Dataset Information

Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.

ABSTRACT:

Background

For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 antibody blocking PD-L1.

Methods

In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety.

Results

As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with IDH-mutant GBM (n = 6) and 13.8% (3.9-31.7%) for patients with IDH-wild-type GBM (n = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n = 6]).

Conclusions

The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.

SUBMITTER: Khasraw M

PROVIDER: S-EPMC8156979 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND TGF- signaling promotes tumor immunosuppression; TGF- inhibition in the tumor microenvironment may enhance the response to antiPD-L1 treatment. M7824 is an innovative, first-in-class, bifunctional fusion protein composed of a human antiPD-L1 IgG1 monoclonal antibody fused with two extracellular domains of TGF RII to function as a TGF- trap. We report safety and efficacy of M7824 in patients with rGBM. METHODS In this efficacy expansion cohort of the ongoing, phase 1 trial NCT02517398, patients with rGBM who progressed after chemoradiation received M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective was disease control rate (DCR) per RANO; secondary objectives included safety/tolerability. RESULTS Among 35 patients, median age was 57 years, 68.6% were male, and 91.4% were at first recurrence. At 15 months minimum follow-up, median treatment duration was 8.1 (range, 2.0–72.1) weeks; four patients remained on treatment at >1 year, and one additional patient decided to stop treatment per protocol at 12 months. Two patients had a partial response, and nine had stable disease (DCR, 31.4% [95% CI, 16.9–49.3]), of which two exhibited early progressive disease and subsequent durable stable disease ongoing for >12 months per investigators assessment. The most common treatment-related adverse events (TRAEs) were gingival bleeding (17.1%), asthenia (14.3%), pruritus, and rash (each 11.4%). Grade 3 TRAEs (6 patients, 17.1%) included diarrhea, eczema, increased liver/pancreatic enzymes, papular rash, papules, one grade 4 asymptomatic increased lipase, and one grade 5 intratumoral hemorrhage (investigator-assessed) coterminous with disease progression. CONCLUSIONS M7824 demonstrated a manageable safety profile and encouraging efficacy in rGBM, including two durable partial responses and a DCR of 31.4%. Further investigation of M7824 in GBM is warranted; future development aims to define molecular characteristics of responders.

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.

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