FDA Places Partial Hold on BNT326/YL202 Trial for NSCLC, Breast Cancer

Developers have paused the enrollment of new patients in the United States for the phase 1 YL202-INT-101-01 trial (NCT05653752) until they have met the FDA’s regulatory requirements.

The FDA has placed a partial hold on the phase 1 YL202-INT-101-01 trial (NCT05653752) assessing HER3-targeted antibody-drug conjugate (ADC) BNT326/YL202 for EGFR-mutated non–small cell lung cancer (NSCLC) and hormone receptor (HR)–positive, HER2-negative breast cancer, according to a regulatory document published by the United States Securities and Exchange Commission.¹

Due to the FDA highlighting an unreasonable and significant risk of illness at exposure to high doses of BNT326/YL202, developer MediLink has paused the enrollment of new patients in the United States until it has met the FDA’s regulatory requirements. Steps required to address FDA requests include reviewing clinical and safety data, sharing available pharmacological data with the agency, and providing information regarding the grade 5 adverse events observed in the YL202-INT-101-01 and YL202-CN-201-01 study (NCT06107686), as well as other safety findings.

In the open-label, first-in-human phase 1 trial, any-grade and grade 3 or higher treatment-related adverse effects (TRAEs) included anemia (71%/20%), white blood cell count decrease (67%/31%), neutrophil count decrease (63%/29%), nausea (52%/0%), decreased appetite (42%/4%), lymphocyte count decrease (37%/23%), platelet count decrease (37%/10%), vomiting (37%/0%), dry mouth (25%/0%), fatigue (25%/0%), stomatitis (23/2%), and alopecia (21%/0%).² Additionally, a single occurrence of interstitial pneumonia was observed following COVID-19 infection.

“YL202/BNT326 demonstrated encouraging efficacy in heavily pretreated locally advanced/ metastatic NSCLC and [breast cancer]. The safety profile showed adequate safety and tolerability,” the authors wrote in an abstract published in Journal of Clinical Oncology.²

The trial’s primary endpoints are safety and tolerability, specifically dose-limiting toxicities and AEs. Secondary endpoints encompass pharmacokinetics and efficacy per RECIST v1.1 criteria, including objective response rate (ORR), disease control rate (DCR), and best overall response (BOR). Other pre-specified endpoints include duration of response, evaluation of time to response, progression-free survival, and overall survival.

Throughout phase 1, YL202/BNT326 was administered at 6 dose levels (DLs) in a Bayesian Optimal Interval (BOIN) dose escalation scheme, which included subsequent cohort backfills at selected doses. YL202 was administered as a 200 mg/vial lyophilized powder given intravenously once every 3 weeks as a cycle.³

Forty-six of the 52 enrolled patients were evaluable for efficacy, with 5 on treatment pending first tumor assessment and 1 discontinuing treatment prior to first assessment.² Furthermore, pharmacokinetic exposure was increased through dose escalation, with no accumulation of YL202/BTN326 upon repeated administration and low systemic exposure of payload.

Additional results in the DL3 to DL5 dose range showed that ORR was 41.0% (95% CI, 25.6%-57.9%) and DCR was 94.9% (95% CI, 82.7%-99.4%) in all tumor types. In breast cancer, ORR was 54.5% (95% CI, 23.4%, 83.3%), and DCR was 100% (95% CI, 71.5%, 100.0%).

Eligibility criteria included adult patients who had provided written informed consent, an ECOG status of 0 to 2, adequate organ and bone marrow function, at least 1 measurable tumor, and a life expectancy of greater than 3 months.³ For patients with NSCLC, they must have had a histologically or cytologically confirmed diagnosis of locally advanced or metastatic disease, documentation of EGFR-activating mutations detected at or after diagnosis, and documentation of disease progression. For patients with breast cancer, they must have had a histologically or cytologically confirmed diagnosis of unresectable locally advanced or metastatic HR-positive, HER2-negative disease with documentation of disease progression.

Exclusion criteria included intolerance to prior treatment with a topoisomerase I inhibitor or an ADC that consists of a topoisomerase I inhibitor, concurrent enrollment in another clinical study apart from non-interventional or post-intervention trials, and inadequate washout period for prior anticancer treatment before the first dose of study drug. Patients were also unable to enroll if they had major surgery within 4 weeks before the first dose of the study drug and prior allogenic bone marrow or solid organ transplantation.

References

1. United States Securities and Exchange Commission. Form 6-K. BioNTech SE. Published June 17, 2024. Accessed June 18, 2024. https://tinyurl.com/retjb335
2. Cheng Y, Zhang X, Liu J, et al. YL202/BNT326, a HER3-targeted ADC, in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer: preliminary results from a first-in-human phase I trial. J Clin Oncol. 2024;42(16). doi:10.1200/JCO.2024.42.16_suppl.3034
3. A Study of YL202 in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer. Updated July 7, 2023. Accessed June 18, 2024. https://www.clinicaltrials.gov/study/NCT05653752?tab=history