Incyte’s oral KRAS G12D inhibitor INCB161734, dosed at 1,200 mg once daily with standard chemotherapy, produced confirmed objective response rates of 81 percent in patients receiving modified FOLFIRINOX and 58 percent in patients receiving gemcitabine plus nab-paclitaxel, in updated Phase 1 data in metastatic pancreatic ductal adenocarcinoma presented at the ESMO Congress on October 26. Disease control rates were 100 and 96 percent, and six month progression free survival rates were 90 and 80 percent, at median follow ups of only 5.6 and 7.2 months. Counting unconfirmed responses, the rates were 89 and 69 percent. A circulating tumor DNA analysis showed molecular responses, defined as at least a 90 percent reduction in KRAS G12D variant allele frequency by week 8, in 69 to 74 percent of patients.
The trial, which enrolled 54 patients whose tumors carried the KRAS G12D mutation, is a Phase 1 dose and combination study, not a randomized comparison, and chemotherapy alone produces responses in this setting. Presenter Antoine Hollebecque of Institut Gustave Roussy said the combination was tolerable at the 1,200 mg dose. The most common treatment related adverse events with modified FOLFIRINOX were diarrhea at 67.9 percent, nausea at 64.3 percent, vomiting at 57.1 percent and decreased neutrophil count at 57.1 percent, a profile that overlaps heavily with the chemotherapy backbone itself.
The commercial frame is the race against Revolution Medicines, whose zoldonrasib is the other leading KRAS G12D program. Incyte president Pablo Cagnoni told Fierce Biotech the company sees itself as neck and neck in the race, and attributed the gap between its two chemotherapy cohorts to the backbones, noting Revolution Medicines has also seen stronger responses with FOLFIRINOX based combinations. Incyte presented three gastrointestinal cancer data sets at ESMO, including INCB161734 in colorectal cancer and its TGF beta R2 by PD-1 bispecific INCA338901 in microsatellite stable colorectal cancer, and describes the two programs as the foundation of its solid tumor portfolio.
Pancreatic cancer kills most patients within a year of a metastatic diagnosis, so even early response data draw attention. Whether these responses convert into survival, and at what toxicity cost over longer treatment, is what the next cohorts and any randomized trial will have to show.