CLDN18.2-targeting antibody-drug conjugate IBI343 in advanced gastric or gastroesophageal junction adenocarcinoma: a phase 1 trial

Abstract

Aberrant expression of claudin18.2 (CLDN18.2) has frequently been observed in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, making it a promising therapeutic target for this aggressive cancer. While a monoclonal antibody targeting CLDN18.2 has been approved for G/GEJ adenocarcinoma, antibody-drug conjugates (ADCs) have also emerged as therapeutic modalities. IBI343 is an ADC consisting of a fully humanized anti-CLDN18.2 monoclonal antibody conjugated to exatecan via site-specific glycol conjugation and a cleavable linker with a drug-to-antibody ratio of 4. Here we present the results from a phase 1 dose escalation and dose expansion study of the IBI343 ADC. A total of 127 patients were enrolled and dosed (19 in the escalation phase and 108 in the expansion phase). Dose-limiting toxicities occurred in two of six participants at a dose of 10 mg kg^-1, including one with myelosuppression (grade 4) and one with both neutropenia (grade 4) and febrile neutropenia (grade 3). Minimal gastrointestinal adverse events (grade ≥3) were observed and no interstitial lung disease was reported. The recommended phase 2 dose of IBI343 was determined to be 6 mg kg^-1 every 3 weeks with a confirmed objective response rate of 29% and median progression-free survival of 5.5 months in CLDN18.2-high (2+/3+ ≥ 75%) G/GEJ adenocarcinoma. IBI343 was well tolerated, with a manageable safety profile and promising efficacy in G/GEJ adenocarcinoma. Further research is required to understand optimal sequencing, and biomarker-informed combination therapy, in G/GEJ tumors given the development of multiple therapies targeting CLDN18.2 in addition to human epidermal growth factor receptor 2 and programmed cell death 1 ligand 1.ClinicalTrials.gov registration: NCT05458219 .

Fig. 1. CONSORT diagram.

AE, adverse events. ^aCLDN18.2-positive expression defined as 1% or more tumor cells with membranous staining of any intensity in tumor tissue using immunohistochemistry (IHC) and measured with the VENTANA CLDN18 (43-14A) IHC assay. ^bNineteen participants from the dose escalation phase and 108 participants with G/GEJ adenocarcinoma from the dose expansion phase. ^cParticipants with either disease progression or clinical deterioration. ^dAs of the cutoff date of 30 June 2024.

Fig. 2. Efficacy of IBI343 in participants with G/GEJ adenocarcinoma with high expression of CLDN18.2 (≥75%).

a, Waterfall plot showing the best change in target lesion in evaluable participants treated at a dose of 6 mg kg⁻¹ (n = 31). The percentage of CLDN18.2 expression is indicated for each participant; PR indicates participants with a confirmed response. b, Swimmer plot showing the duration of treatment and the timing of the tumor response of each participant treated at a dose of 6 mg kg⁻¹ (n = 31). The percentage of CLDN18.2 expression is indicated for each participant. c, Best change in target lesion in evaluable participants treated at a dose of 8 mg kg⁻¹ (n = 16, excludes one participant in the evaluable population who died before tumor assessment). The percentage of CLDN18.2 expression is indicated for each participant. PR indicates participants with a confirmed response. d, Swimmer plot showing the duration of treatment and the timing of the tumor response of each participant during the study (n = 19, includes one participant from the dose escalation phase and 18 participants from the dose expansion phase) treated at a dose of 8 mg kg⁻¹. The percentage of CLDN18.2 expression is indicated for each participant. CR, complete response.

Extended Data Fig. 1. Subgroup analysis of ORR in G/GEJ adenocarcinoma patients with high expression of CLDN 18.2 ( ≥ 75%) treated at 6 mg/kg.

Abbreviations: treatment lines (L), gastric cancer (GC), gastroesophageal junction cancer (GEJC), immuno-oncology (IO).

Extended Data Fig. 2. PFS in G/GEJ adenocarcinoma patients with high expression of CLDN 18.2 ( ≥ 75%).

PFS at 6 mg/kg (n = 31) and 8 mg/kg (n = 19), including 1 patient treated at 8 mg/kg from dose escalation.

Extended Data Fig. 3. OS in G/GEJ adenocarcinoma patients with high expression of CLDN 18.2 ( ≥ 75%).

OS at 6 mg/kg (n = 31) and 8 mg/kg (n = 19), including 1 patient treated at 8 mg/kg from dose escalation.

Extended Data Fig. 4. Subgroup analysis of ORR in G/GEJ adenocarcinoma patients with high expression of CLDN 18.2 ( ≥ 75%) treated at 8 mg/kg.

Abbreviations: treatment lines (L), gastric cancer (GC), gastroesophageal junction cancer (GEJC), immuno-oncology (IO).

Extended Data Fig. 5

Efficacy of IBI343 in all evaluable patients with G/GEJ adenocarcinoma.

Extended Data Fig. 6. IBI343 exposure-safety and efficacy relationship.

Probability of≥G3 Leukopenia vs total antibody C_{max_cycle1} (a), ≥G3 Anemia vs total antibody C_{max_cycle1} (b), ≥G3 neutropenia vs total antibody C_{max_cycle1} (c), ≥G3 Gastrointestinal disorders vs total antibody C_{max_cycle1} (d), Probability of partial response vs total antibody AUC_ss (e) and disease control vs total antibody AUC_ss (f): = 1 for responder; = 0 for non-responder. Dashed line refers to predicted probability by a linear logistic regression model. The shaded area refers to its 95% confidence interval. The grey small circles reflect the observed events. The filled black symbols are the observed probability of events and the error bars are SE [sqrt (P × (1 − P) /N)] for quantiles (at 100× (1/q) th percentiles) of exposures (plotted at the median value within each quantile). Formula is listed in top right corner; p value of intercept is listed in lower right corner. Bottom panel: box plot of exposure metrics at 0.3, 1, 3, 6, 8, 10 mg/kg.