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Clinical Trial
. 2024 Feb 1;130(3):400-409.
doi: 10.1002/cncr.35063. Epub 2023 Oct 21.

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies

Anne Knisely  1 , Jibran Ahmed  2 , Bettzy Stephen  2 , Sarina A Piha-Paul  2 , Daniel Karp  2 , Abdulrazzak Zarifa  2 , Siqing Fu  2 , David Sanghyun Hong  2 , Jordi Rodon Ahnert  2 , Timothy A Yap  2 , Apostolia M Tsimberidou  2 , Anas Alshawa  2 , Ecaterina E Dumbrava  2 , Yali Yang  2 , Juhee Song  3 , Funda Meric-Bernstam  2 , Amir A Jazaeri  1 , Aung Naing  2
Affiliations
Clinical Trial

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies

Anne Knisely et al. Cancer. .

Abstract

Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.

Methods: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression-free survival, and overall survival.

Results: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A-C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1-7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression-free survival was 2.1 months (95% CI, 1.8-3.5 months), and overall survival was 9.4 months (95% CI, 5.6-11.9 months). No dose-limiting toxicities or grade 3-5 immune-related adverse events were observed.

Conclusions: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

Keywords: cervical cancer; endometrial cancer; immune checkpoint blockade; immunotherapy; ovarian cancer.

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Conflict of interest statement

Conflicts of interest:

A.A.J. received institutional research funding from Bristol Myers-Squibb, Iovance, Merck, Pfizer, Imunon, Iovance, Aravive, Macrogenics, AstraZeneca, Imunon, Avenge Bio, Greenfire Bio, and Break Through Cancer and consulting fees from Guidepoint, Alkermes, Gerson Lehrman Group, Adicet Bio, Theolytics, Avenge Bio, Nuprobe, and Greenfire Bio. None of the reported relationships were relevant to the submitted research.

J.R.A reports non financial support and reasonable reimbursement for travel from European Society for Medical Oncology; receiving consulting and travel fees from Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA (including serving on the scientific advisory board); Consulting fees from Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC receiving research funding from Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli and Vall d’Hebron Institute of Oncology/Cancer Core Europe; and serving as investigator in clinical trials with Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bycicle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati Linnaeus Therapeutics, and Cancer Core Europe.

S.P. receives clinical trial research support/grant Funding through the institution from the following sources: AbbVie, Inc.; ABM Therapeutics, Inc.; Acepodia, Inc; Alkermes; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma, Inc.; Chugai Pharmaceutical Co., Ltd; Curis, Inc.; Cyclacel Pharmaceuticals; Daiichi Sankyo; Eli Lilly; ENB Therapeutics; Epigenetix Inc.; Five Prime Therapeutics; F-Star Beta Limited; F-Star Therapeutics; Gene Quantum; Genmab A/S; Gilead Sciences, Inc.; GlaxoSmithKline; Helix BioPharma Corp.; Hengrui Pharmaceuticals, Co., Ltd.; HiberCell, Inc.; Immorna Biotherapeutics, Inc.; Immunomedics, Inc.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Jiangsu Simcere Pharmaceutical Co., Ltd.; Lytix Biopharma AS; Medimmune, LLC.; Medivation, Inc.; Merck Sharp and Dohme Corp.; Nectin Therapeutics, Ltd.; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Phanes Therapeutics; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Purinomia Biotech, Inc.; Rapt Therapeutics, Inc.; Replimune; Seattle Genetics; Silverback Therapeutics; Synlogic Therapeutics; Taiho Oncology; Tesaro, Inc.; TransThera Bio; ZielBio, Inc.; NCI/NIH; P30CA016672 – Core Grant (CCSG Shared Resources). She worked as a consultant in CRC Oncology.

E.E.D. received research/grant funding from Bayer HealthCare Pharmaceuticals Inc., Immunocore LTD, Amgen, Aileron Therapeutics, Compugen Ltd, TRACON Pharmaceuticals Inc., Unum Therapeutics, Gilead Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira, Seagen Inc., Mereo BioPharma 5 Inc., Sanofi, Rain Oncology, Astex Therapeutics, Sotio, Poseida, Mersana Therapeutics, Genentech, and Boehringer Ingelheim. She serves on the advisory boards for BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, and Summit Therapeutics.

Figures

Figure 1.
Figure 1.. Waterfall Plots.
Best response change from baseline (% change; n=33) per (A) Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and (B) immune-related RECIST. Abbreviations: PR=partial response, SD=stable disease, PD=progressive disease.
Figure 1.
Figure 1.. Waterfall Plots.
Best response change from baseline (% change; n=33) per (A) Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and (B) immune-related RECIST. Abbreviations: PR=partial response, SD=stable disease, PD=progressive disease.
Figure 2.
Figure 2.. Kaplan-Meier Plots.
(A) Overall survival for the entire cohort (n=40). (B) Progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death (n=37). (C) Progression-free survival per immune-related RECIST or death (n=37).
Figure 2.
Figure 2.. Kaplan-Meier Plots.
(A) Overall survival for the entire cohort (n=40). (B) Progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death (n=37). (C) Progression-free survival per immune-related RECIST or death (n=37).
Figure 2.
Figure 2.. Kaplan-Meier Plots.
(A) Overall survival for the entire cohort (n=40). (B) Progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death (n=37). (C) Progression-free survival per immune-related RECIST or death (n=37).
See this image and copyright information in PMC

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