In a Phase 1 study, treatment with Incyte’s KRAS G12D inhibitor in combination with standard-of-care chemotherapy elicited an 89% confirmed objective response rate in patients with a type of pancreatic ductal adenocarcinoma, leading analysts to draw comparisons with Revolution Medicines’ zoldonrasib.
Incyte’s KRAS G12D inhibitor achieved an 89% confirmed objective response rate in an early-stage clinical trial for a type of pancreatic cancer, notching another step forward for a patient community that, until earlier this year, had few options.
The updated results are from an ongoing Phase 1 study of Incyte’s INCB161734, also known as zecdarasib, plus chemo in 54 patients with metastatic pancreatic ductal adenocarcinoma (PDAC) with a KRAS G12D mutation. If the result holds through further clinical development, the biotech could someday find itself on the market against pancreatic cancer rival Revolution Medicines.
The new data make Incyte a “firm contender” in the G12D race, analysts at BMO Capital Markets said in a note to investors on Monday.
INCB161734 elicited 89% and 81% objective response rates—a secondary outcome measure in the trial—for confirmed and pending results, respectively, when combined with the chemotherapy regimen mFOLFIRINOX. This pairing also showed 100% disease control rate, another secondary endpoint, and six-month progression-free survival (PFS) rate of 90%, the company said Monday during an oral session at the European Society of Medical Oncology in Madrid.
Combined with a different chemotherapy regimen called GEMNabP, the drug’s objective response rate was lower, at 69% confirmed and 58% pending, with a disease control rate of 96% and six-month PFS of 80%.
As for safety—the Phase 1 trial’s primary endpoint—the candidate’s profile was “manageable” in both PDAC and colorectal cancers, another focus of the study, Pablo Cagnoni, president and global head of Research and Development at Incyte, said in a statement on Monday.
In both groups, totaling 103 patients, adverse events included diarrhea, nausea and decreased neutrophil count. The mFOLFIRINOX arms included incidence of vomiting, but no patients discontinued treatment. With GEMNabP, the adverse events included anemia, and one patient discontinued the regimen. The safety profile “appears broadly consistent” with the established profiles of the standard-of-care chemo regimens, BMO wrote.
While RevMed’s recently approved RAS inhibitor Rasonque also addresses PDAC with G12D mutations, there is plenty of room for new treatment options. These individuals saw a lower objective response rate than those with other mutations, such as G12V, according to FDA review documents published by the FDA earlier this month.
And the G12D PDAC competitive landscape remains neck and neck, analysts from RBC Capital Markets said in an Oct. 26 note.
BMO compared Incyte’s candidate to RevMed’s zoldonrasib, which posted objective response rates of 82% in combination with mFOLFIRINOX and 61% with GEMNabP chemotherapies, according to the analysts. Against zoldonrasib’s benchmark, Incyte’s INCB161734 “appears at least competitive on response, particularly with mFOLFIRINOX,” they wrote.
Compared with zoldonrasib, Incyte’s drug has a longer duration of exposure, providing both more time for treatment but also for adverse events to kick in, Cagnoni said during an investor presentation at ESMO. Analysts pointed to these factors as a small but potentially important differentiator between the two drug candidates.
The sales opportunity for INCB161734 could reach $1.4 billion in PDAC, BMO said, while Truist analysts said Incyte’s drug could get an earlier start in the market if the ongoing global Phase 3 Dawn-303 study, which combines INCB161734 to investigators’ choice of chemo regimens in first-line PDAC, generates a solid objective response rate analysis around the middle of next year. Incyte also plans to embark on a Phase 3 trial in the adjuvant setting next year.
The nuances of addressing KRAS mutations will likely play a role, RBC analysts said. “We think ‘734’s opportunity will likely come down to where G12Ds ultimately fit into the PDAC paradigm,” including whether more differentiation emerges as overall survival and other long-term data mature, and whether chemo-free combos become the standard.
