Toxicity doesn't stop Incyte

Despite ongoing setbacks in the phase 1 trial of Incyte's KRAS G12D inhibitor INCB161734, which remains on hold in several European countries, the company has moved it into pivotal development. 

The first pivotal trial, Dawn-03, has appeared on clinicaltrials.gov. The move is notable not only because it shows a leap straight from phase 1 to phase 3, but also because patient recruitment is already under way despite the phase 1 hold, which was spurred by a fatal case of pneumonitis. 

A company spokesperson told ApexOnco that, following a comprehensive review of preclinical and clinical data, no causal relationship between INCB161734 and this adverse event was identified. Incyte added that the ongoing EU hold was "administrative", while an informed consent form was being updated. The study remains open and actively enrolling in the US, Australia and Japan, the group said.

Meanwhile, Incyte confirmed the discontinuation of its follow-up KRAS G12D inhibitor, INCB186748. The spokesperson said the decision was made for "portfolio prioritisation reasons",  and wasn't related to safety concerns. 

Dawn-03 is designed to evaluate INCB161734 in combination with chemotherapy, versus chemo alone, as a first-line treatment for patients with KRAS G12D-mutant pancreatic cancer. The primary endpoints are overall survival, progression-free survival and overall response rate.

1.2g dose? 

Notably, the new registry entry doesn't specify the dose that will be used in the pivotal study. Presumably this will be the 1.2g daily dose previously identified as optimal by Incyte, though this is the same dose that prompted authorities in Spain, Belgium, Italy and France to halt the phase 1 trial.

It also remains unclear whether any of the patients who experienced serious toxicity in phase 1 had pancreatic cancer specifically. The phase 1 study enrolled patients with a diverse range of solid tumours, including pancreatic ductal adenocarcinoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, and others. 

With Incyte still withholding public comment on the nature of these adverse events, questions continue regarding which tumour types or patient subgroups might be at highest risk, and what additional precautions, if any, will be implemented in the phase 3 setting.

The clinical hold was triggered by a case of grade 5 pneumonitis in a patient. After the fatality, Incyte reviewed the approximately 300 other enrolled patients and identified three additional cases of confirmed or suspected pneumonitis, all linked to the 1.2g dose. Notably, three of the four cases occurred in cohorts receiving the combination with chemotherapy, the same regimen now under investigation in the Dawn-03 trial. 

Ongoing clinical trials evaluating INCB161734

Source: OncologyPipeline.

This story has been updated to include comments from Incyte.