Adagrasib +/- Nivolumab for Non-Small Cell Lung Cancer

(Neo-Kan Trial)

Overseen By Ipshita Faldu, M.S

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Corticosteroids, Immunosuppressives, Proton pump inhibitors, others

Disqualifiers: Prior lung cancer treatment, Brain metastases, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

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: 3

Duration: 6 weeks

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label phase 2 clinical trial evaluating the clinical safety, feasibility and efficacy of neoadjuvant Adagrasib alone or in combination with nivolumab in patients with NSCLC with KRAS G12C mutation.

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 certain medications that affect heart rhythm or interact with the study drugs. It's best to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of the drug Adagrasib +/- Nivolumab for Non-Small Cell Lung Cancer?

Research shows that Nivolumab, when used with other drugs like ipilimumab, has improved outcomes in patients with advanced non-small cell lung cancer (NSCLC). This suggests that Nivolumab could be effective in treating NSCLC, potentially supporting its use in combination with Adagrasib. ^{1 2 3 4 5}

Is the combination of Adagrasib and Nivolumab safe for humans?

Nivolumab, used alone or with other drugs, has been shown to have a manageable safety profile in patients with non-small cell lung cancer, but it can cause immune-related side effects, such as inflammation in the lungs. These side effects are generally considered manageable, but they can vary between individuals. ^{1 6 7 8 9}

What makes the drug Adagrasib +/- Nivolumab unique for treating non-small cell lung cancer?

Adagrasib (Krazati, MRTX-849) is unique because it specifically targets a mutation in the KRAS gene, which is a common driver of cancer growth in non-small cell lung cancer (NSCLC). When combined with Nivolumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, this combination offers a novel approach by addressing both the genetic mutation and enhancing the body's immune response. ^{1 2 3 5 7}

Research Team

Kristen Marrone, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

Adults over 18 with stage IB-IIIA non-small cell lung cancer (NSCLC) and a specific KRAS G12C mutation can join. They must be candidates for potential curative surgery, not pregnant or breastfeeding, willing to use contraception, and have no history of certain diseases or treatments that could interfere with the trial.

Inclusion Criteria

My blood and organ tests are within normal ranges for surgery.

Women of child-bearing potential (WOCBP): Agree to use contraception while participating in this study, and for a period of 6 months following last dose of Adagrasib or nivolumab, as effects of these agents on the developing human fetus are unknown. Men whose partner is a WOCBP must also agree to use contraception during this period, Negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within two weeks of registration, Women must not be breastfeeding or plan to breastfeed for the duration of therapy or 6 months after, Completed informed consent process, including signing IRB/EC-approved informed consent form, Willing and able to comply with clinical trial instructions and requirements. Subjects must be competent to report AEs, understand the drug dosing schedule, and use of medications to control AEs

My lung cancer is confirmed to have a KRAS G12C mutation.

Exclusion Criteria

I am not receiving treatment for any cancer except for certain skin cancers or early-stage cancers in specific areas.

I have had radiation therapy to the chest area before.

I have not received a live vaccine in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral Adagrasib with or without IV Nivolumab for 6 weeks prior to surgery

6 weeks

3 visits (in-person for Nivolumab administration)

Surgical Resection

Participants undergo surgical resection of the tumor

Postoperative Therapy

Participants receive standard postoperative therapy, which may include chemotherapy and/or radiation therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Adagrasib
• Nivolumab

Trial Overview The trial is testing Adagrasib alone or combined with Nivolumab in patients before surgery to see if it's safe and effective. It's an open-label phase 2 study which means everyone knows what treatment they're getting.

Participant Groups

Group I: Arm A Active Control 1 Intervention

Arm A treatment: Oral Adagrasib 600 mg twice daily for 6 weeks prior to surgery. Surgical Resection, then standard postoperative therapy(chemo +/- RT).

Group II: Arm B Active Control 1 Intervention

Arm B treatment: Oral Adagrasib 400 mg twice daily for 6 weeks and IV Nivolumab 240mg every 2 weeks for 3 doses prior to surgery. Surgical Resection, then standard postoperative therapy(chemo +/- RT).

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?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

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

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

In a phase 2 trial involving 117 patients with advanced, refractory squamous non-small-cell lung cancer, nivolumab demonstrated a 14.5% objective response rate, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with 17% of patients experiencing severe treatment-related adverse events, suggesting that while there are risks, the benefits may outweigh them for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Rizvi, NA., Mazières, J., Planchard, D., et al.[2022]

The combination of nivolumab and erlotinib was found to be tolerable in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), with treatment-related grade 3 toxicities occurring in only five out of twenty patients, and no severe grade 4 toxicities reported.

Among the TKI-treated patients, the objective response rate was 15%, with some patients experiencing durable responses lasting up to 38.2 months, indicating potential efficacy of this combination therapy in managing advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC. Gettinger, S., Hellmann, MD., Chow, LQM., et al.[2019]

In a study of 80 patients with advanced gastric cancer treated with nivolumab, 19% showed an objective response, with higher response rates linked to factors like MMR deficiency, high tumor mutation burden, and positive PD-L1 expression.

Patients with favorable characteristics, such as MMR-deficient tumors or high PD-L1 expression, experienced significantly longer progression-free survival, suggesting that these features can help predict the efficacy of nivolumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer. Mishima, S., Kawazoe, A., Nakamura, Y., et al.[2020]

The combination of nivolumab and ipilimumab as neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) was found to be feasible, but the study was terminated early due to significant treatment-related adverse events (TRAEs), with 67% of patients experiencing some form of toxicity.

Despite the challenges, two patients achieved a pathologic complete response (pCR) and remained disease-free for over 24 months, suggesting that further research is needed to identify biomarkers that could predict which patients are more likely to benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. Reuss, JE., Anagnostou, V., Cottrell, TR., et al.[2021]

In a study of 256 patients treated with PD-1/PD-L1 blocking monoclonal antibodies, immune-related pneumonitis (IRP) was observed in 29 patients, indicating a notable risk of this adverse event in real-world settings.

The research found that the risk of IRP was particularly higher in patients with metastatic non-small-cell lung cancer (mNSCLC) who had received metronomic chemotherapy, suggesting that treatment history may influence the likelihood of developing IRP during PD-1/PD-L1 blockade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis. Correale, P., Saladino, RE., Giannarelli, D., et al.[2021]

In a study of 43 patients with non-small cell lung cancer, nivolumab showed the highest median progression-free survival (12.6 months) and overall survival (13.4 months), particularly in patients with fewer metastases and better performance status.

While 85% of patients experienced some adverse effects, the development of vitiligo in patients treated with nivolumab was associated with a more durable response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of atezolizumab, nivolumab and pembrolizumab in metastatic non-small cell lung cancer. Burgos-San José, A., Colomer-Aguilar, C., Martínez-Caballero, D., et al.[2021]

In a study of 184 patients with non-small cell lung cancer treated with immune checkpoint inhibitors, 26.6% developed immune-related adverse events (IRAEs), with certain factors like statin use and previous corticosteroid therapy increasing the risk of IRAEs.

Interestingly, patients who experienced IRAEs had significantly better progression-free survival (41 weeks vs. 9 weeks) and overall survival (89 weeks vs. 28 weeks), suggesting that the occurrence of IRAEs may be linked to improved treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. Serino, M., Freitas, C., Martins, M., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. [2022]

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

Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis. [2021]

7. Spain pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of atezolizumab, nivolumab and pembrolizumab in metastatic non-small cell lung cancer. [2021]

8. Spain pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Association of Immune-Related Adverse Events with Clinical Benefit in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Nivolumab. [2019]