Novel ULK Inhibitor Considered Safe for Solid Tumors Harboring RAS or RAF Mutations

Anthony W. Tolcher, MD

DCC-3116 demonstrated safety and tolerability across various dose levels in patients with solid tumors harboring a RAS or RAF mutation, according to findings from a phase 1/2 trial (NCT04892017) presented at the 2022 ESMO Congress.

As of the June 9, 2022, data cutoff, no dose-limiting toxicities or serious treatment-emergent adverse effects (TEAEs) were reported. Additionally, the disease control rate at week 16 was 29% among 14 response-evaluable patients, with the best overall response being stable disease.

In the 18-patient safety population, the most common TEAEs of any grade included fatigue (39%), dehydration (22%), increased alanine transaminase (ALT; 17%), and anemia (17%). No grade 4 TEAEs or deaths related to DCC-3116 were reported. There were 2 instances of asymptomatic, reversible increased ALT of grade 3 that led to a dose interruption and a dose reduction, respectively.

“DCC-3116 is a first-in-class, potent, and selective small molecule switch-control kinase inhibitor of ULK1/2,” Anthony W. Tolcher, MD, a medical oncologist at Texas Oncology-San Antonio Babcock Next Oncology, said during the presentation. “In preclinical models, it potently inhibits the proximal substrates ATG13 and ATG14 and blocks autophagy. In preclinical studies, when it is combined with a number of different MAP kinase pathway inhibitors, it leads to either additive or synergistic antitumor activity.”

In the phase 1/2 trial, patients with locally advanced or metastatic tumors harboring a RAS or RAF mutation received DCC-3116 monotherapy at a dose of 50 mg twice daily (n = 3), 100 mg twice daily (n = 4), 200 mg twice daily (n = 7), or 300 mg twice daily (n = 4). DCC-3116 was administered orally in 28-day cycles.

The primary objectives of the study were safety, tolerability, and determining the starting dose of DCC-3116 in combination with trametinib (Mekinist), binimetinib (Braftovi), and sotorasib (Lumakras). Additional objectives included antitumor activity, pharmacokinetics, and pharmacodynamics.

The mean age of the overall study population was 61.7 years, with most patients being White (72%) and men (72%), which was consistent across all cohorts. Most of the patients in the trial had a diagnosis of colorectal or pancreatic cancers (83%) and most had disease harboring a KRAS mutation (83%). The median number of prior anticancer regimens was 3 (range, 1-10).

At the 50-mg dose, the mean age was 51.7 years. The median number of prior anticancer regimens was 2 (range, 2-2). Two patients had a KRAS mutation and 1 had a BRAF mutation.

Among patients treated with 100 mg of DCC-3116, the mean age was 58.3 years. Most patients in this cohort had a KRAS mutation (75%). The median number of prior anticancer regimens was 3 (range, 2-4).

In the 200-mg arm, the mean age was 67.4 years, and most patients had a KRAS mutation (86%). The median number of prior anticancer regimens was 3 (range, 1-10). Patients treated at the 300-mg dose level had a mean age of 62.5 years and all patients had a KRAS mutation. The median number of prior anticancer regimens was 3 (range, 2-4).

Additional safety data showed that 2 patients experienced grade 1/2 fatigue at the lowest dose level and 1 patient each experienced grade 1/2 decreased appetite, hyponatremia, and vomiting. There were 2 instances of grade 3 anemia.

At the 100-mg dose level, there was 1 instance each of grade 1/2 fatigue, decreased appetite, nausea, and vomiting. There was 1 case of grade 3 anemia at this dose.

Patients treated the 200-mg dose of DCC-3116 experienced grade 1/2 fatigue (n = 3), dehydration (n = 2), increased AST (n = 2), hyponatremia (n = 1), and vomiting (n = 1).

Finally, patients who received DCC-3116 300 mg experienced 1 instance of grade 3 ALT increase. Grade 1/2 TEAEs included fatigue (n = 1), dehydration (n = 2), increased ALT (n = 1), increased AST (n = 1), decreased appetite (n = 1), hyponatremia (n = 1), and nausea (n = 2).

In terms of pharmacokinetics, the DCC-3116 area under the curve increased proportionally to the dose from 50 mg to 300 mg twice daily. The DCC-3116 area under the curve at all dose levels was at or above the area under the curve of the lowest tested dose that was proven to be effective in preclinical studies.

“From the standpoint of pharmacodynamics, the proximal target ATG14 was examined to see if it was phosphorylated or not,” Tolcher said. “As a function of the plasma concentration, [there was a] fall from baseline of phosphorylated ATG14. We saw that across almost all dose levels and across all concentrations. [Therefore], the proximal target appeared to be well inhibited.”

Tolcher noted that the 100-mg to 300-mg dose cohorts are being expanded to further characterize the safety, pharmacokinetics, and pharmacodynamics of DCC-3116 in order to select the starting dose of the agent for escalation in combination with MEK or KRAS G12C inhibitors.

_Reference

_{Tolcher AW, Hong DS, Vandross A, et al. Initial monotherapy results of a phase I first-in-human study of ULK1/2 inhibitor DCC-3116 alone and in combination with MAPK pathway inhibition. Presented at: ESMO Congress 2022; September 9-13, 2022; Paris, France. Abstract 450O.}