AACR: Ovarian cancer clinical trial shows effects, safety of upfront
immunotherapy and chemotherapy for advanced disease
Results from a clinical trial led by MD Anderson researchers showed that combining the immunotherapy checkpoint inhibitor drug durvalumab with chemotherapy has a tolerable safety profile and achieved a clinical response in the majority of patients with newly diagnosed, advanced stage, high grade serous ovarian cancer.
Limited data for immunotherapy’s effectiveness in treating ovarian cancer
Ovarian cancer is the most deadly gynecologic cancer. In most cases, it is diagnosed at an advanced stage, which explains the poor prognosis of the disease. While important advances have been made in ovarian cancer treatments, the survival rates have only moderately improved. Current first-line treatment of high-grade ovarian cancer includes tumor debulking surgery followed by combination chemotherapy.
Checkpoint inhibitors work best against so-called “hot” tumors, which have molecular features that make them easier for the immune system to recognize. Ovarian cancers tend to be “cold” with limited responses to checkpoint blockade, but preclinical data indicated combining chemotherapy with checkpoint inhibitors could convert cold tumors to hot tumors and make them more sensitive to immunotherapy treatment.
“Currently, the role of immune checkpoint inhibitors in ovarian cancer is uncertain,” Westin says. “The goal of this study was to understand what is happening to the tumor before and after treatment and gather translational data to recognize which patients may see survival benefits.”
Improving personalized therapy approaches for upfront management of high-grade ovarian cancer is a focus of the Ovarian Cancer Moon Shot®, which is co-led by Westin and which provided support for the clinical trial. The effort is part of MD Anderson’s Moon Shots Program®, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Neoadjuvant durvalumab combination for ovarian cancer treatment shows potential
Since this drug combination has not been given previously, a safety lead in of six patients was conducted at the beginning of the study. There were no dose limiting toxicities, and overall patients tolerated the combination well.
The single arm Phase II clinical trial treated 18 patients with untreated stage III/IV ovarian cancer with neoadjuvant durvalumab, weekly paclitaxel, and carboplatin every three weeks. Baseline tissue biopsies were performed by laparoscopy or interventional radiology. This tissue was collected for translational analyses.
After three cycles, patients had tumor reductive surgery with tissue collection. This was followed by three additional cycles of paclitaxel, carboplatin and durvalumab. At the completion of six total cycles of chemotherapy, patients were transitioned to 12 cycles of durvalumab maintenance.
The clinical trial’s primary endpoint was progression-free survival and changes to molecular markers in immune-related pathways.
At 13 months median follow up, the median progression-free survival was 14.5 months, and 69% of participants were alive at 18 months. 70% of patients had an objective response, and 83% achieved an optimal cytoreduction surgery.
The most common adverse events were bone marrow toxicity and fatigue. Immune-related adverse events were rare, however cases of hyperthyroidism, hypothyroidism, diarrhea, and hypophysitis were observed.
Changes in immune-related pathways may impact future ovarian cancer treatment
At the time of analysis, 55 tumor specimens from nine patients had matched pre- and post-treatment tissues. Each patient served as her own control, and protein expression was compared between biopsies from the same location. In general, PD-L1 levels were elevated after exposure to durvalumab in combination with chemotherapy.
Thirteen of 211 proteins showed significant change between pre- and post-treatment. The majority had up-regulation in expression, including PAR, ARID1A and STING. Only XBP-1 was downregulated.
Enriched reactome pathway analysis was performed and revealed that members of the cell cycle, DNA damage, and apoptosis pathways were commonly down-regulated after combination treatment while members of the PI3K/AKT pathway were up-regulated.
“This study demonstrates the feasibility of checking biomarkers during treatment,” says Westin. “The data showed that each tumor reacts differently and holds the potential to allow us to personalize treatment for every patient.”
Future studies are being designed to potentially add drug combinations during ovarian cancer treatment based on biopsy analysis.