Adagrasib + Pembrolizumab for Lung Cancer

Recruiting at 1005 trial locations

Overseen By First line of the email MUST contain the NCT# and Site #.

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Mirati Therapeutics Inc.

Must not be taking: Chemotherapy, Immune checkpoint inhibitors

Disqualifiers: Active brain metastases, Seizures, 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

Compensation: Varies

Number of Visits: Unknown

806 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of two drugs, adagrasib (Krazati or MRTX-849) and pembrolizumab (Keytruda), either alone or combined, for treating advanced non-small cell lung cancer (NSCLC) with a KRAS G12C mutation. The Phase 2 part tests the drugs' effectiveness in patients with varying levels of PD-L1, a protein that can influence the immune response to cancer. The Phase 3 part compares the combination of both drugs to pembrolizumab alone for patients whose cancer cannot be surgically removed and have higher PD-L1 levels. This trial may suit those diagnosed with advanced NSCLC with the KRAS G12C mutation who have not received prior treatments for this condition. As a Phase 2 and Phase 3 trial, it measures initial effectiveness and represents the final step before FDA approval, offering a chance to contribute to groundbreaking cancer treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that adagrasib, also known as MRTX849, is generally safe for patients with non-small cell lung cancer (NSCLC) who have a specific genetic mutation called KRAS G12C. Earlier studies found no new safety issues, and the safety information aligned with existing knowledge about the drug, indicating no unexpected side effects.

When combined with pembrolizumab, a common lung cancer treatment, adagrasib also appears safe. Side effects are typically mild and manageable. Studies have demonstrated that this combination is effective regardless of PD-L1, a protein involved in the body's immune response.

In summary, current research indicates that both adagrasib alone and with pembrolizumab are safe. The treatment is well-tolerated, with most individuals not experiencing serious side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about adagrasib in combination with pembrolizumab for lung cancer because it targets a specific mutation known as KRAS G12C, which is present in some lung cancer tumors. Most current treatments, like chemotherapy and immunotherapy, don't specifically target this mutation. Adagrasib is designed to block the KRAS G12C protein, potentially stopping cancer cell growth more effectively. Furthermore, when combined with pembrolizumab, an immune checkpoint inhibitor, it might enhance the immune system's ability to fight cancer. This dual approach could offer a new, more precise method for tackling lung cancer compared to standard treatments.

What evidence suggests that this trial's treatments could be effective for lung cancer?

Research has shown that adagrasib, one of the treatments studied in this trial, helps delay cancer progression when used alone. Studies found that patients experienced an average of 6.8 months before their cancer advanced. In this trial, some participants will receive adagrasib combined with pembrolizumab, another cancer treatment. Early findings suggest that this combination may extend patients' lives, particularly those with certain genetic changes in their cancer. This treatment is effective regardless of PD-L1 levels, a protein that can influence cancer growth. Overall, these treatments show promise for treating advanced non-small cell lung cancer (NSCLC) with a specific KRAS G12C mutation. ^{1 2 6 7 8}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Adagrasib
• MRTX849
• Pembrolizumab
• Phase 3 comparator arm

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.

How Is the Trial Designed?

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

Who Is Running the Clinical Trial?

Mirati Therapeutics Inc.

Lead 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

Pembrolizumab is a safe and effective immune checkpoint inhibitor that targets the PD-1 receptor, currently approved for treating advanced melanoma and metastatic non-small cell lung cancer (NSCLC).

Ongoing studies are exploring the potential of pembrolizumab in combination with other treatments for lung cancer and other cancer types, while also investigating biomarkers that may predict patient response to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Dang, TO., Ogunniyi, A., Barbee, MS., et al.[2020]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a Phase 2 study involving 35 patients with non-small cell lung cancer, neoadjuvant pembrolizumab was found to be safe and well tolerated, with only one surgery delay due to thyroiditis and no mortality within 90 days post-surgery.

The study showed a high rate of R0 resection (88%) and a major pathologic response in 28% of patients, indicating that pembrolizumab may be more effective than standard neoadjuvant chemotherapy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. Tong, BC., Gu, L., Wang, X., et al.[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]

Adagrasib combined with pembrolizumab shows promising efficacy for patients with newly diagnosed non-small cell lung cancer with a KRASG12C mutation, achieving overall response rates of 49% and 57% in two separate trials.

This drug combination demonstrated a favorable safety profile, exhibiting lower liver toxicity compared to other combinations of checkpoint inhibitors and targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frontline Promise for Adagrasib-Pembrolizumab Combination. [2023]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2204619

Adagrasib in Non–Small-Cell Lung Cancer Harboring a ... Treatment-related adverse events occurred in 97.4% of the patients — grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11534526/

Adagrasib in KRYSTAL-12 has Broken the KRASG12C ... The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with ...

3. 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 ... First presentation of data from Phase 3 KRYSTAL-12 study showed statistically significant and clinically meaningful improvement in ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e20648

Clinical outcomes and safety profile of adagrasib in KRAS ... Adagrasib showed a median overall survival (OS) of 14.74 months (95% CI: 12.06–17.42, I² = 40.4%) and progression-free survival (PFS) of 6.80 ...

5. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)01149-3/fulltext?rss=yes

Adagrasib for KRAS G12C mutated advanced non-small- ... The primary outcome was progression-free survival, which improved from a median of 3·8 months for patients receiving docetaxel to 5·5 months for ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9002

KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in ... Conclusions: Adagrasib is well tolerated and demonstrates promising efficacy in pretreated patients with NSCLC harboring a KRASG12C mutation. A ...

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

Safety and Intracranial Activity of Adagrasib in Patients With ... The median IC duration of response (DOR) was 12.7 months, the median IC progression-free survival (PFS) was 5.4 months, and the median overall ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04685135

NCT04685135 | Phase 3 Study of MRTX849 (Adagrasib) ... This Phase 3 study will evaluate the efficacy of the investigational agent MRTX849 (adagrasib) versus docetaxel in patients who have been previously treated ...