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

Abstract

BackgroundPatients 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.MethodsIn 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.ResultsAs 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.ConclusionsBintrafusp 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 (NCT03833661andNCT04066491).Trial registration numberNCT02699515.

Targeting TGFβ signal transduction for cancer therapy

“…297 Moreover, the evaluation of M7824 for patients with advanced NSCLC or biliary tract cancer is now under investigation in phase 3 clinical trials. 278,298 A recent study discovered that an anti-GARP:TGFβ1 mAb (ABBV151), which selectively blocks TGFβ1 production by T reg cells, can induce the regression of anti-PD-1 immunotherapy-resistant tumors in a mouse cancer model. 299,300 The phase 1 clinical trial of an anti-GARP:TGFβ1 mAb (ABBV151) as monotherapy and in combination with the anti-PD1 mAb budigalimab (ABBV-181) were recently initiated for the evaluation of their safety and tolerability for patients with advanced solid tumors (NCT03821935).…”

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

“…These promising findings resulted in the advancement of bintrafusp alfa to clinical trials. Dose escalation studies (phase I) showed manageable safety profiles while some clinical efficacy seemed to be present at the administered dosage [148][149][150][151][152][153][154]. Currently, a number of phase I and phase I/II trials are ongoing that investigate combinatorial effects of bintrafusp alfa with radiotherapy and chemotherapeutics, among other treatments.…”

Cell of origin in biliary tract cancers and clinical implications

“…A phase I study of bintrafusp alfa, a bifunctional fusion protein 128 targeting both TGFβRII and the immune checkpoint PD-L1 (programmed cell death 1 ligand 1), was able to elicit promising objective response rates of 20% in a non-enriched population of BTCs. 129 …”