IBI343 Is Safe, Generates Preliminary Efficacy in CLDN18.2+ Advanced Gastric/GEJ Adenocarcinoma

The next-generation, Claudin-18.2 (CLDN18.2)–targeted antibody-drug conjugate (ADC) IBI343 was well tolerated and demonstrated signs of efficacy in patients with pretreated, advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma with moderate to high expression of CLDN18.2, according to data from a phase 1a/1b trial (NCT05458219) presented at the 2024 ESMO Gastrointestinal Cancers Congress.¹

Safety findings showed that grade 3 and higher gastrointestinal (GI) adverse effects (AEs) occurred at low rates in patients with gastric/GEJ adenocarcinoma and other advanced solid tumors treated with IBI343 (n = 159). Grade 3 or higher GI AEs included vomiting (1.9%), nausea (1.3%), and decreased appetite (1.3%). Hypoalbuminemia occurred in 24.5% of patients, although all instances were grade 1 or 2. Notably, there were no reports of interstitial lung disease (ILD).

Regarding efficacy in the gastric/GEJ adenocarcinoma population, the overall response rate (ORR) in patients with moderate to high expression CLDN18.2 (immunohistochemistry [IHC] 2+/3+ on at least 40% of tumor cells) treated across all dose levels (n = 89) was 32.6% (95% CI, 23.0%-43.3%), and the disease control rate (DCR) was 80.9% (95% CI, 71.2%-88.5%).

“IBI343 is a next-generation ADC targeting CLDN18.2 with unique Fc silencing and was well tolerated in [the] phase 1a/1b trial, with low GI toxicity and no cases of ILD,” lead study author Jia (Jenny) Liu, MD, PhD, FRACP, stated in a presentation of the data. “Encouraging efficacy of IBI343 was observed in [patients with] CLDN18.2-moderate [and] -high expression [in] gastric/GEJ adenocarcinoma, in addition to [those with] pancreatic and biliary tumors.”

Liu is a senior research officer at ProCan Children’s Medical Research Institute, a clinical lecturer at the University of Sydney, and a conjoint senior lecturer at the University of NSW, the Kinghorn Cancer Centre, St Vincent’s Hospital, in Sydney, Australia.

IBI343 is a fully human anti-CLDN18.2 antibody with unique IgG1 Fc silencing with a site-specific conjugation and cleavable linker attached to a topoisomerase inhibitor payload. The agent has demonstrated in vivo safety with no antibody-dependent cellular cytotoxicity–mediated GI toxicity and in vivo efficacy with on-target and bystander killing effects.

The phase 1a/1b trial consisted of dose-escalation and -expansion portions. The dose-escalation portion enrolled patients with advanced solid tumors that were evaluable or measurable per RECIST 1.1 criteria regardless of CLDN18.2 expression. Eligibility criteria for the expansion portion included advanced gastric/GEJ adenocarcinoma or pancreatic ductal adenocarcinoma (PDAC) with positive CLDN 18.2 expression, defined as any intensity membranous staining on at least 1% of tumor cells. Patients in dose expansion also needed to have measurable disease per RECIST 1.1 criteria.

During dose escalation, eligible patients received intravenous (IV) IBI343 once every 3 weeks at 10 mg/kg (n = 6), 8 mg/kg (n = 3), 6 mg/kg (n = 3), 3 mg/kg (n = 5), 1 mg/kg (n = 1; accelerated titration), or 0.3 mg/kg (n = 1; accelerated titration).

In dose expansion, patients with second-line or greater gastric/GEJ adenocarcinoma or PDAC and a CLDN18.2 expression of at least IHC 2+ on at least 40% of tumor cells were given IBI343 at 8 mg/kg. Another cohort further evaluated the 6-mg/kg dose in patients with second-line or greater gastric/GEJ adenocarcinoma or PDAC with a CLDN18.2 expression of at least IHC 2+ on 1% to 39% of tumor cells or at least 40% of tumor cells. The 3-mg/kg dose was also further investigated in patients with second-line or greater gastric/GEJ adenocarcinoma with a CLDN18.2 expression of at least IHC 2+ on at least 40% of tumor cells.

The primary end points of the study were safety and determination of the recommended phase 2 dose. Secondary end points consisted of efficacy outcomes per RECIST 1.1 criteria.

Notably, dose escalation was completed in 19 patients, and 140 were included in dose expansion. Dose-limiting toxicities were reported in 2 of 6 patients receiving IBI343 at 10 mg/kg during dose escalation, including 1 patient who had grade 4 myelosuppression and another patient who experienced grade 4 decreased neutrophil count and grade 3 febrile neutropenia.

Although a total of 419 patients were prescreened, 159 were enrolled/dosed; 47.8% of patients enrolled in either dose escalation or expansion were still ongoing treatment at the data cutoff of January 15, 2024. Reasons for patient ineligibility (n = 260) included being CLDN ineligible (43.4%), lack of target lesions (23.1%), consent withdrawn (1.6%), death (0.4%), or other (31.5%).

Discontinuation rates by dose across both portions of the trial included 100% for 0.3 mg/kg, 100% for 1 mg/kg, 80.0% for 3 mg/kg, 54.4% for 6 mg/kg, 35.3% for 8 mg/kg, and 50.0% for 10 mg/kg. Reasons for discontinuation across all cohorts included disease progression (34.6%), death (5.0%), AEs (2.5%), and other (10.1%).

The median age of all patients enrolled (n = 159) was 58.0 years (range, 25-84). The majority of patients were male (61.0%), were East Asian (94.3%), and had an ECOG performance status of 1 (82.4%). Patients had either gastric/GEJ adenocarcinoma (66.7%), PDAC (25.2%), and other tumors (8.1%). Additionally, patients received either 1 (30.5%), 2 (41.5%), or at least 3 (29.0%) prior lines of treatment. Previous immunotherapy was reported for 61.0% of patients, and prior irinotecan was administered to 30.2% of patients.

In the efficacy-evaluable population of patients with CLDN 18.2-positive gastric/GEJ adenocarcinoma who received at least 1 post-baseline tumor assessment (n = 99), 73.7% had 2 or more prior lines of therapy, and 82.0% had prior immunotherapy. Fifty-six percent of these patients expressed CLDN18.2 on at least 75% of tumor cells; 34% of patients had CLDN18.2 expression on 40% to 74% of tumor cells; and 10% of patients expressed CLDN18.2 on 1% to 39% of tumor cells.

“No response was observed in 10 [patients] with CLDN18.2-low expression [defined as 1% to 39% of tumor cells],” Liu explained.

Liu and colleagues analyzed ORR and DCR based on IBI343 dose level and CLDN18.2 expression level in patients with advanced gastric/GEJ adenocarcinoma. Patients with a CLDN18.2 expression of IHC 2+/3+ on at least 40% of tumor cells who received the 6-mg/kg dose (n = 48) achieved a respective ORR and DCR of 31.2% (95% CI, 18.7%-46.3%) and 89.6% (95% CI, 77.3%-96.5%). Those respective rates were 36.7% (95% CI, 19.9%-56.1%) and 93.3% (95% CI, 77.9%-99.2%) in patients given 6 mg/kg of IBI343 who had a CLDN18.2 expression of IHC 2+/3+ on at least 75% of tumor cells (n = 30).

In patients with advanced gastric/GEJ adenocarcinoma who had a CLDN18.2 expression of IHC 2+/3+ on at least 40% of tumor cells and received IBI343 at 8 mg/kg (n = 29), the ORR was 41.4% (95% CI, 23.5%-61.1), and the DCR was 82.8% (95% CI, 64.2%-94.2%). Those respective rates were 47.1% (95% CI, 23.0%-72.2%) and 88.2% (95% CI, 63.6%-98.5%) in patients given the ADC at 8 mg/kg who had a CLDN18.2 expression of IHC 2+/3+ on at least 75% of tumor cells.

In patients with a CLDN18.2 expression of IHC 2+/3+ on at least 40% of tumor cells, the median duration of response (DOR) was 5.8 months (95% CI, 4.2-NC) for the 6-mg/kg dose. The median DOR was not calculable (NC; 95% CI, 3.1-NC) at 8 mg/kg.

The median progression-free survival (PFS) in patients with a CLDN18.2 expression of IHC 2+/3+ on at least 40% of tumor cells was 5.6 months (95% CI, 4.2-7.3) at 6 mg/kg and 5.5 months (95% CI, 4.2-NC) at 8 mg/kg at median follow-ups of 7.2 months and 4.6 months, respectively. In patients with a CLDN18.2 expression of IHC 2+/3+ on at least 75% of tumor cells, the median PFS was 6.8 months (95% CI, 4.2-NC) at 6 mg/kg and 5.5 months (95% CI, 4.2-NC) at 8 mg/kg at median follow-ups of 7.2 and 4.6 months, respectively.

Across all dose levels for all treated patients, irrespective of tumor type, any-grade treatment-emergent AEs (TEAEs) occurred in 93.7% of patients, including 49.7% who experienced a grade 3 or higher TEAE and 37.7% who had a grade 3 or higher treatment-related TEAE. The rates of serious AEs and serious treatment-related AEs were 32.7% and 18.2%, respectively.

TEAEs and treatment-related TEAEs led to dose interruption in 37.7% and 27.7% of patients, respectively; led to dose reduction in 8.8% and 7.5% of patients, respectively; and led to treatment discontinuation in 5.7% and 1.3% of patients, respectively. TEAEs led to death in 3 patients (1.9%); 2 patients died of pneumonia and 1 patient experienced sudden death. No deaths were considered treatment related.

IBI343 will be further evaluated vs investigator’s choice of therapy in patients with pretreated, CLDN18.2-positive, HER2-negative gastric/GEJ adenocarcinoma during the phase 3 G-HOPE-001 trial (NCT06238843).

Disclosures: Dr Liu reported receiving honoraria from MSD and Specialised Therapeutics; consulting for Starpharma and Greywolf Therapeutics; receiving travel expenses from Innovent Biologics, Starpharma, and ImmVirx; and receiving institutional research funding from Innovent Biologics, MSD, Regeneron, Bristol Myers Squibb, AbbVie, AVEO, Starpharma, Virocure, Covus Pharmaceuticals, Relay Therapeutics, ALX Oncology, IDEAYA Biosciences, and Greywolf Therapeutics.

Reference

Liu JJ, Yu X, Zhang J, et al. Anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate (ADC) IBI343 in patients (pts) with solid tumors and gastric/gastro-esophageal junction adenocarcinoma (G/GEJ AC): a phase I study. Ann Oncol. 2024;35(suppl 1):S160. 10.1016/j.annonc.2024.05.311