FDA Awards Orphan Drug Designation to Avutometinib Plus Defactinib in Pancreatic Cancer

The FDA granted an orphan drug designation to the combination of avutometinib and defactinib for use as a potential therapeutic option in patients with pancreatic cancer.¹

The doublet paired with standard-of-care (SOC) gemcitabine and nab-paclitaxel (Abraxane) is under investigation as a first-line treatment in the phase 1b/2 RAMP 205 study (NCT05669482).2 Data reported at the 2024 ASCO Annual Meeting demonstrated that when avutometinib was given at 2.4 mg twice weekly for 3 out of every 4 weeks with defactinib given at 200 mg twice daily for 3 out of every 4 weeks, gemcitabine at 800 mg/m2 and nab-paclitaxel at 125 mg/m2 on days 1, 8, and 15 (dose level 1, n = 6), the combination elicited an objective response rate (ORR) of 83%. Five of 6 patients experienced a partial response and 1 patient achieved stable disease by RECIST 1.1 criteria. The median time to response was 4.6 months (range, 1.9-6.1).

One dose-limiting toxicity (DLT) was reported in those who received this dose level in the form of febrile neutropenia. The maximum tolerated dose (MTD) has not yet been reached.

“The FDA orphan drug designation for the combination of avutometinib and defactinib for the treatment of pancreatic cancer recognizes the substantial unmet treatment need for patients with pancreatic cancer,” Dan Paterson, president and chief executive officer of Verastem Oncology, stated in a news release.¹ “We believe avutometinib and defactinib in combination with SOC has an opportunity to provide a different approach in treating this challenging cancer. We look forward to reporting updated data from across dose cohorts in the ongoing RAMP 205 trial in the first quarter of 2025.”

A first-in-class oral RAF/MEK clamp, avutometinib, inhibits MEK kinase activity and simultaneously blocks reactivation of MEK by upstream RAF, and defactinib is a FAK inhibitor.2 Preclinical data indicated that pairing avutometinib with FAK inhibition and chemotherapy resulted in tumor regression and prolonged survival in preclinical models of pancreatic ductal adenocarcinoma (PDAC).

The multicenter, open-label, single-arm study enrolled patients with histologic or cytologic confirmed metastatic PDAC who had not received prior systemic treatment for advanced or metastatic disease. They needed to have measurable disease by RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and an acceptable tissue sample to determine KRAS mutational status.

Part A of the study evaluated varying doses of the combination and examined DLTs utilizing a standard 3+3 design with the goal of determining the MTD and recommended phase 2 dose (RP2D) to further test in part B.

Those who received dose level -1 (n = 11) received avutometinib at 2.4 mg twice weekly for 3 out of every 4 weeks plus 200 mg of defactinib twice daily for 3 out of every 4 weeks, 800 mg/m2 of gemcitabine, and 100 mg/m2 of nab-paclitaxel on days 1, 8, and 15. Those given dose level 1a (n = 12) received 3.2 mg of avutometinib twice weekly for 3 out of every 4 weeks, 200 mg of defactinib twice daily for 3 out of every 4 weeks, 800 mg/m2 of gemcitabine, and 125 mg/m2 of nab-paclitaxel on days 1 and 15. Lastly, those who received dose level 2a (n = 12) were given 3.2 mg of avutometinib twice weekly for 3 out of every 4 weeks, 200 mg of defactinib twice daily for 3 out of every 4 weeks, 1000 mg/m2 of gemcitabine, and 125 mg/m2 of nab-paclitaxel on days 1 and 15.

Part B will utilize a Simon 2-stage design and consist of RP2D expansion with a primary end point of ORR.

The total median patient age was 64 years (range, 36-79) and 46.3% of patients were male. The majority of patients were White (61.0%), had an ECOG performance status of 1 (48.8%), and 3 or more metastatic sites (68.3%).

Analyses reported at the meeting had a data cutoff date of May 14, 2024. At this time, follow-up for those in dose level -1, 1a, and 2a were immature. Most of these patients were recently enrolled to the study and were still receiving treatment with the regimen.

Additional preliminary efficacy showed that all patients with an elevated CA19-9 at baseline (n = 5) experienced a reduction by at least 60%; 3 of the 5 patients achieved with decrease in CA19-9 by week 8 of treatment with the combination.

Treatment-emergent serious adverse effects (SAEs) occurred in 19 patients, with 11 experiencing grade 3 or higher effects. Grade 3 or higher treatment-emergent SAEs comprised increased blood bilirubin (n = 2), biliary obstruction (n = 2), febrile neutropenia (n = 2), pulmonary embolism (n = 2), sepsis (n = 2), anemia (n = 1), pneumoperitoneum (n = 1), septic shock (n = 1), skin infection (n = 1), malignant neoplasm progression (n = 1), and vomiting (n = 1).

Treatment-emergent AEs (TEAEs) that occurred in at least 20% of patients and grade 3 or higher TEAEs reported in at least 5% of patients included nausea (any grade, 58.5%; grade ≥3, 0%), fatigue (53.7%; 2.4%), constipation (48.8%; 0%), diarrhea (41.5%; 0%), alopecia (34.1% 0%), decreased neutrophil count (31.7%; 26.8%), maculopapular rash (31.7%; 0%), vomiting (31.7%; 2.4%), anemia (22.0%; 14.6%), decreased appetite (22.0%; 0%), and increased alanine aminotransferase (17.1%; 9.8%).

A total of 2 patients experienced treatment-related AEs that ultimately led to discontinuation in the form of febrile neutropenia, increased blood bilirubin, and detachment of retinal pigment epithelium.

Avutometinib with and without defactinib is also under investigation in patients with low-grade serous ovarian cancer as part of the phase 2 RAMP 201 study (NCT04625270).3 Data showed that single-agent avutometinib (n = 31) induced an ORR of 10%. When combined with defactinib (n = 29), the regimen produced an ORR of 45%.

References

1. Verastem Oncology receives FDA orphan drug designation for avutometinib and defactinib for the treatment of pancreatic cancer. News release. Verastem Oncology. July 29, 2024. Accessed July 29, 2024. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-fda-orphan-drug-designation
2. Lim K-H, Spencer KR, Safyan RA, et al. Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: initial safety and efficacy of phase 1b/2 study (RAMP 205). J Clin Oncol. 2024;42(suppl 16):4140. doi:10.1200/JCO.2024.42.16_suppl.4140
3. A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Updated May 9, 2024. Accessed May 9, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06072781