Kura Oncology has published early data on darlifarnib in combination with Bristol Myers Squibb’s Krazati, linking the drug candidate to response rates of up to 69% when given with the KRAS inhibitor.
BMS’ Krazati and Amgen’s Lumakras, both of which inhibit KRAS G12C, were scientific breakthroughs, but the clinical data leave room for improvement. Kura identified persistent mTORC1 activity as a driver of resistance to the drugs, leading it to study molecules that block activation of the pathway. Darlifarnib, a farnesyl transferase inhibitor, is Kura’s latest effort to overcome resistance to multiple targeted therapies.
Kura shared first-in-human data on darlifarnib in combination with Krazati ahead of a presentation at the American Society of Clinical Oncology annual meeting this week. The trial enrolled heavily pretreated patients with advanced, KRAS G12C-mutated solid tumors.
The biotech reported partial responses in four of six pancreatic ductal adenocarcinoma patients who received the combination. None of the patients had previously received a KRAS inhibitor such as Krazati or Lumakras.
Kura saw partial responses in three of six non-small cell lung cancer (NSCLC) patients. Krazati achieved (PDF) a 43% objective response rate (ORR) in the pivotal trial that supported FDA approval. Kura’s NSCLC cohort included three patients who previously received a KRAS inhibitor. One of the three patients had a partial response, another had stable disease and the third progressed.
Half of the 14 colorectal cancer patients had previously received a KRAS inhibitor. None of those people responded to the combination, with stable disease being the best outcome in the subpopulation. Kura reported two partial responses among the seven KRAS inhibitor-naive colorectal cancer patients, resulting in a 29% response rate. Krazati achieved a 34% ORR in the pivotal trial that supported FDA approval.
Median follow-up time across the three tumor types ranged from 6.7 months to 8.9 months. As of the data cutoff, 37% of patients remained on study treatment. The combination was well tolerated with a manageable safety profile, Kura said. The biotech has opted against advancing the 8 mg darlifarnib dose, the highest tested in the phase 1a trial, for further evaluation in combination with Krazati.
The Krazati-combination data build on earlier results in patients who received darlifarnib with VEGFR tyrosine kinase inhibitors and PI3Kα inhibitors. The biotech has gone “three-for-three” across the readouts, Kura CEO Troy Wilson, Ph.D., said in a statement. Kura’s first-generation farnesyl transferase inhibitor, tipifarnib, failed to achieve sufficient clinical activity to support FDA approval.