4059 Background: Anti-PD1 antibody has significantly improved survival in patients with HER2-overexpressing and PD-L1 combined positive score (CPS) ≥1 GC/GEJC when added to trastuzumab and chemotherapy. Recent trials revealed that HER2-targeted antibody-drug conjugates, including RC48 and Trastuzumab Deruxtecan, combined with anti-PD1 antibody, have also shown promising efficacy in this population. This study reports updated survival results of RC48 combined with tislelizumab and the oral fluoropyrimidine S-1 as first-line therapy for patients with HER2-overexpressing GC/GEJC. Methods: This single-arm, multicenter clinical trial enrolled patients with unresectable or metastatic HER2-overexpressing (IHC 3+ or 2+, regardless of FISH status) first-line GC/GEJC. Patients received RC48 (2.5 mg/kg), tislelizumab (200 mg), and S-1 (40-60 mg BID for 14 days) every 3 weeks until disease progression (PD) or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 57 patients from 9 centers were enrolled, 71.9% HER2 IHC 3+, 17.5% IHC 2+/FISH+, and 10.5% IHC 2+/FISH-. 14.9% and 36.2% had CPS≥5 and ≥1, respectively. Median follow-up was 11.8 months. In the intent-to-treat population, the confirmed ORR (cORR) was 89.4% (51/57, 95% CI: 78.5-96.0%), the median PFS (mPFS) was 12.7 months (95% CI: 10.9-NA), and the 18-month OS rate (18m-OSr) was 72.7% (95% CI: 60.0-88.5%). In the per-protocol set (excluding patients with no PD at the first assessment but refused a second evaluation), the cORR was 92.7% (51/55, 95% CI: 82.4-98.0%), the mPFS was 13.2 months (95% CI: 10.9-NA), and the 18m-OSr was 76.3% (95% CI: 63.0-91.7%). In the HER2-positive and -negative subgroups, the ORRs were 92.1% (95% CI: 81.1-97.8%) and 66.7% (95% CI: 22.3-95.7%), the mPFS was 12.6 months (95% CI: 11.0-NA) and 7.7 months (95% CI: 7.1-NA), and the 18m-OSr was 74.7% (95% CI: 61.3-91.1%) and 62.5% (95% CI: 32.0-100%), respectively. In the CPS ≥1 and CPS < 1 subgroups, ORRs were 92.3% (95% CI: 74.9-99.1%) and 87.1% (95% CI: 70.2-96.4%), the mPFS was 16.8 months (95% CI: 11.3-NA) and 11.4 months (95% CI: 8.5-NA), and the 18m-OSr was 80.4% (95% CI: 62.1-100%) and 67.4% (95% CI: 50.7-89.5%), respectively. The grade 3-4 treatment-related adverse events (AEs) was 63.2%. The most common AEs were neutropenia, fatigue, and leukopenia. An exploratory study with longitudinal sequencing of circulating tumor DNA is ongoing. Conclusions: The combination of RC48, tislelizumab and S-1 as a first-line therapy shows encouraging response rates and survival benefits in HER2-overexpressing GC/GEJC, especially in HER2-positive or CPS ≥1 patients, supporting further evaluation in randomized controlled trials. Clinical trial information: NCT05586061 .
Chemotherapy-induced peripheral neuropathy (CIPN) is the primary dose-limiting toxicity in albumin-bound paclitaxel chemotherapy regimens. Current assessment methods based on clinical scales are limited by strong subjectivity and insufficient sensitivity, while most emerging technologies remain in the preclinical stage. Therefore, the development of objective and non-invasive imaging biomarkers is urgently needed. This review focuses on the transformative role of non-invasive imaging techniques in addressing unmet clinical needs such as the accurate imaging assessment of CIPN, and systematically analyzes the complementary value of musculoskeletal ultrasound (MSUS) and magnetic resonance imaging (MRI) in evaluating nervous system damage induced by albumin-bound paclitaxel-related CIPN. For key peripheral nerves including the radial nerve, ulnar nerve, median nerve, and common peroneal nerve, MSUS can visualize morphological abnormalities and hemodynamic changes in real time through high-frequency probes, enabling rapid, radiation-free anatomical assessment, and serial monitoring. MRI can detect early neurostructural damage, nerve edema, and abnormal nerve fascicle signals, while also evaluating soft-tissue lesions in the nerve trajectory area. Future research should conduct systematic validation of standardized imaging data to clarify the clinical value of these techniques as predictive biomarkers for risk stratification of CIPN. This article aims to construct a novel clinical diagnostic approach for CIPN, provide a more precise and efficient diagnostic pathway for patients with peripheral neuropathy symptoms, further support the timely formulation and implementation of targeted clinical treatment plans, and ultimately contribute to improving patient prognosis.
e14513 Background: OX40, an immune costimulatory receptor mainly expressed on activated T cells, plays a role in T cell survival, proliferation, and proinflammatory cytokine expression. BGB-A445 is a novel mAb agonist against OX40 with high specificity and affinity that showed preclinical antitumor activity. BGB-A445 preserves binding of OX40 to its endogenous ligand, reducing the hook effect (antibody excess) seen with other OX40 agents and maximizing antitumor activity. HPK1 is a negative regulator in antitumor immunity. Preclinical studies of BGB-A445 in combination with the HPK1i BGB-15025 show potentially enhanced antitumor effects. We report results from Part 1 of a ph 2, randomized, open-label, multicenter trial of BGB-A445 plus docetaxel or BGB-15025 in previously treated NSCLC pts (NCT06029127). Methods: This trial was conducted in China and South Korea. In Part 1, pts were randomized to BGB-A445 in combination with docetaxel (Arm A) or BGB-15025 (Arm B). Eligible pts were ≥18 with advanced/metastatic NSCLC without actionable genomic alterations and ≤2L of prior systemic therapies, which must have included anti-PD-(L)1 treatment and a platinum-based CT. Primary endpoint was ORR; secondary endpoints were safety/tolerability, DOR, DCR, CBR, PK, and host immunogenicity; exploratory endpoints were biomarkers and PFS. Results: As of Jul 1, 2024, 21 pts were randomized to Arm A and 14 to Arm B. In Arms A and B, respectively, median (range) ages were 65.0 (38.0-74.0) and 60.5 (45.0-79.0); 23.8% and 14.3% were female; 61.9% and 57.1% had squamous cell carcinoma. Median exposure to BGB-A445 was 2.7 mo in A and 1.4 mo in B. Median study follow up was 3.2 mo in A and 3.3 mo in B. There were no confirmed responses. In Arms A and B, respectively, DCR (95% CI) was 71.4% (47.8-88.7) and 21.4% (4.7-50.8); CBR was 9.5% (1.2-30.4) and 0% (0-23.2); median PFS was 2.8 (1.8-4.3) mo and 1.4 (1.2-1.4) mo. Low expression of OX40 in tumor tissue may contribute to lack of efficacy. TEAEs occurred in most pts, with 66.7% in A and 7.1% in B having gr ≥3 TEAEs (Table). Most common gr ≥3 TEAEs in A were neutrophil count decreased and WBC count decreased; two gr 3 TEAEs (pneumonia; hypertension) occurred in the same pt in B. In both Arms, there were no TEAEs leading to death or discontinuation and no gr ≥3 imAEs. The most common (≥2 pts) imAE was rash. Conclusions: BGB-A445 plus docetaxel or BGB-15025 was generally well tolerated in pts with advanced NSCLC and showed limited antitumor activity. Clinical trial information: NCT06029127 . Safety. Arm ABGB-A445 + docetaxel(N=21) Arm BBGB-A445 + BGB-15025(N=14) Any treatment-emergent AE 20 (95.2) 12 (85.7) Gr ≥3 14 (66.7) 1 (7.1) Serious 7 (33.3) 1 (7.1) Any treatment-related treatment-emergent AE 20 (95.2) 11 (78.6) Gr ≥3 14 (66.7) 1 (7.1) Serious 5 (23.8) 0 Any immune-mediated AE 3 (14.3) 4 (28.6) Infusion-related reactions 4 (19.0) 1 (7.1) Pts with multiple AEs are counted once. All AEs are n (%).
e16075 Background: PD-1 antibodies in combination with chemotherapy have become the standard first-line treatment for advanced GC/GEJC. However, it is unknown whether immunotherapy should be continued in the second-line setting. This trial aimed to evaluate the efficacy and safety of the PD-1 antibody serplulimab in combination with an anti-angiogenic multi-kinase inhibitor lenvatinib and paclitaxel in patients with GC/GEJC for whom first-line treatments of immunotherapy (IO) and chemotherapy failed. Methods: Eligible GC/GEJC patients met at least one of the following 3 criteria: 1) PD-L1 combined positive score (CPS) ≥1; 2) previous partial or complete response, or 3) progression-free survival (PFS) ≥6 months in first-line therapy. Patients received serplulimab (300 mg), lenvatinib (8 mg QD), and paclitaxel 135-175 mg/m² or nab-paclitaxel 260 mg/m², every 3 weeks for six cycles, followed by maintenance therapy with serplulimab and lenvatinib. The primary endpoint was objective response rate (ORR), and secondary endpoints included PFS, overall survival (OS), and safety. Results: A total of 47 patients from 8 centers were enrolled. Patients with CPS ≥1 accounted for 55.3%. The median first-line PFS (mPFS) was 8.3 months (range: 1.6-37.9 months), with 9.1 months for CPS<1 and 7.8 months for CPS≥1. Median follow-up duration was 6.3 months. Among the 41 patients who had undergone at least one assessment, the ORR was 51.2% (95% CI: 35.1%-67.1%). The mPFS was 7.1 months (95% CI: 6.1-NA) and the median OS (mOS) was 13.7 months (95% CI: 11.6-NA). In the CPS <1 and CPS ≥1 subgroups, the ORRs were 50.0% (95% CI: 27.2%-72.8%) and 52.4% (95% CI: 29.8%-74.3%), respectively. The mPFS was 14.5 months (95% CI: 6.1-NA) for CPS <1 and 6.2 months (95% CI: 3.0-NA) for CPS ≥1, with a hazard ratio (HR) of 0.3 (95% CI: 0.1-1.0, log-rank P = 0.045). The mOS was 14.5 months (95% CI: 10.2-NA) for CPS <1 and 11.6 months (95% CI: 6.7-NA) for CPS ≥1, with an HR of 0.3 (95% CI: 0.1-1.1, log-rank P=0.054). In subgroups with mPFS≥6 and <6 months in first-line treatment, mPFS was 11.3 (95% CI: 6.1-NA) and 4.3 months (95% CI: 2.9-NA; HR: 0.4, 95% CI: 0.1–1.6, log-rank P=0.20) and mOS was 14.5 (95% CI: 10.2-NA) and 13.4 months (95% CI: 5.1-NA; HR: 0.5, 95% CI: 0.1-2.0, log-rank P=0.35), respectively. The overall incidence of adverse events (AEs) was 72.3%, with 17.0% of patients experiencing grade 3-4 treatment-related AEs. The most common AEs were leukopenia, neutropenia, and numbness. Conclusions: Continual IO with serplulimab, combined with lenvatinib and paclitaxel, demonstrated promising efficacy and manageable safety in GC/GEJC patients who have benefited from prior IO. This regimen represents a potential new treatment option for patients for whom first-line immunochemotherapy failed. Clinical trial information: NCT05585580 .
