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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of two treatments, adagrasib (a new potential drug) and stereotactic radiosurgery (SRS), to evaluate their effectiveness against brain metastases in individuals with KRAS G12C-mutated non-small cell lung cancer. The goal is to determine if this combination can effectively manage cancer that has spread to the brain. Suitable participants have this type of lung cancer with brain metastases that are either untreated or have progressed in previously treated areas. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that the combination of adagrasib and SRS is likely to be safe for humans?

Research has shown that adagrasib, a treatment for a type of lung cancer with a specific mutation, is generally well-tolerated by patients. Studies indicate it is safe, even for those whose cancer has spread to the brain, with no reports of serious side effects.

Stereotactic radiosurgery (SRS), another component of the treatment, is also safe and effective for brain tumors. It precisely targets tumors without harming the rest of the brain. Research confirms it does not cause serious side effects or negatively affect brain function.

Together, adagrasib and SRS have demonstrated promising safety results for treating brain tumors from lung cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lung cancer?

Unlike the standard treatments for lung cancer with brain metastases, which typically include chemotherapy and whole-brain radiation, adagrasib offers a targeted approach by specifically inhibiting the KRAS G12C mutation. This mutation is a common driver in certain lung cancers, and by directly targeting it, adagrasib aims to halt cancer growth more effectively. Researchers are excited because this precision in targeting could lead to better outcomes with potentially fewer side effects compared to broader treatments. Additionally, adagrasib is combined with stereotactic radiosurgery (SRS), a highly focused form of radiation, to further enhance its effectiveness against brain metastases.

What evidence suggests that adagrasib plus SRS could be effective for brain metastases in lung cancer?

Research has shown that adagrasib may help treat brain metastases in patients with KRAS G12C-mutated non-small cell lung cancer. In earlier studies, patients lived for an average of 5.4 months without their brain cancer worsening and had an overall survival time of 11.4 months. Notably, 12 out of 16 patients with brain metastases maintained stable disease, meaning their cancer did not grow. In this trial, all participants will receive a combination of adagrasib and stereotactic radiosurgery (SRS). SRS, a precise form of radiation treatment, effectively controls brain metastases, even with multiple tumors. Combining adagrasib with SRS could offer a promising approach to managing brain metastases in lung cancer patients. ^{4 6 7 8 9}

Who Is on the Research Team?

Ryan Gentzler, MD

Principal Investigator

University of Virginia

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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. SRS will occur between 4 weeks prior to and up to 3 weeks after initiation of adagrasib. 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

Published Research Related to This Trial

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, 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9662862/

Activity of Adagrasib (MRTX849) in Brain Metastases Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended ...

2. mdanderson.org mdanderson.org/newsroom/adagrasib-effective-patients-kras-g12c-mutant-lung-cancer-untreated-brain-metastases.h00-159619434.html

Adagrasib effective for patients with KRAS G12C-mutant ... The median intracranial progression-free survival (PFS) was 5.4 months, while the median overall survival (OS) reached 11.4 months. “Patients ...

3. ascopubs.org ascopubs.org/doi/10.1200/PO.23.00447

Safety and Intracranial Activity of Adagrasib in Patients ... We report clinical details and IC efficacy outcomes of five patient cases with NSCLC and untreated CNS metastases from the KRYSTAL-1 CNS ...

4. actr.amegroups.org actr.amegroups.org/article/view/9710/html

Intracranial efficacy of adagrasib in patients with KRAS G12C ... However, out of the 16 patients with brain metastases evaluable using central RANO-BM criteria, 12 patients showed stable disease and 2 showed ...

5. news.bms.com news.bms.com/news/details/2024/KRAZATI-adagrasib-Demonstrated-Statistically-Significant-Improvement-in-Progression-Free-Survival-in-Patients-with-Pretreated-Locally-Advanced-or-Metastatic-KRASG12C-Mutated-Non-Small-Cell-Lung-Cancer/default.aspx

KRAZATI (adagrasib) Demonstrated Statistically Significant ... KRAZATI demonstrated intracranial response among patients with central nervous system (CNS) metastases at baseline, with a response rate per ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10860949/

Safety and Intracranial Activity of Adagrasib in Patients With ... CNS metastases occur in 27%-42% of patients with non–small-cell lung cancer (NSCLC) that harbor KRASG12C mutations at diagnosis. Prognosis is ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/28/15/3318/707087/Activity-of-Adagrasib-MRTX849-in-Brain-Metastases

Activity of Adagrasib (MRTX849) in Brain Metastases ... Patients with KRAS-mutant non–small cell lung cancer with brain metastases have a poor prognosis. Here, we report data supporting central nervous system ...

8. ascopubs.org ascopubs.org/doi/abs/10.1200/PO.23.00447

Safety and Intracranial Activity of Adagrasib in Patients ... Safety and intracranial activity of adagrasib in patients with KRAS G12C-mutated non–small-cell lung cancer and untreated CNS metastases in the KRYSTAL-1 trial.

9. krazatihcp.com krazatihcp.com/nsclc/moa

Mechanism of Action | KRAZATI® (adagrasib) for NSCLC Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRAS G12C-mutant non-small cell lung cancer.