Novel Kinase Inhibitor Shows Encouraging Disease Control in Heavily Pretreated GIST

Neeta Somaiah, MD

Neeta Somaiah, MD

A novel kinase switch control inhibitor, DCC-2618, demonstrated an encouraging disease control rate (DCR) of 76% at 12 weeks in heavily pretreated patients with gastrointestinal stromal tumors (GIST) treated with a daily ≥100-mg dose, according to findings of a phase I first-in-human, dose-escalation trial.¹

Neeta Somaiah, MD, an assistant professor in the Department of Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center, presented findings from the study during the 2017 Connective Tissue Oncology Society (CTOS) Annual Meeting that demonstrated that the novel agent was also well tolerated at doses up to 200 mg twice daily.

Tyrosine kinase inhibitors (TKIs) approved for the treatment of patients with GIST generally inhibit either mutations in the KIT ATP binding pocket or a subset of activation loop mutations, but not both. These mutations are known to cause resistance to imatinib (Gleevec), a frontline standard-of-care for patients with GIST.

DCC-2618 is a pan-KIT and PDGFRα kinase switch control inhibitor that was designed to be active across a broad range of mutations that occur at initiation and/or resistance.

In the ongoing phase I first-in-human, dose-escalation study, patients with GIST, aggressive systemic mastocytosis, and advanced cancers were enrolled to be treated with oral DCC-2618 (NCT02571036). Somaiah presented findings at CTOS of 57 patients with GIST enrolled in the study.

The study enrolled patients with pretreated advanced refractory disease with an ECOG performance status of 0 or 1 and adequate end organ function. Prior treatment with KIT or PDGFRα inhibitors were allowed and the median number of prior therapies was 3.

Next-generation sequencing of plasma cell-free DNA was performed throughout the study to measure KIT, PDGFRα, and other alterations, and compared with tumor tissue collected at baseline and after 2 cycles.

According to a safety analysis of all 70 patients enrolled in the study that was presented at the 2017 ESMO Annual Congress, treatment-emergent adverse events (TEAEs) observed were relatively mild, according to Filip Janku, MD, PhD, also of MD Anderson Cancer Center, who presented the findings at the ESMO Congress.²

Three laboratory dose-limiting toxicities were observed, including 2 grade 3 lipase increases, one at a dose of 100 mg twice daily and the other at 200 mg twice daily, and 1 case of grade 4 creatine phosphokinase increase at 150 mg daily.

Other TEAEs of interest included 18 events of grade 3/4 anemia at ≥100 mg/day, and Janku noted that the investigators believed that the anemia was mostly not related to treatment. There was 1 patient death due to dyspnea.

At the recommended phase II dose of 150 mg daily, there were 2 grade 3/4 events of lipase increase, and 1 each of grade 3/4 decreased appetite and grade 3/4 blood bilirubin increase.

In 32 patients with GIST treated with ≥100 mg/day, 22 patients achieved a partial metabolic response, and 9 had stable disease. At 12 weeks, the DCR (complete response + partial response + stable disease) was 76%, and 24 weeks the DCR was 57%. Among 8 patients treated at the recommended phase II dose, 3 had a partial metabolic response and 5 had stable disease.

“The analysis presented at CTOS supports the selection of 150 mg once daily as the recommend dose and supports the planned evaluation of DCC-2618 in a placebo-controlled, randomized, pivotal Phase III trial in patients with GIST, who have previously failed all 3 approved therapies [imatinib, sunitinib (Sutent), and regorafenib (Stivarga)],” Michael D. Taylor, PhD, president and CEO of Deciphera Pharmaceuticals, said in a press release. “There are no approved therapies for these fourth-line GIST patients and new treatment options are desperately needed.”

In patients treated with <100 mg/day of DCC-2618, the median progression-free survival (PFS) was 15.2 weeks; the median PFS was not reached in patients treated with &ge;100 mg/day.

Nineteen patients harboredKITmutations (exons 9, 11, 13, 14, 17 and 18) and were evaluable for plasma cell-free DNA. Next-generation sequencing showed reduced mutation allele frequency from treatment with DCC-2618 across all mutations associated with resistance.

&ldquo;The clinical profile of DCC-2618 continues to demonstrate good tolerability and durable responses in patients with GIST who were resistant to other kinase inhibitors,&rdquo; Oliver Rosen, MD, chief medical officer of Deciphera Pharmaceuticals, said in a press release. &ldquo;The extent of the reductions inKITmutant allele frequencies observed at doses as low as 100 mg daily across the spectrum of exons 9, 11, 13, 14, 17 and 18 mutations both supports the selection of 150 mg once daily as the recommend dose and provides clinical evidence in these patients of the pan-KIT profile of DCC-2618.&rdquo;

The study authors noted that the encouraging findings support further study of the kinase switch control inhibitor in a planned randomized phase III study.

References:

1. Somaiah N, Razak A, Gordon M, et al. DCC-2618, a novel pan-KIT and PDGFRa kinase switch control inhibitor demonstrates encouraging activity in patients (pts) with gastrointestinal stromal tumors (GIST). Presented at: 2017 CTOS Annual Meeting; November 8-11, 2017; Maui, HI. Abstract 039.
2. Janku F, Razak ARA, Gordon MS, et al. Encouraging activity of novel pan-KIT and PDGFR&alpha; inhibitor DCC-2618 in patients (pts) with gastrointestinal stromal tumor (GIST).Ann Oncol. 2017;28(suppl_5):v521-v538. doi: 10.1093/annonc/mdx387.