Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer

Abstract

Background: Patients with biliary tract cancer (BTC) have poor prognosis with few treatment options. Bintrafusp alfa, a first-in-class 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 antibody blocking programmed death ligand 1 (PD-L1), has shown clinical efficacy in multiple solid tumors.

Methods: In this phase I, open-label trial expansion cohort, Asian patients with BTC whose disease progressed after first-line chemotherapy received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint is safety/tolerability, while the secondary endpoints include best overall response per Response Evaluation Criteria in Solid Tumors version 1.1.

Results: As of August 24, 2018, 30 patients have received bintrafusp alfa for a median of 8.9 (IQR 5.7-32.1) weeks; 3 patients remained on treatment for >59.7 weeks. Nineteen (63%) patients experienced treatment-related adverse events (TRAEs), most commonly rash (17%), maculopapular rash and fever (13% each), and increased lipase (10%). Eleven (37%) patients had grade ≥3 TRAEs; three patients had grade 5 events (septic shock due to bacteremia, n=1; interstitial lung disease (reported term: interstitial pneumonitis), n=2). The objective response rate was 20% (95% CI 8 to 39) per independent review committee (IRC), with five of six responses ongoing (12.5+ to 14.5+ months) at data cut-off. Two additional patients with durable stable disease had a partial response per investigator. Median progression-free survival assessed by IRC and overall survival were 2.5 months (95% CI 1.3 to 5.6) and 12.7 months (95% CI 6.7 to 15.7), respectively. Clinical activity was observed irrespective of PD-L1 expression and microsatellite instability-high status.

Conclusions: Bintrafusp alfa had clinical activity in Asian patients with pretreated BTC, with durable responses. Based on these results, bintrafusp alfa is under further investigation in patients with BTC (NCT03833661 and NCT04066491).

Trial registration number: NCT02699515.

Keywords: gastrointestinal neoplasms; immunotherapy; programmed cell death 1 receptor; tumor microenvironment.

Conflict of interest statement

Competing interests: CY reports honorarium from Merck Serono, Tokyo, Japan, an affiliate of Merck KGaA, Darmstadt, Germany. MO is an employee of Merck Biopharma, Tokyo, Japan, an affiliate of Merck KGaA. CH is an employee of Merck KGaA. ID is an employee of EMD Serono, Billerica, Massachusetts, USA, a business of Merck KGaA. MI reports research funding from Merck Serono, an affiliate of Merck KGaA. All other authors declare no competing interests.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Trial profile.

Figure 2

Change in target lesions from baseline as adjudicated by the IRC. Responses were assessed in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The upper dotted line represents progression at 20% increase in size of target lesions, and the lower dotted line represents the RECIST boundary for complete response or partial response at 30% decrease in size of target lesions. Patients with no postbaseline assessment (n=2) or no target lesions identified by the IRC before first dose (n=2) are not displayed. *Patients with MSI-H phenotype. †MSI phenotype not available due to no leftover sample. ‡Patients with unavailable tumor mutation count data. §Patient with poststudy tumor shrinkage of non-target lesions. ‖Patients with an investigator-assessed best overall response of partial response. #Patient with a partial response following pseudoprogression per investigator assessment (best overall response per investigator, progressive disease). CR, complete response; MSI-H, microsatellite instability-high; PR, partial response.

Figure 3

Time to and duration of response as adjudicated by the IRC. Responses were assessed in accordance with Response Evaluation Criteria in Solid Tumors version 1.1.

Figure 4

Kaplan-Meier analysis of progression-free survival as adjudicated by the IRC (A) and overall survival (B).