Dataset Information

Selection of the Recommended Phase 2 Dose for Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-? and PD-L1.

ABSTRACT: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-?RII receptor (TGF-? "trap") fused to a human IgG1-blocking PD-L1, showed a manageable safety profile and clinical activity in phase I studies in patients with heavily pretreated advanced solid tumors. The recommended phase 2 dose (RP2D) was selected based on integration of modeling, simulations, and all available data. A 1,200-mg every 2 weeks (q2w) dose was predicted to maintain serum trough concentration (Ctrough ) that inhibits all targets of bintrafusp alfa in circulation in > 95% of patients, and a 2,400-mg every 3 weeks (q3w) dose was predicted to have similar Ctrough . A trend toward an association between exposure and efficacy variables and a relatively stronger inverse association between clearance and efficacy variables were observed. Exposure was either weakly or not correlated with probability of adverse events. The selected intravenous RP2D of bintrafusp alfa is 1,200 mg q2w or 2,400 mg q3w.

SUBMITTER: Vugmeyster Y

PROVIDER: S-EPMC7484916 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Selection of the Recommended Phase 2 Dose for Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1.

Vugmeyster Yulia Y Wilkins Justin J Koenig Andre A El Bawab Samer S Dussault Isabelle I Ojalvo Laureen S LS De Banerjee Samrita S Klopp-Schulze Lena L Khandelwal Akash A

Clinical pharmacology and therapeutics 20200303 3

Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (TGF-β "trap") fused to a human IgG1-blocking PD-L1, showed a manageable safety profile and clinical activity in phase I studies in patients with heavily pretreated advanced solid tumors. The recommended phase 2 dose (RP2D) was selected based on integration of modeling, simulations, and all available data. A 1,200-mg every 2 weeks (q2w) dose was predicted to maintain serum ...[more]

PMID: 31955412

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Project description: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)-?RII receptor (a TGF-? '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.

Project description:BACKGROUND:We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor ? (TGF-?)RII receptor (a TGF-? 'trap') fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN). METHODS:In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or <6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety. RESULTS:As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2-97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 25%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths. CONCLUSIONS:Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors. TRIAL REGISTRATION NUMBER:NCT02517398.

Dataset Information

Selection of the Recommended Phase 2 Dose for Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-? and PD-L1.

Publications

Selection of the Recommended Phase 2 Dose for Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1.

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