Adagrasib + Pembrolizumab for Lung Cancer

Recruiting in Palo Alto (17 mi)

+842 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Mirati Therapeutics Inc.

Must not be taking: Chemotherapy, Immune checkpoint inhibitors

Disqualifiers: Active brain metastases, Seizures, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests two drugs, MRTX849 and pembrolizumab, in patients with advanced lung cancer who have a specific genetic mutation. MRTX849 targets the mutation to stop cancer growth, while pembrolizumab boosts the immune system to fight the cancer. The study aims to see how well these treatments work alone and together.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those who have had prior systemic treatment for advanced NSCLC. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Adagrasib and Pembrolizumab for lung cancer?

Early trials show that the combination of Adagrasib and Pembrolizumab is effective for patients with a specific type of lung cancer (KRASG12C mutation), with response rates of 49% and 57% in two different studies. Additionally, this combination has lower liver toxicity compared to other similar treatments. ^{1 2 3 4 5}

Is the combination of Adagrasib and Pembrolizumab safe for humans?

Early trials suggest that the combination of Adagrasib and Pembrolizumab is generally safe for patients with non-small cell lung cancer, showing lower levels of liver toxicity compared to other similar treatments. Pembrolizumab alone has been associated with some side effects like fatigue, cough, and nausea, and can cause immune-related issues such as inflammation in the lungs or liver. ^{1 2 3 5 6}

How is the drug combination of Adagrasib and Pembrolizumab unique for lung cancer treatment?

The combination of Adagrasib and Pembrolizumab is unique because it targets a specific mutation (KRASG12C) in non-small cell lung cancer and has shown promising response rates with lower liver toxicity compared to other similar treatments. ^{1 2 3 4 7}

Eligibility Criteria

This trial is for adults with advanced non-small cell lung cancer (NSCLC) that has a specific mutation called KRAS G12C. Participants must have measurable disease and no prior treatments for metastatic NSCLC. Those with certain brain metastases can join if they don't require immediate treatment.

Inclusion Criteria

My brain scans show no signs of cancer, or I have brain cancer that doesn't need immediate treatment.

My NSCLC is inoperable or has spread, with a KRAS G12C mutation.

You have a measurable disease according to RECIST criteria.

Exclusion Criteria

I have had treatments like chemotherapy or immunotherapy for advanced lung cancer.

I don't have large untreated brain lesions, brainstem lesions, high steroid use for brain symptoms, frequent seizures, or worsening neurological symptoms due to brain lesions.

I have active cancer spread to my brain.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 2 Treatment

Participants receive MRTX849 monotherapy or in combination with pembrolizumab for advanced NSCLC with KRAS G12C mutation

22 months

Phase 3 Treatment

Participants receive adagrasib in combination with pembrolizumab versus pembrolizumab alone for advanced NSCLC with KRAS G12C mutation

36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Adagrasib (Small Molecule Drug)
• MRTX849 (Small Molecule Drug)
• Pembrolizumab (Checkpoint Inhibitor)
• Phase 3 comparator arm (Chemotherapy)

Trial Overview The study tests MRTX849 alone and combined with Pembrolizumab in Phase 2, while Phase 3 compares Adagrasib plus Pembrolizumab against only Pembrolizumab in patients whose tumors show high levels of a protein called PD-L1.

Participant Groups

Group I: Phase 3 Cohort 3 Investigational Arm Experimental Treatment 1 Intervention

Adagrasib BID in combination with pembrolizumab

Group II: Phase 2 Cohort 2: PD-L1 TPS ≥1% Experimental Treatment 1 Intervention

Cohort 2: Adagrasib BID in combination with pembrolizumab

Group III: Phase 2 Cohort 1b: PD-L1 TPS <1% Experimental Treatment 1 Intervention

Cohort 1b: Adagrasib BID monotherapy

Group IV: Phase 2 Cohort 1a: PD-L1 TPS <1% Experimental Treatment 1 Intervention

Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab

Group V: Phase 3 Cohort 4 Comparator Arm Active Control 1 Intervention

Pembrolizumab

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Local Institution - 007-556-A Goodyear, AZ

Local Institution - 007-568-A Safford, AZ

Local Institution - 007-568-B Safford, AZ

Local Institution - 007-568-C Safford, AZ

More Trial Locations

Who Is Running the Clinical Trial?

Mirati Therapeutics Inc. Lead Sponsor

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022] A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.

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

Frontline Promise for Adagrasib-Pembrolizumab Combination. [2023] Two trials offer early evidence that adagrasib plus pembrolizumab is a safe and effective regimen for patients with newly diagnosed non-small cell lung cancer harboring a KRASG12C mutation. The overall response rate in one trial was 49%, and in the other it was 57%. The drug combination showed lower levels of liver toxicity than other combinations of checkpoint inhibitors and targeted therapies.

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017] New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.

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

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. [2022] Pembrolizumab is a programmed death receptor-1 masking antibody approved for metastatic non-small cell lung cancer. This Phase 2 study (NCT02818920) of neoadjuvant pembrolizumab in non-small cell lung cancer had a primary end point of safety and secondary end points of efficacy and correlative science.

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

Another KRAS Inhibitor Holds Its Own. [2021] According to the KRYSTAL-1 study, the KRASG12c inhibitor adagrasib, also known as MRTX849, is largely well tolerated and shows considerable efficacy in patients with non-small cell lung cancer harboring this mutation. The drug is also active, albeit more modestly, in colorectal cancer and several other solid tumor types.

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021] On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp &amp; Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (&#8805;20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. &#169;2017 AACR.

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

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. [2020] The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.