PD-1/PD-L1 Inhibitors Show Safety and Efficacy in Advanced Ovarian Cancer

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Mary "Nora" L. Disis, MD

Patients with pretreated advanced ovarian cancer demonstrated encouraging signs of antitumor activity with monoclonal antibodies against programmed death-1 (PD-1) and its ligand PD-L1, according to findings from two clinical studies presented at the 2015 ASCO Annual Meeting.

In the first phase Ib trial, the PD-L1 inhibitor avelumab demonstrated clinical activity and a low toxicity profile in patients with ovarian cancer who were treatment-refractory and unselected.¹Additionally, in a separate phase Ib study, the PD-1 inhibitor pembrolizumab demonstrated activity in patients who were heavily pretreated and who had PD-1—positive disease.²

The objective response rate (ORR) by RECIST criteria was 10.7% (95% CI, 4.7-19.9) with avelumab, after a median follow-up duration of 5 months. With pembrolizumab, the ORR was 11.5% (95% CI, 2.4-30.2) at an 11-month follow-up. Side effects in both studies were mild and generally manageable.

Avelumab in Unselected Patients

In a phase Ib trial, 75 patients with refractory or recurrent ovarian cancer received treatment with intravenous avelumab at 10 mg/kg every 2 weeks. The median age of patients was 62 years. The majority of patients had serous histology (70.7%) and received ≥3 prior therapies (68%). PD-L1-positivity was not required for admission into the study.

The primary endpoint of the trial assessed safety and tolerability, with secondary outcome measures focused on ORR, progression-free survival, overall survival (OS), and PD-L1 status. Responses were gauged via RECIST and immune-related response criteria (irRC).

The stable disease rate was 44%, with a disease control rate (DCR) of 54.7%. The median duration of treatment was 12 weeks, with a median time to response of 9 weeks. The median duration of response was 21 weeks, with 62.5% of responses ongoing.

“Although the analysis of immune-related response criteria is still ongoing, you can see that there appears to be pseudoprogression developing in some of these patients,” said lead investigator Mary "Nora" L. Disis, MD, medical oncologist, Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance, during her presentation.

Tumor shrinkage by ≥30% was observed in 14.7% of patients, including those with clear cell histology (n = 2). Of those patients with tumor shrinkage, eight had partial responses by RECIST, and two were deemed responders by irRC.

Responses were assessed in each treatment subgroup, with higher ORRs seen in those with a lower tumor burden (≤58 mm; n = 40), fewer prior therapies (≤1), and platinum-sensitive disease (>12 month progression-free interval).

In the low tumor burden group the ORR by RECIST was 15% compared with 5.7% in those with a high tumor burden (>58 mm; n = 35). Additionally, patients who received ≥3 prior therapies had a lower ORR compared with those who received ≤1 therapy (7.8% vs 21.4%). The ORR in those with platinum-resistant disease was 9.1% compared with 20% in the platinum-sensitive group.

“These data, of course, because of the short follow-up rate, are fairly immature. But we will continue to explore these trends as the data do mature,” Disis said.

Treatment-related adverse events (AEs) of all-grades were reported by 69.3% of patients enrolled. The most common AEs were grade 1/2 and included fatigue (16%), chills (12%), nausea (10.7%), diarrhea (10.7%), infusion-related reactions (8%), rash (8%), vomiting (8%), constipation (5.3%), and hypothyroidism (5.3%).

“The rate of clinically relevant grade 3 and 4 treatment-related AEs was low, at 8%. This is pretty consistent with other antibodies in this class,” said Disis. “No grade 3 treatment-related AES occurred in more than one patient, and there were no grade 4 or grade 5 AEs, including no treatment-related deaths.”

Avelumab is a fully-human PD-L1 IgG1 antibody that inhibits interaction between PD-L1 and PD-1 while leaving interaction between PD-1 and PD-L2 intact. Early research has suggested that antitumor activity may also be related to antibody-dependent cell-mediated cytotoxicity.

The treatment is being explored across a variety of solid tumor settings as part of the JAVELIN research program. These studies include patients with solid tumors, and particularly those with non—small cell lung cancer (NSCLC) and Merkel cell carcinoma. Overall, there are 11 types of cancer being explored in the JAVELIN program.

“This is the largest reported trial to-date with an anti—PD-L1 monoclonal antibody in this refractory population of ovarian cancer patients,” Disis noted. “Phase III clinical development is planned.”

Pembrolizumab in PD-L1—Positive Tumors

In this phase Ib study, membranous PD-L1 positivity (≥1% expression) was assessed using the 22C3 antibody clone. Of the 96 patients screened, 49 (51%) were deemed PD-L1 positive. These patients went on to receive pembrolizumab at 10 mg/kg every 2 weeks, with 26 evaluable for response.

The median age of patients enrolled was 57.5 years, the majority of patients were white (61.5%), the primary histology was adenocarcinoma (46.2%), and 34.6% of patients had high-grade serous carcinoma. Adjuvant or neoadjuvant therapy was administered to 53.8% of patients, and 80.8% of patients had received ≥4 prior therapies.

The 11.5% ORR was comprised of one complete response (3.8%) and two partial responses (7.7%). Tumor shrinkage >30% was seen in an additional 11.5% of patients. Six patients (23.1%) had stable disease, for a DCR of 34.6%. The median time to response was 8 weeks, and the median response duration was not yet reached.

“Pembrolizumab demonstrated antitumor activity in heavily pretreated metastatic ovarian cancer patients,” lead author Andrea Varga, MD, from the Gustave Roussy Institute of Oncology, Villejuif, France, said during her presentation. “Analyses of the relationship between response and PD-L1 expression, as well as other potential predictive biomarkers are still ongoing.”

All-grade AEs were apparent in 69.2% of patients, including arthralgia (23.1%), diarrhea (11.5%), nausea (11.5%), hypothyroidism (11.5%), and fatigue (7.7%). Hyperthyroidism, pruritus, rash, and thrombocytopenia were seen in 7.7% of patients. The only high-grade side effect was transaminases increase (3.8%).

“Pembrolizumab has a manageable safety and toxicity profile,” said Varga. “There was not mortality related to treatment, and there were no discontinuations due to treatment-related adverse events.”

Pembrolizumab is a high-affinity humanized IgG4-kappa antibody against PD-1. It is currently being developed in more than 30 tumor types and is FDA approved as a treatment for patients with advanced melanoma following progression on ipilimumab or a BRAF inhibitor, if applicable.

On June 1, 2015, the FDA granted a priority review to pembrolizumab as a potential therapy for patients with NSCLC following prior treatment with chemotherapy or a targeted therapy, if applicable. The treatment was granted a breakthrough therapy designation for NSCLC in October 2014.

References

1. Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: a phase Ib, open-label expansion trial.J Clin Oncol. 2015;33 (suppl; abstr 5509).
2. Varga A, Piha-Paul SA, Ott PA, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: interim results from a phase Ib study.J Clin Oncol. 2015;33 (suppl; abstr 5510).