Avutometinib + Sotorasib for Lung Cancer

(RAMP203 Trial)

Recruiting at 33 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

Trial Summary

What is the purpose of this trial?

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 Non-Small Cell Lung Cancer (NSCLC) in patients who have been exposed to prior G12C inhibitor and those who have not been exposed to prior G12C inhibitor.

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.

What data supports the effectiveness of the drug Avutometinib + Sotorasib for lung cancer?

Sotorasib has been shown to be effective for treating non-small cell lung cancer (NSCLC) with a specific KRAS mutation, with a 36% response rate in patients who had already tried other treatments. This suggests that sotorasib, as part of the combination with Avutometinib, may offer benefits for similar lung cancer cases. ^{1 2 3 4 5}

Is the combination of Avutometinib and Sotorasib safe for humans?

Sotorasib, also known as Lumakras, has been approved for treating certain lung cancers and is generally considered safe, though common side effects include diarrhea, muscle pain, nausea, fatigue, liver issues, and cough. There is no specific safety data available for the combination of Avutometinib and Sotorasib, but Sotorasib alone has a manageable safety profile. ^{1 2 3 6 7}

What makes the drug Avutometinib + Sotorasib unique for lung cancer?

The combination of Avutometinib and Sotorasib is unique because it targets KRAS G12C mutations in non-small cell lung cancer (NSCLC), with Sotorasib being the first approved drug specifically for this mutation. This combination may offer a new option for patients who have already undergone other treatments. ^{1 2 3 4 8}

Research Team

MD Verastem

Principal Investigator

Verastem, Inc.

Eligibility Criteria

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

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

Timeline

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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 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 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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Sotorasib: First Approval. [2022]

2. France pubmed.ncbi.nlm.nih.gov

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

3. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

An evaluation of sotorasib for the treatment of patients with non-small cell lung cancer with KRASG12C mutations. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. United States 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. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Sotorasib for Lung Cancers with KRAS p.G12C Mutation. [2022]