BY PATRICE WENDLNG in ASCO Annual Meeting on June 9th, 2015
CHICAGO – Two monoclonal antibodies were clinically active in heavily pretreated advanced ovarian cancer in a pair of phase Ib studies presented at the annual meeting of the American Society of Clinical Oncology.
In the JAVELIN trial, the objective response rate with avelumab was 10.7% after a median follow-up of 5 months in patients who were not preselected for PD-L1 (programmed death ligand 1) positivity at enrollment.
The objective response rate in the KEYNOTE-028 trial was 11.5% with the PD-1 inhibitor pembrolizumab (Keytruda) after a median follow-up of 11 months in PD-L1–positive patients.
The investigational agent avelumab inhibits PD-1 and PD-L1 interactions, but preclinical models have also suggested that antibody-dependent cellular cytotoxicity, which can directly result in lysing of tumor cells, is an additional mechanism of action, lead investigator Dr. Mary “Nora” L. Disis of the Fred Hutchinson Cancer Research Center, Seattle, and the Seattle Cancer Care Alliance said.
The expansion phase of the phase Ib JAVELIN trial has enrolled more than 840 patients with solid tumors in 11 indications and evaluated avelumab 10 mg/kg IV every 2 weeks until progression in 75 unselected patients with refractory or recurrent ovarian cancer. Most had received at least three previous lines of therapy (68%), and 70.7% had serous histology.
The objective response rate of 10.7% was based on eight partial responses by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, 44% of patients have stable disease, resulting in a disease control rate of 54.7%. The median time to response was 9 weeks, and the median duration of response was 21 weeks.
“The majority of responses are durable and ongoing at the time of this report,” Dr. Disis said.
Tumor shrinkage by at least 30% was observed in 11 patients (14.7%), including both patients enrolled with clear cell histology. Two additional patients have a partial response by immune-related response criteria, boosting the objective response rate to about 15%, she said.
A subgroup analysis showed intriguing trends for higher response rates in patients with lower vs. higher tumor burden (15% vs. 5.7%), with at least one prior line of treatment vs. two lines or at least three lines (21.4% vs. 10% vs. 7.8%, respectively), and with platinum-sensitive vs. platinum-resistant disease (20% vs. 9.1%), Dr. Disis said.
“These data, of course, because of the short follow-up rate are fairly immature, but we’ll continue to explore these trends as the data do mature,” she said.
Treatment-related adverse events of any grade were reported in 69.3% of patients, most commonly fatigue, chills, nausea, and diarrhea. Six patients (8%) had a grade 3 treatment-related adverse event, with no grade 4 or 5 adverse events or deaths related to avelumab reported, Dr. Disis said. Nine patients (12%) discontinued treatment because of an adverse event.
She noted that this is the largest reported dataset of patients with refractory or recurrent ovarian cancer treated with anti–PD-L1 therapy and that phase III clinical development is planned.
The KEYSTONE-028 trial was conducted in 26 women with PD-L1–positive ovarian cancer, of whom 81% had received at least four previous lines of therapy, Dr. Andrea Varga of Institut Gustave Roussy, Villejuif, France, said. The histology was adenocarcinoma in 46.2%, high-grade serous carcinoma in 34.6%, and other in 19.3%.
Of the 96 patients screened for the trial, 51% had PD-L1–positive tumors.
The 11.5% response rate for pembrolizumab 10 mg/kg every 2 weeks was based on one complete response and two partial responses. Stable disease was reported insix patients, for a disease control rate of 34.6%, Dr. Varga said. “Keep in mind, we are talking about a very heavily pretreated cohort of patients,” she added.
Overall, 23% of patients had at least a 30% decrease in tumor size. At the time of the analysis, the complete response and two partial responses were ongoing.
The median time to response was relatively early at 8 weeks, and the median duration of response has not been reached, indicating the durable nature of the responses, she said.
Adverse events of any grade were reported in 69.2% of patients, typically arthralgia, diarrhea, and nausea that was tolerable and easily managed. One patient had a grade 3-4 treatment-related increase in transaminase levels, and one patient had grade 3 pancreatitis. There were no treatment-related deaths or discontinuations because of an adverse event.
An analysis of the relationship between response and PD-L1 expression as well as other potential predictive biomarkers is ongoing, Dr. Varga said.
Pembrolizumab is approved as second-line therapy in advanced melanoma.
The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.