avutometinib (VS-6766) / Verastem, Roche - LARVOL DELTA

Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer (clinicaltrials.gov) - P2 | N=33 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center | Initiation date: Oct 2024 ➔ Apr 2025

Combination therapy • Metastases • Trial initiation date • Colorectal Cancer • Oncology • Solid Tumor

Avutometinib plus cetuximab after chemotherapy in patients with KRAS-mutated metastatic colorectal cancer: Results of phase 1 dose escalation. (ASCO-GI 2025) - P1/2 | "Clinical Trial Registration Number: NCT05200442. The abstract will be released to the public on January 21, 2025 at 10:00 PM UTC"

Clinical • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Verastem Oncology Provides a Clinical Update for RAMP 203 Trial in Advanced KRAS G12C Mutant Non-Small Cell Lung Cancer (Businesswire) - P1/2 | N=153 | RAMP203 (NCT05074810) | Sponsor: Verastem, Inc. | "Avutometinib and defactinib are administered on a three out of four weeks schedule.​ Two of the three patients demonstrated initial tumor reductions of at least 20% at the first scan. As of the data cutoff, all three patients remain on treatment.​ With no DLTs observed in the first triplet combination cohort, the Company anticipates the enrollment of additional patients to the triplet combination prior to presenting the data at a medical meeting next year.​ As previously reported, the doublet combination of avutometinib with sotorasib has completed enrollment (n=28) in the G12C inhibitor treatment-naïve Stage 1 Part B cohort.​ The KRAS G12C inhibitor prior-treated Stage I Part B cohort is still enrolling patients and is anticipated to complete enrollment in early 2025."

Enrollment status • P1/2 data • Non Small Cell Lung Cancer

Phase 2 trial of defactinib in combination with avutometinib in patients with advanced diffuse-type gastric cancer. (ASCO-GI 2025) - P2 | "Clinical Trial Registration Number: NCT06487221. The abstract will be released to the public on January 21, 2025 at 10:00 PM UTC"

Clinical • Combination therapy • Metastases • P2 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Verastem Oncology Reports Third Quarter 2024 Financial Results and Highlights Recent Business Updates (Businesswire) - "Third Quarter 2024 and Recent Updates: Avutometinib and Defactinib Combination in Low-Grade Serous Ovarian Cancer (LGSOC)....(i) The Company continued its commercial preparation activities for a potential U.S. launch in mid-2025; (ii) The Japanese Gynecologic Oncology Group (JGOG) dosed the first patient in a Phase 2 Verastem sponsored clinical trial, called RAMP201J, evaluating the safety and efficacy of avutometinib in combination with defactinib for recurrent LGSOC in Japan in October 2024."

Launch US • Trial status • Ovarian Serous Adenocarcinoma

Effect of epithelial-mesenchymal transition status on the efficacy of RAF/MEK clamp and FAK inhibitor combination therapy for KRAS-mutated lung cancer (ESMO Asia 2024) - "Results FAK phosphorylation/activation was increased after avutometinib treatment and synergy between avutometinib and FAK inhibitor, defactinib, was observed in KRAS-mutated NSCLC cells with an epithelial rather than mesenchymal phenotype. Conclusions These results demonstrate that the epithelial-mesenchymal transition status may be a promising biomarker for the efficacy of combination therapy with avutometinib and defactinib in KRAS-mutated NSCLC."

Clinical • Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Novel dual MEK inhibitors for RAS-mutated colorectal cancer as a single agent or in combination with known therapies including aPD-1 (SITC 2024) - "While the known MEK inhibitors such as Cobimetinib block the phospho-ERK (pERK) formation in BRAF-V600E mutated situation, their combination with selective BRAF inhibitors has been successfully used clinically, except colorectal cancer (CRC)...Targeted-therapy to KRAS-mutated CRC have been evaluated in clinical studies, such as KRAS-G12C inhibitors Sotorasib and Adagrasib...Methods Avutometinib and its close analogs such as IMM-1-104 and NST-628 are in clinical development...In a HCT116 xenograft model (human CRC cell-line with KRAS-G13D mutation), ABM-4095 dose-dependently inhibited tumor growth, similar to that of Avutometinib at its maximal-tolerant dose. In a CRC SW837 (KRAS-G12C, insensitive to Adagrasib) model, ABM-4218 showed synergic effect with Adagrasib, as well as the EGFR antibody Cetuximab...Conclusions In summary, A series of novel dual MEK inhibitors have been studied for the possible treatment of colorectal cancer by modulating the pERK level via the..."

Combination therapy • IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS • MAP2K1

Combination treatment with RAF/MEK and FAK inhibition enhances tumor growth inhibition in meningioma (SNO 2024) - "The cells were plated in Matrigel-coated wells, treated with defactinib (FAK inhibitor), VS-6766 (RAF/MEK inhibitor, avutometinib) and the combination over a 7-day period and assessed for cell viability using the CellTiter-Glo 3D assay. In vivo, we tested the efficacy of the FAK inhibitor VS-4718 (possessing favorable pharmacokinetic properties in mice) and RAF/MEK inhibitor VS-6766, both given daily via oral gavage, in athymic nude mice bearing IOMM-Lee or CH157-MN tumors... Treatment with FAK and RAF/MEK inhibitors showed synergistic or combination effects in the NF2 mutant CH157-MN model in vitro and in vivo. RAF/MEK inhibitor monotherapy was effective for the IOMM-Lee model (NF2 wild-type), without clear benefit of combining with the FAK inhibitor. Investigations in intracranial tumor models are underway."

Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • CDKN2A • NF2

Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma. (PubMed, Cell Rep Med) - "MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited...In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells."

Journal • Melanoma • Oncology • Solid Tumor • NF1

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

Combination therapy • Enrollment closed • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Verastem Oncology Reports Third Quarter 2024 Financial Results and Highlights Recent Business Updates (Businesswire) - "Third Quarter 2024 and Recent Updates: (i) Avutometinib in Combination with KRAS G12C Inhibitors in Non-Small Cell Lung Cancer (NSCLC):...Expect to report updated interim data from the doublet combination of avutometinib plus sotorasib and provide initial safety data and a status of enrollment for the triplet combination of avutometinib, sotorasib and defactinib in the RAMP 203 trial by the end of 2024...; (ii) Avutometinib and Defactinib Combination in First-Line Metastatic Pancreatic Cancer:...Expect to report updated data from the ongoing RAMP 205 trial in Q1 2025....; (iii) VS-7375/GFH375: Oral KRAS G12D (ON/OFF) Inhibitor:...After evaluating initial dose escalation data from the Phase 1 study of VS-7375/GFH375 in China, Verastem anticipates filing a U.S. investigational new drug (IND) application by Q1 2025​."

IND • P1/2 data • Non Small Cell Lung Cancer • Pancreatic Cancer

Focal Adhesion Kinase (FAK) in Chromosome 8 Gain-Associated Malignant Peripheral Nerve Sheath Tumors (MPNST) (SNO 2024) - "These results demonstrate the potential therapeutic efficacy of FAK inhibitors, both alone and in combination with RAF/MEKi, for the treatment of MPNST."

Brain Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • CASP3 • NF1 • STAT3 • TYK2

FOCAL ADHESION KINASE FAK) IS A THERPEUTIC TARGET IN CHROMOSOME 8 GAIN-ASSOCIATED MALIGNANT PERIPHERAL NERVE SHEATH TUMORS MPNST) (CTOS 2024) - "Recently, the combination of defactinib, a FAKi, and avutometinib, a Raf/MEKi, was granted FDA orphan drug designation for ovarian cancer. In summary, FAK plays a critical role in MPNST pathogenesis. These results demonstrate the potential therapeutic efficacy of a FAKi, both alone and in combination with a Raf/MEKi, for the treatment of MPNST."

Brain Cancer • Neurofibrosarcoma • Oncology • Ovarian Cancer • Sarcoma • CASP3 • NF1 • STAT3

A Study of Avutometinib (VS-6766) and Defactinib in People with Mesonephric Gynecologic Cancer (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | N=20 ➔ 40

Enrollment change • Gynecologic Cancers • Oncology

RAMP201J: A Study of Avutometinib + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer in Japanese Patients (clinicaltrials.gov) - P2 | N=15 | Recruiting | Sponsor: Verastem, Inc.

Combination therapy • New P2 trial • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Verastem Oncology Completes Rolling NDA Submission to the FDA for Avutometinib Plus Defactinib as a Treatment for Recurrent KRAS Mutant Low-Grade Serous Ovarian Cancer (Businesswire) - "Company seeking accelerated approval and priority review of its NDA submission in patients with KRAS mutant low-grade serous ovarian cancer; FDA filing decision expected before the end of 2024 with potential for FDA approval decision by mid-2025....Updated results from the Phase 2 registration-directed RAMP 201 study were presented in a late-breaking oral plenary presentation at the International Gynecologic Cancer Society 2024 Annual Meeting and demonstrated in patients with KRAS mutant LGSOC, a confirmed overall response rate (ORR) of 44%, a median progression free survival (PFS) of 22 months, and a disease control rate at 6 months of 70%."

FDA filing • Gynecologic Cancers • Oncology • Ovarian Cancer

Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy. (PubMed, Sci Transl Med) - "Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies."

Journal • Stroma • Fibrosarcoma • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • CAFs • KRAS • MYC

The novel dual MEK inhibitor ABM-4095 for RAS-mutated lung cancer as a single agent or in combination with known therapies (EORTC-NCI-AACR 2024) - "While the known MEK inhibitors such as Cobimetinib block the phospho-ERK (pERK) formation in BRAF-V600E mutated situation, their combination with selective BRAF inhibitors has been successfully used clinically...Targeted-therapy to KRAS-mutated lung cancers have been extensively evaluated, resulting in the recent FDA approval of KRAS-G12C inhibitors such as Sotorasib and Adagrasib... Avutometinib and its close analogs such as IMM-1-104 and NST-628 are in clinical development...ABM-4095 showed synergic effect with erlotinib in lung cancers (KRAS-G12C H358 xenograft model)... In summary, ABM-4095 is a potent dual MEK inhibitor with activities against the RAS mutant lung cancer. ABM-4095 inhibited cell growth in vitro, and to induce tumor regression in vivo as a single agent and in combination with approved agents for the treatment of lung cancer."

Combination therapy • Lung Cancer • Oncology • Solid Tumor • KRAS

A PHASE 3, RANDOMIZED TRIAL EVALUATING AVUTOMETINIB PLUS DEFACTINIB COMPARED WITH INVESTIGATOR'S CHOICE OF THERAPY IN PATIENTS WITH RECURRENT LOW-GRADE SEROUS OVARIAN CANCER: GOG-3097/ENGOT-OV81/NCRI/RAMP 301 (IGCS 2024) - P1, P2, P3 | "Prior treatment with chemotherapy, hormonal therapy, bevacizumab, and MEK/RAF inhibitors are allowed. Patients will be randomized 1:1 to either 3.2 mg avutometinib PO BIW 3/4 weeks + 200 mg defactinib PO BID 3/4 weeks or ICT (pegylated liposomal doxorubicin, paclitaxel, topotecan, letrozole, or anastrozole)...Secondary endpoints: investigator-assessed PFS, overall survival, ORR, duration of response, disease control rate, safety, tolerability, pharmacokinetics, and quality of life. Results N/A (Trial In Progress) Conclusion/Implications N/A (Trial in Progress)"

Clinical • P3 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

Late-Breaking Abstract: EFFICACY AND SAFETY OF AVUTOMETINIB ± DEFACTINIB IN RECURRENT LOW GRADE SEROUS OVARIAN CANCER: PRIMARY ANALYSIS OF ENGOT-OV60/GOG-3052/RAMP 201 (IGCS 2024) - "Prior therapies included endocrine (86%), bevacizumab (51%), and MEK inhibitor (22%). Conclusion/Implications A+D was well tolerated allowing prolonged exposure to therapy. ORR and durable responses observed are clinically meaningful in this heavily pretreated population and support the potential of A+D as a new standard of care for recurrent LGSOC."

Clinical • Late-breaking abstract • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

5G-RUBY: Avutometinib and Defactinib in Malignant Brain Tumours (clinicaltrials.gov) - P1/2 | N=182 | Recruiting | Sponsor: Institute of Cancer Research, United Kingdom

Combination therapy • New P1/2 trial • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • BRAF

Verastem Oncology to Present Mature RAMP 201 Data in Low-Grade Serous Ovarian Cancer at the International Gynecologic Cancer Society 2024 Annual Meeting (Businesswire) - "Verastem Oncology...announced the acceptance of a late-breaking abstract of the mature data from the ongoing Phase 2 RAMP 201 (ENGOT-ov60/GOG-3052) clinical trial to be presented as an oral presentation at a plenary session at the International Gynecologic Cancer Society (IGCS) Annual Meeting taking place October 16-18, 2024 in Dublin, Ireland. The presentation will include updated safety and efficacy data from the RAMP 201 trial evaluating the combination of avutometinib, a RAF/MEK clamp, and defactinib, a selective FAK inhibitor, in patients with low-grade serous ovarian cancer (LGSOC), including overall response rate, progression free survival, and duration of response....'We also remain on track to finalize our clinical module and complete our NDA submission in the fourth quarter of this year'."

FDA filing • Late-breaking abstract • P2 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Verastem Oncology Presents Positive Updated RAMP 201 Data for Avutometinib and Defactinib Combination in Recurrent Low-Grade Serous Ovarian Cancer at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting (Businesswire) - P2 | N=225 | RAMP 201 (NCT04625270) | Sponsor: Verastem, Inc. | "Robust overall response rates observed (31% overall, 44% in KRAS mutant, 17% in KRAS wild-type) in patients whose cancer had progressed despite prior treatment with chemotherapy and/or MEK inhibitors and/or bevacizumab; Patients on avutometinib and defactinib achieved a median progression free survival of more than one year (12.9 months); 22 months in KRAS mutant population...A Type A meeting was recently held with the U.S. Food and Drug Administration (FDA), during which the Company aligned with the FDA on the Company’s plans to complete the New Drug Application (NDA) submission in October 2024 for adult patients with recurrent KRAS mt LGSOC, who received at least one prior systemic therapy, based on the mature data from the RAMP 201 trial."

FDA filing • P2 data • Oncology • Ovarian Cancer • Solid Tumor

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer. (PubMed, Int J Gynecol Cancer) - P3 | "The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. ClinicalTrials.gov NCT06072781."

Journal • P3 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

Verastem Oncology Announces Details for the Oral Presentation of the Mature RAMP 201 Data Evaluating Avutometinib Plus Defactinib in Recurrent Low-Grade Serous Ovarian Cancer at the IGCS 2024 Annual Meeting (Businesswire) - "Verastem Oncology...announced further details for its late-breaking presentation of mature data from the ongoing Phase 2 RAMP 201 (ENGOT-ov60/GOG-3052) clinical trial to be presented as an oral presentation at a plenary session at the International Gynecologic Cancer Society (IGCS) Annual Global Meeting taking place October 16-18, 2024 in Dublin, Ireland....The oral presentation will include updated safety and efficacy data from the RAMP 201 trial evaluating the combination of avutometinib, an oral RAF/MEK clamp, and defactinib, an oral, selective FAK inhibitor, in patients with recurrent low-grade serous ovarian cancer (LGSOC), including overall response rate, progression free survival, and duration of response."

Late-breaking abstract • P2 data • Ovarian Cancer