Selection of the recommended phase 2 dose (RP2D) for M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-β and PD-L1.

Vugmeyster, Yulia; Wilkins, Justin; Harrison-Moench, Eleanor; Geng, Wanping; Köenig, Andre; Cao, Liang; Gulley, James L.; Dussault, Isabelle; Khandelwal, Akash

doi:10.1200/jco.2018.36.15_suppl.2566

Cited by 9 publications

(12 citation statements)

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“…Integrated analysis of bintrafusp alfa exposure, response and progression-free survival (PFS) supported a flat dose of 1200 mg every 2 weeks, 32 and this dose was used in the expansion cohorts. Patients received bintrafusp alfa via intravenous infusion over 1 hour once every 2 weeks until confirmed progressive disease (PD), unacceptable toxicity or trial withdrawal.…”

Section: Methodsmentioning

confidence: 99%

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

Cho

Daste

Ravaud

et al. 2020

J Immunother Cancer

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BackgroundWe 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 β (TGF-β)RII receptor (a TGF-β ‘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).MethodsIn 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.ResultsAs 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.ConclusionsBintrafusp 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 numberNCT02517398.

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Section: Methodsmentioning

confidence: 99%

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

Cho

Daste

Ravaud

et al. 2020

J Immunother Cancer

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“…Overall, the pharmacokinetic profile of bintrafusp alfa in Asian patients (Table ) was similar to that in the global study . Based on an integrated analysis of clinical activity and safety, the pharmacokinetic profile of bintrafusp alfa observed in the dose‐escalation phase of both studies, the pharmacodynamic profile of bintrafusp alfa from the global study, and reported data from cohorts of these studies exploring 500‐mg and 1200‐mg Q2W dosing , a dose level of 1,200 mg was evaluated in multiple additional expansion cohorts .…”

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confidence: 86%

Phase I Study of the Bifunctional Fusion Protein Bintrafusp Alfa in Asian Patients with Advanced Solid Tumors, Including a Hepatocellular Carcinoma Safety-Assessment Cohort

et al. 2020

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Lessons Learned Bintrafusp alfa had a manageable safety profile and demonstrated preliminary clinical activity in heavily pretreated patients with solid tumors (including hepatocellular carcinoma) with no or limited treatment options. Findings from this study suggest bintrafusp alfa may be a novel therapeutic approach for patients with advanced solid tumors. Additional trials are needed to further explore safety and efficacy of bintrafusp alfa in specific tumor types. Background Bintrafusp alfa is a first‐in‐class bifunctional fusion protein composed of the extracellular domain of transforming growth factor‐β (TGF‐β) RII receptor (a TGF‐β “trap”) fused to a human immunoglobulin (Ig) G1 antibody blocking programmed death‐ligand 1 (PD‐L1). Bintrafusp alfa is designed to neutralize TGF‐β signaling by “trapping” and sequestering all TGF‐β isoforms, and this trap function is physically linked to PD‐L1 blockade in the tumor microenvironment. Methods NCT02699515 was a phase I, open‐label, dose‐escalation study of bintrafusp alfa (3, 10, and 20 mg/kg every 2 weeks) in Asian patients with advanced solid tumors, including a hepatocellular carcinoma (HCC) safety‐assessment cohort. The primary objective was safety and tolerability; the secondary objective is best overall response. Results As of August 24, 2018, 23 patients (including 9 in the HCC cohort) received bintrafusp alfa. Eight patients experienced treatment‐related adverse events (TRAEs). Three patients had grade 3 TRAEs (13.0%; hypoacusis, hyponatremia, hypopituitarism, increased blood creatine phosphokinase, and intracranial tumor hemorrhage); one had grade 4 hyponatremia (4.3%). No treatment‐related deaths occurred. In the dose‐escalation cohort, two patients had a confirmed partial response, and 3 had stable disease (SD), for an overall response rate of 14.3% and a disease control rate (DCR) of 35.7%. In the HCC cohort, one patient had SD (DCR, 11.1%). A dose‐proportional pharmacokinetics profile was observed at doses of >3 mg/kg. Conclusion Bintrafusp alfa had a manageable safety profile and preliminary efficacy in heavily pretreated patients with advanced solid tumors, including HCC.

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“…13,15 In a phase 1 dose-escalation study (NCT02517398), bintrafusp alfa had a manageable safety profile and revealed encouraging antitumor activity, including one ongoing confirmed complete response in a group of patients (n ¼ 19) with heavily pretreated advanced solid tumors. 16,17 To obtain further exposure-response data after the dose-escalation part of this phase I study, patients in this cohort were randomized to receive 500 mg or 1200 mg doses, the latter being the recommended phase 2 dose. 17 On the basis of complete PD-L1 target occupancy and TGF-b trapping, 16 both doses are expected to provide full pharmacologic effects.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 To obtain further exposure-response data after the dose-escalation part of this phase I study, patients in this cohort were randomized to receive 500 mg or 1200 mg doses, the latter being the recommended phase 2 dose. 17 On the basis of complete PD-L1 target occupancy and TGF-b trapping, 16 both doses are expected to provide full pharmacologic effects. 17 A manuscript that describes in detail the data associated with 1200 mg every 2 weeks as the recommended phase 2 dosage is currently under preparation.…”

Section: Introductionmentioning

confidence: 99%

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Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial

Paz‐Ares¹,

Kim

Vicente

et al. 2020

Journal of Thoracic Oncology

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Introduction: The safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor b (TGF-b) receptor II (a TGF-b "trap") fused to a human immunoglobulin G1 antibody blocking programmed deathligand 1 (PD-L1), was evaluated in patients with advanced NSCLC.Methods: This expansion cohort of NCT02517398, an ongoing, phase 1, open-label trial, includes 80 patients with advanced NSCLC that progressed after platinum doublet therapy or after platinum-based adjuvant or neoadjuvant treatment and those who also have not received previous immunotherapy. Patients were randomized at a one-to-one ratio to receive either bintrafusp alfa 500 mg or the recommended phase 2 dosage of 1200 mg every 2 weeks. The primary end point was the best overall response (by Response Evaluation Criteria in Solid Tumors 1.1 as adjudicated by independent review committee) and was assessed by the objective response rate (ORR).Results: A total of 80 patients were randomized to receive bintrafusp alfa 500 or 1200 mg (n ¼ 40 each). Median follow-up was 51.9 weeks (IQR, 19.6-74.0). The ORR in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 25.0% (10 of 40) for the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), respectively. At the 1200 mg dose, patients with PD-L1-positive and PD-L1-high (80% expression on tumor cells) had ORRs of 36.0% (10 of 27) and 85.7% (six of seven), respectively. Treatment-related adverse events occurred in 55 of the 80 patients (69%) and were graded as greater than or equal to 3 in 23 of the 80 patients (29%). Of the 80 patients, eight (10%) had a treatment-related adverse event that led to treatment discontinuation; no treatment-related deaths occurred.Conclusions: Bintrafusp alfa had encouraging efficacy and manageable tolerability in patients with NSCLC previously treated with platinum.

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Selection of the recommended phase 2 dose (RP2D) for M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-β and PD-L1.

Cited by 9 publications

References 0 publications

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

Phase I Study of the Bifunctional Fusion Protein Bintrafusp Alfa in Asian Patients with Advanced Solid Tumors, Including a Hepatocellular Carcinoma Safety-Assessment Cohort

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial

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