Having taken "a little bit of time to dig out" from last September's setback with VS-6063 (defactinib), Verastem Inc. CEO Robert Forrester told BioWorld Today the firm "made a point of talking with the outside world" about the potential of focal adhesion kinase (FAK) inhibitors.

Convinced are Pfizer Inc. and Merck KGaA, which together inked an agreement with Boston-based Verastem to test the pharma giants' anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 monoclonal antibody avelumab (MSB0010718C) in combination with VS-6063 against advanced ovarian cancer. A phase I/Ib trial is expected to begin in the second half of this year. Financial terms of the pact were not disclosed.

New York-based Pfizer, and Merck, of Darmstadt, Germany, earlier joined forces with each other in PD-L1 to the tune of potentially $2.85 billion, the two companies pooling resources in PD-L1 and programmed cell death protein 1 (PD-1) inhibitors. Merck took a 50 percent interest in Pfizer's PD-1 effort, and the two share costs as well as revenues across the two programs. (See BioWorld Today, Nov. 18, 2014.)

"Pfizer paid an awful lot of money up front for this drug [$850 million]," Forrester said, calling his company's deal "one of the first" to try a combo therapy with Pfizer/Merck. The true first is Waltham, Mass.-based Syndax Pharmaceuticals Inc., which Wednesday priced its $52.8 million initial public offering. (See story in this issue.)

"The big reason Syndax got public was on the back of this collaboration with Pfizer [and Merck] around avelumab," he said. Syndax disclosed the arrangement at the start of this year. Specifically, avelumab will be tested with Syndax's entinostat, an investigational oral small molecule that targets immune regulatory cells (myeloid-derived suppressor cells and regulatory T cells), in patients with heavily pre-treated, recurrent ovarian cancer.

"Over the last few years, we've really come to appreciate that FAK inhibition does more than just attack cancer stem cells," Forrester said. In particular, the mechanism reduces the density of the stroma, "the skin that one sees around a number of tumors," such as pancreatic, "that prevents drugs and the immune system from getting in," he said. With the so-called "cold tumors," many of the PD-1 and PD-L1 "literally have zero percent response rate." Ovarian cancer turns up a response rate of only about 10 percent to 15 percent. In the case of ovarian with avelumab, the rate is 10.7 percent. "That's why Pfizer and Merck are so interested to collaborate with us around the FAK program," he said. "We've been working with them for about a year now." Other avelumab work continues apace by the pharma giants. "They're just starting multiple phase IIIs," he said, with five to 10 expected to begin shortly.

Verastem's phase II failure last year with VS-6063 in malignant pleural mesothelioma (MPM) had several causes, Forrester said, among them that MPM is simply "a really tough disease" that has foiled many candidates. Earlier this week, London-based Astrazeneca plc reported tremelimumab's phase IIb defeat in the indication, where the cytotoxic T-lymphocyte protein-4 inhibitor could not improve overall survival. Also, the Verastem trial's biomarker, merlin, "actually didn't work," he said. In the end, "expecting a cancer stem cell drug on its own to have a material benefit for patients in this rapidly progressing tumor. . . . It's hard; it's a really high hurdle to expect of any drug," he said, though the MPM study did show VS-6063 safe and well tolerated. (See BioWorld Today, Sept. 29, 2015, and March 3, 2016.)

Combo seemed the way to go. "We're letting the other drugs do a lot of the de-bulking, and bringing in our drug to finish the job," Forrester said. "That's what you're seeing in the ovarian cancer trial" under way by Verastem at an early stage with VS-6063 and paclitaxel. "We've got patients who have been on drug for more than two years," one of whom has shown a complete response, he said. "It looks encouraging," and the company wanted to build on the findings made so far, "which is what this collaboration with Pfizer and Merck is all about."


Two other firms have ongoing FAK inhibitor programs: London-based Glaxosmithkline plc and Boehringer Ingelheim GmbH, of Ingelheim, Germany. "It's always good to have high-quality competition like that," Forrester said. "We're probably neck and neck, maybe a little bit ahead [of them]." Verastem would like to do another collaboration in non-small-cell lung cancer. "Obviously, it requires a lot of good things to happen," he said. "We can't do it on our own, but we are hopeful we can pull that off this year as well." At the end of 2015, Verastem had $100 million in the bank, enough to take the firm into 2018. "We have the capital to fully execute on everything that we're doing and get to the proof-of-concept points," he said.

Verastem's second FAK inhibitor, VS-4718, has shown a generally well-tolerated safety profile in a single-agent ascending-dose study and was found suitable to advance. Planned for this year are confirmatory work to determine the best phase II dose as well as expansion cohorts in patients with disease susceptible to biopsy. A combo trial of VS-4718 and gemcitabine/Abraxane (nab-paclitaxel, Celgene Corp.) recently started, with results of the dose-escalation experiment due by the end of this year. Once that's done, an expansion cohort of VS-4718 plus gemcitabine/Abraxane vs. gemcitabine/Abraxane alone in patients with pancreatic cancer is planned.

Jonathan Pachter, head of research at Verastem, noted that – unlike the GSK and BI candidates – Verastem's inhibit both FAK and protein tyrosine kinase 2 beta (Pyk2). The latter has been found to decrease macrophages in tumors. "We think that's an advantage that will play out over time," he told BioWorld Today, adding that PD-1 and PD-L1 represent "the tip of the immuno-oncology [IO] iceberg," and FAK/Pyk2 inhibitors are "really applicable to all of the IO therapies that you think about. We're exploring that preclinically now." Others are busy, too. Washington University in St. Louis has a phase I, dose-escalation study under way with VS-6063 and Kenilworth, N.J.-based Merck & Co.'s anti-PD-1 drug Keytruda (pembrolizumab) plus gemcitabine in pancreatic cancer.

Roth Capital Partners analyst Joseph Pantginis, in a research report triggered by Verastem's earnings, said those at his firm "believe there still remains a lack of confidence in VS-6063 following the failure of the monotherapy, pivotal COMMAND study [in MPM]. However, the company is making strides in looking to answer the question as to why FAK is still relevant." He maintained a "neutral" rating on the stock with a $2 price target. "We remain on the sidelines, as the company has gone back to early stage drug development and is using a science-driven approach to define future plans." Shares (NASDAQ:VSTM) closed Thursday at $1.43, up 17 cents, after trading as high as $1.70.

CEO Forrester kept the faith. With help from collaborators, Verastem hopes to investigate an array of new tumor types. "I see this [Pfizer/Merck deal] as a proof of concept to show that one plus one equals three," he said, pointing to "complete responses in patients that really had no hope before."