The combination of the PD-1/VEGF bispecific antibody AK112 and the PARP inhibitor olaparib is under investigation as a potential treatment option for patients with BRCA1/2 germline wild-type, platinum-sensitive, recurrent ovarian cancer as part of a phase 1b/2 trial.
The combination of the PD-1/VEGF bispecific antibody AK112 and the PARP inhibitor olaparib (Lynparza) is under investigation as a potential treatment option for patients with BRCA1/2 germline wild-type, platinum-sensitive, recurrent ovarian cancer as part of a phase 1b/2 trial (NCT04999605).1
Although PARP inhibitors have demonstrated improvements in progression-free survival (PFS) in patients with platinum-sensitive ovarian cancer who harbor a BRCA mutation and experience disease recurrence, limited options are available to those with BRCA wild-type disease.
Previously, results from a phase 2 trial (NCT01116648) showed that the combination of the VEGF inhibitor cediranib and olaparib was found to improve the median PFS compared with single-agent olaparib in 46 patients with recurrent, platinum-sensitive ovarian cancer, at 17.7 months (95% CI, 14.7–not reached) and 9.0 months (95% CI, 5.7-16.5), respectively (HR, 0.42; 95% CI, 0.23-0.76; P = .005).2
Moreover, in 806 patients with newly diagnosed, advanced, high-grade ovarian cancer who received frontline platinum-based chemotherapy and bevacizumab (Avastin), the addition of maintenance olaparib resulted in a significant PFS benefit.3 Data from the phase 3 PAOLA-1 trial (NCT-3477644) showed that the median PFS with olaparib plus bevacizumab was 22.1 months vs 16.6 months with bevacizumab alone (HR, 0.59; 95% CI, 0.49-0.72; P < .001).
The triplet combination comprised of olaparib, durvalumab (Imfinzi), and bevacizumab resulted in a higher objective response rate (ORR) and better median PFS than what has been reported with a PD-1 agent plus a PARP inhibitor, PARP monotherapy, or VEGF monotherapy in patients with germline BRCA wild-type, platinum-sensitive, relapsed ovarian cancer.4
Results from the phase 1/2 MEDIOLA trial (NCT02734004) showed that the triplet elicited an ORR of 87.1% (95% CI, 70.2%-96.4%) vs 34.4% (95% CI, 18.6%-53.2%) with olaparib plus durvalumab. The median PFS with the triplet was 14.7 months (95% CI, 10.0-18.1) vs 5.5 months (95% CI, 3.6-7.5) with the doublet.
Based on all these data, investigators hypothesized that the combination of AK112, a bispecific antibody against both PD-1 and VEGF, and a PARP inhibitor could produce a stronger antitumor effect in patients with recurrent ovarian cancer.
To this end, the multicenter, open-label, phase 1b/2 trial has been launched to examine the safety and efficacy of the combination in patients with BRCA1/2 germline wild-type, platinum-sensitive, recurrent ovarian cancer.
To be eligible for enrollment, patients must have received at least 2 prior lines of platinum-based chemotherapy, have at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and acceptable organ function.
They could not have previously received treatment with a PARP inhibitor, nor could they have ovarian, fallopian tube, or primary peritoneal cancer of nonepithelial origin. Other exclusion criteria included previous targeted therapy using small molecule and/or antiangiogenic therapy, active autoimmune disease requiring systemic treatment in the past 2 years, prior history or concurrent malignant neoplasm with certain exceptions, or a history of abdominal fistula or gastrointestinal perforation linked with anti-VEGF therapy.
In the phase 1b portion of the research, investigators will examine the safety and efficacy of the combination regimen. AK112 will be evaluated at the following dose levels: 10 mg/kg, 20 mg/kg, and 30 mg/kg. The agent will be combined with olaparib, which will be given at a fixed dose of 300 mg. A 3+3 trial design will be used to identify the recommended phase 2 dose of AK112.
In the second phase of the trial, the safety and efficacy of the combination will be further evaluated in approximately 100 patients.
The primary end points for the phase 1b portion of the research are ORR per RECIST v1.1 criteria, dose-limiting toxicities, and adverse effects (AEs). In the phase 2 portion, the primary end point is ORR per RECIST v1.1 criteria and safety.
Other key end points include disease control rate, duration of response (DOR), time to response, PFS, and overall survival per RECIST v1.1 criteria. Investigators will evaluate serum PK concentrations of AK112 and the number and percentage of patients with antidrug antibodies.
They will also explore the correlation between PD-L1 expression and efficacy of the combination, link between germline BRCA1/2 mutational status in the peripheral blood and antitumor activity, and correlations between clinical activity and homologous recombination deficiency and tumor-infiltrating lymphocytes in tumor tissues.
Investigators will utilize computed tomography or magnetic resonance imaging per RECIST v1.1 criteria to evaluate ORR, PFS, and DOR every 6 weeks until progressive disease, a new anticancer treatment is initiated, consent is withdrawn, or death, whichever occurs first.
They will monitor for AEs throughout the trial and for up to 30 days following the last dose of treatment, or 30 days after the last dose if the patient starts a new therapy, whichever is sooner during the follow-up period. Events will be graded using the Common Terminology Criteria for Adverse Events v5.0.
Samples will be collected at multiple time points throughout the trial to evaluate serum concentrations of AK112. Moreover, antidrug antibody assays will be done and reported as either positive or negative.