Cytomx Therapeutics Inc. CEO Sean McCarthy said earlier this month that the firm was “not ready to guide on specific response rates” that the company hopes for in the phase II study with anti-PD-L1 Probody CX-072 in combination with ipilimumab, or ipi (Yervoy, Bristol-Myers Squibb Co.) in patients with relapsed refractory melanoma.

But he pointed to “very encouraging” phase I dose-escalation results: a 19% response rate in the all-comer setting, “And, by the way, that was across multiple doses of Probody and ipi,” he said during a conference call with investors, as the scramble for anti-PD-L1 therapies goes on, as do efforts to combine cancer prospects.

Cytomx’s Probody drugs are designed to take advantage of high levels of protease activity in the tumor microenvironment, with their target-binding regions masked to limit activity and toxicity in healthy tissue. When such therapeutics meet active proteases near tumor tissue, their substrates cleave, removing their masks and activating them to bind to their tumor targets. The approach could turn the disease against itself, South San Francisco-based Cytomx said.

During the call on earnings, Cantor Fitzgerald analyst Varun Kumar asked for more color on the Probody strategy in triple-negative breast cancer (TNBC), “one indication where we have seen activity from both the CX-072 program as well as CX-2009. Certainly, there is a lot of unmet need in this indication, and I could see some large pharma being interested to partner” any combo in the space. CX-2009 is a CD166-directed Probody-drug conjugate.

McCarthy said the firm’s “vision for CX-072 is for this differentiated Probody to become a centerpiece with combinations,” and the ipi pairing is the first to enter a phase II experiment. “We have always said that we would consider it to be a potential combination partner for other molecules coming from our pipeline, and the concept of combining CX-072 with CX-2009, we think, is pretty interesting. To do that in TNBC, obviously, is a possibility,” though he offered “no specific guidance at this point.” On the subject of partnering, the company believes the CX-072 program could benefit from a partner “at the right time,” he added.

Meanwhile, Cytomx is enrolling patients in the Proclaim-CX-2009 study, a phase I/II effort testing CX-2009 as a monotherapy in patients with select advanced solid tumors, including breast cancer, castration-resistant prostate cancer, cholangiocarcinoma, endometrial cancer, head and neck cancer, non-small-cell lung cancer and ovarian cancer. CD166 turns up widely on solid tumor cells but has been considered undruggable, given its expression on normal tissues. Probody-drug conjugates targeting CD166 in preclinical work have led to complete regressions in models of breast and lung cancers at therapeutically relevant doses, the company said, and are well-tolerated in nonhuman primates. The candidate is conjugated with cytotoxic drug DM4, developed by and licensed from Immunogen Inc., of Waltham, Mass.

Heavy use in frontline melanoma

But the melanoma program with CX-072 has piqued analysts’ curiosity, given the dismal outlook for people with melanoma that has repeatedly failed to respond to treatment. On the call, Cowen’s Boris Peaker was already talking about regulatory strategies and wanted to know “if you decide to advance CX-072 into pivotal combo studies with ipi, will you have to include [a] monotherapy arm of CX-072” or other data. Regulatory moves, McCarthy said, are “in the early stages of being developed for the program. We're highly focused on this first 40 patients to see what this combination could do for us,” and “at the end of the day, the regulatory path that we follow is going to be very much a function of the activity that we see of the combination.” Chief Development Officer Amy Peterson put in that “given the nature in which the regulatory environment has evolved in the last couple of years, I think everybody's hopeful that we don't have to conduct as rigorous evaluation of what monotherapy might be or what standard-of-care therapy might be. There's certainly a lot of studies that are attempting to look at real-world data as they file for registrational approval. Suffice it to say that we are going to be as creative as we can and we will do whatever we do in collaboration with the health authorities globally.”

The effort has skeptics, including Wainwright’s Raghuram Selvaraju, who predicted that ipi plus CX-072 in melanoma “would not be able to generate significant revenues.” Recent history may explain his doubt. In 2017, an article in the European Journal of Cancer detailed findings of research by Lisa Zimmer and others at the University Duisburg-Essen in Germany. They determined that nivolumab (Opdivo, Bristol-Myers Squibb Co.) 1 mg/kg plus ipi 3 mg/kg elicited a 21% objective response rate (ORR) in advanced melanoma patients (more than three median prior treatments) who were relapsed or refractory to anti-PD-1 frontline therapy in a retrospective study. Data from CX-072 10 mg/kg plus nivolumab 1 mg/kg “demonstrate similar receptor occupancy saturations,” Selvaraju noted, and because Cytomx is combining CX-072 with the same ipi dose as Zimmer et al. did, “we find it unlikely that CX-072 plus Yervoy would demonstrate a significantly higher ORR than [nivolumab plus ipi] in a similar patient population.” In a Nov. 8 report, he allowed that the longer treatment duration could mean fewer grade 3 or 4 treatment-related adverse events (TRAEs) and thus a longer response. Adding a wrinkle to the story is what he deems a “highly probable” effort by BMS to study BMS-986249, a Probody version of ipi, plus nivolumab. Since ipi is the more toxic of the two drugs, nivolumab has a “relatively good chance” of turning up fewer TRAEs, in his view.

Another, more recent publication adds fuel to Selvaraju’s thesis. The Journal of Comparative Effectiveness Research found high rates of ipi-plus-nivolumab use in frontline melanoma, which reduces the number of patients who would be retreated with an anti-PD-1 plus an anti-CTLA4 pairing in the second-line setting.

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