Avmapki (avutometinib) / Verastem, Roche - LARVOL DELTA

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

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

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

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

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

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

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 | "Clinical Trial Registration Number: NCT05669482 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Metastases • P1/2 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

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

Preclinical evaluation of RAS pathway inhibitors in gastroesophageal adenocarcinoma (AACR 2025) - "The allosteric SHP2 inhibitor RMC-4550 demonstrated an IC50 of 0.08-6.67 μM in KRASAMP and KRASG12D lines...There was no adaptive signaling through PI3K pathways based on suppressed p-AKT levels, in comparison to trametinib which resulted in increases in pAKT. The RAF/MEK clamp VS-6766 also inhibits signaling through MAPK as evidenced by decreased p-AKT, and an EC50 for p-ERK of 131.83 nM (KRASAMP) and 10.4725 nM (KRASMUT) GEA cells...Our results suggest that combination strategies will be essential to overcome adaptive resistance and maximize therapeutic benefit in KRASAMP cells. Future in vivo studies will validate the potential of these inhibitors and combination approaches."

Preclinical • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • KRAS

Distant Brain Metastases in Cutaneous Melanoma May Be Mitigated With Multiple Pathway Inhibitors (DocWire) - "Results were published in Cell Reports Medicine. The researchers used YUMM3.2 cells that express BRAF, which was the specific cutaneous melanoma variant target. To test the efficacy of FAK inhibition alone, the cells were treated with increasing doses of either a defacitinib surrogate (VS-4718) or avutometinib for 72 hours, and confluence was assayed every 2 hours....The combination of VS-4718 and avutometinib significantly reduced cell viability compared to VS-4718 alone (P≤0.001) or avutometinib alone (P≤0.001), showing comparable efficacy to the combination of VS-4718 and encorafenib. Adding encorafenib to the avutometinib and VS-4718 combination did not enhance its in vitro effectiveness."

Preclinical • Cutaneous Melanoma

Correlative preclinical studies to elucidate mechanisms of synergy of the combination of the RAF/MEK clamp avutometinib and the FAK inhibitor defactinib in low grade serous ovarian cancer (AACR 2025) - P1, P2, P3 | "This organoid model was used in in-vivo experiments with vehicle, avutometinib, VS-4718 (FAK inhibitor) and the combination for 2 weeks. The combination of avutometinib with defactinib has shown preclinical and clinical activity in LGSOC greater than avutometinib alone, and is being evaluated in a randomized phase 3 trial in patients with LGSOC (RAMP-301; NCT06072781). These preclinical studies show that avutometinib + FAK inhibitor inhibits MAPK pathway signaling more strongly than avutometinib alone. Further, putative mechanisms of resistance to avutometinib, including MYC and PI3K signaling, were overcome by the combination of avutometinib with a FAK inhibitor in LGSOC models."

Preclinical • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CCND1 • ETV4 • ETV5 • KRAS

RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models (AACR 2025) - P3 | "The combination of avutometinib with the focal adhesion kinase (FAK) inhibitor defactinib has shown clinical activity for patients with low-grade serous ovarian cancer and is currently being investigated in a Phase 3 confirmatory study (RAMP 301; NCT06072781)...In contrast to the tumor regressions induced by avutometinib plus exarafenib in this ME9518 model, the combination of the MEK-only inhibitor binimetinib with exarafenib caused substantial body weight loss and failed to show tumor regression. Strong tumor regressions in all mice were also observed with the combination of avutometinib and the pan-RAFi belvarafenib in an NRAS mutant xenograft model (SKMEL2). Mechanistically, the deep tumor regressions observed with the combination of avutometinib plus exarafenib corresponded with virtually complete elimination of MAPK pathway markers such as pMEK, DUSP4 and pS6 in the tumors relative to avutometinib or exarafenib alone which conferred less complete inhibition...."

Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • DUSP4 • KRAS • NRAS

A single-arm phase 1 trial of avutometinib (RAF/MEK inhibitor), abemaciclib (abema), and fulvestrant in CDK4/6 inhibitor (CDK4/6i)-pretreated patients (pts) with HR+ metastatic breast cancer (MBC) (AACR 2025) - "Pts had median age 61 yrs, 31% had visceral disease, all had received prior endocrine therapy for MBC (median 2 lines, range 1-5), all had received prior CDK4/6i (69% palbociclib, 19% ribociclib, 19% abema), 69% had spent >12 mos on a prior CDK4/6i for MBC, 44% received prior fulvestrant, 63% received any prior selective estrogen receptor degrader, and 25% received prior chemo for MBC. The combination of avutometinib, abema, and fulvestrant showed a manageable safety profile and preliminary efficacy in HR+/HER2- MBC resistant to CDK4/6i. A single-arm phase 2 trial is ongoing to further evaluate the clinical efficacy in this population."

Clinical • Metastases • P1 data • Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2

Mechanistic rationale for combination of RAF/MEK glue avutometinib with a pan-RAF inhibitor for RAS-mutant tumor-selective therapy (AACR 2025) - "Thus, increasing tumor selectivity by differentially targeting native conformations of non-genetically altered oncogene effector proteins in tumor and normal cells represents a novel paradigm in targeted cancer therapy. These data provide mechanistic understanding and preclinical support for the clinical evaluation of the combination of avutometinib with a pan-RAFi for patients with RAS-mutant tumors."

Late-breaking abstract • Oncology

RO5126766 attenuates osteoarthritis by inhibiting osteoclastogenesis and protecting chondrocytes through mediating the ERK pathway. (PubMed, J Orthop Translat) - "By demonstrating its ability to inhibit osteoclast differentiation and protect articular cartilage, RO could offer a new avenue for disease-modifying treatments in OA. Thus, this paper provides valuable insights into understanding the molecular mechanisms and treatment of OA."

Journal • Immunology • Oncology • Osteoarthritis • Pain • Rheumatology • FOS • NFATC1

Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma (EADO-WCM 2025) - "Results We show that avutometinib, a MEK inhibitor that limits MEK phosphorylation and ERK reactivation, is more effective in the NF1-null context than earlier inhibitors like trametinib and PD-901/mirdametinib. Conclusions Together, BI-3406 and avutometinib specifically target NF1-null melanoma cells. These preclinical findings provide a strong foundation for clinical evaluation of this drug combination[1]."

IO biomarker • Melanoma • Oncology • Solid Tumor • BRAF • NF1

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 | Trial completion date: Mar 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Gynecologic Cancers • Oncology

RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models (Businesswire) - "Verastem Oncology announces multiple presentations focused on RAS/MAPK pathway inhibition at AACR Annual Meeting 2025....Abstract #: 4393....Combining avutometinib with a pan-RAF inhibitor (exarafenib or belvarafenib) led to strong tumor regressions in multiple NRAS- and BRAF-driven tumor models corresponding with nearly complete inhibition of RAS/MAPK pathway signaling."

Preclinical • Solid Tumor

Correlative preclinical studies to elucidate mechanisms of synergy of the combination of the RAF/MEK clamp avutometinib and the FAK inhibitor defactinib in low-grade serous ovarian cancer (Businesswire) - "Verastem Oncology announces multiple presentations focused on RAS/MAPK pathway inhibition at AACR Annual Meeting 2025....Abstract #: 6368....In a patient-derived LGSOC xenograft model, addition of a FAK inhibitor with avutometinib augmented tumor regression, more strongly inhibited RAS/MAPK pathway signaling compared to avutometinib alone and suppressed multiple putative mechanisms of resistance to avutometinib monotherapy including PI3K and YAP/TEAD signaling."

Preclinical • Ovarian Cancer

Key Milestones Expected for 2025: (Businesswire) - "Plan for FDA decision on NDA submitted for the combination of avutometinib plus defactinib in KRAS mutant recurrent LGSOC, expected by June 30, 2025; Plan to submit for NCCN guideline inclusion upon FDA approval; Primary analysis from both the FRAME and RAMP 201 clinical trials anticipated to be published in H1 2025."

Clinical data • FDA event • Ovarian Cancer

Fourth Quarter 2024 Financial Results (Businesswire) - "Verastem Oncology ended the fourth quarter of 2024 with cash, cash equivalents and investments of $88.8 million...additional sources of capital along with the existing cash, cash equivalents, and investments provide an expected cash runway through a potential launch of avutometinib and defactinib for recurrent LGSOC into Q4 2025."

Commercial • Ovarian Cancer

RAMP 205: Avutometinib Plus Defactinib in Combination with Chemotherapy in First-Line Metastatic Pancreatic Cancer (Businesswire) - P1b/2a | N=40 | RAMP205 (NCT05669482) | Sponsor: Verastem, Inc. | "Verastem announced an interim update on RAMP 205...A new dose level '0' was added to evaluate the doses of avutometinib and defactinib used in LGSOC, 3.2 mg of avutometinib, 200 mg of defactinib, in combination with 800 mg/m2 of gemcitabine and 100 mg/m2 of Nab-paclitaxel on a schedule of day 1, 8, and 15; All dose levels have been expanded to 12 patients each; 59 of 60 patients have been treated and enrollment is on track to be completed in Q1; Based on the initial safety and efficacy data from these cohorts, dose level 1 or 0 is anticipated to be chosen for expansion; Adverse events across all dose cohorts remained generally consistent with the previously announced safety and tolerability profile, and no new safety signals have emerged...Plan to present additional data at a medical meeting mid-year 2025. Select the recommended Phase 2 Dose (RP2D) for trial expansion in H1 2025."

P1/2 data • Trial status • Pancreatic Ductal Adenocarcinoma

Key Milestones Expected for 2025 (Businesswire) - "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 • P2 data • Ovarian Cancer

Avutometinib/Defactinib Combo Drives Responses in Recurrent Low-Grade Serous Ovarian Cancer (OncLive) - P2 | N=225 | RAMP 201 (NCT04625270) | Sponsor: Verastem, Inc. | "Treatment with the combination of avutometinib (VS-6766) and defactinib (VS-6063) led to a clinically meaningful overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) in patients with recurrent low-grade serous ovarian cancer, according to data from the RAMP 201 trial...presented at the 2025 Society of Gynecological Oncology Annual Meeting on Women’s Cancer....Findings showed that evaluable patients treated with avutometinib at 3.2 mg and defactinib at 200 mg (n = 109) experienced a confirmed ORR of 31% comprising a complete response (CR) rate of 2% and a partial response (PR) rate of 29%. The stable disease (SD) and progressive disease (PD) rates were 57% and 8%, respectively, and 4% of patients were not evaluable for response."

P2 data • Ovarian Cancer