With Celgene Corp. gaining strategically important rights to a PD-1 inhibitor developed by Beigene Ltd. earlier this month and with activity in the PD space still revving, Cytomx Therapeutics Inc. CEO Sean McCarthy told BioWorld Insight it's important that oncology "not get too stuck [on a single drug class] and continue to ask questions" scientifically.

"An important question that I would expect every oncology R&D group is asking today," McCarthy said, is: "How much should we be investing in new biology, new targets, coming at this from an orthogonal perspective, as opposed to getting too completely bogged down in the PDs?"

Summit, N.J.-based Celgene agreed to pay $263 million to in-license the candidate, BGB-A317, for the treatment of solid tumors in the U.S., Europe, Japan and rest of the world outside Asia, while Beigene, of Beijing, retained exclusive rights for the development and commercialization of BGB-A317 for blood cancers globally and for solid tumors in Asia (with the exception of Japan). As part of the deal, Celgene is also investing about $150 million in Beigene, taking about a 6 percent stake in the company and pledging to collaborate with it on up to eight registrational studies for the candidate in solid tumors, including studies currently being planned by Beigene. As the deal moves ahead, Beigene stands to earn up to $980 million in regulatory, development and commercial milestone payments. (See BioWorld, July 12, 2017.)

"Celgene jumping in is significant because they've clearly taken the view that they need to own and control a PD of their own, and I think that is the sentiment broadly in the field, that everybody needs to have one," McCarthy said, but "how you differentiate them is going to be important."

Bernstein analyst Aaron Gal noted that Thousand Oaks, Calif.-based Amgen Inc. has "adopted an alternative view, which is that it can compete effectively by accessing PD-(L)1 through partnerships, combining them with its own agents. The question is, can it be done in a world where most of the other companies own both a PD-(L)1 and the combination asset? Our take is that it will be increasingly more difficult," Gal wrote in a research report July 7. "Unless Amgen's assets are truly unique, the owners of the various PD-(L)1s will prioritize assets they own/license tightly, disadvantaging Amgen's programs. Our take is that Amgen is increasingly likely to buy or tightly partner with a PD-(L)1 or accept becoming a more marginal player in the immuno-oncology [I-O] field."

Skate where the puck is going to be

In any case, McCarthy said oncology firms should try as well to "skate to where the puck is going to be," and look closely at new modalities such as T-cell bispecifics and chimeric antigen receptor T cells (CAR Ts) as well as the more personalized therapies made possible by neoantigen profiling. Also this month, members of the FDA's Oncologic Drugs Advisory Committee voted unanimously in support of Basel, Switzerland-based Novartis AG's CTL-019 (tisagenlecleucel), the first CAR T immunotherapy to be considered by the panel. (See BioWorld, July 13, 2017.)

South San Francisco-based Cytomx has some chips on PD-L1 with its Probody therapeutic, CX-072, undergoing a phase I/II experiment. The company has designed Probody drugs to stay inert until activated by proteases in the tumor microenvironment, thereby sparing healthy tissue. Also in the clinic is CD166-targeting Probody drug conjugate (PDC) CX-2009. The company is enrolling patients in the PROCLAIM-CX-2009 study, a phase I/II experiment evaluating CX-2009 as a monotherapy in patients with select advanced solid tumors, including non-small-cell lung cancer, breast cancer, ovarian cancer, endometrial cancer, cholangiocarcinoma (bile duct cancer), head and neck cancer and castration-resistant prostate cancer. While CD166 is widely and highly expressed on solid tumor cells, it has been previously considered "undruggable," given its expression on normal tissues, the company noted. In preclinical studies, PDCs targeting CD166 have led to complete regressions in models of lung and breast cancer at therapeutically relevant doses, and are well-tolerated in nonhuman primates. CX-2009 has been conjugated with cytotoxic DM4 to deliver the highest payload to the tumor across a greater number of cancers. DM4 was developed by and licensed from Immunogen Inc., of Waltham, Mass.

Side effects still odious

Cytomx has been successful in partnering over the years, McCarthy said, pointing to such deals as the one struck in 2014 with New York-based Bristol-Myers Squibb Co. (BMS), which agreed to pay $50 million for rights to use Cytomx's Probody platform to discover and develop up to four new immunotherapies for cancer, including one targeting CTLA-4, the same receptor targeted by BMS' melanoma therapy, Yervoy (ipilimumab). The deal included undisclosed additional preclinical payments and up to $298 million in milestones per target, plus potential royalties. It was Cytomx's second big pharma score after Pfizer Inc. pledged in 2013 $25 million up front to develop Cytomx-identified candidates. BMS has rights to substitute up to two collaboration targets. (See BioWorld Today, May 28, 2014.)

"We didn't need to put any of our crown jewels into that deal" with BMS, McCarthy noted. "Ultimately, our objective will be to combine these [clinical-stage molecules owned by Cytomx] and own both sides of the equation." The company also has a pact with North Chicago-based Abbvie Inc. that brought $30 million up front as well as the promise of $470 million more if development, regulatory and commercial goals are met in the co-development of a Probody-drug conjugate against CD71, also known as transferrin receptor 1, widely expressed in solid tumors and hematological cancer. Late last month, Cytomx said it had advanced CX-2029 in collaboration with Abbvie into GLP toxicology studies, a key step on the path to filing an investigational new drug application in 2018. Upon commencement of the GLP toxicology study, Cytomx was to receive a $15 million milestone payment. (See BioWorld Today, April 25, 2016.)

McCarthy said I-O has opened a "new world" in cancer treatments, but a world that is still evolving. "We would all agree in the field that it's not good enough," he said. "We need to do better, because we're still not getting enough patients into long-term, durable remission. The race is on, for sure, to find the next generation of highly active combinations."

More than 1,000 combo trials are ongoing. "Basically everything is being combined with a PD agent, one way or another," although little to show for it surfaced during this year's American Society of Clinical Oncology (ASCO) meeting in Chicago, he said, a lack that he found "striking. This field is still playing itself out," with "enormous amounts of capital" going into "many redundant PD molecules." Four separate agents in the PD family have been approved by the FDA for bladder cancer. "The agency is open to serial approvals," but how circumstances will configure themselves remains "a very open question," he said.

I-O side effects, unlike those with chemotherapy, manifest in a "stochastic manner," with some of them "severe, debilitating and long-term in nature. The field is still coming to grips with these side effects," whereas the effects of chemo – though hardly pleasant – are "relatively well-managed." Researchers either need to come up with I-O therapies that bring fewer off-target problems or find drugs that offer benefits to justify the woes.

"If you're going to put a patient through this, wouldn't it be better if they came out the other end with a higher likelihood of a long-term, durable response?" he said. "That's the way we think about it at Cytomx."