Abstract CT154: Combination of cinrebafusp alfa with ramucirumab and paclitaxel is well tolerated and elicits encouraging clinical activity in patients with HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinoma (2023)

Abstract Introduction: Cinrebafusp alfa is a first-in-class bispecific antibody-Anticalin® fusion protein that targets HER2 and the costimulatory receptor 4-1BB, leading to enhanced activation of T cells in the tumor, while avoiding liver toxicity. In a Phase 1 monotherapy study, cinrebafusp alfa was well tolerated and showed single agent activity in patients with HER2-positive malignancies. Based on pharmacokinetics (PK), pharmacodynamics and clinical efficacy data, a loading dose of 18mg/kg Q2W in cycle 1 followed by 8mg/kg Q2W in subsequent cycles as maintenance dose was chosen for the Phase 2 study. Methods: This Phase 2 study enrolled patients with metastatic gastric/gastroesophageal junction cancer and confirmed HER2-high status (IHC 3+ or IHC 2+ with HER2/neu gene amplification) who had received one or two prior lines of treatment. Patients received cinrebafusp alfa in combination with ramucirumab and paclitaxel. Primary endpoint was objective response rate (ORR), and key secondary endpoints included safety profile, PK, and immunogenicity. Summary of data: 5 patients were enrolled before enrollment ceased for reasons unrelated to safety or efficacy profile. As of the cut-off date (19-Dec-2022), 5 out of 5 patients achieved a partial response (PR) as best overall response with tumor lesion shrinkage ranging between 35% and 66%. Two of the PRs have been confirmed, one PR is unconfirmed, and 2 patients with currently unconfirmed PRs are continuing to receive treatment. In total, 2 of 5 patients discontinued treatment due to disease progression after 140 and 113 days (patient discontinued cinrebafusp alfa after 42 days but continued on ramucirumab and paclitaxel); 3 patients remain on treatment. Median duration of response was 3.8 months at time of data cut-off. The most frequent treatment emergent adverse events (TEAEs) included Grade 1/2 fatigue (4 patients) and Grade 1-3 diarrhea (4 patients). Infusion related reactions (Grade 2/3) were seen in 1 patient, leading eventually to discontinuation of cinrebafusp alfa. With regards to prior treatment history, all patients received trastuzumab and chemotherapy. 2 patients also received trastuzumab deruxtecan while 4 patients previously received anti-PD1 therapy. Conclusions: The combination of cinrebafusp alfa with ramucirumab and paclitaxel was safe and tolerated in the 5 patients treated. Preliminary activity of cinrebafusp alfa in combination with ramucirumab and paclitaxel demonstrated a high response rate indicating that the combination can elicit clinical responses in patients who have progressed on trastuzumab deruxtecan or checkpoint inhibitor regimens. Citation Format: Geoffrey Ku, Jeeyun Lee, Kayti Aviano, Tim Demuth, Laura-Carolin Hasenkamp, Shane A. Olwill. Combination of cinrebafusp alfa with ramucirumab and paclitaxel is well tolerated and elicits encouraging clinical activity in patients with HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT154.