Phase III Ovarian Cancer Study Terminated After Frontline Avelumab Falls Short

At a planned interim analysis of the phase III JAVELIN Ovarian 100 study evaluating frontline avelumab (Bavencio) in ovarian cancer, an independent panel determined the study would not meet its primary endpoint of progression-free survival (PFS). Merck KGaA and Pfizer, the co-developers of the PD-L1 inhibitor, have announced they will terminate the trial on this basis.

A total of 998 treatment-naive patients with locally advanced or metastatic (stage III/IV) epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were included in the trial. Patients were randomized to carboplatin/paclitaxel; carboplatin/paclitaxel with maintenance avelumab; or avelumab plus carboplatin/paclitaxel followed by maintenance avelumab.

At the time of the planned interim analysis, an independent data monitoring panel determined that neither of the 2 avelumab arms would demonstrate a PFS benefit over the control arm of chemotherapy alone. There were no new safety signals, and the safety data were similar to findings from other research in the companies’ JAVELIN clinical program, according to the agent's co-developers.

The companies also reported that health authorities and study investigators have been made aware of the decision to terminate the trial. Additionally, Merck KGaA and Pfizer plan to share the specific data from the trial at a later date.

Avelumab plus PLD led to an HR for PFS of 0.78, which did not meet the prespecified criteria for superiority (repeated confidence interval [RCI], 0.587-1.244; one-sidedPvalue = .0301). The OS endpoint with the avelumab combination was also not met (HR, 0.89; RCI, 0.744-1.241; one-sided Pvalue = .2082).

Avelumab monotherapy also missed the PFS endpoint (HR, 1.68; RCI, 1.320-2.601; one-sidedPvalue >.99) and OS endpoint (HR, 1.14; RCI, 0.948-1.580; one-sidedPvalue = .8253). Merck and Pfizer noted that these data are currently being analyzed, and detailed results will be presented at a later date.

In the multicenter, randomized, phase III JAVELIN Ovarian 200 trial (NCT02580058), 556 patients with platinum-resistant or -refractory ovarian cancer were randomized to receive either avelumab intravenously (IV) at 10 mg/kg every 2 weeks in 4-week cycles, avelumab IV at 10 mg/kg every 2 weeks in 4-week cycles plus PLD at 40 mg/m²IV every 4 weeks in 4-week cycles, or PLD at 40 mg/m²IV every 4 weeks in 4-week cycles.

Patients had histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, platinum-resistant/-refractory disease, previously received up to 3 lines of systemic therapy, and measurable disease. The primary endpoints were superior OS or PFS for one or both avelumab arms versus PLD; objective response rate (ORR) was a secondary endpoint.

The ORR was 13.3% (95% CI, 8.8%-19.0%) for avelumab combined with PLD, 3.7% (95% CI, 1.5%-7.5%) for single-agent avelumab, and 4.2% (95% CI, 1.8%-8.1%) for PLD alone. There were no new safety signals reported with either avelumab monotherapy or with the combination.

Exploration of avelumab in ovarian cancer continues in other trials, including the JAVELIN Ovarian PARP 100 study (NCT03642132). This phase III trial is assessing the potential of avelumab combined with chemotherapy followed by maintenance with avelumab plus the PARP inhibitor talazoparib (Talzenna) in treatment-naive patients with advanced ovarian cancer.

Overall, researchers have struggled to determine the optimal approach to using immune checkpoint inhibitors in ovarian cancer. Single-agent studies have shown only modest results, so, as with the JAVELIN program, researchers have been turning to combinations. 

One such study is NRG GY009 (NCT02839707), a 3-arm randomized trial of patients with platinum-resistant recurrent ovarian cancer who have had 1 to 2 prior lines of therapy. Patients randomized to arm 1 will receive 40 mg/m²of PLD for 4 weeks plus 800 mg of atezolizumab (Tecentriq) every 2 weeks. Arm 2 mirrors arm 1, with the addition of 10 mg/kg of bevacizumab (Avastin) every 2 weeks. Patients randomized to arm 3 will receive 40 mg/m²of PLD every 4 weeks and 10 mg/kg of bevacizumab every 2 weeks.

Another study is IMaGYN050, a double-blinded, randomized, placebo-controlled, multicenter study of atezolizumab versus placebo in combination with paclitaxel, carboplatin, and bevacizumab in previously untreated patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients enrolled on this trial are either stage III or stage IV or are in the adjuvant setting with advanced disease.

The phase I/II TOPACIO/KEYNOTE-162 study (NCT02657889) is a dose-finding combination trial of niraparib (Zejula) plus pembrolizumab (Keytruda) in patients with metastatic triple-negative best cancer or recurrent platinum-resistant epithelial ovarian cancer.

Additionally, the ATHENA trial (NCT03522246) is a phase III randomized trial of rucaparib (Rubraca) and nivolumab (Opdivo) as maintenance treatment following response to first-line platinum-based chemotherapy. There are currently 1012 patients enrolled on this trial, and they are being randomized to either rucaparib plus nivolumab, rucaparib plus placebo, placebo plus nivolumab, or oral placebo plus intravenous placebo.

This is the second recent report of a phase III trial of avelumab in ovarian cancer that has missed its primary endpoint. Last month, Merck KGaA and Pfizer reported that findings from the phase III JAVELIN Ovarian 200 trial showed that avelumab alone or in combination with pegylated liposomal doxorubicin (PLD) did not induce a statistically significant improvement in overall survival (OS) or PFS versus PLD alone in patients with platinum—resistant/refractory ovarian cancer, missing the primary endpoints of the study