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

• Published in: Cancer Vol. 130; no. 3; pp. 400 - 409
• Main Authors: Knisely, Anne, Ahmed, Jibran, Stephen, Bettzy, Piha‐Paul, Sarina A., Karp, Daniel, Zarifa, Abdulrazzak, Fu, Siqing, Hong, David Sanghyun, Rodon Ahnert, Jordi, Yap, Timothy A., Tsimberidou, Apostolia M., Alshawa, Anas, Dumbrava, Ecaterina E., Yang, Yali, Song, Juhee, Meric‐Bernstam, Funda, Jazaeri, Amir A., Naing, Aung
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2024
• Subjects: Agonists; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Cancer; Cervical cancer; Criteria; Disease control; Effectiveness; Endometrial cancer; Female; Genital Neoplasms, Female - drug therapy; Humans; immune checkpoint blockade; Immune checkpoint inhibitors; Immunoglobulin G; Immunotherapy; Malignancy; Monoclonal antibodies; Neoplasm Recurrence, Local - pathology; Ovarian cancer; Radiation therapy; Safety; Solid tumors; Survival; Targeted cancer therapy; Tumor necrosis factor; Tumors; Uterine cancer; Uterine Cervical Neoplasms - drug therapy; endometrial cancer; ovarian cancer; cervical cancer; immunotherapy; immune checkpoint blockade
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.35063

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. In a phase 1/2 trial of heavily pretreated patients who had recurrent gynecologic cancers, avelumab in combination with a 4‐1BB agonist, an OX40 agonist, and/or radiation was safe and had a similar rate of immune‐related adverse events compared with single‐agent immune checkpoint blockade. The combination of multiple immune‐modulating agents, however, did not result in increased efficacy.