PF-8600 and utomilumab are fully human IgG2 agonistic monoclonal antibodies directed at tumor necrosis factor receptor superfamily receptors OX40 and 4-1BB, respectively. In general, OX40 has a greater impact on CD4 T cell function, while 4-1BB has more impact on CD8 T cell function. Dual targeting of OX40 and 4-1BB synergistically induced CD8 and cytotoxic CD4 T cell clonal expansion in pre-clinical models. A Phase I study (NCT02315066), evaluated PF-8600 alone and in combination with utomilumab. As seen previously for utomilumab alone, PF-8600 monotherapy was tolerable at all dose levels, providing rationale to combine PF-8600 with utomilumab.
Non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma, bladder, gastric or cervical cancer patients (pts) unresponsive to available therapies or where no standard therapy is available are treated with PF-8600 at dose levels 0.1 mg/kg to 3 mg/kg q2w in combination with utomilumab at either 20 mg or 100 mg q4w intravenously. Blood was collected for PK/PD analysis.
At time of data cut-off on 30-Jan 2017 (study ongoing), 28 pts had enrolled in 4/5 planned dose cohorts. No drug-related deaths, dose-limiting toxicities, or suspected unexpected serious adverse reactions have been confirmed to date. All drug-related adverse events (AEs) were grade (G) 1-2. The most common were nausea (10.7%), decreased appetite (7.1%) and fatigue (7.1%). Nine (32.1%) G3, 3 (10.7%) G4 and 2 (7.1%) G5 all-causality AEs were reported (G5 AEs in lowest dose cohort). Combination treatment resulted in greater increases in expression of activation and proliferation markers on CD8 memory T cells, in particular, and memory T cell subsets overall, than PF-8600 alone. Preliminary PK and efficacy data will be shown.
To date, dose escalation combining active monotherapy doses of PF-8600 and utomilumab has not demonstrated toxicity beyond that expected from either alone. Safety, efficacy, PK, and PD data from dose escalation will aid selection of optimal biologic doses for further evaluation and expansion.
Clinical trial identification
Legal entity responsible for the study
O. Hamid: Consulting/Advising: Amgen, Novartis, Roche, Bristol-Myers Squibb, Merck; Speakers\' Bureau Bristol-Myers Squibb, GNE, Novartis, Amgen; Research Funding (Institution): AstraZeneca, Bristol-Myers Squibb, Celldex, GNE, Immunocore, Incyte, Merck, Merck Serono, MedImmune, Novartis, Pfizer, Rinat, Roche. J.A. Thompson: Honoraria: Celledex Consulting or advisory role: Celledex Research Funding (to institution): Bristol-Myers Squibb Agensys Seattle Genetics Pfizer Trillium Therapeutics Merck Inc. S. Hu-Lieskovan: Consulting: Amgen, Merck, Novartis, Vaccinex, Emergent BioSolutions Contracted Research: Pfizer, Plexxikon, Genentech, Neon Research Support: Bristol-Myers Squibb, Merck Travel Support: Amgen, Merck, Novartis, Vaccinex, Emergent BioSolutions, Neon. F.A.L.M. Eskens: Consulting or Advisory Role: Daiichi Sankyo Ipsen Pfizer Merck Inc. Novartis Pharma KK Travel, Accommodations, Expenses Daiichi Sankyo Ipsen Roche-Peru. A. Diab: Consulting/advisory: Nektar, CureVac, Celgene Travel/accomodations/expenses: Nektar Research funding (to institution): Nektar, Idera, Celgene, Pfizer. T. Doi: Advisory: Lilly, Chugai, Kyowa Hakko Kirin, Nippon BI, Novartis, MSD, Daiichi Sankyo, Amgen Funding to institution: Taiho, Novartis, Merck Serono, Astellas, MSD, Janssen, BI, Takeda, Pfizer, Lilly, Sumitomo, Chugai, Bayer, Kyowa, Daiichi Sankyo, Celgene. J. Wasser: Have received research support from Pfizer by means of a material transfer agreement. J-P. Spano: Adboard with Pfizer (Breast cancer). N.A. Rizvi: Advisory Board: Merck, AstraZeneca, Roche, Bristol-Myers Squibb, Novartis, Pfizer, Lilly, Novartis, Abbvie Co-founder and shareholder: Gritstone Oncology Scientific Advisory Board: Nilogen Oncosystems. A. Chiappori: Participated in advisory boards for Genentech, Novartis, Bristol-Myers Squibb, ARIAD and have also received honoraria from Genentech, Merck, Celgene, Boehringer Ingelheim. Received honoraria from Pfizer too, but not within the last year. P.A. Ott: Grants to the institution and personal fees from Bristol-Myers Squibb, CytomX, Celldex, Pfizer and Merck, personal fees from Neon Therapeutics, Amgen, Novartis, and Roche/Genentech, and grants from AstraZeneca/MedImmune, outside of the submitted work. B.J. Ganguly, K. Liao, T. Joh, J. Chou, C. Fleener: Employee and stockholder of Pfizer Inc. V. Dell: Contractor for Pfizer. A. El-Khoueiry: Advisory: CytomX, Bristol-Myers Squibb, AstraZeneca Speakers Bureau: Merrimack Honoraria: Merrimack, Bayer, Novartis, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.