On May 23, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported 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 (Press release, Verastem, MAY 23, 2024, View Source [SID1234643623]). 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) (Free ASCO Whitepaper) Annual Meeting on June 1, 2024, in a poster session from 1:30-4:30 pm CDT in Chicago, IL.
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"The initial interim results from the RAMP 205 trial evaluating avutometinib and defactinib in combination with standard of care first-line chemotherapy are encouraging and demonstrate the importance of targeting the RAS/MAPK pathway, as more than 90% of pancreatic tumors have a KRAS mutation. We continue to progress the study evaluating other dose and schedule regimens to determine the recommended Phase 2 dose in the trial," said John Hayslip, M.D., chief medical officer of Verastem Oncology. "Metastatic pancreatic cancer continues to be a challenging cancer to treat and these data support the intent behind the Therapeutic Accelerator Award that we received from PanCAN to develop new therapies faster and more efficiently than in historical studies."
"Verastem was the inaugural recipient of the PanCAN Therapeutic Accelerator Award, which has been an important part of PanCAN’s approach to advancing innovative treatments for pancreatic cancer," said Anna Berkenblit, M.D., MMSc, Chief Scientific and Medical Officer at PanCAN. "We look forward to Verastem presenting their initial data from the Phase 1b/2a trial of avutometinib and defactinib in combination with standard care gemcitabine and Nab-paclitaxel in previously untreated metastatic pancreatic cancer at ASCO (Free ASCO Whitepaper). There is a critical need for new treatment options in this disease, and we hope that the results from this study lead to improved outcomes for patients with pancreatic cancer."
Initial Interim Data from RAMP 205 from the Ongoing Phase 1/2 Clinical Trial
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.
Initial Interim Safety Data from All Dose Cohorts
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.
Conference Call and Webcast Information
Verastem will hold an investor conference call and webcast on Friday, May 24 at 8:00 am EDT, to review the initiation of the NDA submission in low-grade serous ovarian cancer and limited, topline data from the RAMP 201 trial, with a minimum follow-up of five (5) months and the RAMP 205 update. The call will feature members of Verastem’s management team. To access the conference call, please dial (844) 763-8274 (local) or (412) 717-9224 (international) at least 10 minutes prior to the start time and ask to be joined into the Verastem Oncology conference call. A live audio webcast of the call, along with accompany slides, will be accessible here.
About Metastatic Pancreatic Cancer
Pancreatic cancer is the third leading cancer in the U.S. and seventh leading cause of cancer-associated mortality worldwide. Metastatic pancreatic cancer is defined as stage IV cancer, where the cancer spreads to other organs. In the U.S., over 30,000 patients are diagnosed with metastatic pancreatic cancer each year1,2, for which the five-year survival rate is 3%2. Globally, over 240,000 patients are diagnosed with metastatic pancreatic cancer each year3. More than 90% of pancreatic cancers have a KRAS mutation4. The standard of care consists of surgery, chemotherapy, radiation or a combination of these approaches5.
About RAMP 205 Phase 1/2 Study
RAMP 205 is a multicenter, open-label, single arm Phase 1b/2a study designed to evaluate the safety, tolerability and efficacy of avutometinib and defactinib in combination with standard of care chemotherapy (gemcitabine and Nab-paclitaxel) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma. Part A of the study will evaluate different dose and schedule combinations to determine the recommended Phase 2 dose for expansion into Part B. RAMP 205 is supported by a PanCAN Therapeutic Accelerator Award.
About the Avutometinib and Defactinib Combination
Avutometinib is an investigational RAF/MEK clamp that is designed to induce inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. Avutometinib is designed to block both MEK kinase activity and the ability of RAF to phosphorylate MEK. This differentiated proposed mechanism potentially allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation of the investigational combination of avutometinib and defactinib, a selective FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.
Verastem Oncology is currently conducting clinical trials with avutometinib in RAS/MAPK driven tumors as part of its Raf And Mek Program or RAMP. RAMP 301 (NCT06072781) is an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent LGSOC. RAMP 201 (NCT04625270) is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and enrollment has been completed in each of the dose optimization and expansion phases and the low-dose evaluation.
Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) in combination with avutometinib and defactinib and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 (NCT05074810) and RAMP 204 (NCT05375994) trials, respectively. The RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/Nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award.