Biomarker-guided targeted therapy in platinum-resistant ovarian cancer (AMBITION; KGOG 3045): a multicentre, open-label, five-arm, uncontrolled, umbrella trial

Abstract

Objective: Management of heavily pre-treated platinum-resistant ovarian cancer remains a therapeutic challenge. Outcomes are poor with non-platinum, single-agent chemotherapy (CT); however, molecularly targeted anticancer therapies provide new options.

Methods: This open-label, investigator-initiated, phase 2 umbrella trial (NCT03699449) enrolled patients with platinum-resistant ovarian cancer (at least 2 prior lines of CT and Eastern Cooperative Oncology Group 0/1) to receive combination therapy based on homologous recombination deficiency (HRD) and programmed death ligand 1 (PD-L1) status determined by archival tumour sample assessment. HRD-positive patients were randomised to either olaparib 200mg bid tablet + cediranib 30mg qd (arm 1) or olaparib 300mg bid tablet + durvalumab 1,500mg q4w (arm 2). HRD-negative patients were allocated to either durvalumab 1,500 mg q4w + pegylated liposomal doxorubicin (PLD) or topotecan or weekly paclitaxel (6 cycles; arm 3, those with PD-L1 expression) or durvalumab 1,500 mg q4w + tremelimumab 75mg q4w (4 doses) + PLD or topotecan or weekly paclitaxel (4 cycles; arm 4, those without PD-L1 expression). Arm 5 (durvalumab 1,500 mg q4w + tremelimumab 300mg [1 dose] + weekly paclitaxel [60 mg/m² D1,8,15 q4w for 4 cycles] was initiated after arm 4 completed. The primary endpoint was objective response rate (ORR; Response Evaluation Criteria in Solid Tumours 1.1).

Results: Between Dec 2018 and Oct 2020, 70 patients (median 57 years; median 3 prior treatment lines [range 2-10]) were treated (n=16, 14, 5, 18, and 17, respectively). Overall ORR was 37.1% (26/70, 95% confidence interval=25.9, 49.5); 2 achieved complete response. ORR was 50%, 42.9%, 20%, 33.3%, and 29.4%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients, respectively. No TRAEs leading to treatment discontinuation and no grade 5 TRAEs were observed.

Conclusion: This study, the first biomarker-driven umbrella trial in platinum-resistant recurrent ovarian cancer, suggests clinical utility with biomarker-driven targeted therapy. All treatment combinations were manageable, and without unexpected toxicities.

Trial registration: ClinicalTrials.gov Identifier: NCT03699449.

Keywords: Biomarker; Immunotherapy; Molecular Targeted Therapy; Ovarian Cancer; Platinum Resistant.

Conflict of interest statement

JYL reports grants from AstraZeneca during the conduct of the study; grants and personal fees from Beigene, Bergenbio, Clovis Oncology, Immunogen, Janssen, Merck, MSD, Novartis, Roche, Seagen, Synthon, and Takeda. All other authors have no conflicts of interest to disclose.

Copyright © 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.

Figures

Fig. 1. Study overview and trial profile. Arm 1, O+C (O 200 mg bid + C 30 mg qd); arm 2, O+D (O 300 mg bid + D 1,500 mg q4w); arm 3, D+CT (D 1,500 mg q4w + PLD or topotecan or weekly paclitaxel [6 cycles]) in patients with high PD-L1 expression; arm 4, D+T75+CT (D 1,500 mg q4w + T 75 mg q4w [4 doses] + PLD or topotecan or weekly paclitaxel [4 cycles]) ; arm 5, D+T300+CT (D 1,500 mg q4w + T 300 mg [1 dose] + weekly paclitaxel [60 mg/m2 days 1, 8, and 15 q4w for 4 cycles]).

bid, twice daily; C, cediranib; CT, chemotherapy; D, durvalumab; HRD, homologous recombination deficiency; O, olaparib; PD-L1, programmed death ligand 1; PLD, pegylated liposomal doxorubicin; q4w, every 4 weeks; qd, once daily; T, tremelimumab; T300, tremelimumab 300 mg (1 dose); w-P, weekly paclitaxel.

Fig. 2. Tumour responses. (A) Waterfall plot of the maximum percentage change in target lesion size in treated patients who had at least one post-baseline scan. Each bar presents a patient. The colour indicates type of response. (B) Swimmer’s plot for patients with a confirmed response. Each bar presents a patient. From 61 patients who had at least one post-baseline efficacy assessment.

d, day; HRD, homologous recombination deficiency; HRR, homologous recombination repair; q4w, every 4 weeks; w-P, weekly paclitaxel.

Fig. 3. Kaplan-Meier plots of PFS (A) and OS (B) in patients with modified intent-to-treat population.

OS, overall survival; PFS, progression-free survival.