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Clinical responses in pancreaticobiliary cancer patients who received bintrafusp alfa (BA) or BA plus CXCR1/2 inhibitor (SX-682) plus CEA/MUC1-targted vaccine (CV301)
Background
Immune checkpoint blockade (ICB) is minimally active in unselected pancreaticobiliary cancer (PBC) patients. Treatment regimens combining ICI with agents that may provide synergistic immune enhancement are under investigation. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 anti-PDL1 antibody. CV301 is a poxviral vaccine against CEA and MUC1 tumor antigens. SX-682 is an oral small-molecule dual inhibitor of the CXCR1 and CXCR2 chemokine receptors.
Methods
Patients who received ≥1 systemic chemotherapy (1L) regimen for unresectable, locally advanced, or metastatic pancreatic ductal adenocarcinoma (PDAC) received BA 1200 mg IV Q2W alone on the expansion cohort of a global phase 1, open-label trial (NCT02517398). Patients with advanced, or metastatic solid tumors with prior 1L systemic treatment received BA in combination with CV301 and SX-682 (triplet) as part of a phase 1 dose escalation of SX-682 with BA + CV301 (NCT04574583). After 2 weeks of SX-682 (25, 50 or 100 mg BID) alone, patients received BA 1200 mg IV Q2W + CV301 combination. The primary endpoint for BA alone was objective response. The primary endpoint for the triplet was to determine combination safety and the maximal tolerated dose of SX-682 in combination.
Results
Among 36 evaluable PDAC patients who received BA alone, 1 patient had a confirmed partial response, 3 had stable disease (SD), 1 had non-complete response/non-progressive disease (PD) (disease control rate, 13.9%), and 22 had progressive disease (PD) as best response per RECISTv1.1. For BA alone, 15 patients (41.7%) experienced treatment-related adverse events (TRAEs). There was a total of 6 (16.7%) grade 3 TRAEs and 1 (2.8%) grade 4 TRAE (lipase increase). There were no treatment-related deaths. Among 7 PBC patients (5 PDAC, 2 cholangiocarcinoma) who received the triplet, 4 were evaluable for response. Two patients (1 PDAC, 1 cholangiocarcinoma) with microsatellite stable (MSS) and non-measurable disease by RECISTv1.1 had deep, durable CA-19-9 decreases associated with SD for 12+ and 7+ months; 2 PDAC patients had PD, and 3 patients came off treatment for a TRAE prior to response assessment. All patients (n=11) who received the triplet experienced a TRAE and 5/11 (46%) experienced a grade 3 TRAE related to bleeding, including esophageal varices hemorrhage, hematuria, anemia, or upper gastrointestinal hemorrhage. Mean and median time to resolution of grade 3 events were 10 and 4 days, respectively (range 3-17 days). This incidence of bleeding triggered the study’s stopping rule.
Conclusions
BA is minimally active as monotherapy for PDAC. BA in combination with CV301 + SX-682 produced durable biochemical responses and disease control in 2/4 (50%) evaluable PBC patients with MSS disease. With this triplet, grade 3 bleeding was observed at a substantially higher rate than expected (rate of grade ≥ 3 bleeding = 8.6% with BA alone). In PBC patients, investigation of an ICB that does not potentiate bleeding, combined with SX-682 + CV301 (or other vaccine against the MUC1 and CEA tumor antigens) is warranted.
Clinical trial identification
NCT04574583.
Legal entity responsible for the study
National Cancer Institute.
Funding
The Center for Cancer Research at the National Cancer Institute is the sponsor of this study funded by the federal government of the United States. Additional resources were provided by the following entities via Cooperative Research and Development Agreements: Merck KGaA, Darmstadt, Germany; Bavarian Nordic, Kvistgaard, Denmark; Syntirix Biosystems, Auburn, Washington, US.
Disclosures
M. Javle: Honoraria (self): QED Therapeutics, Inc., AstraZeneca/MedImmune, EMD Serono/Merck, TransThera Biosciences; Advisory / Consultancy: QED Therapeutics, Inc., Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono, Derazantinib; Research grant / Funding (institution): Transthera, Novartis, Eli Lilly. K. Kelly: Advisory / Consultancy: EMD Serono. N. Pavlakis: Honoraria (self): Boehringer Ingelheim, Pfizer, Roche, Takeda, Pierre-Faber; Advisory / Consultancy: Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Pfizer, Roche, Amgen, Beigene, Novartis, AllVascular; Research grant / Funding (institution): Bayer, Pfizer, Roche. C. Pico-Navarro: Full / Part-time employment: Baarian Nordic Inc until December 2021, Cytovation since Jan 2022. J. Zebala: Leadership role: Syntrix Biosystems, Inc.; Full / Part-time employment: Syntrix Biosystems, Inc.; Officer / Board of Directors: Syntrix Biosystems, Inc. R. Ito: Full / Part-time employment: Merck Biopharma Co.Ltd. All other authors have declared no conflicts of interest.
