Avutometinib + Sotorasib for Lung Cancer

(RAMP203 Trial)

Recruiting at 39 trial locations

Overseen By Verastem Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Verastem, Inc.

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Prior malignancy, Brain metastases, Heart disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

153 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment combination for individuals with Non-Small Cell Lung Cancer (NSCLC) who have a specific mutation called KRAS G12C. The treatment includes drugs called avutometinib (a Raf/MEK inhibitor) and sotorasib, sometimes with an additional drug, defactinib. The trial will evaluate how these combinations work for those who have or have not previously taken a similar KRAS inhibitor. This trial targets individuals with NSCLC who have already tried one or two other treatments and have the KRAS G12C mutation. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong CYP3A4 inhibitors or inducers (types of drugs that affect how your body processes medications) at least 14 days before starting the study and during the trial. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of avutometinib and sotorasib has been tested in patients with KRAS G12C non-small cell lung cancer (NSCLC). Sotorasib, one of the drugs in this combination, has already received FDA approval for this cancer, indicating it has passed safety checks for this use.

Studies on the combination of avutometinib and sotorasib have found that it usually does not cause serious side effects. Most reported side effects have been mild or moderate, such as tiredness or skin problems.

When defactinib is added to the treatment, early research in other types of cancer suggests it is also mostly well-tolerated. Some patients experienced mild to moderate side effects, but these were manageable.

Since this trial is in the early stages, it offers an opportunity to further confirm the safety of these treatments. However, current data suggests that the treatments are generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Avutometinib (VS-6766) and Sotorasib for lung cancer because it offers a novel approach to targeting KRAS G12C mutations, which are notoriously tough to treat. Unlike traditional chemotherapy, which affects all rapidly dividing cells, this combo zeroes in on the specific mutant protein driving cancer growth. Additionally, adding Defactinib in some treatment arms targets cancer cell survival pathways, potentially enhancing effectiveness. This targeted strategy aims to provide more precise treatment with possibly fewer side effects, offering new hope for patients with limited options.

What evidence suggests that this trial's treatments could be effective for KRAS G12C Non-Small Cell Lung Cancer?

Research has shown that combining the drugs avutometinib and sotorasib may help treat KRAS G12C non-small cell lung cancer. Early studies found that 25% of patients experienced tumor shrinkage with this combination. In this trial, some participants will receive avutometinib and sotorasib, while others will also receive defactinib, which might enhance the treatment's effectiveness. Defactinib targets pathways that help cancer cells survive, possibly making them more responsive to treatment. Initial studies suggest this combination could be promising, especially for patients who haven't tried G12C inhibitors before. ^{2 6 7 8 9}

Who Is on the Research Team?

MD Verastem

Principal Investigator

Verastem, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with a specific mutation in their lung cancer (G12C KRAS). They must have tried some treatments but not more than two, and can't have used a KRAS inhibitor if they want to join certain parts of the study. Participants need good organ function, no recent other cancers or severe illnesses, and agree to use birth control.

Inclusion Criteria

My cancer has a KRAS G12C mutation.

I've had 1-2 treatments for advanced lung cancer.

Agreement to use highly effective method of contraceptive

Exclusion Criteria

I haven't had any cancer treatments in the last 4 weeks.

I haven't taken strong CYP3A4 affecting drugs in the last 14 days.

I've needed treatment for a skin condition in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive avutometinib (VS-6766) in combination with sotorasib with or without defactinib to determine the recommended phase 2 dose (RP2D) and assess efficacy

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib (VS-6766)
• Sotorasib

Trial Overview The trial tests avutometinib combined with sotorasib on patients with G12C Non-Small Cell Lung Cancer. It's looking at how safe and effective this combo is for those who've had previous treatment with a G12C inhibitor and those who haven't.

How Is the Trial Designed?

Group I: avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive Experimental Treatment 1 Intervention

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients

Group II: avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed Experimental Treatment 1 Intervention

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients

Group III: avutometinib (VS-6766)+sotorasib+defactinib Experimental Treatment 1 Intervention

To determine the recommended phase 2 dose (RP2D) for avutometinib (VS-6766) in combination with sotorasib and defactinib in KRAS G12C inhibitor exposed patients

Group IV: avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve Experimental Treatment 1 Intervention

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients

Group V: avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed Experimental Treatment 1 Intervention

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients

Group VI: avutometinib (VS-6766)+sotorasib Experimental Treatment 1 Intervention

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) is already approved in United States for the following indications:

Approved in United States as Avutometinib for:

• Recurrent low-grade serous ovarian cancer (Breakthrough Therapy Designation)

Who Is Running the Clinical Trial?

Verastem, Inc.

Lead Sponsor

Trials

42

Recruited

2,800+

Amgen

Industry Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Published Research Related to This Trial

Sotorasib is a first-in-class oral medication that specifically targets the KRAS G12C mutation in non-small cell lung cancer (NSCLC), showing a clinically relevant objective response rate in patients during the CodeBreaK 100 trial.

The drug has a manageable safety profile, allowing for dose adjustments to handle any side effects, making it a valuable treatment option for patients with advanced KRAS G12C mutation-positive NSCLC who have already undergone other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotorasib: A Review in KRAS G12C Mutation-Positive Non-small Cell Lung Cancer. Lee, A.[2022]

Sotorasib (Lumakras) received accelerated FDA approval for treating advanced non-small cell lung cancer (NSCLC) with a KRAS G12C mutation, showing an overall response rate of 36% in a study of 124 patients.

The median duration of response to sotorasib was 10 months, with common side effects including diarrhea, musculoskeletal pain, and nausea, highlighting its efficacy and safety profile as a targeted therapy for this specific cancer mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC. Nakajima, EC., Drezner, N., Li, X., et al.[2022]

Sotorasib and adagrasib, both KRAS G12C-targeting agents, have shown promising efficacy in treating non-small cell lung cancer (NSCLC), with sotorasib achieving an overall response rate of 41% and a progression-free survival of 6.3 months, while adagrasib had an overall response rate of 42.9% and a progression-free survival of 6.5 months.

Both drugs have received accelerated FDA approval and are now recommended as second-line treatment options for patients with KRAS G12C-mutated NSCLC, although they come with common side effects like diarrhea and fatigue, highlighting the need for further studies to refine their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Therapies for Previously "Undruggable" KRAS-Mutated Non-Small Cell Lung Cancer: A Review of Sotorasib and Adagrasib. Mausey, N., Halford, Z.[2023]

In a phase 2 trial involving 126 patients with KRAS p.G12C-mutated advanced non-small-cell lung cancer (NSCLC), sotorasib demonstrated a 37.1% objective response rate, including complete responses in 3.2% of patients, indicating its efficacy in this difficult-to-treat population.

The treatment was associated with a median overall survival of 12.5 months and a median progression-free survival of 6.8 months, with manageable safety profiles, as 69.8% of patients experienced treatment-related adverse events, mostly of grade 3 severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotorasib for Lung Cancers with KRAS p.G12C Mutation. Skoulidis, F., Li, BT., Dy, GK., et al.[2022]

Sotorasib is the first commercially available KRASG12C inhibitor, showing promise in improving outcomes for patients with KRASG12C-mutated non-small cell lung cancer (NSCLC), which is prevalent among smokers.

Despite its potential, there are ongoing questions about sotorasib's effectiveness in the brain, optimal dosing, and how it compares to standard treatments, highlighting the need for further research on resistance mechanisms and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of sotorasib for the treatment of patients with non-small cell lung cancer with KRASG12C mutations. Strohbehn, GW., Sankar, K., Qin, A., et al.[2022]

Sotorasib is an irreversible small molecule inhibitor specifically targeting the KRAS G12C mutation, which is found in 13% of lung adenocarcinomas, and has shown significant tumor regression in preclinical studies and clinical trials.

In a reported case, a patient with metastatic KRAS G12C-mutated NSCLC responded remarkably well to sotorasib as a first-line therapy, suggesting its potential as an effective initial treatment option for this type of cancer, particularly in patients with additional health challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotorasib as First-Line Treatment for Advanced KRAS G12C-Mutated Non-Small Cell Lung Carcinoma: A Case Report. Iska, S., Alley, EW.[2023]

In a study of 105 patients with advanced KRAS G12C-mutant non-small cell lung cancer treated with sotorasib, the median real-world progression-free survival was 5.3 months and the median overall survival was 12.6 months, indicating the drug's efficacy in a real-world setting.

Patients with KEAP1 comutations experienced shorter progression-free and overall survival, while those who had recent exposure to anti-PD-(L)1 therapy were more likely to develop severe treatment-related adverse events, particularly hepatotoxicity, suggesting that prior treatments can influence both the effectiveness and safety of sotorasib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Genomic Features of Response and Toxicity to Sotorasib in a Real-World Cohort of Patients With Advanced KRAS G12C-Mutant Non-Small Cell Lung Cancer. Thummalapalli, R., Bernstein, E., Herzberg, B., et al.[2023]

Sotorasib (LUMAKRAS™) is an innovative treatment specifically targeting KRAS G12C mutations in solid tumors, particularly effective for non-small cell lung cancer (NSCLC) and colorectal cancer.

In May 2021, sotorasib received accelerated approval from the US FDA for adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have undergone at least one prior treatment, marking a significant milestone in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotorasib: First Approval. Blair, HA.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05074810

NCT05074810 | Phase 1/2 Study of Avutometinib (VS-6766 ... This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C ...

2. researchgate.net researchgate.net/publication/371296289_RAMP_202_A_phase_2_study_of_avutometinib_VS-6766_defactinib_in_patients_with_advanced_KRAS_G12V_mutant_non-small_cell_lung_cancer_NSCLC

A phase 2 study of avutometinib (VS-6766) ± defactinib, in ... Preliminary data from the phase I/II RAMP203 trial demonstrated an ORR of 25% from the combination of avutometinib and sotorasib in KRAS G12C ...

3. dana-farber.org dana-farber.org/clinical-trials/21-749

A Phase 1/2 Study of Avutometinib in Combination with ... This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05074810/phase-1-2-study-of-avutometinib-vs-6766-sotorasib-with-or-without-defactinib-in-kras-g12c-nsclc-patients

Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib ... This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in ...

5. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT05375994

Avutometinib (VS-6766) + Adagrasib in KRAS G12C NSCLC ... This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with adagrasib in patients with G12C Non-Small Cell Lung Cancer (NSCLC)

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS9148

A phase 1/2 study of VS-6766 (RAF/MEK clamp) in ... The G12C inhibitor (G12Ci) sotorasib has recently received FDA approval for patients with KRAS G12C NSCLC. Several studies have shown that ...

7. verastem.com verastem.com/wp-content/uploads/2025/01/WCLC-2021-Virtual-PPT-Pachter-Verastem-final.ppt.pdf

Dual RAF/MEK inhibitor VS-6766 for treatment of KRAS ... Synergy of VS-6766 + G12C inhibitor AMG 510 across. G12C mutant NSCLC, CRC & Pancreatic cancer cell lines. VS-6766 & FAKi potentiate AMG 510 efficacy in KRAS ...

8. aacrjournals.org aacrjournals.org/mcr/article/21/5_Supplement/B025/725806/Abstract-B025-The-RAF-MEK-clamp-avutometinib-VS

Abstract B025: The RAF/MEK clamp avutometinib (VS-6766 ... Avutometinib (VS-6766; avuto) is a RAF/MEK clamp that potently inhibits MEK kinase activity and induces a dominant negative RAF-MEK complex.

9. jto.org jto.org/article/S1556-0864(21)02972-5/fulltext

P52.05 Dual RAF/MEK Inhibitor VS-6766 for Treatment ... Strikingly, triple combination of VS-6766, sotorasib and FAK inhibitor conferred tumor reductions of ≥35% in all mice in both models. In KRAS G12V mt NSCLC, ...