Xiaorong Dong

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.

9096 Background: We previously reported (Lu, ASCO 2021, abstract # 9013) that treatment with aumolertinib (Au), a 3 rd generation EGFR TKI, led to robust improvement in progression free survival (PFS) (median PFS 19.3 to 9.9 months, HR = 0.46, p &lt; 0.0001) when compared to gefitinib (G) with a predictable and encouraging safety profile. This benefit was maintained across all prespecified stratification factors including the subset of ̃ 27% of patients (pts) with CNS metastases (HR = 0.38). Here we undertook this analysis to more fully characterize the activity and benefit of Au as compared to G in this clinically important subset of EGFR mutant NSCLC pts. Methods: Pts with previously untreated metastatic or locally advanced NSCLC with EGFR sensitizing mutations were enrolled and randomly assigned in a 1:1 ratio to receive either Au (110 mg QD) or G (250 mg QD). Predefined stratification factors were EGFR-mutated status (Ex19del vs L858R) and CNS metastases (yes vs no). Patients with stable, asymptomatic CNS metastases were eligible for enrollment. All pts had baseline brain imaging by magnetic resonance imaging or computed tomography. The primary endpoint was PFS assessed by investigator per RECIST v1.1 in full analysis set (systemic analysis). Independent CNS efficacy was performed both in pts with baseline CNS metastases (CNS full analysis set, cFAS) and in pts with baseline CNS target lesions (CNS evaluable-for-response set, cEFS) by blinded independent central neuroradiology review (BICR) per RECIST v1.1. Results: Of 429 pts, 106 pts (Au, n = 51; G, n = 55) were found to have CNS metastases (cFAS) and 61 pts (Au, n = 29; G, n = 32) had CNS target lesions as defined by RECIST 1.1 (cEFS) at baseline by BICR. At the cutoff date (Aug 6, 2021), based on cEFS, CNS PFS events were observed in 11 pts (38%) treated with Au versus 20 pts (63%) who were randomized to receive G. Treatment with Au significantly prolonged CNS median PFS compared with G (29.0 vs 8.3 months; HR = 0.300; 95% CI, 0.137-0.657; P = 0.0015). Estimated CNS PFS rate at 12 and 18 months were 71% and 62% in Au arm compared with 23% and 0% in G arm. The confirmed CNS ORR were 82.8% and 75.0% in pts treated with Au and G, respectively (odds ratio = 1.600; 95% CI, 0.457-5.597; P = 0.4621). Au also achieved longer CNS median PFS over G in cFAS (29.0 vs 8.3 months; HR = 0.323; 95% CI, 0.181-0.576; P &lt; 0.0001). No new safety findings were observed. Conclusions: Au demonstrated superior clinical efficacy against CNS metastases over G as first-line therapy in EGFR-mutated advanced NSCLC, and the safety profile was consistent with that reported previously. Additional randomized studies of Au in pts with CNS metastases are ongoing (NCT04870190). Clinical trial information: NCT03849768.

9040 Background: Besides the well-known antiangiogenic effects, anti-VEGF agents also modulate the tumor immune micro-environment, leading to synergic anti-tumor effects. AK112 is a humanized IgG1 bispecific antibody against PD-1 and VEGF. Here, we reported results of an ongoing phase Ib/II trial of AK112 in advanced NSCLC pts. Methods: Pts with stage IIIB/IIIC/IV NSCLC, ECOG PS 0-1 and negative oncogenic drivers were enrolled and given AK112 (10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W or 30 mg/kg Q3W) intravenously. The primary endpoints were ORR per RECIST v1.1 and safety. Results: At data cutoff (January 5, 2022), 94 pts were enrolled: median age 66.0 years (range: 48-75), PS 1 90.4%, male 85.1%, non-squamous 48.9%, PD-L1 positive (TPS ≥1%) 70.2% and treatment-naïve 84.0%. Of 83 pts evaluable for efficacy, ORR (unconfirmed, similarly hereinafter) and DCR were 22.2%/88.9%, 44.0%/92.0%, 37.9%/93.1% and 100%/100% at doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W and 30 mg/kg Q3W, respectively. When doses of AK112 &gt; 10mg/kg Q3W, ORR and DCR were 42.9% (24/56) and 92.9% (52/56) in 56 evaluable pts, 56.3% (18/32) and 100% (32/32) in pts with TPS≥1% at 1 st line setting, and 23.5% (4/17) and 76.5% (13/17) in pts with PD-L1 TPS &lt; 1%, respectively. Grade≥3 treatment-related adverse events (TRAEs) occurred in 10.6% (10/94) pts, in which the most common event (occurring in &gt; 1 pt) was pneumonia (2.1%, 2/94). No TRAEs led to permanent treatment discontinuation. Most frequent TRAEs (incidence ≥10%) were proteinuria (17.0%), hypertension (16.0%), lipase increase (12.8%), alanine aminotransferase increase (12.8%), blood urea increase (10.6%), apolipoprotein E increase (10.6%) and hyperglycaemia (10.6%). No significant difference in the incidences of TRAEs were observed between non-squamous and squamous pts. Conclusions: In advanced NSCLC, AK112 was well-tolerated and presented remarkable anti-tumor efficacy. Further phase III studies are planned to validate the findings of this study. Clinical trial information: NCT04900363.

3110 Background: IBI351(GFH925) is an irreversibly covalent inhibitor of KRAS G12C . In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI351 (GFH925) in patients (pts) with advanced solid tumors harboring the KRAS p.G12C mutation. Methods: Pts with locally advanced, recurrent or metastatic solid tumors with KRAS G12C mutation for whom standard therapy had failed were enrolled. Phase I dose escalation had an accelerated titration design for dose level 250mg QD and a BOIN design with 450/700/900mg QD. The primary end points were safety and tolerabilityThe secondary end points were pharmacokinetics (PK) and anti-tumor activity of IBI351(GFH925) monotherapy per RECIST v1.1. Results: As of Feb 07 2022, 15 pts (13 men, 2 women; median age: 62 yrs, range: 48–74 yrs) were enrolled, among whom 12 had non-small cell lung cancer (NSCLC), and 3 had colorectal cancer (CRC). 4 pts had ≥3 prior lines of treatment (tx). Median tx duration was 66.5 ds (range: 21–98 ds). No dose-limiting toxicity (DLT) or any ≥grade 3 treatment-related adverse events were observed in any dose cohorts. A total of 12 patients (80.0%) had treatment-related adverse events (grade 1, n = 6; grade 2, n = 6). By investigator-assessment, tumor response was evaluated in 9 pts (4 with ≥2 assessments); 6 pts had not reached their first assessment. 2 pts had PR (1 NSCLC at wks 12, 450mg, tx ongoing; 1 CRC at wks 6, 700mg, tx ongoing), 4 pts (NSCLC) had SD, and 3 pts had PD (1 NSCLC at wks 12, 2 CRC at wks 6). As data cut-off date, 11 pts were continuing to receive IBI351 (GFH925). Conclusions: IBI351(GFH925) was well-tolerated without unanticipated adverse events across all doses explored in pts with advanced solid tumors harboring the KRAS p.G12C mutation. The data also demonstrated the preliminary efficacy signal of IBI351 (GFH925) in previously treated advanced NSCLC and CRC. Clinical trial information: NCT05005234.

Abstract IBI351 (also known as fulzerasib or GFH925), an irreversible covalent inhibitor of KRAS G12C , has demonstrated promising anti-tumour activity in patients with solid tumours. In this study, data were pooled from the phase I part of two clinical studies (NCT05005234 and NCT05497336), aiming to evaluate the efficacy and safety of IBI351 monotherapy in KRAS G12C inhibitor-naïve Chinese patients with KRAS G12C -mutated metastatic colorectal cancer (CRC). The objective response rate (ORR) was the primary endpoint. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). As of December 13, 2023, 56 patients treated with IBI351 monotherapy were included. The median duration of treatment was 7.7 months (range: 0.3–16.7). The confirmed ORR was 44.6% (95% CI: 31.3–58.5), with a DCR of 87.5% (95% CI: 75.9–94.8). With a median follow-up of 13.8 months, the median PFS was 8.1 months (95% CI: 5.5–13.8). The median OS was 17.0 months (95% CI: 12.6–not reached). Treatment-related adverse events (TRAEs) occurred in 53 patients (94.6%), with grade 3 TRAEs in 14 patients (25.0%). No grade 4 or 5 TRAEs were observed. The most common grade 3 TRAEs were anaemia ( n = 4, 7.1%) and gamma-glutamyltransferase increased ( n = 3, 5.4%). TRAEs led to dose interruption in 12 patients (21.4%) and dose reduction in six patients (10.7%). No TRAEs resulted in treatment discontinuation. IBI351 demonstrated encouraging clinical efficacy and a manageable safety profile in KRAS G12C inhibitor-naïve Chinese patients with KRAS G12C -mutated metastatic CRC.