Verastem Oncology announced the initial interim safety and efficacy results from the ongoing RAMP 205 Phase 1/2 clinical trial evaluating avutometinib plus defactinib in combination with gemcitabine and Nab-paclitaxel in the first-line in patients with metastatic pancreatic cancer. As of May 14, 2024, patients receiving the combination of avutometinib and defactinib with gemcitabine and Nab-paclitaxel in dose level 1 cohort achieved a confirmed overall response rate (ORR) of 83% (5/6), one dose-limiting toxicity (DLT) was observed in the dose level 1 cohort, and the dose level was subsequently cleared after additional patients were enrolled. The initial interim results will be presented at the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting on June 1, 2024, in a poster session from 1:30-4:30 pm CDT in Chicago, IL.??

As of a data cutoff of May 14, 2024, 41 patients had been treated in one of four dose and schedule cohort regimens of avutometinib and defactinib with gemcitabine and Nab-paclitaxel: In dose level 1, 6 patients received 2.4 mg of avutometinib twice a week (BIW), 200 mg of defactinib twice a day (BID) for 3 weeks out of every 4 and 800 mg/m2 of gemcitabine and 125 mg/m2 of Nab-paclitaxel on a schedule of day 1, day 8 and day 15. In dose level -1, 11 patients received 2.4 mg of avutometinib twice a week (BIW), 200 mg of defactinib twice a day (BID) for 3 weeks out of every 4 with 800 mg/m2 of gemcitabine and 100 mg/m2 of Nab-paclitaxel on a schedule of day 1, day 8 and day 15. In dose level 1a, 12 patients received 3.2 mg of avutometinib twice a week (BIW), 200 mg of defactinib twice a day (BID) for 3 weeks out of every 4 with 800 mg/m2 of gemcitabine and 125 mg/m2 of Nab-paclitaxel on a schedule of day 1 and day 15.

In dose level 2a, 12 patients received 3.2 mg of avutometinib twice a week (BIW), 200 mg of defactinib twice a day (BID) for 3 weeks out of every 4 with 1000 mg/m2 of gemcitabine and 125 mg/m2 of Nab-paclitaxel on a schedule of day 1 and day 15. As of May 14, 2024, in the dose level 1 cohort, 83% (5/6) of patients achieved a confirmed partial response with more than six months of follow-up at the time of data cutoff. Of the 26 patients in all cohorts who have had the opportunity to have their first scan while on treatment, 21 have experienced a reduction of the change in target lesion sum of diameters.

Patients in the trial had a median age of 64 years, 46% were male and 49% had an Eastern Cooperative Oncology Group (ECOG) Performance Status of one. As of the May 14, 2024 data cutoff, 12 patients experienced 19 treatment emergent serious adverse events (SAEs), 11 patients with grade =3. Grade =3 treatment emergent SAEs included blood bilirubin increased (n=2), biliary obstruction (n=2), febrile neutropenia (n=2), pulmonary embolism (n=2), sepsis (n=2), anaemia (n=1), pneumoperitoneum (n=1), septic shock (n=1), skin infection (n=1), malignant neoplasm progression (n=1) and vomiting (n=1). Two patients discontinued treatment due to treatment emergent adverse events (febrile neutropenia, blood bilirubin increased, and detachment of retinal pigment epithelium).

One dose-limiting toxicity of febrile neutropenia was observed in the dose level 1 cohort and the dose cohort was cleared after additional patients were evaluated. In the additional dose cohorts enrolled more recently (-1, 1a, and 2a), follow up is ongoing and most patients remained on treatment at data cutoff.