Approval Probability
TA Base Rate
Adjusted LOA
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Label 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 [see Clinical Studies (14) ]. FDA label
Also known as VS-6766, avutometinib (VS-6766), CH-5126766, CKI-27, R-7304, RG 7304, RO5126766
Avutometinib · 16 trials · 39 indications
Progression-free survival (PFS) according to RECIST version 1.1, per blinded independent central review (BICR)
Treatment exposure will be summarized descriptively for participants receiving continued treatment with avutometinib in combination with defactinib after completion of Study VS-6766-201 (RAMP-201).
Confirmed overall response rate (ORR; partial response \[PR\] + complete response \[CR\] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\]) as assessed by the blinded independent central radiology review committee (BICR)
To determine the efficacy of combination defactinib and avutometinib in patients with metastatic diffuse gastric cancer (DGC) as measured by 6-month progression-free survival (PFS) rate. PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
To evaluate the efficacy of Avutometinib (VS-6766) + defactinib in endometrioid, MOC, HGSOC and solid gynecological cancer patients with RAS/BRAF/NF1 mutations on confirmed overall response rate (ORR; partial response \[PR\] + complete response \[CR\] defined according to RECIST 1.1) as assessed by the investigator.
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed ORR defined according to RECIST 1.1
The maximum tolerated dose of VS-6766 in combination with cetuximab in participants who have KRAS-mutated metastatic colorectal cancer after disease progression or evidence of intolerance to fluorouracil (5- FU) /capecitabine, oxaliplatin, irinotecan and bevacizumab (if indicated). Doctors leading the study will find the maximum tolerated dose by assessing the rate of serious side effects (known as "dose limiting toxicities") among participants according to the NCI Common Terminology Criteria (CTCAE) for Adverse Events Version 5.
Objective response rate or participants who take the maximum tolerated dose (MTD) of VS-6766 combined with cetuximab that was established in phase 1 (the dose-finding portion) of the study. The objective response rate (how the participant's cancer responds to the study drugs) will be measured and assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
For each participant, we will determine DLTs during first cycle of neoadjuvant therapy
PR (partial response) or CR (complete response) per RECIST criteria
To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0
Antitumour activity will be defined on the basis of the following outcomes. If any of the following occur, patients will be considered to have clinically benefitted: For relapsed GBM: Achievement of overall response of CR or PR per Response Assessment in Neuro-Oncology (RANO) within 6 months or Free of disease progression or death at 6 months For front line unmethylated GBM (MRD): • Progression-free survival (PFS)
Antitumour activity will be defined on the basis of the following outcomes: Progression-free survival (PFS), defined as the time from enrolment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RANO Overall survival (OS), defined as the time from enrolment to death from any cause
Assessment of Dose-limiting toxicities (DLTs)
Confirmed overall response rate (ORR) (partial response \[PR\] + complete response \[CR\] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST 1.1\])
Determine maximum tolerated dose (MTD) of VS-6766 in combination with abemaciclib and fulvestrant using Bayesian Optimal Interval Design
Determine Recommended Phase II Dose (RP2D) of VS-6766 in combination with abemaciclib and fulvestrant using Bayesian Optimal Interval Design
The primary endpoint in phase II is assessment of the clinical benefit rate (CBR; complete response + partial response + stable disease for \>/=24 weeks)
Assessment of Dose-limiting toxicities (DLTs)
Confirmed overall response rate per RECIST 1.1
Assessment of Dose-limiting toxicities (DLTs)
Confirmed overall response rate per RECIST 1.1
To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT) as specified in the protocol.
To assess the safety and toxicity profile of VS-6766 and Defactinib. To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Defactinib concentration will be measured in a sample of the glioblastoma, brain around the glioblastoma, and in a serum sample from each subject receiving Defactinib. Descriptive statistics, such as mean and standard deviation, will be generated with these results. Concentration will be compared between dose levels within study drug using two-sample t-tests or non-parametric equivalents such as Mann Whitney U tests.
VS-6766 concentration will be measured in a sample of the glioblastoma, brain around the glioblastoma, and in a serum sample from each subject receiving VS-6766. Descriptive statistics, such as mean and standard deviation, will be generated with these results. Concentration will be compared between dose levels within study drug using two-sample t-tests or non-parametric equivalents such as Mann Whitney U tests.
Will be assessed by quantification of the recognized side effects of this agent including fatigue, nausea, diarrhea, vomiting, hyperbilirubinemia, decreased appetite, peripheral edema, dizziness, and headache and by monitoring for new or undescribed adverse events. Summary statistics will include frequencies and percentages of adverse events.
Will be assessed by quantification of the recognized side effects of this agent including rash, creatine phosphokinase elevation, visual disturbances, hypoalbuminemia, and fatigue and by monitoring for new or undescribed adverse events. Summary statistics will include frequencies and percentages of adverse events.
| Arm | Type | Description |
|---|---|---|
| avutometinib + defactinib | EXPERIMENTAL | Avutometinib 3.2 mg, PO, twice weekly for 21 days on, 7 days off in a 28-day (4 weeks) cycle in combination with defactinib 200 mg, PO, twice daily for 21 days on, 7 days off in a 28-day(4 week) cycle. |
| Investigator Choice of Treatment (ICT) | ACTIVE_COMPARATOR | Patients will receive one of the following therapies as determined by the Investigator: * Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle. * Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle. * Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle. |
| Continued Treatment of Avutometinib + Defactinib | EXPERIMENTAL | To provide continued treatment with avutometinib in combination with defactinib for participants with recurrent LGSOC who are deriving continued clinical benefit after completion of the VS-6766-201 (RAMP-201) study |
| Avutometinib & Defactinib | EXPERIMENTAL | Avutometinib: Study participants will receive Avutometinib 3.2mg orally two times per week for three weeks in a row followed by one week of rest Defactinib: Study participants will receive Defactinib 200mg twice daily for three weeks in a row followed by one week of rest |
| Avutometinib (VS-6766) + Defactinib | EXPERIMENTAL | Avutometinib (VS-6766): will be administered at 3.2 mg orally twice a week Defactinib: will be administered at 200 mg orally twice a day (BID). |
| Arm 1: avutometinib (VS-6766) monotherapy | EXPERIMENTAL | in patients with NSCLC KRAS-G12V tumor |
| Arm 2: avutometinib (VS-6766) in combination with defactinib | EXPERIMENTAL | in patients with a NSCLC KRAS-G12V tumor |
| Arm 3: avutometinib (VS-6766) in combination with defactinib | EXPERIMENTAL | in patients with a NSCLC KRAS-other (non-G12V) tumor |
| Arm 4: avutometinib (VS-6766) in combination with defactinib | EXPERIMENTAL | in patients with a NSCLC BRAF-V600E tumor |
| Arm 5:avutometinib (VS-6766) in combination with defactinib | EXPERIMENTAL | in patients with a NSCLC BRAF-non-V600E tumor |
| Part A | EXPERIMENTAL | To determine the optimal regimen, either avutometinib(VS-6766) monotherapy or avutometinib (VS-6766) in combination with defactinib, for subsequent evaluation for efficacy in the Expansion Phase (Part B) |
| Part B | EXPERIMENTAL | To determine the efficacy of the optimal regimen identified from Part A |
| Part C: | EXPERIMENTAL | To evaluate additional efficacy parameters for the optimal regimen identified in Part A. |
| Part D | EXPERIMENTAL | To evaluate additional efficacy parameters for a lower dose of avutometinib in combination with defactinib |
| Phase 1(Dose-Finding Arm): Group 1 - Dose Level 1 (Starting Dose) | EXPERIMENTAL | This study will use two dose levels (a starting dose at level 1 and a second dose highest dose at level 2) of the VS-6766 and cetuximab regimen. If participants in group 1 don't experience severe negative side effects to the starting dose of the regimen, then more participants will be assigned to group 2 at a higher dose until the safest/ most tolerable dose is found. If participants show toxic side effects to the first pre-determined dose, the dose will be decreased to the next lower dose level. Group 1/ Dose Level 1: Participants in group 0 will receive the starting dose of study drugs (below): * VS-6766 (2.4mg) orally twice a week * cetuximab (500mg) via intravenous (IV) needle in vein every 2 weeks During phase 1, VS-6766 and cetuximab will be given in 28-day "cycles" (a period of time when participants receive study drugs). Participants in this portion of the study will receive 12 cycles of VS-6766 and cetuximab. |
| Phase 1(Dose-Finding Arm): Group 2- Dose Level 2 (Second Highest Dose) | EXPERIMENTAL | This study will use two dose levels (a starting dose at level 1 and a second dose highest dose at level 2) of the VS-6766 and cetuximab regimen. If participants in group 1 don't experience severe negative side effects to the starting dose of the regimen, then more participants will be assigned to group 2 at a higher dose until the safest/ most tolerable dose is found. If participants show toxic side effects to the first pre-determined dose, the dose will be decreased to the next lower dose level. Participants in group 2 will receive the second highest dose of study drugs (below): * VS-6766 (3.4mg) orally twice a week * cetuximab (500mg) via intravenous (IV) needle in vein every 2 weeks During phase 1, VS-6766 and cetuximab will be given in 28-day "cycles" (a period of time when participants receive study drugs). Participants in this portion of the study will receive 12 cycles of VS-6766 and cetuximab. |
| Phase 1(Dose-Finding Arm): Group 3 - Lower Dose Level 1 | EXPERIMENTAL | Participants in this group will received a lower dose of the VS6766 and cetuximab regimen. Inclusion in this group is optional and based on whether the participant reports serious side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * VS-6766 (2.4mg) orally twice a week * cetuximab (400mg) via intravenous (IV) needle in vein every 2 weeks |
| Phase 1(Dose-Finding Arm): Group 4 - Lower Dose Level 2 | EXPERIMENTAL | Participants in this group will received the second lowest dose of the VS6766 and cetuximab regimen. Inclusion in this group is optional and based on whether the participant reports serious side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * VS-6766 (2.4mg) orally twice a week * cetuximab (300mg) via intravenous (IV) needle in vein every 2 weeks |
| Phase 2 (Efficacy Arm/ Expansion Cohort) | EXPERIMENTAL | Participants in this arm will help test the efficacy of the VS-6766 and cetuximab dose established in phase 1 of the study. Participants will take the same two drugs ( VS-6766 and cetuximab) at the best tolerated dose that was found during the first phase of the study. Participants in this group will also keep a pill diary. This helps you keep track of when you take your pills. The study team at your doctor's office will show you how to use this diary. Each time you visit the clinic, you must bring the pill diary, any remaining pills, and the pill bottle. |
| Neoadjuvant avutometinib + defactinib with standard of care chemotherapy | EXPERIMENTAL | Avutometinib and defactinib will be taken for 3 weeks, followed by a 1-week rest period in each 4 week cycle. |
| Phase 1b | EXPERIMENTAL | The Phase 1b will evaluate the safety and tolerability of combination of avutometinib and defactinib and determine its preliminary antitumour activity when administered at the recommended Phase 2 dose (RP2D) in patients with molecularly defined malignant brain tumours. |
| Phase 2 | EXPERIMENTAL | The Phase 2 part of the study will determine the antitumour activity of investigational agents administered at the RP2D in patients with molecularly defined malignant brain tumours. Avutometinib and defactinib may be administered in combination with temozolomide (TMZ). |
| Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib | EXPERIMENTAL | To determine the recommended phase 2 dose (RP2D) for gemcitabine Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib in patients with untreated metastatic PDAC. |
| Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib RP2D | EXPERIMENTAL | To determine the efficacy of the RP2D identified in Part A in untreated metastatic PDAC patients |
| Phase 1 Dose Escalation | EXPERIMENTAL | During 28 day/4 week study cycle, participants will receive: * VS-6766 2x weekly for 3 out of the 4 week cycle * Abemaciclib 2x daily * Fulvestrant on day 1 of each study cycle (and day 15 of cycle 1 only) |
| Phase 2 Dose Expansion | EXPERIMENTAL | Participants will receive VS-6766 with abemaciclib and fulvestrant at the recommended phase II doses determined in the phase I portion of the study. |
| avutometinib(VS-6766)+adagrasib | EXPERIMENTAL | To determine the recommended phase 2 dose (RP2D) for VS-6766 in combination with adagrasib in G12C inhibitor exposed patients |
| avutometinib (VS-6766)+adagrasib RP2D | EXPERIMENTAL | To determine the efficacy of the RP2D identified from Part A in G12C inhibitor exposed patients |
| avutometinib (VS-6766)+sotorasib | EXPERIMENTAL | To determine the recommended phase 2 dose (RP2D) for avutometinib (VS 6766) in combination with sotorasib in KRAS G12C inhibitor naïve and exposed patients |
| avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve | EXPERIMENTAL | To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients |
| avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed | EXPERIMENTAL | To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients |
| avutometinib (VS-6766)+sotorasib+defactinib | EXPERIMENTAL | To determine the recommended phase 2 dose (RP2D) for avutometinib (VS-6766) in combination with sotorasib and defactinib in KRAS G12C inhibitor exposed patients |
| avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive | EXPERIMENTAL | To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients |
| avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed | EXPERIMENTAL | To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients |
| Dose Escalation Phase | EXPERIMENTAL | Escalating doses of VS-6766 (RO5126766) and Defactinib (VS-6063) were evaluated in patients with advanced solid tumours to establish the recommended phase II dose. Dose escalation followed a 3+3 design with a maximum of four patient cohorts. This arm is now complete. |
| Dose Expansion KRAS mutant NSCLC Cohort | EXPERIMENTAL | The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS mutant NSCLC (20 patients). This arm is now complete. |
| Dose Expansion biopsy cohort | EXPERIMENTAL | The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients advanced RAS mutant solid tumours with biopsiable disease (6 patients). This arm is now complete. |
| Dose Expansion LGSOC cohort | EXPERIMENTAL | The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with LGSOC (20 patients). |
| Dose Expansion CRC cohort | EXPERIMENTAL | The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with CRC (10 patients). This arm is now complete. |
| Dose Expansion KRAS G12V mutant NSCLC cohort | EXPERIMENTAL | The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS G12V mutant NSCLC (10 patients). |
| Dose Expansion RAS/RAF mutant endometrioid cancer cohort | EXPERIMENTAL | The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) (10 patients). |
| Dose Expansion pancreatic cancer | EXPERIMENTAL | The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with pancreatic cancer (10 patients). |
| Arm I (Defactinib) | EXPERIMENTAL | Patients receive 1 dose of defactinib PO while on study, prior to planned tumor resection. Patients undergo blood collection and donate resected tumor tissue while on study. |
| Arm II (Avutometinib) | EXPERIMENTAL | Patients receive 1 dose of avutometinib PO while on study, prior to planned tumor resection. Patients undergo blood collection and donate resected tumor tissue while on study. |
| Name | Type | Description |
|---|---|---|
| avutometinib | DRUG | Avutometinib: administered orally |
| Defactinib | DRUG | Defactinib: administered orally |
| Pegylated liposomal doxorubicin | DRUG | administered intravenously |
| Paclitaxel | DRUG | administered intravenously |
| Letrozole | DRUG | administered orally |
| Anastrozole | DRUG | administered orally |
| avutometinib + defactininb combination | DRUG | Avutometinib: administered orally twice a week Defactinib: administered orally twice daily |
| Avutometinib (VS-6766) + Defactinib (VS-6063) | DRUG | combination therapy |
| Avutometinib (VS-6766) + defactinib | DRUG | Avutometinib (VS-6766): will be administered at 3.2 mg orally twice a week Defactinib: will be administered at 200 mg orally twice a day (BID). Treatment will be for 3 weeks, followed by a 1-week rest period, in each 4-week (28 day) cycle. |
| avutometinib (VS-6766) | DRUG | Monotherapy |
| avutometinib (VS-6766) and Defactinib | DRUG | Combination therapy |
| VS-6766/avutometinib | DRUG | An oral anti-cancer medication. |
| Cetuximab | DRUG | A chemotherapy drug used to treat head, neck and colorectal cancer. |
| Pill Diary | OTHER | A diary where participants in phase 2 of study will log their medications and times they are taken on study. |
| Temozolomide | DRUG | Temozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules. |
| avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel | DRUG | The RP2D of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel determined in Part A will be used in Part B dose expansion. |
| VS-6766 | DRUG | Taken Orally |
| Abemaciclib | DRUG | Taken Orally |
| Fulvestrant | DRUG | Administered by intramuscular injection |
| avutometinib (VS-6766) and adagrasib | DRUG | The RP2D of VS-6766 + adagrasib determined in Part A will be used in Part B dose expansion |
| avutometinib and sotorasib | DRUG | The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion |
| avutometinib and sotorasib and defactinib | DRUG | The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion |
| Biospecimen Collection | PROCEDURE | Undergo blood and tissue sample collection |
Inclusion Criteria: Patients may be eligible for inclusion in the study if they meet the following criteria: 1. Histologically proven LGSOC (ovarian, fallopian, peritoneal) 2. Documented mutational status of KRAS by a validated tumor-tissue based diagnostic test. 3. Suitable for treatment with at ...
Avutometinib is an investigational small molecule oncology drug being developed by Verastem, Inc. (VSTM). It is a MAP2K1 and MAP2K2 inhibitor studied in solid tumors and brain tumors, including breast cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, and low-grade serous ovarian cancer. It is most often evaluated in combination with defactinib.
Avutometinib targets MAP2K1 and MAP2K2, also known as MEK1 and MEK2. It is classified as an inhibitor of these kinases. By targeting MAP2K1 and MAP2K2, avutometinib is designed to interfere with signaling through the MAPK pathway, which is frequently altered in the tumor types under study.
Avutometinib is developed by Verastem, Inc., which trades on the Nasdaq under the ticker VSTM. Verastem is running the clinical program for avutometinib, including studies of the drug in combination with defactinib in ovarian cancer, pancreatic cancer, and malignant brain tumors.
Avutometinib is investigational and remains in clinical development. Its trials include Phase 1 and Phase 2 studies, such as the Phase 1 5G-RUBY study in malignant brain tumors and Phase 2 studies in recurrent low-grade serous ovarian cancer. It is not described as an approved therapy.
Avutometinib is being studied in several registered trials. These include NCT06630260 (5G-RUBY) in malignant brain tumors, NCT06682572 in recurrent low-grade serous ovarian cancer in Japanese patients, NCT07747506, a continued access study in recurrent low-grade serous ovarian cancer, and NCT07824960 in pancreatic adenocarcinoma.
Yes. Avutometinib is also known as VS-6766, and the two names refer to the same compound. Other names used in study listings include avutometinib (VS-6766) and combinations such as avutometinib and defactinib, avutometinib and sotorasib, and avutometinib and adagrasib.