Phase 1/2 study of spevatamig (PT886) in combination with gemcitabine plus nab-paclitaxel (GnP) in frontline (1L) treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC).

709 Background: Spevatamig (PT886) is an IgG1-based bispecific antibody targeting claudin 18.2 (CLDN18.2) and CD47 with an optimized anti-CD47 arm that has higher binding to CD47 on cancer cells than that on human red blood cells (RBCs). Spevatamig is expected to mediate enhanced killing of CLDN18.2-expressing cancer cells by innate immune cells and potentially by T cells. In addition, the binding of CD47 on cancer cells by spevatamig potentially enables anti-tumor activity against low CLDN18.2-expressing cancer cells. In combination with chemotherapy which induces “eat me” signals, the immune-activation and cancer killing activities of spevatamig are expected to be further stimulated. Methods: TWINPEAK is a multi-cohort phase 1/2 dose escalation and expansion study (NCT05482893) of spevatamig as monotherapy or in combination with chemotherapy and/or an immune-checkpoint inhibitor in patients with GI cancers. Here we report the initial data from the cohort of spevatamig + GnP in 1L mPDAC with ≥ 10% moderate to strong tumor cell staining for CLDN18.2 at two dose levels: 2 mg/kg QW (n=15) and > 2 mg/kg QW (with 3 dosing regimens) (n=15). Endpoints include safety, tolerability, disease control rate (DCR), objective response rate (ORR), median progression-free survival (mPFS), 6-month PFS rate, and 6-month and 12-month overall survival (OS) rates. Results: As of August 24, 2025, 90 patients have been treated with spevatamig in the US collectively in monotherapy and combination therapy; favorable safety profile has been observed. No CRS has been observed. No grade ≥ 3 treatment-emergent anemia, neutropenia or thrombocytopenia have been observed in the monotherapy study. In the 2 mg/kg QW spevatamig + GnP 1L mPDAC cohort (n=15) Grade 1 and 2 treatment-emergent nausea and vomiting events were predominantly observed as a single occurrence in the days following treatment. No Grade ≥ 3 treatment-emergent nausea or vomiting event was reported. The rates of anemia, neutropenia and thrombocytopenia were comparable to those observed in the GnP treatment arms in historical trials. The mPFS was 7.3 months with the 6-month PFS rate at 59%. The 6-month OS rate was 93% while mOS is still maturing. The DCR was 93%. The ORR was 33%, with 5 patients achieving confirmed partial response; there is no apparent correlation between ORR and CLDN18.2 score. Currently, 4 patients remain on the study, and 7 patients are in long-term follow-up; 90% of patients received subsequent anti-cancer therapies upon progression. The data for the > 2 mg/kg QW dose level (n=15) is still maturing. Conclusions: Overall, spevatamig + GnP is well tolerated, with no significant additive toxicity to GnP. Spevatamig + GnP showed promising efficacy when compared with published studies of GnP in 1L mPDAC, suggesting that spevatamig + GnP may provide additional clinical benefit to patients. Clinical trial information: NCT05482893 .