Merck KGaA and Pfizer Inc. have begun a phase III registration study to test the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in combination with or as follow-on treatment to platinum-based chemotherapy in patients with metastatic, previously untreated epithelial ovarian cancer.

Called Javelin Ovarian 100, the open label study is designed to evaluate the potential superiority of avelumab combined with carboplatin/paclitaxel vs. platinum-based chemo alone, as assessed by progression-free survival. The 950 stage III-IV patients expected to be enrolled will be randomized 1:1:1 to receive concurrent avelumab and chemotherapy, avelumab following chemotherapy, or chemotherapy alone.

Despite being part of a field crowded with immune checkpoint inhibitor combination studies, this is the first phase III to test adding one of the immunotherapies to standard of care in first-line treatment for metastatic ovarian cancer. The effort is part of an expansive $2.85 billion deal Merck and Pfizer struck in November 2014. Avelumab was initially discovered and developed by Merck.

Ovarian cancer is one of the most common and lethal forms of cancer affecting women today, with nearly a quarter of a million women diagnosed with the cancer annually worldwide, according to the World Health Organization. Incidence is highest in Europe and Northern America.

"Ovarian cancer is an important tumor type for us," Chris Boshoff, Pfizer's head of early development, translational and immuno-oncology, told BioWorld Today.

Although responses to single-agent checkpoint inhibitors in ovarian cancer have been seen in earlier tests, they're not as good as responses seen in some of the other tumor types with the single-agent checkpoint inhibitors, he said. "Our strategy in ovarian cancer is really a combination strategy."

Certain chemotherapeutics elicit immunogenic cell death, Boshoff explained. "When the cells die, they elicit an immune response – essentially inflammation – attracting T-cells to the tumor microenvironment. You remove the brake from those T-cells with your checkpoint inhibitor and you could have additive or synergistic activity," something that has been previously shown with Doxcil and other checkpoint inhibitors, he said.

Javelin Ovarian 100 is the second phase III registration study looking at avelumab and chemotherapy. The first, JAVELIN Ovarian 200, is enrolling women whose tumors are cisplatin-resistant – those patients which are most difficult to treat and who have the worst prognosis. The study is comparing avelumab alone to avelumab plus pegylated liposomal doxorubicin (PLD) and to PLD alone to demonstrate that avelumab given alone or in combination with PLD is superior to PLD alone in prolonging overall survival.

Given the successes seen with using anti-PD-L1 therapy in treating melanoma, lung and bladder cancer, there could be applicability in ovarian cancer, Don Dizon, clinical co-director of gynecologic oncology at Massachusetts General Hospital Cancer Center, told BioWorld Today.

"A study in women who are newly diagnosed is a very provocative idea," Dizon said. "Although we are very successful in treating the disease and getting people into remission following surgery and chemotherapy, the risk of relapse is very high. And if a woman does have a relapse, that is not a curable situation. So, if we can improve the outcomes in the start, there is a potential that we can improve the cure rates in ovary cancer," he said.

Dizon also expressed interest in the study's design. Given the immune response immunotherapies can produce, "a lot of us are thinking about sequencing more thoughtfully," he said. "We're not sure how chemotherapy alongside immunotherapy will either induce or inhibit an immune response. So, testing it the way they are, alongside chemo and also looking at it following chemo is a smart idea."

The 2014 deal between the two companies included $850 million up front and about $2 billion more in regulatory and commercial milestones. The companies agreed to pool their resources in both PD-L1 and PD-1 inhibition. Darmstadt, Germany-based Merck took a 50 percent interest in Pfizer's PD-1 inhibitor program and pledged to help its partner steer the molecule toward the clinic. The companies are sharing costs and revenues across the two programs. Pfizer declined to say whether or not the Ovarian 100 trial start triggered a milestone payment under the deal's terms. (See BioWorld Today, Nov. 18, 2014.)

As of May 2016, the complete JAVELIN clinical development program for avelumab includes approximately 2,200 patients enrolled, being treated across more than 15 tumor types. Overall, Pfizer has up to 30 different programs with avelumab in the clinic now, with up to 10 potential registrations studies ongoing said Boshoff. “Important ongoing combination studies for Pfizer include those with the 4-1BB agonist utomilumab and an OX40 agonist. A trial testing a triplet combining those drugs with avelumab is planned for 2017.”

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