Avmapki (avutometinib) / Verastem, Roche - LARVOL DELTA

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

DDU RAF/MEK: Phase I Trial of VS-6766 Alone and in Combination With Everolimus (clinicaltrials.gov) - P1 | N=104 | Active, not recruiting | Sponsor: Royal Marsden NHS Foundation Trust | Recruiting ➔ Active, not recruiting | Trial completion date: May 2024 ➔ Jun 2025 | Trial primary completion date: May 2024 ➔ Jun 2025

Enrollment closed • Trial completion date • Trial primary completion date • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • KRAS • NRAS

Study of Avutometinib (VS-6766) + Adagrasib in KRAS G12C NSCLC Patients (clinicaltrials.gov) - P1/2 | N=85 | Active, not recruiting | Sponsor: Verastem, Inc. | Trial completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Onco360 Has Been Selected as a National Specialty Pharmacy Partner for AVMAPKI FAKZYNJA CO-PACK (GlobeNewswire) - "Onco360, the nation’s leading independent specialty pharmacy, has been selected as a national pharmacy partner by Verastem Oncology for AVMAPKI FAKZYNJA CO-PACK (avutometinib capsules; defactinib tablets), for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy."

Commercial • Low Grade Serous Ovarian Cancer

Verastem Oncology Reports First Quarter 2025 Financial Results and Highlights Recent Business Updates (Businesswire) - "Avutometinib and Defactinib Combination in Low-Grade Serous Ovarian Cancer (LGSOC) - Key Milestones Expected for 2025: Primary analysis from both the FRAME and RAMP 201 clinical trials anticipated to be published in H1 2025. Complete enrollment for the international Phase 3 confirmatory RAMP 301 clinical trial for patients with recurrent LGSOC regardless of KRAS mutation status by the end of 2025. Report initial data from the RAMP 201J Phase 2 clinical trial being conducted in Japan with JGOG in H2 2025. Continue to advance the regulatory pathway in Japan and Europe."

Enrollment status • P1 data • P2 data • Regulatory • Ovarian Cancer

Avutometinib/Abemaciclib/Fulvestrant Combo Is Active, Safe in CDK4/6 Inhibitor–Resistant HR+/HER2– Metastatic Breast Cancer (OncLive) - P1/2 | N=63 | NCT05608252 | "The combination of avutometinib (VS-6766), abemaciclib (Verzenio), and fulvestrant (Faslodex) demonstrated a manageable safety profile and preliminary efficacy in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer (HR+/HER2– MBC) resistant to CDK4/6 inhibitors, according to findings from a phase 1 trial (NCT05608252) presented at the 2025 AACR Annual Meeting. The maximum tolerated dose (MTD) was determined using a Bayesian Optimal Interval design; dose-limiting toxicities (DLTs) were reported in 3 of 4 patients at the highest dose level. No DLTs were observed among the 9 patients treated at the intermediate dose level. The recommended phase 2 dosing regimen was established as abemaciclib at 100 mg orally twice daily, avutometinib at 3.2 mg orally twice weekly, and fulvestrant at 500 mg intramuscularly every 28 days."

P1/2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer (FDA) - "On May 8, 2025, the Food and Drug Administration granted accelerated approval to the combination of avutometinib and defactinib (Avmapki Fakzynja Co-pack, Verastem, Inc.) for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy...Efficacy was evaluated in RAMP-201 (NCT04625270), an open-label, multicenter trial that included 57 adult patients with measurable KRAS-mutated recurrent LGSOC."

Accelerated approval • Low Grade Serous Ovarian Cancer

Verastem Oncology Reports First Quarter 2025 Financial Results and Highlights Recent Business Updates (Businesswire) - "RAMP 205: Avutometinib Plus Defactinib in Combination with Chemotherapy in First-Line Metastatic Pancreatic Cancer - Key Milestones Expected for 2025: Plan to report additional data when ASCO abstracts are live on May 22, 2025. Select the recommended Phase 2 Dose (RP2D) for trial expansion in H1 2025. RAMP 203: Avutometinib Plus Defactinib in Combination with a KRAS G12C Inhibitor in Non-Small Cell Lung Cancer (NSCLC): Completed enrollment in the KRAS G12C inhibitor prior-treated Stage 1 Part B doublet cohort in Q1 2025. Completed enrollment in the planned dose level evaluation cohorts for the triplet combination in Q1 2025. Key Milestones Expected for 2025: Present an interim update of both doublet and triplet data at a medical meeting in H2 2025."

P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models (AACR 2025) - P1/2 | "Furthermore, GFH375 was more potent than other KRAS G12D inhibitors (e.g. RMC-9805, MRTX1133) in reducing the level of RAF1-bound active KRAS G12D-GTP (ON) and inhibiting cell proliferation in MEFs expressing human KRAS G12D...Combination with the RAF/MEK clamp avutometinib also enhanced the anti-tumor efficacy of GFH375...Altogether, GFH375 is a potent and selective orally active inhibitor of KRAS G12D (ON/OFF) and demonstrated promising anti-tumor activity in multiple KRAS G12D tumor models in vivo as single agent and in combination with other anticancer therapies including cetuximab. These results support the ongoing clinical evaluation of GFH375 for treatment of patients with KRAS G12D mutant cancers (NCT06500676)."

Combination therapy • Preclinical • Colorectal Cancer • Endometrial Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

PHI-501 as a potent pan-RAF/DDRs inhibitor suppresses lung cancer cell proliferation and overcomes KRAS G12C inhibitor resistance (AACR 2025) - "The growth inhibitory activity of PHI-501 in KRASG12V, KRASG12S, KRASQ61H and NRASQ61K lung cancer cells was superior to that of G12Ci (sotorasib and adagrasib) and BRAF inhibitors (encorafenib and avutometinib). The treatment of PHI-501 alone showed robust growth inhibition in lung cancer cells harboring KRAS wild-type or KRAS and NRAS mutation. Our results suggest that PHI-501 as the pan-RAF/DDRs dual inhibitor is beneficial for the treatment of lung cancer and even helps overcome the resistance of previous G12Ci treatments."

Lung Cancer • Oncology • Solid Tumor • DDR1 • EGFR • KRAS • NRAS