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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for non-small cell lung cancer (NSCLC) with a specific genetic change called the KRAS G12C mutation. The study examines the use of a drug called Adagrasib (also known as Krazati), either alone or with another medication, Nivolumab, to assess their safety and effectiveness before surgery. Suitable candidates have stage IB-IIIA NSCLC with the KRAS G12C mutation and plan to undergo surgery to remove the cancer. As a Phase 2 trial, this 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 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.

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

Research has shown that Adagrasib is generally well-tolerated by patients with non-small cell lung cancer (NSCLC) who have the KRAS G12C mutation. Among these patients, about 47% experienced more serious side effects, classified as grade 3 or higher, while 52.6% had mild side effects, classified as grade 1 or 2.

For those considering Adagrasib with Nivolumab, earlier studies suggest promising results, though safety information for this combination remains limited. Adagrasib alone has demonstrated that 45% of patients responded positively, with their cancer showing improvement.

Overall, while some risks of side effects exist, Adagrasib has shown strong potential in treating certain lung cancers. Consulting a healthcare provider is crucial to understanding personal risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Adagrasib for non-small cell lung cancer because it targets a specific mutation in the KRAS gene, which is often considered "undruggable." Unlike traditional chemotherapy that attacks all rapidly dividing cells, Adagrasib specifically inhibits the KRAS G12C mutation, making it a more targeted therapy. Additionally, when combined with Nivolumab, an immune checkpoint inhibitor, it may enhance the body's immune response against cancer cells. This combination approach aims to improve effectiveness and potentially lead to better outcomes for patients compared to standard chemo and radiation treatments.

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

Research shows that adagrasib may help treat non-small cell lung cancer (NSCLC) with the KRAS G12C mutation. In earlier studies, about 42% of patients experienced tumor shrinkage, and around 58% maintained this improvement for at least six months. In this trial, participants in Arm A will receive oral adagrasib alone, while Arm B will involve a combination of oral adagrasib and nivolumab, an immune therapy. Results have been encouraging when adagrasib is used with nivolumab. One study found that tumors shrank in nearly half of the patients treated, with a 43% response rate. Additionally, the combination treatment stopped cancer from worsening in 80% of patients. These findings suggest that both treatments could effectively manage this specific type of lung cancer. ^{3 5 6 7 8}

Who Is on the Research Team?

Kristen Marrone, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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 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]

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 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]

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]

Citations

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

Adagrasib in Non–Small-Cell Lung Cancer Harboring a ... The median overall survival was 11.7 months (95% CI, 9.2 to not evaluable); with an updated data cutoff date of January 15, 2022 (median follow- ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12554495/

Adagrasib in the treatment of KRASG12C-mutated non- ... In the phase II KRYSTAL-1 clinical trial, adagrasib demonstrated clinical efficacy in patients with previously treated KRASG12C-mutated non-small cell lung ...

3. 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 ...

4. 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 ... KRYSTAL-12 study showed statistically significant and clinically meaningful improvement in progression-free survival with KRAZATI compared to standard of care ...

5. krazatihcp.com krazatihcp.com/nsclc/efficacy

Efficacy | KRAZATI® (adagrasib) for NSCLC 58% HAD A RESPONSE DURATION OF ≥6 MONTHS2. 42% of patients (n=112) achieved a PR, and 0.9% of patients achieved a CR3.

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 ... CNS metastases occur in 27%-42% of patients with non–small-cell lung cancer (NSCLC) that harbor KRASG12C mutations at diagnosis.

8. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)00866-9/abstract

mutated non-small-cell lung cancer (KRYSTAL-12): a ... Grade 3 and above treatment-related adverse events occurred in 140 (47%) of 298 patients treated with adagrasib and 64 (46%) of 140 with ...