Avmapki (avutometinib) / Verastem, Roche - LARVOL DELTA

Avutometinib and Defactinib: First Approval. (PubMed, Drugs) - "In May 2025, avutometinib and defactinib was approved in the USA for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This article summarizes the milestones in the development of avutometinib and defactinib leading to this first approval for KRAS-mutated recurrent LGSOC."

Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS • TYK2

PRIMARY ANALYSIS: PHASE II STUDY OF AVUTOMETINIB AND DEFACTINIB IN WOMEN WITH ADVANCED OR RECURRENT GYNECOLOGIC MESONEPHRIC CANCER (IGCS 2025) - No abstract available

Clinical • Metastases • P2 data • Oncology

Verastem Oncology Reports Second Quarter 2025 Financial Results and Highlights Recent Business Updates (Businesswire) - "Achieved net product revenue of $2.1 million in the first six weeks of launch. AVMAPKI FAKZYNJA CO-PACK was launched in the U.S. within one week of FDA Approval. AVMAPKI FAKZYNJA CO-PACK is now available through a distribution network in the U.S. that includes specialty pharmacies, specialty distributors, and group purchasing agreements that are in place. Prescriptions for patients are being received from both academic and community centers, including both repeat prescriptions from physicians prescribing to multiple patients and refills for individual patients and there has been broad payer coverage and reimbursement. A support program for patients prescribed AVMAPKI FAKZYNJA CO-PACK, called Verastem Cares, went operational immediately following launch."

Launch US • Sales • US reimbursement • Low Grade Serous Ovarian Cancer

Avutometinib and Defactinib Combination in LGSOC (Businesswire) - "Enrollment in the Phase 2 RAMP 201J trial in Japan has been completed, and the Company has activated sites in Japan to join the global RAMP 301 trial....Key Milestones Expected for the Second Half of 2025: (i) Report outcome of the IDMC’s sample-size re-estimation recommendation for RAMP 301 in Q4 2025; (ii) Report initial data from the RAMP 201J Phase 2 clinical trial being conducted in Japan with JGOG in Q4 2025; (iii) Continue to advance the regulatory pathway in Japan and Europe."

P2 data • Regulatory • Trial status • Low Grade Serous Ovarian Cancer

A Study of VS-6766 and Cetuximab in Patients With Advanced Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=53 | Suspended | Sponsor: University of Chicago | Trial completion date: Aug 2025 ➔ Feb 2027 | Trial primary completion date: Aug 2025 ➔ Feb 2027

Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • KRAS • MSI • PD-L1

RAMP 205: Avutometinib Plus Defactinib in Combination with Chemotherapy in First-Line Metastatic PDAC (Businesswire) - "Key Milestones Expected for the Second Half of 2025: Complete enrollment in the RAMP 205 expansion cohort in Q3 2025."

Enrollment status • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

RAMP 203: Avutometinib Plus Defactinib in Combination with a KRAS G12C Inhibitor in NSCLC (Businesswire) - "Key Milestones Expected for 2025: Report an interim update on the safety and efficacy results in RAMP 203 from both the doublet and triplet combinations in Q4 2025."

P1/2 data • Non Small Cell Lung Cancer

Anti-tumor efficacy of RAF/MEK inhibitor VS6766 in KRAS-mutated colorectal cancer cells. (PubMed, Cancer Chemother Pharmacol) - "Taken together, this study provides the first experimental evidence to demonstrate that all G12 mutation cell lines are sensitive to VS6766 applied either alone or combined with 5-FU or AKT inhibitor."

Journal • Colorectal Cancer • Oncology • Solid Tumor • KRAS

The RAS-MEK-ERK pathway in low-grade serous ovarian cancer. (PubMed, Gynecol Oncol) - "Treatment of recurrent LGSC with the MEK inhibitor trametinib demonstrated improved clinical outcomes relative to other treatment options (chemotherapy, hormonal therapy) in a phase 3 trial...However, some trials of MEK inhibitors showed more limited benefit (e.g. binimetinib), and RAS pathway mutations do not always correlate with increased efficacy, highlighting the need for further clinical and translational research in RAS-MEK-ERK pathway targeted therapeutics...Novel approaches to targeting the RAS-MEK-ERK pathway include the RAF/MEK clamp avutometinib, which has been evaluated in combination with the FAK inhibitor defactinib, and this combination received United States Food and Drug Administration (FDA) accelerated approval in 2025. Multiple newly developed inhibitors of KRAS, including KRAS G12C or G12D inhibitors, as well as pan-RAS inhibitors, including RAS (ON) inhibitors such as RMC-6236, are being evaluated in solid tumors. These emerging strategies for..."

IO biomarker • Journal • Review • Epithelial Ovarian Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BCL2 • BCL2L1 • BRAF • CDK4 • KRAS • NRAS

20P.1113: Defactinib and VS-6766 for the Treatment of Patients With Metastatic Uveal Melanoma (clinicaltrials.gov) - P2 | N=13 | Terminated | Sponsor: Thomas Jefferson University | Active, not recruiting ➔ Terminated; Trial enrollment was stopped early by study sponsors (before the anticipated accrual of 18 patients) due to no patients having significant reduction in disease.

Trial termination • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Avmapki Fakzynja Co-Pack for ovarian cancer. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Oncology • Ovarian Cancer • Solid Tumor

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201. (PubMed, J Clin Oncol) - P3 | "The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC. A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781)."

Journal • Fibrosarcoma • Hematological Disorders • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Sarcoma • Solid Tumor • KRAS

Verastem Oncology Announces Publication of the Primary Results from the Phase 2 RAMP 201 Trial of Avutometinib in Combination with Defactinib in Patients with Recurrent Low-Grade Serous Ovarian Cancer in the Journal of Clinical Oncology (Businesswire) - P2 | N=225 | RAMP 201 (NCT04625270) | Sponsor: Verastem | "Robust objective response rates were observed (31% overall, 44% in KRAS-mutant, and 17% in KRAS wild-type) in patients whose cancer had progressed after multiple prior lines of therapy. The majority of patients (82%) had some reduction in target lesions, regardless of KRAS mutation status. Median progression-free survival was 12.9 months overall, 31.0 months in KRAS-mutant, and 12.8 months in KRAS wild-type....The Company will submit the RAMP 201 publication and the recent publication of the FRAME study to the National Comprehensive Cancer Network (NCCN) in support of its consideration of inclusion of the KRAS wild-type population evaluated in these trials in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)."

NCCN guideline • P2 data • Low Grade Serous Ovarian Cancer

Avmapki: Newly added patents in Orange Book (Orange Book) - Expiry on Feb 9, 2027, Apr 17, 2028, Aug 21, 2029, Oct 29, 2038, Sep 11, 2040 and Dec 29, 2042

Patent • Epithelial Ovarian Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Verastem Oncology Announces Nature Medicine Publication of the Results from the First-in-Human Phase 1 FRAME Study of Avutometinib in Combination with Defactinib in Solid Tumors, including Low-Grade Serious Ovarian Cancer (Businesswire) - P1 | N=87 | FRAME (NCT03875820) | "Verastem Oncology...announced that updated results from the Phase 1/2 FRAME study...were published online in Nature Medicine....In 26 patients with LGSOC who were evaluable for efficacy, the overall response rate (ORR) was 42.3% (11/26) and median progression-free survival (mPFS) was 20.1 months. In the 24 patients whose samples could be sequenced for KRAS mutations, ORR and mPFS were 58.3% (7/12) and 30.8 months in the 12 patients with KRAS mutations, and 33.3% (4/12) and 8.9 months in the 12 patients without KRAS mutations. In 11 patients who had previously received a MEK inhibitor, the ORR was 27.3% (3/11). Additionally, in two patients with LGSOC who had brain metastases prior to enrolling, MRI imaging at 30 months post-treatment with the combination showed the metastases had shrunk in both patients."

P1 data • Low Grade Serous Ovarian Cancer

Defactinib with avutometinib in patients with solid tumors: the phase 1 FRAME trial. (PubMed, Nat Med) - P1 | "This study demonstrates the importance of intermittent dosing schedules in combined targeting of the mitogen-activated protein kinase and focal adhesion kinase pathways to improve tolerability, and has acquired proof of concept of anti-tumor activity against low-grade serous ovarian cancer, a tumor relatively resistant to chemotherapy. ClinicalTrials.gov identifier NCT03875820 ."

Journal • P1 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

RAMP205: Study of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=40 | Recruiting | Sponsor: Verastem, Inc. | Trial completion date: Dec 2025 ➔ Aug 2027 | Trial primary completion date: May 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Blood ctDNA vs tumor tissue screening for the detection of KRAS mutations in low-grade serous ovarian cancer (ESMO-GC 2025) - P2 | "Methods Samples from a phase II study (ENGOT-OV60/GOG-3052; RAMP-201; NCT04625270) evaluating the combination of avutometinib (RAF/MEK clamp) + defactinib (FAK inhibitor) versus avutometinib monotherapy in patients with LGSOC were assessed. Clinical trial identification NCT04625270. Legal entity responsible for the study Verastem Oncology."

Circulating tumor DNA • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

Avutometinib + defactinib: "Impressive efficacy signals and a manageable safety profile, Dose level 1 selected as the RP2D, 10/12 patients in dose level 1 achieved an objective response"; Pancreatic ductal adenocarcinoma (Verastem) - ASCO 2025

P1/2 data • Gastrointestinal Cancer • Oncology • Pancreatic Ductal Adenocarcinoma

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Updated safety and efficacy of a phase 1b/2 study (RAMP 205). (ASCO 2025) - P1/2 | "A/D + GnP have been combined in 5 dose cohorts. The MTD has not been reached. Enrollment and evaluation of mature data are ongoing to identify the recommended phase 2 dose."

Clinical • Metastases • P1/2 data • Alopecia • Anemia • Dermatitis • Dermatology • Fatigue • Febrile Neutropenia • Hematological Disorders • Hepatology • Immunology • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Thrombocytopenia • KRAS

Combination therapy of avutometinib and MRTX1133 synergistically suppresses cell growth by inducing apoptosis in KRASG12D-mutated pancreatic cancer. (PubMed, Mol Cancer Ther) - "In in vivo experiments, the combination therapy markedly delayed tumor growth compared to either therapy alone. Therefore, the combination of avutometinib and MRTX1133 may represent a promising therapeutic approach for KRASG12D-mutated pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BIRC5 • KRAS

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) and the NCCN Drugs & Biologics Compendium (NCCN Compendium) for Ovarian Cancer, Version 2.2025. (NCCN)

NCCN guideline • Low Grade Serous Ovarian Cancer • Ovarian Cancer

Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Emory University | Trial completion date: Jun 2026 ➔ Sep 2028 | Trial primary completion date: Aug 2025 ➔ Mar 2028

IO biomarker • Trial completion date • Trial primary completion date • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Tempus Announces a Collaboration with Verastem to Develop CDx for First-Ever FDA-Approved KRAS-Mutant Recurrent Low-Grade Serous Ovarian Cancer Combination Treatment (Yahoo Finance) - "Tempus AI, Inc....today announced a collaboration to develop a companion diagnostic (CDx) test with Verastem Oncology...for patients with RAS/MAPK pathway-driven cancers. Tempus completed confirmatory testing in Verastem’s Phase 2 RAMP-201 clinical trial, which evaluated the combination of avutometinib and defactinib to treat recurrent low-grade serous ovarian cancer (LGSOC) and was the basis of the recent U.S. Food and Drug Administration’s (FDA) accelerated approval of the combination in KRAS-mutated recurrent LGSOC....Continuing our collaboration to fully develop a CDx assay is part of our post-marketing commitment to the FDA for our recent accelerated approval of avutometinib plus defactinib and is a critical step in bringing targeted therapies to patients with recurrent KRAS-mutant LGSOC..."

Diagnostic • Licensing / partnership • Low Grade Serous Ovarian Cancer • Oncology

Verastem Oncology Announces Positive Updated Results from RAMP 205 Evaluating Avutometinib Plus Defactinib in Combination with Standard-of-Care Chemotherapy in Frontline Metastatic Pancreatic Ductal Adenocarcinoma (Businesswire) - P1b/2a | N=40 | RAMP205 (NCT05669482) | Sponsor: Verastem, Inc. |"As of April 25, 2025, 60 patients (12 per cohort) had been treated in one of five dose regimens with the combination of avutometinib and defactinib with gemcitabine and Nab-paclitaxel in frontline metastatic PDAC. In the dose level 1 cohort, 12 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, 83% (10/12) of patients achieved partial responses (8 confirmed and 2 unconfirmed who remain on treatment)....The Company is now developing plans for a registrational Phase 3 front-line metastatic PDAC trial to begin in 2026....Company will host an R&D investor webcast on Monday, June 2 at 11:00 am CDT to review the updated RAMP 205 data as well as updated data on VS-7375 presented at ASCO."

New P3 trial • P1/2 data • Pancreatic Ductal Adenocarcinoma