What is the mechanism of action of this treatment?

Common treatments for Non-Small Cell Lung Cancer (NSCLC) often involve targeted therapies that focus on specific genetic mutations within the cancer cells. Sotorasib, a KRASG12C inhibitor, binds to the mutant KRAS protein to inhibit its activity, thereby blocking the signaling pathways that drive tumor growth. RMC-4630, an SHP2 inhibitor, disrupts the RAS-MAPK signaling pathway, which is essential for cancer cell proliferation. These treatments are significant for NSCLC patients as they provide a more personalized approach, potentially improving efficacy and reducing side effects compared to conventional chemotherapy.

What side effects are associated with this type of intervention?

Common treatments for NSCLC, particularly those targeting KRASG12C mutations like Sotorasib, include side effects such as liver function test abnormalities, diarrhea, anemia, hepatitis, and hyponatremia. Adagrasib, another KRASG12C inhibitor, shares similar side effects, including fatigue, nausea, and increased liver function tests. Serious adverse events, although less common, can include cardiac failure and pulmonary hemorrhage. For SHP2 inhibitors like RMC-4630, specific side effects are not detailed in the provided context, but they may share similar profiles with other targeted therapies, including gastrointestinal issues and liver function abnormalities.

What prior FDA approvals exist?

The FDA has approved several targeted therapies for the treatment of Non-Small Cell Lung Cancer (NSCLC). Sotorasib, a KRASG12C inhibitor, was approved for patients with NSCLC harboring the KRASG12C mutation. Other targeted therapies include osimertinib for EGFR mutations, alectinib and crizotinib for ALK rearrangements, and entrectinib for ROS1 and NTRK fusions. Immunotherapies such as pembrolizumab and atezolizumab have also been approved for NSCLC, often in combination with chemotherapy. These treatments focus on specific genetic alterations or immune checkpoints to improve patient outcomes.

What other types of research exist?

Promising alternatives to Sotorasib and RMC-4630 for NSCLC patients include: 1) Larotrectinib and Entrectinib for patients with NTRK gene fusions, both of which have shown high response rates in early-phase trials. 2) Crizotinib for patients with ROS1 rearrangements, which has demonstrated efficacy in lung adenocarcinoma and squamous cell carcinoma. 3) Cabozantinib, a multitargeted tyrosine kinase inhibitor, which has shown activity in various cancers and may be considered for off-label use in NSCLC. These alternatives offer targeted approaches based on specific genetic alterations in NSCLC.

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Small Molecule Inhibitor

RMC-4630 + Sotorasib for Lung Cancer

Phase 2

Waitlist Available

Research Sponsored by Revolution Medicines, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Subject must be ≥18 years of age.

Subject must have pathologically documented, locally advanced or metastatic KRASG12C NSCLC (not amenable to curative surgery) that has progressed on prior standard therapies (no more than 3 prior lines of therapies are allowed)

Must not have

Primary central nervous system (CNS) tumors

Known or suspected leptomeningeal or brain metastases or spinal cord compression

Timeline

Screening 3 weeks

Treatment Varies

Follow Up approximately 12 months

Awards & highlights

No Placebo-Only Group

Summary

This trial tests sotorasib and RMC-4630 in patients with a specific type of lung cancer that hasn't responded to other treatments. The drugs work by blocking a mutation and stopping cancer cells from surviving. Sotorasib is the first approved treatment for this specific lung cancer mutation.

Who is the study for?

This trial is for adults over 18 with advanced or metastatic KRASG12C mutant Non-Small Cell Lung Cancer (NSCLC) that worsened after standard treatments. They must not have had more than three prior therapies, no brain tumors or severe heart disease, and can't have taken drugs targeting KRASG12C or SHP2 before.

What is being tested?

The study tests the combination of two drugs, RMC-4630 and Sotorasib, to see their effectiveness against NSCLC with a specific mutation (KRASG12C). It's for patients who've tried other treatments without success.

What are the potential side effects?

Possible side effects include allergic reactions to the drug components, issues from drug interactions affecting the heart or gastrointestinal system, and complications related to autoimmune diseases if previously treated.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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My advanced lung cancer has a specific KRASG12C mutation and has worsened despite up to 3 treatments.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My cancer originated in the brain or spinal cord.

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I have or might have cancer spread to my brain, spinal cord, or its coverings.

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I have a serious heart condition.

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I have a digestive issue that affects how my body absorbs medicine.

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I haven't had major surgery in the last 28 days or minor surgery in the last 7 days.

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I have previously been treated with a KRASG12C or SHP2 inhibitor.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ approximately 12 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~approximately 12 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and approximately 12 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Objective response rate (ORR)

Secondary study objectives

Adverse Events

Clinical laboratory test values

Concentration of RMC-4630

+8 more

Side effects data

From 2022 Phase 1 & 2 trial • 113 Patients • NCT03989115

100%

diarrhoea

75%

decreased appetite

50%

dehydration

50%

dizziness

25%

oedema peripheral

25%

thrombocytopenia

25%

fatigue

25%

cough

25%

pleural effusion

25%

constipation

25%

vomiting

25%

dry mouth

25%

lymphocyte count decreased

25%

hypoalbuminaemia

25%

anaemia

25%

fall

25%

weight decreased

25%

hypophosphataemia

25%

dermatitis acneiform

25%

gait disturbance

25%

dyspnoea

25%

platelet count decreased

25%

hyponatraemia

100%

80%

60%

40%

20%

Study treatment Arm

Intermittent RMC-4630 140mg (D1D2) + Osimertinib 80mg (QD)

Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 40mg QD (21/7)

Intermittent RMC-4630 140mg (D1D4) + Cobimetinib 20mg QD (21/7)

Intermittent RMC-4630 80mg (D1D4) + Cobimetinib 20mg QD (21/7)

Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 20mg QD (21/7)

Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 40mg (D1D2)

Intermittent RMC-4630 140mg (D1D2) + Cobimetinib 60mg D1D2

Intermittent RMC-4630 100mg (D1D2) + Osimertinib 80mg (QD)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: RMC-4630 and sotorasib, Safety Run-inExperimental Treatment2 Interventions

Safety Run-In: RMC-4630 and sotorasib

Group II: RMC-4630 and sotorasib, ExpansionExperimental Treatment2 Interventions

Dose Expansion: RMC-4630 and sotorasib

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

RMC-4630

2019

Completed Phase 2

~120

Sotorasib

2021

Completed Phase 1

~370

0 / 8Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Non-Small Cell Lung Cancer (NSCLC) often involve targeted therapies that focus on specific genetic mutations within the cancer cells. Sotorasib, a KRASG12C inhibitor, binds to the mutant KRAS protein to inhibit its activity, thereby blocking the signaling pathways that drive tumor growth. RMC-4630, an SHP2 inhibitor, disrupts the RAS-MAPK signaling pathway, which is essential for cancer cell proliferation. These treatments are significant for NSCLC patients as they provide a more personalized approach, potentially improving efficacy and reducing side effects compared to conventional chemotherapy.

Sotorasib: a treatment for non-small cell lung cancer with the KRAS G12C mutation.Tailoring tyrosine kinase inhibitors to fit the lung cancer genome.Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies.