Adagrasib + SRS for Lung Cancer with Brain Metastases

Overseen By Amber Ryba

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ryan Gentzler, MD

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: KRAS G12C inhibitor, Active infection, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single arm phase 2 trial is to evaluate the efficacy of SRS plus adagrasib for the treatment of brain metastases for patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC). A total of 30 patients will be enrolled on this study.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take medications that strongly affect the CYP3A enzyme. If you are on such medications, you need to stop them at least 7 days before starting the trial treatment.

What data supports the effectiveness of the drug Adagrasib for lung cancer with brain metastases?

Research shows that Adagrasib, a drug targeting a specific mutation in lung cancer, shrank brain metastases in 33% of patients in a clinical trial. It also demonstrated a strong response rate in lung cancer patients, suggesting potential effectiveness for brain metastases. ^{1 2 3 4 5}

Is the combination of Adagrasib and SRS safe for humans?

Adagrasib, also known as MRTX849, has been shown to be generally well tolerated in patients with non-small cell lung cancer, with most side effects being related to the digestive system. Serious side effects occurred in about 45% of patients, but no new safety concerns have emerged over time, indicating that its long-term safety is manageable. ^{1 2 3 6 7}

What makes the drug Adagrasib unique for treating lung cancer with brain metastases?

Adagrasib is unique because it is an oral drug that specifically targets the KRASG12C mutation, which is common in certain lung cancers, and it can penetrate the brain to help control brain metastases. This is important because brain metastases are difficult to treat, and Adagrasib has shown promise in shrinking them in some patients. ^{1 2 3 4 5}

Research Team

Ryan Gentzler, MD

Principal Investigator

University of Virginia

Eligibility Criteria

This trial is for adults over 18 with stage IV non-small cell lung cancer (NSCLC) that has spread to the brain and have a specific mutation called KRAS G12C. They should be relatively healthy, able to perform daily activities with ease or minor difficulty, and have not treated their brain metastases yet. Up to 10 untreated brain tumors are allowed, but none larger than 3 cm.

Inclusion Criteria

Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

My lung cancer is at stage IV or has returned and spread after treatment.

My organs are functioning well.

Exclusion Criteria

Treatment with any investigational drug within 28 days prior to registration.

Pregnant or breastfeeding.

I have been treated with a KRAS G12C inhibitor before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral adagrasib 600mg twice daily and SRS for the treatment of brain metastases

3 months

Regular visits for SRS and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 months

Treatment Details

Interventions

• Adagrasib
• Stereotactic Radiosurgery

Trial Overview The study tests how well Adagrasib combined with Stereotactic Radiosurgery (SRS), which is a precise form of radiation therapy, works in treating NSCLC patients whose cancer has spread to the brain. All participants will receive this combination treatment.

Participant Groups

Group I: Adagrasib + SRS (Stereotactic Radiosurgery) Experimental Treatment 2 Interventions

All patients will receive oral adagrasib 600mg twice daily for every cycle and SRS which will be administered as standard of care. Initiation of adagrasib and treatment with SRS will occur within 3 weeks of each other, in whichever order. Patients may have received SRS prior to study enrollment. Cycle 1 Day 1 will begin on the first day of adagrasib dosing. Adagrasib should be held the day before and the day of SRS. There is no maximum duration of treatment.

Adagrasib is already approved in United States, European Union for the following indications:

Approved in United States as Krazati for:

• KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)
• KRAS G12C-mutated locally advanced or metastatic colorectal cancer

Approved in European Union as Krazati for:

• KRAS G12C mutation non-small cell lung cancer

Who Is Running the Clinical Trial?

Ryan Gentzler, MD

Lead Sponsor

Trials

1

Recruited

30+

University of Virginia

Collaborator

Trials

802

Recruited

1,342,000+

Mirati Therapeutics Inc.

Industry Sponsor

Trials

73

Recruited

8,900+

Dr. Charles M. Baum

Mirati Therapeutics Inc.

Chief Executive Officer since 2023

MD, PhD

Dr. Joseph Leveque

Mirati Therapeutics Inc.

Chief Medical Officer since 2021

MD

Findings from Research

Adagrasib (MRTX849) is a promising treatment for patients with KRAS-mutant non-small cell lung cancer (NSCLC) and brain metastases, showing the ability to penetrate the central nervous system and achieve effective concentrations in cerebrospinal fluid.

In preclinical models and preliminary clinical data from two patients, adagrasib demonstrated tumor regression in brain metastases, indicating its potential efficacy in treating this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Sabari, JK., Velcheti, V., Shimizu, K., et al.[2023]

In the phase II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib demonstrated a 43% overall response rate and an 80% disease control rate in patients with previously treated KRASG12C-mutant non-small cell lung cancer, indicating its efficacy in this specific cancer type.

Patients treated with adagrasib had a median overall survival of 11.7 months, and the drug was effective in reducing brain metastases in 33% of patients with such conditions, highlighting its potential for managing advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib Response Remains Strong in NSCLC. [2022]

The KRYSTAL-1 study found that adagrasib (MRTX849), a KRASG12c inhibitor, is generally well tolerated by patients with non-small cell lung cancer, indicating a favorable safety profile.

Adagrasib demonstrated significant efficacy in treating non-small cell lung cancer with the KRASG12c mutation, and it also showed some activity in colorectal cancer and other solid tumors, although to a lesser extent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Another KRAS Inhibitor Holds Its Own. [2021]

In a phase I/IB study involving 25 patients with advanced KRASG12C-mutant solid tumors, adagrasib (600 mg twice daily) demonstrated significant antitumor activity, with 53.3% of patients with non-small-cell lung cancer achieving a confirmed partial response after a median follow-up of 19.6 months.

Adagrasib was well tolerated, with the most common side effects being nausea (80%), diarrhea (70%), and fatigue (45%), indicating a manageable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). Ou, SI., Jänne, PA., Leal, TA., et al.[2023]

Adagrasib (MRTX849), a KRAS inhibitor, shows promise in controlling KRASG12C brain metastases, based on preclinical models and early data from the KRYSTAL-1 phase Ib clinical trial.

This research suggests that adagrasib may effectively penetrate the central nervous system, which is crucial for treating brain metastases, a challenging area in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trials, Tribunals, and Opportunities for Lung Cancer KRASG12C Brain Metastases. Kommalapati, A., Mansfield, AS.[2022]

Adagrasib demonstrates durable efficacy in patients with advanced KRASG12C non-small cell lung cancer, with about one in three patients surviving after 2 years of treatment.

The long-term safety profile of adagrasib remains manageable, as no new toxicities were reported during the study, indicating it is a safe option for previously treated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib's Efficacy Sustained in KRASG12C NSCLC. [2023]

Adagrasib, a newly approved KRASG12C-targeted therapy, shows a clinical efficacy with an objective response rate of 42.9% and a median duration of response of 8.5 months in patients with advanced KRASG12C-mutated non-small-cell lung cancer.

While adagrasib is effective, it is associated with a high incidence of treatment-related adverse events, primarily gastrointestinal, affecting 97.4% of patients, with 44.8% experiencing severe (grade 3+) side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib: a novel inhibitor for KRASG12C-mutated non-small-cell lung cancer. Guo, MZ., Marrone, KA., Spira, A., et al.[2023]

References

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

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. [2023]

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

Adagrasib Response Remains Strong in NSCLC. [2022]

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

Another KRAS Inhibitor Holds Its Own. [2021]

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

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). [2023]

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

Trials, Tribunals, and Opportunities for Lung Cancer KRASG12C Brain Metastases. [2022]

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

Adagrasib's Efficacy Sustained in KRASG12C NSCLC. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Adagrasib: a novel inhibitor for KRASG12C-mutated non-small-cell lung cancer. [2023]