Novel Kinase Inhibitor Combo Promising for Refractory GI Stromal Tumors

By Marilynn Larkin

July 15, 2021

NEW YORK (Reuters Health) - The type I and type II KIT inhibitors PLX9486 and sunitinib were safe and beneficial when coadministered to patients with refractory gastrointestinal stromal tumors (GIST) in a phase 1, first-in-human study.

"One novel aspect of this study is that these agents are complementary in their mechanism of action as well as their efficacy against resistance KIT mutations found in GISTs," Dr. Jonathan Trent of the University of Miami told Reuters Health by email. "One agent binds the active conformation of GIST, while the other binds the inactive conformation."

"Additionally," he said, "one targets the most common resistance mutation while the other targets the second most common resistance mutation."

"The phase 1 study provided compelling evidence this combination is safe and effective," he said. "We believe these results support a phase 3 registration study to determine whether the combination is safe and effective in a larger population, with the goal of approval by regulatory agencies and widespread availability to all GIST patients who need treatment options."

As reported in JAMA Oncology, the team discovered PLX9486 after an X-ray crystallography study of KITD816V provided a detailed molecular understanding of acquired resistance to standard-of-care tyrosine kinase inhibitors.

Dr. Trent and colleagues tested the type I KIT inhibitor in a two-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated the PLX9486-sunitinib combination in patients with GIST.

Thirty-nine PLX9486-naive patients (median age, 57; 56.4% men; 89.7% with refractory GIST) were enrolled in the dose escalation and extension parts. Participants received 250 mg, 350 mg, 500 mg, and 1,000 mg of PLX9486 alone (part 1) or 500 mg and 1,000 mg of PLX9486 together with 25 mg or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal.

The recommended phase 2 dose of PLX9486 was 1,000 mg daily because at this dose, it could be safely combined with sunitinib.

GIST patients who received PLX9486 at a dose of 500 mg or less had a median progression-free survival (PFS) of 1.74; for the 1,000 mg dose, PFS was 5.75; and for 1,000 mg plus sunitinib, PFS was 12.1 months; clinical benefit rates - defined as complete response, partial response, or stable disease that lasted for at least 16 weeks - were 14%; 50%; and 80%, respectively.

Dr. Trent said, "Stay tuned for a large phase 3 study of PLX-9486 plus sunitinib for patients with metastatic or inoperable GIST. The combination will be available in a clinical trial for sarcoma patients prior to evaluation by the FDA."

Dr. Salman Punekar, a medical oncologist and assistant professor of medicine at Perlmutter Cancer Center and NYU Langone Health in New York City, commented on the study by email. "GISTs, and sarcomas in general are relatively rare and are a very heterogenous group of malignancies," he told Reuters Health. "Specifically in this case, patients had varying mutational profiles, which always makes study of these malignancies difficult to generalize."

"Furthermore," he said, "this patient population was heavily pretreated, as is expected for an early-stage trial, and thus may not be entirely predictive of...patients who have not been so heavily pretreated."

"As research of this novel compound progresses, it would naturally make sense for it to be used in an earlier line of therapy, particularly as it is promising in combination with an already proven drug (sunitinib)," he noted. "Further study of molecular resistance to combination type I and type II KIT inhibitors would be a worthwhile next step in understanding refractory GIST."

The study was sponsored by Plexxikon Inc, Berkeley, California, a wholly owned subsidiary of Daiichi Sankyo Group. Dr. Trent and seven coauthors have received funds from the company.

SOURCE: JAMA Oncology, online July 8, 2021.