Abstract
The first oral PD-L1 inhibitor to enter clinical testing has been discontinued for toxicity reasons, but several other small-molecule drugs targeted at the same checkpoint molecule appear to be safe with antitumor activity demonstrated in early trials. Compared with antibodies, these oral agents could offer advantages of convenience, safety, and increased tissue penetration.
The first selective oral inhibitor of PD-L1 to enter clinical testing has proven too toxic to merit further development, but several other early-stage small-molecule pills appear to be safe with antitumor activity demonstrated in first-in-human trials.
At the Society for Immunotherapy of Cancer (SITC) Annual Meeting, convened November 10–12 in Boston, MA, Incyte disclosed that its once-leading oral PD-L1 inhibitor, INCB086550, caused such debilitating peripheral neuropathy that the company discontinued further evaluation of it.
But another orally administered PD-L1 blocker in Incyte’s portfolio, INCB099280, passed its initial safety test, with one complete response and eight partial responses observed among 80 recipients, the company reported at the SITC meeting.
That drug is moving into mid-stage trials as a monotherapy and in combination with the KRASG12C inhibitor adagrasib (Mirati Therapeutics). “It looks active,” said Jason Howe, DHA, a senior director of clinical drug development at Incyte in Wilmington, DE, “and we’re going into phase II.”
INCB099318, the third in Incyte’s three-pronged approach to finding the best oral PD-L1 inhibitor through parallel development of multiple drug candidates, looks to be well tolerated with signs of antitumor activity as well. According to Incyte’s Jennifer Pulini, PharmD, further dose escalation and expansion are planned before the company decides whether to launch additional trials.
Meanwhile, ChemoCentryx—now part of Amgen following a $3.7 billion acquisition completed in October—reported at the SITC meeting that its PD-L1–blocking pill, CCX559, had on-target immunomodulatory effects consistent with the activity of approved PD-L1–directed antibody therapies. None of the first 20 recipients of CCX559 developed severe side effects either. By comparison, 22 of 138 patients given Incyte’s discontinued INCB086550 experienced neuropathies that proved difficult to manage, even with intermittent dosing protocols.
Other oral PD-L1 inhibitors in early clinical development include ASC61 (Ascletis Pharma) and ABSK043 (Abbisko Therapeutics), with several more assets that display anti–PD-L1 selectivity soon to enter human testing as well. Scientists from HealZen Therapeutics described one such preclinical candidate, HZ-G206, at the SITC meeting. Another drug, called CA-170 (Curis), which shows activity against three checkpoint molecules—PD-L1, PD-L2, and VISTA—is currently in phase II testing.
The selling points for these therapeutic candidates boil down to the convenience of pills and the pharmacologic properties of small-molecule drugs.
Contrasting with approved anti–PD-L1 antibodies, such as atezolizumab (Tecentriq; Genentech) and durvalumab (Imfinzi; AstraZeneca), small molecules may penetrate deeper into cancerous tissue. That gives them “the potential to infiltrate bulky tumors,” said Emil deGoma, MD, head of clinical development at ChemoCentryx.
The shorter half-life of small molecules—just 8.6 hours for INCB086550, for example, compared to 27 days for atezolizumab—also makes it easier to titrate doses and help patients recover faster from immune-related adverse events if they occur. “It should work quickly, but it should also wash out quickly,” said Kathleen Sullivan, PhD, head of biology at ChemoCentryx.
“There are some patients who might do better on a small molecule than a biologic,” she added. “Having different modalities is advantageous.” –Elie Dolgin
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