Novel therapy shows encouraging disease control for gastrointestinal stromal tumors

WAILEA, Hawaii — DCC-2618 induced disease control, objective responses and prolonged stable disease among pretreated patients with gastrointestinal stromal tumors, according to results of a dose-escalation study presented at the Connective Tissue Oncology Society Annual Meeting.

DCC-2618 (Deciphera Pharmaceuticals) also appeared well tolerated.

Tyrosine kinase inhibitors approved for gastrointestinal stromal tumors inhibit mutations in the KIT ATP binding pocket region or activation loop, but have not demonstrated notable activity among regions that emerge due to imatinib resistance.

“DCC-2618 is a potent pan-KIT and PDGFR alpha kinase switch control inhibitor active across a broad range of mutations,” Neeta Somaiah, MD, assistant professor of sarcoma medical oncology at The University of Texas MD Anderson Cancer Center, said during her presentation. “In nonclinical analyses, DCC-2618 showed activity against all initiation and resistance mutations tested, including mutations in both the activation loop and the ATP binding pocket.”

Based on these data, Somaiah and colleagues conducted a dose-escalation study that tested doses up to 400 mg among 13 patients with advanced refractory cancers, with a focus on gastrointestinal stromal tumors. Researchers did not identify a maximum tolerated dose and selected a 150-mg daily dose for phase 2 expansion.

The expansion phase included 57 patients (median age, 62 years) with gastrointestinal stromal tumors who progressed on or were intolerant to imatinib and other TKIs. Patients had received a mean 3.3 prior agents and had an ECOG performance status of 1.

Patients harbored KIT exon 9 (n = 13), KIT exon 11 (n = 27), KIT exon 17 (n = 4), PDGR alpha exon 18 (n = 4) or other (n = 9) mutations.

Safety data were available from all 70 patients. The drug was generally well tolerated, Somaiah said. Grade 3 and grade 4 toxicities included an increase in lipase, anemia and hypertension.

“Among the patients who received the 150-mg dose, the rate of toxicities decreased significantly,” Somaiah said.

Seven patients have been on therapy for at least 9 months.

Thirty-three patients underwent PET/CT scans. Results showed that 69% of patients who received at least a 100-mg dose and 38% of patients who received the 150-mg dose achieved partial metabolic response. Stable metabolic disease occurred among 22% of patients who received at least 100 mg and 63% of patients who received 150 mg.

These data appeared consistent with the disease control rate by RECIST, Somaiah said. In the gastrointestinal stromal tumor cohort, 76% of patients showed disease control at 12 weeks and 57% did so at 24 weeks.

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Based on the observation of a reduction of mutation frequency, researchers deemed 100 mg as the therapeutic dose. All patients with gastrointestinal stromal tumors who demonstrated tumor shrinkage received at least the 100-mg dose, including five patients who achieved partial response.

“These are heavily pretreated patients, and in this setting we do not expect any responses,” Somaiah said. “Thirty-four of these patients had received all three prior standard lines of therapy, including TKIs.”

Median PFS had not been reached among patients who received at least the 100-mg dose, and was 15.2 weeks (95% CI, 4.4-24) among those who received a lower dose.

“These encouraging results strongly support testing of DCC-2618 in the planned placebo-controlled randomized, pivotal phase 3 study in patients who have received at least three prior agents,” Somaiah said. – by Alexandra Todak

Reference:

Somaiah N, et al. Abstract 039. Presented at: CTOS Annual Meeting; Nov. 8-11, 2017; Maui, Hawaii.

Disclosures: Please see the abstract for a full list of the authors’ relevant financial disclosures.