Spevatamig (PT886), a claudin 18.2 (CLDN18.2)/CD47 bispecific antibody, in combination with gemcitabine plus nab-paclitaxel (GnP) in frontline (1L) treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC).

Abstract

4192 Background: Spevatamig is an IgG1-based bispecific antibody targeting CLDN18.2 and CD47 with an optimized anti-CD47 arm designed to bind to CD47 more highly on cancer cells than on human red blood cells. We have previously described its monotherapy safety data and preliminary combination efficacy data in 1L mPDAC (Saeed et al., J Clin Oncol. 2026). Herein, we provide updated data from patients in the 1L mPDAC cohort, including additional efficacy data from the 2 mg/kg QW spevatamig + GnP dose level and new safety data from the 3 mg/kg QW spevatamig + GnP dose level. Methods: TWINPEAK is a multi-cohort Phase 1/2 dose escalation and expansion study (US: NCT05482893; China: CTR20252758) of spevatamig as monotherapy or combination therapy (with chemotherapy and/or an immune-checkpoint inhibitor) in patients with select gastrointestinal (GI) cancers. Here we report data from the Phase 2 cohort of spevatamig + GnP in 1L mPDAC at 2 dose levels: 2 mg/kg QW (N=22) and 3 mg/kg QW (N=22). Key endpoints include safety and tolerability, objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS). Results: As of January 15, 2026, 151 patients have been treated with spevatamig collectively in monotherapy and combination settings. In the 2 mg/kg QW spevatamig + GnP dose level (N=22), spevatamig continues to demonstrate tolerability when combined with chemotherapy, with cytopenia rates not exceeding those anticipated with GnP and no grade ≥ 3 nausea or vomiting events. The ORR is 48%, DCR is 90%, mPFS is 7.3 months (95% confidence interval: 5.6 months - not yet reached) and mOS is > 13 months (still maturing), with a median follow-up duration of 8.9 months. Antitumor activity was demonstrated irrespective of tumor CLDN18.2 expression levels and RAS mutational status. In the 3 mg/kg QW spevatamig + GnP dose level (N=22), no significant additive toxicity was noted when compared to the adverse event profile anticipated with GnP alone among patients with available safety data. No grade ≥ 3 nausea or vomiting events occurred. Updated safety data will be provided at the meeting for patients in this dose level. Conclusions: Overall, spevatamig 2 mg/kg QW or 3 mg/kg QW + GnP is well tolerated, with no significant additive toxicity compared to the adverse event profile anticipated with GnP alone. The additional efficacy data from patients treated at the 2 mg/kg QW spevatamig + GnP dose level continues to demonstrate promise when compared to pivotal trials of GnP in 1L mPDAC; enrollment into the 3 mg/kg QW spevatamig + GnP dose level is ongoing with maturing efficacy data. These two dose levels exhibit good combinability with chemotherapy and can be assessed in future combination studies with novel targeted therapies such as KRAS inhibitors. Clinical trial information: NCT05482893 .