M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with heavily pretreated CRC: Preliminary results from a phase I trial.

Abstract

764 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in patients (pts) with heavily pretreated colorectal cancer (CRC), an area of high unmet need since these pts no longer respond to standard therapies. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02517398, pts with heavily pretreated (≥3rd line) advanced CRC receive M7824 1200 mg q2w until confirmed progressive disease (PD), unacceptable toxicity or trial withdrawal. The primary objective is best overall response (BOR) per RECIST v1.1; secondary objectives include safety/tolerability. Results: As of 28 June 2017, 32 heavily pretreated pts with advanced CRC (87.5% had ≥3 prior therapies) received M7824 for a median duration of 7.1 (range: 2-38) weeks; 2 pts remained on treatment. Among the 29 evaluable pts, 1 had a confirmed partial response (PR; ongoing at 8 months), 1 had stable disease (SD) and 27 had PD as BOR per independent read. The pt with a PR had CRC that was microsatellite stable (MSS), consensus molecular subtype (CMS) 4, KRAS mutant (mt) and PD-L1+; this pt had the highest tumor cell PD-L1 expression in our cohort (20%; PD-L1 expression was generally low among the other 24 pts with available results). 4 pts (12.5%) experienced 5 different grade 3 treatment-related adverse events (AEs; adrenal insufficiency, anemia, blood bilirubin increased, enteritis [leading to discontinuation] and fatigue); there were no grade ≥4 treatment-related AEs or treatment-related deaths. Conclusions: In heavily pretreated pts with advanced CRC, 1 pt (MSS, CMS 4, KRAS mt and PD-L1+) had a durable PR, 1 had SD and 27 had PD as BOR. M7824 showed a manageable safety profile. Updated data – including PD-L1, TGF-β and CMS results – will be presented. A study in pts with CMS 4 is in preparation. Clinical trial information: NCT02517398.

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

“…Overall, the pharmacokinetic profile of bintrafusp alfa in Asian patients (Table 2) was similar to that in the global study [8,9]. 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 [12][13][14]19], a dose level of 1,200 mg was evaluated in multiple additional expansion cohorts [8,20].…”

“…Additionally, a manageable safety profile and encouraging early signs of clinical activity have been reported with bintrafusp alfa across all doses tested (0.3-20 mg/kg) in a first-in-human global phase I, 3 + 3 dose-escalation study (NCT02517398), which enrolled patients with heavily pretreated advanced solid tumors [8]. This promising antitumor activity and manageable tolerability profile have also been demonstrated in multiple expansion cohorts of the same trial [11][12][13][14].…”

Stromal Fibroblasts Mediate Anti–PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma

“…Although studies investigating the small-molecule type I TGFβ serine/threonine kinase inhibitors in combination with anti–PD-1 antibodies are still ongoing, early clinical data has been reported for M7824, a bifunctional fusion protein comprised of anti–PD-L1 and the extracellular domain of the type II TGFβ receptor that effectively functions as a TGFβ trap (52). Although clinical responses are being reported in pre-treated patients with a variety of solid tumor types, larger studies with longer follow-up will be necessary to fully assess the clinical utility and ideal patient population of this therapeutic approach (54–57). This work underscores the importance of gaining a mechanistic understanding of the impact of pharmacologic agents on the tumor immune microenvironment and how these alterations may, in turn, affect the ultimate generation of effector antitumor immune responses.…”

Targeting TGFβ signal transduction for cancer therapy

“…289 M7824 showed a manageable safety profile and encouraging clinical efficacy in phase 1 clinical trials, including patients with advanced solid tumors, NSCLCs, recurrent glioblastoma, cervical cancer, metastatic TNBC, heavily pretreated CRC, or human papillomavirus (HPV)-associated cancers. [290][291][292][293][294][295][296] M7824 is now being evaluated in a phase 2 clinical trial for patients with advanced/metastatic biliary tract cancer, gallbladder cancer, recurrent respiratory papillomatosis, thymoma, CRC, head and neck squamous cell cancer, advanced pancreas cancer, or recurrent prostate cancer. 297 Moreover, the evaluation of M7824 for patients with advanced NSCLC or biliary tract cancer is now under investigation in phase 3 clinical trials.…”