Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors

Abstract

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ "trap."Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response.Results: Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid).Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287-95. ©2018 AACR.

Figure 1.

A, Concentration versus time profile following intravenous administration of M7824. B, PD-L1 target occupancy following intravenous administration of M7824. C, Total TGFβ1, -β2, and -β3 plasma concentrations following intravenous administration of M7824.

Figure 2.

Largest change from baseline in the sum of longest diameters according to RECIST v1.1. The dotted line at −30% indicates the threshold for a PR. Because the patient with a confirmed CR had lymph node-only disease, the sum of diameters does not reach 0. NE, not evaluable; RECIST, Response Evaluation Criteria In Solid Tumors.

Figure 3.

A, This 49-year-old woman with metastatic cervical cancer after cisplatin/taxol followed by carboplatin/taxol plus bevacizumab was enrolled with two pathologically enlarging mediastinal lymph nodes (arrows in left side of figure). Restaging scan 7.5 months after enrollment showed reduction in lymph nodes to <1 cm by short-axis measurement, meeting RECIST v1.1 criteria for a CR. CR was durable as of her 13-month restaging scan (right side of figure). B, CEA curve for patient with ongoing durable confirmed CR. C, This 61-year-old man with locally advanced pancreatic cancer s/p FOLFIRINOX, gemcitabine/abraxane, and XELOX was enrolled with an enlarging tumor in the pancreatic bed (arrow in left side of figure). Restaging scans at 3 months showed a PR, which was confirmed at 4.5 months. Scans at 6 months showed a 49% reduction in his disease by long-axis measurement (right side of figure). D, CEA curve for patient with pancreatic cancer with durable confirmed PR. CEA, carcinoembryonic antigen; FOLFIRINOX, leucovorin, fluorouracil, irinotecan, and oxaliplatin; RECIST, Response Evaluation Criteria In Solid Tumors; XELOX, oxaliplatin and capecitabine.