A phase Ib/II study of modakafusp alfa alone and in combination with pembrolizumab in patients with advanced or metastatic solid tumors

David Gill^1*Charles L Cowey²Gregory A Daniels³David Sommerhalder⁴Raghad Abdul-Karim⁵John M Kirkwood⁶Joanna Kolodney⁷Inderjit Mehmi⁸Rachel Roberts-Thomson⁹James Strauss¹⁰Sajeve Thomas¹¹Eric Whitman¹²Yan Xing¹³Meredith McKean¹⁴Sabrina Collins¹⁵Cheryl Li¹⁵Gurpanna Saggu¹⁵Tian Chen¹⁵Shining Wang¹⁵Marina Lewis¹⁵Xavier Parot¹⁵Melissa Johnson¹⁴

• ¹Intermountain Healthcare, Salt Lake City, United States
• ²Baylor Charles A. Sammons Cancer Center, Texas Oncology, Dallas, United States
• ³University of California San Diego, La Jolla, United States
• ⁴NEXT Oncology, San Antonio, Texas, United States
• ⁵Nova Oncology, McAllen, United States
• ⁶UPMC Hillman Cancer Center and the University of Pittsburgh, Pittsburgh, United States
• ⁷West Virginia University, Morgantown, West Virginia, United States
• ⁸The Angeles Clinic and Research Institute, Los Angeles, California, United States
• ⁹The Queen Elizabeth Hospital, Adelaide, Australia
• ¹⁰Mary Crowley Cancer Research, Dallas, United States
• ¹¹Medical Oncology, Advent Health, Orlando, United States
• ¹²Atlantic Health System, Morristown, New Jersey, United States
• ¹³City of Hope Comprehensive Cancer Center, Duarte, United States
• ¹⁴Sarah Cannon Research Institute, Nashville, Tennessee, United States
• ¹⁵Takeda Development Center Americas, Inc. (TDCA), Cambridge, United States

Background: Modakafusp alfa is a novel immunocytokine comprising two attenuated interferon-ɑ2b molecules fused to an anti-CD38 IgG4 monoclonal antibody. Modakafusp alfa has shown immune cell activation and antitumor activity in preclinical mouse models, including in combination with an anti- programmed cell death (PD-1) receptor in tumors that do not express CD38, and demonstrated clinical responses and immune activation in patients with relapsed/refractory multiple myeloma. Methods: In phase Ib, adult patients with advanced/metastatic solid tumors received escalating doses of modakafusp alfa 0.1–1.5 mg/kg intravenously every 3 weeks (Q3W) across six dosing cohorts. In phase II, patients with unresectable/metastatic cutaneous melanoma and resistance to ≤2 anti-PD-1 therapies in the metastatic setting received modakafusp alfa 1 mg/kg Q3W in combination with pembrolizumab Q6W. Primary objectives were to determine the safety/tolerability as a single agent in phase I, and efficacy in combination with pembrolizumab in phase II. Results: Twenty-one and 24 patients were enrolled across phases Ib and II, respectively. The recommended phase II dose of modakafusp alfa was 1 mg/kg. The most common drug-related adverse events were infusion-related reactions (IRRs; 52.4%) and thrombocytopenia (28.6%) in phase Ib; and headache (58.3%), fatigue (54.2%), IRRs (41.7%), neutropenia (37.5%), and nausea (33.3%) in phase II. In phase Ib, 7 patients had a best response of stable disease (SD); in phase II, 1 patient had a confirmed complete response, 1 had a confirmed partial response, and 7 had SD. All immunogenicity-evaluable patients were anti-drug antibodies (ADAs) positive following treatment with modakafusp alfa; neutralizing ADAs were reported in 82.4% and 90.9% of patients in phases Ib and II, respectively, which was associated with drug exposure reduction. Pharmacodynamic analyses demonstrated innate and adaptive immune activation in peripheral blood and within tumors. Paired biopsy analysis revealed two subgroups of patients defined by differences in CD38 upregulation, accompanied by differential intratumoral pharmacodynamic changes. Correlative analysis was inconclusive. Conclusions: Modakafusp alfa induces innate and adaptive immune responses, supporting its hypothesized mechanism of action (MoA) in patients with advanced solid tumors. High immunogenicity and the potentially limited treatment effect of the IFN MoA may have contributed to limited efficacy in these patients.