chemotherapy arm. The prespecified subgroup analysis showed PFS benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including in patients who progressed on the third-generation EGFR-TKIs therapy (HR 0.48, 95% CI 0.35-0.66), those with brain metastases (HR 0.40, 0.22-0.73), those with EGFR mutation of deletion 19 (HR 0.48, 0.32-0.73), and individuals with T790M mutation positive (HR 0.22, 0.09-0.54). The ORR were 50.6% and 35.4%, respectively. Grade ≥3 TEAEs occurred in 99 (61.5%) patients versus 79 (49.1%) patients, the most common grade ≥3 TEAEs were chemotherapy related adverse events. Grade ≥3 immune-related adverse events occurred in 10 (6.2%) patients versus 4 (2.5%). Grade ≥3 VEGF blocking related adverse events occurred in 5 patients (3.1%) versus 4 patients (2.5%). Conclusions: Ivonescimab plus chemotherapy significantly improved PFS while maintaining a manageable safety profile in patients who had failed EGFR-TKIs treatments. Clinical trial information: NCT05184712 .

9014 Background: This study aimed to evaluate the safety and preliminary efficacy of YK-029A, a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in treated or untreated patients with advanced NSCLC. Methods: This dose-escalation and dose-expansion phase 1 trial recruited previously untreated or treated patients with EGFR ex20ins mutant locally advanced or metastatic NSCLC and previously treated patients with EGFR T790M or rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. In the treatment-naïve cohort of EGFR ex20ins mutant NSCLC, patients were administered oral YK-029A 200 mg once daily in a 28-day cycle, and efficacy was assessed by the independent review committee. The study was registered (chinadrugtrials.org.cn,CTR20180350). Results: A total of 108 were included in the safety analysis set. DLT did not occur in dose-escalation phase. MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade and grade≥3 occurred in 106 (98.1%) and 41 (38.0%) patients, respectively. Treatment-related adverse events (TRAEs) of any grade and grade≥3 occurred in 102 (94.4%) and 30 (27.8%) patients, respectively. One patient had liver abscess related to YK-029A and died. Three patients terminated the treatment because of TEAEs. The most common TRAEs were diarrhea (46.3%), anemia (38.0%), and rash (32.4%). For the treatment-naïve EGFR ex20ins mutant cohort, 26 patients were included in the efficacy analysis set. Most patients were adenocarcinoma (96.4%) and at stage IV (85.7%). At the cut-off date on October 30, 2022, 19 patients (73.1%) had partial remission, five patients (19.2%) had stable disease, and two patients (7.7%) developed disease progression. The confirmed objective response rate achieved 73.1% (95% confidence interval [CI], 52.21% to 88.43%). The median progression-free survival was 9.3 months (95% CI, 5.85 to not evaluated). Conclusions: YK-029A was well tolerated and showed preliminary efficacy in treatment-naïve EGFR ex20ins mutant patients with locally advanced or metastatic NSCLC. [Table: see text]

Introduction Treatment options for treatment-naive patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations are limited. This study evaluated the safety, tolerability, and pharmacokinetics of YK-029A, a third-generation EGFR tyrosine kinase inhibitor, and the preliminary efficacy of YK-029A in treatment-naive patients with EGFR ex20ins mutation. Methods This multicenter, dose-escalation, and dose-expansion phase 1 clinical trial enrolled patients with NSCLC harboring EGFR mutations. During the dose-escalation phase, YK-029A was orally administered using the traditional 3+3 principle at 50, 100, 150, 200, and 250 mg/d. In the dose-expansion phase, treatment-naive patients with EGFR ex20ins mutations were enrolled and administered YK-029A 200 mg/d. The primary end point was safety and tolerability. Results The safety analysis included 108 patients. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common treatment-emergent adverse events were anemia (50.9%), diarrhea (49.1%), and rash (34.3%). There was minimal drug accumulation after multiple doses. A total of 28 treatment-naive patients with EGFR ex20ins mutations were enrolled in the dose-expansion and 26 were included in the efficacy analysis. According to the independent review committee evaluation, the objective response rate was 73.1% (95% confidence interval: 52.21%-88.43%), and the disease control rate was 92.3% (95% confidence interval: 74.87%-99.05%). Conclusions YK-029A was found to have manageable safety and be tolerable in patients with NSCLC harboring EGFR mutations and have promising antitumor activity in untreated patients with EGFR ex20ins mutations.

Introduction: As a novel third-generation EGFR tyrosine kinase inhibitor (TKI), SH-1028 (formerly oritinib) is developed to inhibit both sensitizing EGFR mutations and EGFR T790M mutation. Methods: This was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807). Eligible patients were those with advanced NSCLC with centrally confirmed EGFR T790M mutation who progressed after first-or second-generation EGFR TKIs or with primary EGFR T790M mutations. Each patient received SH-1028 tablets orally at 200 mg/d until disease progression or intoler-able toxicity. Tumor response was evaluated every 6 weeks per the Response Evaluation Criteria in Solid Tu-mors, version 1.1. The primary end point was objective response rate by an independent review committee. The secondary end points were progression-free survival, overall survival (OS), disease control rate, safety, and so on.Results: A total of 286 patients with EGFR T790M-positive advanced NSCLC were enrolled in this study, including 59 patients in part A (dose-verification study) and 227 pa-tients in part B (second-line registration study). By data cutoff on September 17, 2021, the independent review committee-assessed objective response rate was 55.9% (95% confidence interval [CI]: 42.4-68.8) in part A and 60.4% (95% CI: 53.7-66.8) in part B. The median progression-free survival was 12.4 months (95% CI: 8.3- 20.8) in part A and 12.6 months (95% CI: 9.7-15.3) in part B. The median OS was 26.0 months (95% CI: 23.3-not reached) in part A, and OS was immature in part B. Among the 286 patients, 44 of them experienced at least one grade 3 or higher treatment-related adverse event, with the most common ones as increased serum creatinine phosphoki-nase level (13 [4.5%]), diarrhea (six [2.1%]), and pro-longed QT interval (three [1.0%]). Treatment-related skin rash was reported in 26 patients (9.1%), all grade 1 or 2. There was no interstitial lung disease reported in this study.Conclusions: SH-1028 is efficacious and tolerable in second-line treatment of patients with advanced NSCLC with positive EGFR T790M.(c) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

9076 Background: SAF-189s is a potent, brain-penetrant, next-generation anaplastic lymphoma kinase (ALK) inhibitor with preclinical activity against most known resistance mutations of ALK. We investigated safety, population pharmacokinetics, efficacy, and antitumor activity of SAF-189s in advanced, ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: In this first-in-human phase 1/2 trial (NCT04237805), patients aged ≥18 years with histologically or cytologically confirmed, advanced, ALK+ NSCLC (with or without brain metastases) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 41 hospitals in China. Oral SAF-189s was given in escalating doses of 20–210 mg once daily in continuous, 21-day cycles until disease progression, unacceptable toxicity, consent withdrawal, or death. Phase 1 data were presented at ASCO 2020. Here, we report updated phase 1 results and preliminary phase 2 data. Results: At a clinical cutoff date of January 18, 2022, 45 patients with prior systemic therapy enrolled in phase 1 and 150 were enrolled in phase 2. SAF-189s was well tolerated, the most common grade 3–4 treatment-related adverse events were hyperglycemia (7%), hypertension (6%) and diarrhea (3%). No treatment-related death was reported. 160 mg was chosen as the recommended phase 2 dose. In phase 1, 11 (24%) patients were ALK inhibitor (ALKi)-naive and 34 (76%) were ALKi-pretreated. Median progression-free survival (PFS) was 33.1 and 22.1 months (95% CI 6.9–not reached: 13.8–26.6) in ALKi-naive and ALKi-pretreated patients, respectively. Disease control rates (DCRs) were 100% in both ALKi-naive and ALKi-pretreated patients. Most patients in phase 2 were ALKi-naive (n=104, 69%), 26 (17%) received prior crizotinib only and 20 (12%) were pretreated with ≥1 non-crizotinib ALKi. The median duration of follow-up was 11.7 months (range 10.3–16.8), ORRs were comparable between the full analysis set and the 71 patients with brain metastases at 78.7% (95% CI 71.2–84.9) and 74.6% (95% CI 62.9–84.2) respectively. ALKi-naive patients had ORR of 92.3% (95% CI 85.4–96.6), compared to 65.4% (95% CI 44.3–82.8) in the crizotinib-pretreated group. DCR was 98.1% in ALKi-naive and 88.5% in crizotinib-pretreated patients. PFS data are not mature. Conclusions: SAF-189s showed clinical antitumor activity and was well tolerated in patients with advanced, ALK+ NSCLC, including those with brain metastases and pretreated with crizotinib. SAF-189s represents a promising, next-generation, targeted therapy for patients with ALK+ NSCLC. Clinical trial information: NCT04237805. [Table: see text]

Background Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. Methods This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). Results In total, 171 patients were enrolled (dose-escalation: n =17; dose-expansion, n =33; clinical-expansion, n =121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4–36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5–73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. Conclusions SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. Trial registration ClinicalTrials.gov , NCT03710265