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

다국어 초록 (Multilingual 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 CTand 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.

번역하기

참고문헌 (Reference)

1 Lee JY, "Tumor evolution and intratumor heterogeneity of an epithelial ovarian cancer investigated using next-generation sequencing" 15 : 85-, 2015

2 Kelley RK, "Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma : randomized expansion of a phase I/II study" 39 : 2991-3001, 2021

3 Hamanishi J, "Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer" 33 : 4015-4022, 2015

4 Lee JY, "Real-world effectiveness of bevacizumab based on AURELIA in platinum-resistant recurrent ovarian cancer(REBECA) : a Korean Gynecologic Oncology Group study(KGOG 3041)" 152 : 61-67, 2019

5 Zamarin D, "Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer : an NRG oncology study" 38 : 1814-1823, 2020

6 Vanderstichele A, "Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer" 37 : 5507-, 2019

7 Hamanishi J, "Programmed cell death 1ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer" 104 : 3360-3365, 2007

8 Shin HT, "Prevalence and detection of low-allele-fraction variants in clinical cancer samples" 8 : 1377-, 2017

9 Varga A, "Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer : analysis of KEYNOTE-028" 152 : 243-250, 2019

10 Kaufman B, "Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation" 33 : 244-250, 2015