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

To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer.

Start Date24 Feb 2025

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

NCT06630260

/ RecruitingPhase 1/2IIT

A Phase 1/2 Trial of the Doublet Combination of Avutometinib and Defactinib and As a Triplet in Combination with Temozolomide in Patients with High Grade Malignant Brain Tumours Within the 5G Platform

The purpose of this clinical trial is to evaluate the safety and tolerability of avutometinib and defactinib and to determine the preliminary antitumour activity of avutometinib and defactinib administered at the recommended Phase 2 dose (RP2D). In the Phase 1b of this study parallel biomarker defined arms will be opened, initially in the relapsed GMB setting, enrolling 12 patients onto each arm. These patients will be treated with avutometinib and defactinib double therapy. Avutometinib will be administered orally at 3.2mg twice a week (e.g., on Monday / Thursday or Tuesday / Friday) with or without a meal. The total weekly dose of avutometinib is 6.4mg. Defactinib will be administered orally, at 200mg, twice a day within 30 min after a meal. The total daily dose of defactinib is 400mg.
Once a treatment in any biomarker arm has met the "GO" decision (≥3 successes/12 patients) for relapsed GBM in Phase 1b, that arm can progress to Phase 2. The primary objective of Phase 2 is to determine the antitumour activity of investigational agents administered at the RP2D in patients with molecularly defined malignant brain tumours.

Start Date15 Nov 2024

Sponsor / Collaborator

The Institute of Cancer Research: Royal Cancer Hospital

[+5]

NCT06487221

/ RecruitingPhase 2IIT

A Phase II Trial of Avutometinib in Combination With Defactinib in Metastatic Diffuse Gastric Cancer

The purpose of this study is to determine if the combination study treatment with avutometinib and defactinib will prolong life in participants, is effective in decreasing the size of the tumor(s), and if it is safe in subjects with diffuse-type stomach cancer.

Start Date28 Oct 2024

Sponsor / Collaborator

Columbia University

[+1]

100 Clinical Results associated with Defactinib

100 Translational Medicine associated with Defactinib

100 Patents (Medical) associated with Defactinib

177

Literatures (Medical) associated with Defactinib

01 Jul 2025·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Discovery of potent focal adhesion kinase (FAK) inhibitor A8 with enhanced antitumor activity

Article

Author: Zhang, Chenyu ; Gan, Lu ; Li, Ye ; Zhang, Huabei ; He, Yong

FAK has emerged as a promising therapeutic target for cancer treatment due to its role in tumor survival, metastasis, and invasion. Herein, we report the rational design, synthesis, and comprehensive evaluation of a novel FAK inhibitor, compound A8. Our structure-activity relationship (SAR) studies identified A8 as a potent FAK inhibitor, with an FAK-IC₅₀ value of 0.87 nM, superior to VS6063 (1.49 nM). In vitro studies demonstrated that A8 significantly suppressed tumor cell viability, cancer stem cell activity, and cell migration in A549 and SKOV-3 cell lines. Mechanistic insights were provided by surface plasmon resonance (SPR) analysis, revealing high-affinity binding of A8 to FAK with a Kd value of 15 μM. Radiolabeling studies with [¹⁸F]A8 highlighted favorable tumor uptake and retention in S180 tumor-bearing mice. Notably, A8 efficiently penetrated the blood-brain barrier, with brain uptake values reaching 2.63 ± 0.63 %ID/g at 15 min and 1.62 ± 0.77 %ID/g at 120 min. In vivo antitumor efficacy trials in A549 and SKOV-3 tumor models confirmed A8's robust activity, with tumor inhibition rates of 59.15 % and 57.9 %, respectively, surpassing VS6063 and standard chemotherapeutics. Combination therapy with paclitaxel further enhanced A8's antitumor effects in SKOV-3 models. Acute toxicity studies indicated that A8 was well-tolerated up to 2000 mg/kg in mice, with no observed acute toxicity. Molecular docking and dynamics simulations substantiated the stable binding of A8 to the FAK protein. Collectively, our findings underscore the potential of compound A8 as a lead candidate for FAK-targeted cancer therapeutics, warranting further preclinical and clinical investigations.

03 May 2025·Journal of biomolecular structure & dynamics

Combining QSAR techniques, molecular docking, and molecular dynamics simulations to explore anti-tumor inhibitors targeting Focal Adhesion Kinase

Article

Author: Xing, Yi-chaung ; Tong, Jian-Bo ; Liu, Yuan ; Gao, Peng ; Xiao, Xue-chun ; Fan, Xuan-lu

Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__q2= 0.715, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__r2= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__q2= 0.707, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__r2= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors.

01 Apr 2025·INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER

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

Article

Author: Lustgarten, Stephanie ; Oaknin, Ana ; Monk, Bradley J ; Grisham, Rachel ; Harter, Philipp ; Van Nieuwenhuysen, Els ; Colombo, Nicoletta ; Cobb, Lauren ; Mirza, Mansoor Raza ; Lee, Yeh Chen ; Aghajanian, Carol A ; O'Malley, David M ; Oza, Amit M ; Gershenson, David ; Thaker, Premal ; Youssoufian, Hagop ; Banerjee, Susana ; Moore, Kathleen Nadine ; Coleman, Robert L ; Fabbro, Michel ; Choi, Chel Hun

Background:

There are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib has demonstrated efficacy and a consistent safety profile in two clinical trials in recurrent low grade serous ovarian cancer, and a lower discontinuation rate due to adverse events compared with historical rates for standard of care.

Primary Objective:

To compare the progression free survival of the combination of avutometinib with defactinib versus investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer.

Study Hypothesis:

Combination treatment with avutometinib–defactinib will significantly improve progression free survival compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer.

Trial Design:

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 is a phase 3, randomized, international, open label study designed to compare avutometinib with defactinib versus investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer who have progressed on a previous platinum based therapy. On confirmation of disease progression using a blinded independent central review, patients on the investigator’s choice of treatment arm may cross over to the avutometinib–defactinib arm.

Major Inclusion/Exclusion Criteria:

Patients must have recurrent low grade serous ovarian cancer (KRASmutant or wild-type) and have documented progression (radiographic or clinical) or recurrence of low grade serous ovarian cancer after at least one platinum based chemotherapy regimen. Unlimited additional previous lines of therapy are allowed, including previous MEK/RAF inhibitor. Patients will be excluded if they have co-existing high grade ovarian cancer or had previous treatment with avutometinib, defactinib, or any other FAK inhibitor.

Primary Endpoint:

Progression free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded-independent central review.

Sample Size:

Approximately 270 patients will be randomized in a 1:1 fashion to either the combination avutometinib with defactinib arm (n~135) or the investigator’s choice of treatment arm (n~135).

Estimated Dates for Completing Accrual and Presenting Results:

The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031.

Trial Registration:

ClinicalTrials.govNCT06072781

News (Medical) associated with Defactinib

09 May 2025

·pipelinereview.com

FDA Approves the AVMAPKI™ FAKZYNJA™ Combination Therapy as the First-Ever Treatment for Adult Patients with KRAS-mutated Recurrent Low-Grade Serous Ovarian Cancer

AVMAPKI plus FAKZYNJA to be commercially available by prescription as a convenient oral combination co-packaged together and will be known as “AVMAPKI FAKZYNJA CO-PACK” Accelerated approval, well ahead of the June 30, 2025 PDUFA action date, was based on the Phase 2 RAMP 201 study that demonstrated a 44% overall response rate in patients with KRAS mutant recurrent LGSOC Verastem to host investor conference call and webcast today at 2:30 pm ET BOSTON, MA, USA I May 08, 2025 I Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with RAS/MAPK pathway-driven cancers, today announced that the U.S. Food and Drug Administration (FDA) has approved 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 received prior systemic therapy. AVMAPKI FAKZYNJA CO-PACKis the first and only FDA-approved medicine for this disease. This indication is approved under accelerated approval based on the tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. AVMAPKI plus FAKZYNJA is only commercially available in the U.S. as an oral combination co-pack with the two prescription products, known as “AVMAPKI FAKZYNJA CO-PACK.” “Today’s approval of AVMAPKI FAKZYNJA CO-PACK for patients with KRAS-mutated recurrent low-grade serous ovarian cancer represents not only the first-ever FDA-approved treatment specifically for this rare cancer but also a new day for people living with this disease who have been in desperate need of new treatment options,” said Dan Paterson, president and chief executive officer of Verastem Oncology. “We are very proud to bring two innovative medicines in one combination treatment to the LGSOC community. We thank the researchers, patients, and their families participating in our clinical trials, the patient advocacy community, the FDA, and everyone at Verastem for their dedication and commitment to helping us bring AVMAPKI FAKZYNJA CO-PACK to patients in the U.S.” The accelerated approval of AVMAPKI FAKZYNJA CO-PACKis based on the Phase 2 RAMP 201 clinical trial, which evaluated the combination of AVMAPKI and FAKZYNJA in adult patients with measurable KRAS-mutated recurrent LGSOC. “Low-grade serous ovarian cancer is a rare and highly recurrent cancer with limited effective treatment options. This first-ever FDA approval in this disease was based on the primary analysis of the Phase 2 RAMP 201 trial, in which the combination of avutometinib and defactinib resulted in a significant overall response rate for patients with a KRAS mutation while being generally well tolerated,” said Rachel Grisham, M.D., Section Head, Ovarian Cancer at Memorial Sloan Kettering Cancer Center in New York, NY and Global Lead Principal Investigator of GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301. “The approval of avutometinib plus defactinib brings a much-needed therapeutic option to patients and establishes this combination as the new standard of care for women with recurrent low-grade serous ovarian cancer harboring a KRAS mutation. I look forward to progressing the confirmatory Phase 3 trial, RAMP 301, where we look to continue to support the ongoing body of research of this combination in women with and without a KRAS mutation.” “To see our early research in both the FRAME and RAMP 201 trial in recurrent low-grade serous ovarian cancer advance the combination of avutometinib and defactinib to now be the first-ever FDA-approved therapy for this disease is what gives us real hope when treating patients with rare or difficult-to-treat gynecological cancers,” said Professor Susana Banerjee, M.B.B.S., M.A., Ph.D., F.R.C.P, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London and Global Lead Principal Investigator of ENGOTov60/GOG3052 /NCRI/RAMP201. “With this approval, we thank all of the patients and researchers who participated in this trial, and the low-grade serous ovarian cancer community for their contributions to help bring the first FDA-approved treatment for KRAS-mutated recurrent LSGOC and changing the treatment possibilities for RAS/MAPK-pathway-driven cancers. We now need to build on this milestone to bring this new treatment to patients around the world.” Prior to this approval, there were no FDA-approved treatments specifically for KRAS-mutated recurrent LGSOC, a rare and distinct ovarian cancer that differs from high-grade serous ovarian cancer in both its biology and how it responds to treatment. “One of the most devastating aspects of my LGSOC diagnosis was learning there are no FDA-approved treatments for this rare cancer. While there were some treatment options at the time that I could try, I made it my mission to advocate for research specific to my disease,” said Nicole Andrews, chair of the STAAR Low-Grade Serous Ovarian Cancer Foundation. “Today we’re celebrating a milestone with the first-ever FDA-approved treatment option specifically for patients with recurrent LGSOC with a KRAS mutation. The low-grade serous ovarian cancer community is hopeful and excited about the potential benefits of this treatment and the progress toward improving the diagnosis, awareness, and research for LGSOC.” AVMAPKI FAKZYNJA CO-PACK is the first treatment to receive regulatory approval anywhere in the world, specifically for KRAS-mutated recurrent LGSOC. The Company believes AVMAPKI FAKZYNJA CO-PACK is also the first-ever oral, novel/novel combination therapy approved in oncology. Verastem initiated a rolling new drug application (NDA) with the FDA in May 2024 and completed its NDA submission in October 2024. The FDA granted Priority Review, and the approval was received in advance of its Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025. The FDA granted Breakthrough Therapy Designation for the treatment of patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy, in May 2021. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC. The AVMAPKI FAKZYNJA CO-PACK is expected to be available for adult patients with KRAS-mutated recurrent LGSOC in the U.S. in one week. Verastem’s Commitment to Patient Support Verastem Oncology is committed to providing patient access and reimbursement support through its Verastem Cares™ program in the U.S. Verastem Cares™ offers a range of patient access and reimbursement support services to help U.S. patients prescribed AVMAPKI FAKZYNJA CO-PACK receive treatment access. Verastem Cares™ case managers can be reached at 1-866-351-8372 between 8:00 am-8:00 pm Eastern Time, Monday through Friday. Verastem to Host Investor Call on AVMAPKI FAKZYNJA CO-PACK FDA Approval Verastem will hold an investor conference call and webcast today at 2:30 pm ET, to discuss the FDA approval of AVMAPKI FAKZYNJA CO-PACK. To access the conference call, please dial (844) 763-8274 (local) or (412) 717-9224 (international) at least 10 minutes prior to the start time and ask to be joined into the Verastem Oncology conference call. A live audio webcast of the call, along with accompanying slides, will be accessible under “Events & Presentations” in the Investors & Media section of the Company’s website at www.verastem.com . Basis of Approval: RAMP 201 Trial Results The efficacy of AVMAPKI and FAKZYNJA, in combination, was evaluated in the RAMP 201 clinical trial (NCT04625270), an open-label, multicenter study that included 57 adult patients with measurable KRAS -mutated recurrent LGSOC. Patients were required to have received at least one prior systemic therapy, including a platinum-based drug. Patients received AVMAPKI 3.2 mg orally twice weekly for the first three weeks out of a four-week cycle and FAKZYNJA 200 mg orally twice daily for the first three weeks out of a four-week cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent review committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. An additional efficacy outcome measure was duration of response (DOR). Tumor response assessments occurred every eight weeks for the first 72 weeks and every 12 weeks thereafter. In the study, AVMAPKI and FAKZYNJA, in combination, showed in patients with a KRAS mutation a confirmed ORR by BICR of 44% (25/57; 95% CI: 31-58). The median DOR ranged from 3.3 to 31.1 months in the KRAS mutant population. The safety of AVMAPKI and FAKZYNJA, in combination, was evaluated in 57 patients with KRAS- mutated recurrent LGSOC. Possible serious side effects with AVMAPKI FAKZYNJA CO-PACK include ocular disorders, skin toxicities (rash), hepatotoxicity, rhabdomyolysis, and fetal harm when administered during pregnancy. The most common side effects, including laboratory changes, of AVMAPKI FAKZYNJA CO-PACK include increased levels of an enzyme in the blood (CPK), nausea, fatigue, abnormal liver test (AST), and rash. About Low-Grade Serous Ovarian Cancer (LGSOC) LGSOC is a rare ovarian cancer that is insidious and persistent. LGSOC is distinct and different from high-grade serous ovarian cancer (HGSOC) and requires different treatment. LGSOC is highly recurrent and less sensitive to chemotherapy compared to HGSOC. Approximately 6,000-8,000 women in the U.S. and 80,000 worldwide are living with this disease. LGSOC affects younger women with bimodal peaks of diagnosis at ages between 20-30 and 50-60 and has a median survival of approximately ten years. Approximately 70 percent of LGSOC shows RAS pathway-associated mutations, and 30 percent of people with LGSOC have a KRAS mutation. The majority of patients report a negative impact of LGSOC on their mental and physical health, fertility, and long-term quality of life. The current standard of care for LGSOC includes hormone therapy and chemotherapy. About AVMAPKI and FAKZYNJA Combination Therapy AVMAPKI (avutometinib) inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway. Blocking RAF and/or MEK activates FAK, a key mediator of drug resistance. FAKZYNJA (defactinib) is a FAK inhibitor and together, the avutometinib and defactinib combination was designed to provide a more complete blockade of the signaling that drives the growth and drug resistance of RAS/MAPK pathway-dependent tumors. Additional clinical investigations: Verastem Oncology is conducting clinical trials with avutometinib with and without defactinib in RAS/MAPK-driven tumors as part of its Raf And Mek Program or RAMP. RAMP 301 (GOG-3097/ENGOT-ov81/GTG-UK) (NCT06072781), is an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC) with and without a KRAS mutation. RAMP 203 (NCT05074810) is a Phase 1/2, multicenter, open-label, dose evaluation/expansion study, being conducted in collaboration with Amgen, evaluating the efficacy and safety of avutometinib and sotorasib with or without defactinib in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have been previously treated with a KRAS G12C inhibitor (NCT05074810). RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award. Avutometinib and defactinib are not approved by the FDA or any other regulatory authority, either in combination or with other therapies, for any of these investigative uses. Neither avutometinib nor defactinib are approved by the FDA or any other regulatory authority on a stand-alone basis for any use. Additional media assets are available on Verastem Oncology’s website . AVMAPKI FAKZYNJA CO-PACK U.S. Indication Indication AVMAPKI FAKZYNJA CO-PACK is indicated for the treatment of adult patients with KRAS -mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Click here for full Prescribing Information . About Verastem Oncology Verastem Oncology (Nasdaq: VSTM) is a biopharmaceutical company committed to developing and commercializing new medicines to improve the lives of patients diagnosed with RAS/MAPK pathway-driven cancers. Verastem markets AVMAPKI™ FAKZYNJA™ CO-PACK in the U.S. Our pipeline is focused on novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition, FAK inhibition, and KRAS G12D inhibition. For more information, please visit www.verastem.com and follow us on LinkedIn . SOURCE: Verastem Oncology

Clinical ResultDrug ApprovalPhase 3Phase 2Breakthrough Therapy

08 May 2025

·firstwordpharma.com

Verastem's ovarian cancer combo cleared for patients with KRAS mutations

The FDA on Thursday granted accelerated approval to Verastem's cancer combo, Avmapki Fakzynja Co-pack (avutometinib and defactinib), though the indication was narrower than investors had been hoping for. Specifically, the doublet was cleared to treat adults with KRAS-mutated, recurrent, low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. Avutometinib and defactinib — a RAF/MEK clamp and selective FAK inhibitor, respectively — had earned breakthrough therapy designation for LGSOC in 2021, regardless of KRAS mutation status. Last May, when Verastem started its rolling submission to the FDA for the combo to treat KRAS-mutated LGSOC, rather than the general LGSOC population, the stock market reacted unfavourably. At the time, the drugmaker had assured investors that "the proposed indication for final submission of the clinical module can be expanded in the event Verastem provides data that demonstrates a substantial improvement over available therapy in the KRAS wild-type population."Regardless of the indication, Verastem has been readying to commercialise Avmapki Fakzynja Co-pack. The company raised $75 million in a private placement last month to fuel the drug's rollout. Pancreatic cancer up nextThe doublet, which was assessed under priority review, was greenlit based on data from the Phase II trial RAMP 201. In the study, 57 adults with KRAS-mutated recurrent LGSOC received an oral 3.2-mg dose of avutometinib twice weekly, and two oral daily doses of 200 mg defactinib.The doublet achieved a confirmed overall response rate of 44%, while duration of response ranged from 3.3 months to 31.1 months.The most common adverse reactions that occurred in a quarter or more of patients include nausea, fatigue, rash, diarrhoea and musculoskeletal pain, among others.Verastem is also evaluating Avmapki Fakzynja Co-pack in the Phase I/II RAMP 205 study in patients with front-line metastatic pancreatic cancer.

Clinical ResultPhase 2Drug ApprovalPriority ReviewBreakthrough Therapy

08 May 2025

·www.fda.gov

FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer

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.Full prescribing information for Avmapki Fakzynja Co-pack will be posted on Drugs@FDA.Efficacy was evaluated in RAMP-201 (NCT04625270), an open-label, multicenter trial that included 57 adult patients with measurable KRAS-mutated recurrent LGSOC. Patients were required to have received at least one prior systemic therapy, including a platinum-based regimen. KRAS mutation status was determined by prospective local testing of tumor tissue. Patients received avutometinib 3.2 mg orally twice weekly (Day 1 and Day 4) and defactinib 200 mg orally twice daily, both taken for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent review committee according to RECIST v1.1. An additional efficacy outcome measure was duration of response (DOR). Confirmed ORR was 44% (95% CI: 31, 58) and the DOR range was 3.3 months to 31.1 months.The most common adverse reactions (≥25%), including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, increased blood bilirubin, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, dermatitis acneiform, vitreoretinal disorders, increased alkaline phosphatase, stomatitis, pruritus, visual impairment, decreased platelet count, constipation, dry skin, dyspnea, cough, urinary tract infection, and decreased neutrophil count.The recommended avutometinib dose is 3.2 mg (four 0.8 mg capsules) taken orally twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. The recommended defactinib dose is 200 mg (one tablet) taken orally twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.This application was granted priority review. Avutometinib in combination with defactinib was granted breakthrough therapy designation and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.Follow the Oncology Center of Excellence on X: @FDAOncology.

Priority ReviewDrug ApprovalBreakthrough TherapyClinical ResultAccelerated Approval

100 Deals associated with Defactinib

External Link

KEGG	Wiki	ATC	Drug Bank
D10618	-	-	DB12282

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Ovarian Serous Tumor	United States	Verastem Oncology	08 May 2025

Developing

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Borderline serous tumour of ovary	NDA/BLA	United States	Verastem, Inc.	24 May 2024
Glioblastoma Multiforme	Phase 2	United Kingdom	Verastem, Inc.	15 Nov 2024
Advanced Lung Adenocarcinoma	Phase 2	United States	Emory University	31 Jul 2024
BRAF V600E Mutation-Positive Melanoma	Phase 2	United States	Verastem, Inc.	07 Mar 2024
Brain metastases	Phase 2	United States	Verastem, Inc.	07 Mar 2024
Locally Advanced Melanoma	Phase 2	United States	Verastem, Inc.	07 Mar 2024
Melanoma, Cutaneous Malignant	Phase 2	United States	Verastem, Inc.	07 Mar 2024
Differentiated Thyroid Gland Carcinoma	Phase 2	United States	Verastem, Inc.	16 Aug 2023
Refractory Thyroid Gland Carcinoma	Phase 2	United States	Verastem, Inc.	16 Aug 2023
thyroid gland poorly differentiated carcinoma	Phase 2	United States	Verastem, Inc.	16 Aug 2023

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04439331 (MATCH, CTgov)	Phase 2	Refractory Malignant Solid Neoplasm \| Advanced Malignant Solid Neoplasm \| Advanced Lymphoma ... View more	35	Defactinib Hydrochloride	arobtncdmr = xmswwnwkig djvovpbacz (tgefdxbqnk, mdcrfmkebj - cxyfzeuofw) View more	-	08 Apr 2025
NCT05074810 (RAMP 203, BusinessWire) Manual	Phase 1/2	KRAS G12C mutant Non-small Cell Lung Cancer KRAS G12C	3	Defactinib，Avutometinib, sotorasib	yohwtxfhxu(hcenpvubau) = None awuyleadgw (xkxezmbzte ) View more	Positive	18 Dec 2024
NCT04625270 (RAMP 201 \| ENGOTov60/GOG3052, Company_Website) Manual	Phase 2	Ovarian Serous Tumor	109	Avutometinib and Defactinib Combination	hupjinilgd(ooccoajfff) = wabongsvmm lxcanvboyl (wcffbijdtx, 23 - 41) View more	Positive	17 Oct 2024
				Avutometinib and Defactinib Combination (KRAS mutant)	hupjinilgd(ooccoajfff) = nrltafwcxx lxcanvboyl (wcffbijdtx, 31 - 58) View more
NCT05669482 (RAMP 205, ASCO2024) Manual	Phase 1/2	Metastatic Pancreatic Ductal Adenocarcinoma First line	18	Avutometinib/defactinib + gemcitabine/nab-paclitaxel	esmlzvjdrg(icyakyuiab) = nntxtjgroy mremvbswka (abnulffnpd ) View more	Positive	24 May 2024
NCT02004028 (CTgov)	Phase 2	Malignant Pleural Mesothelioma	35	Defactinib (Cohort 1)	hszlhndogq(tdjoslqaji) = rafvfvpakr uawomjkqkn (ejqiyseaoo, wimlrvtwfl - fprboibbjz) View more	-	20 Feb 2024
				Defactinib (Cohort 2)	hszlhndogq(tdjoslqaji) = tzwpjjtnbu uawomjkqkn (ejqiyseaoo, tlgctigqxe - gixmmftfce) View more
NCT04625270 (ENGOT-Ov60/GOG-3052/RAMP 201, ESGO2023)	Phase 2	Ovarian Serous Tumor KRAS mutant \| KRAS wild-type	151	Avutometinib	zrmmglfzun(nglejkasch) = xnjguninru zailjyeyac (dcbdzctyyh ) View more	Positive	27 Sep 2023
				Avutometinib + Defactinib	zrmmglfzun(nglejkasch) = gltfecvkwm zailjyeyac (dcbdzctyyh ) View more
NCT04625270 (RAMP 201, ASCO 12023 \| ASCO 22023) Manual	Phase 2	Ovarian Cancer	121	avutometinib 4 mg	eihsjhrmrx(ceyykqpdiu) = ewysbsyigs zpkuimbtyb (ivnhfcndqj ) View more	Positive	31 May 2023
				avutometinib 3.2 mg+defactinib 200 mg	eihsjhrmrx(ceyykqpdiu) = ofypsbxokg zpkuimbtyb (ivnhfcndqj ) View more
NCT03727880 (ASCO2023) Manual	Phase 2	Pancreatic Ductal Adenocarcinoma Neoadjuvant \| Adjuvant	-	Pembrolizumab+Defactinib	tupuhddgvq(ipzabbwehh) = tcezvnnvfm hobsvdmkwd (qmnpyxunqt ) View more	Positive	31 May 2023
				Pembrolizumab	tupuhddgvq(ipzabbwehh) = gjmbdrlcbp hobsvdmkwd (qmnpyxunqt ) View more
NCT02546531 (ASCO2022) Manual	Phase 1	Pancreatic Cancer	-	Defactinib+Pembrolizumab+gemcitabine (PDAC)	wdoygsbhko(goqprcbour) = bffzcvnyix ttyundkrff (zoashltjbz ) View more	Positive	02 Jun 2022
				Defactinib+Pembrolizumab+gemcitabine (PDAC in maintenance cohort)	wdoygsbhko(goqprcbour) = prllprlqfr ttyundkrff (zoashltjbz ) View more
NCT03875820 (ESMO 12021 \| ESMO 22021) Manual	Phase 1	Ovarian Cancer	25	VS-6766+defactinib	qfmlyyxsof(uqycczipjq) = etnqcettid djtfzgwsng (vqpeivsysa ) View more	Positive	19 Sep 2021
				VS-6766+defactinib (pts with KRAS mutations)	qesvkvbnon(costtkbhru) = bofhjvsxyu udblwntqpi (tsfxsbyhtk, 35 - 85)

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