Avelumab Shows Promise in Early Trial for Advanced Ovarian Cancer

Mary L. Disis, MD

Avelumab, a fully human anti—PD-L1 IgG1 antibody, showed activity in patients with heavily pretreated recurrent or refractory ovarian cancer with an acceptable toxicity profile, according to findings from the phase Ib JAVELIN Solid Tumor trial presented at the 2016 ASCO Annual Meeting.

Partial response was seen in 12 or 124 patients for an objective response rate (ORR) of 9.7%. The disease control rate (ORR plus stable disease) was 54%. Responses were seen in 6 patients by the time of first assessment at week 6, and 10 patients had responses by week 10. Median progression-free survival (PFS) was 11.3 months, and median overall survival (OS) was 10.8 months.

“Although avelumab response rates are less than what we see in other inflamed tumors like melanoma or squamous cell non—small cell lung cancer, I think when you look at the patient population, [which is] very heavily pretreated, having a 10% to 14% response rate, with a few deep and very durable responses, sets the stage of avelumab as backbone to immunotherapy, as something to be brought in to cause inflammation in this low inflamed cancer, ovarian cancer,” said lead author Mary L. Disis, MD, University of Washington, Seattle.

The primary objective of the trial was to assess the safety and tolerability of avelumab. Secondary objectives included assessment of the best overall response, PFS, and OS, as well as of the association between PD-L1 expression on tumor cells and immune cells within the tumor and the clinical activity of avelumab.

Patients were eligible if they had confirmed recurrent or refractory stage III or IV ovarian cancer that had progressed within 6 months of platinum-based therapy or after subsequent therapy for previously relapsed disease.

Other eligibility criteria included adequate performance status, estimated life expectancy of at least 3 months, measurable disease per RECIST v1.1 criteria, and availability of fresh biopsy or archived tumor material for analysis of PD-L1 expression using a proprietary immunohistochemistry assay at defined cut-off levels of expression. However, patients were not selected based upon PD-L1 expression.

Patients received avelumab at 10 mg/kg as a 1-hour intravenous infusion every 2 weeks until progression, unacceptable toxicity, or withdrawal from the study. Efficacy was assessed every 6 weeks according to RECIST, and the collection of blood for CA-125 testing was required. BRCA1/2 mutational status was determined retrospectively from medical records.

The 124 patients in the study received a median of 6 doses (range, 1 to 26) for a median duration of 12 weeks (range, 2 to 54 weeks). Median follow-up was 12.4 months, and 17 patients remained on treatment at the time of analysis.

The ORR was 16% in patients with wild-type BRCA, and there were no responses in patients with BRCA-mutated tumors. The disease control rates were 48% and 11.1% in patients with tumors that were wild-type BRCA and BRCA-mutated, respectively.

Of the 72 patients evaluable for CA-125, concentration increased in 81.9% and decreased in 18.1%; 1 of the 10 patients with a response by RECIST had a decrease in CA-125 concentration from baseline.

There were 74 specimens (59.7%) evaluable for PD-L1 expression. There were no statistically significant differences in ORR, median PFS, or median OS between patients with PD-L1 positive or negative tumors.

Single-agent avelumab had acceptable safety with some clinical activity in heavily pretreated patients with ovarian cancer in the largest study of anti-PD-(L)1 agents in this patient population to date. No relationship between the potential biomarkers tested, including PD-L1 level, CA-125 concentration, or BRCA mutational status and response to avelumab was seen.

Treatment-related adverse events (TRAE) occurred in 66.1% of patients. Of these, 8 (6.5%) were grade ≥3. TRAE resulted in discontinuation in 10 patients, and included grade 3 colitis, myositis, arthritis, edema, and grade 4 hyperglycemia (1 patient each), as well as grade ≥3 immune-mediated TRAEs in 2 patients. There were no treatment-related deaths.

Additional trials of avelumab are ongoing, including phase III trials in combination with pegylated liposomal doxorubicin (PLD) versus PLD alone for platinum-resistant/refractory ovarian cancer, and in combination with and/or following paclitaxel plus carboplatin in previously untreated ovarian cancer. The potential relationship between biomarkers, such as germline BRCA mutational status, and the probability of response is also being investigated.

Disis ML, Patel M, Pant S, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. J Clin Oncol 34, 2016 (suppl; abstr 5533).