Defactinib + Avutometinib + Nivolumab for Lung Cancer

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Conor Steuer

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Emory University

Must not be taking: Warfarin, Strong CYP3A4

Disqualifiers: Auto-immune conditions, Brain metastasis, Hepatitis, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well defactinib and avutometinib in combination with nivolumab works in treating patients with LKB1-mutant non-small cell lung cancer that has not responded (refractory) to an anti-PD1 treatment and may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Defactinib and avutometinib belong to a class of drugs called kinase inhibitors. These drugs target kinase proteins found in tumor cells. Tumor cells need these proteins to survive and grow. By blocking these proteins, defactinib and avutometinib may cause tumors to stop growing or grow more slowly. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. Giving defactinib and avutometinib in combination with nivolumab may kill more tumor cells in patients with anti-PD1 refractory LKB1-mutant advanced non-small cell lung cancer.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop all current medications. However, you cannot have had systemic therapy within 3 weeks before the study, and you must avoid medications that interact with defactinib, such as strong CYP3A4 or CYP2C9 inhibitors or inducers, and strong P-glycoprotein inhibitors or inducers. If you're on warfarin, you need to switch to low-molecular-weight heparin or direct oral anticoagulants.

What data supports the idea that Defactinib + Avutometinib + Nivolumab for Lung Cancer is an effective drug?

The available research does not provide specific data on the effectiveness of Defactinib + Avutometinib + Nivolumab for lung cancer. However, it does highlight the effectiveness of Nivolumab, one of the drugs in the combination, when used with Ipilimumab for advanced non-small cell lung cancer (NSCLC). Studies show that Nivolumab combined with Ipilimumab can lead to longer survival compared to chemotherapy. This suggests that Nivolumab is a promising component in lung cancer treatment, but more specific research is needed to evaluate the full combination with Defactinib and Avutometinib. ^{1 2 3 4 5}

What safety data is available for the treatment with Defactinib, Avutometinib, and Nivolumab for lung cancer?

The provided research primarily discusses the safety and efficacy of Nivolumab (Opdivo) in the treatment of non-small cell lung cancer (NSCLC). Nivolumab has been shown to have a favorable safety profile in various studies, including CHECKMATE 017 and CheckMate 9LA, where it was used in combination with other treatments like ipilimumab and chemotherapy. However, there is no specific safety data available in the provided research for the combination of Defactinib, Avutometinib, and Nivolumab. Further research or clinical trial data would be needed to assess the safety of this specific combination. ^{2 4 6 7 8}

Is the drug combination of Avutometinib, Defactinib, and Nivolumab promising for lung cancer?

Yes, the drug combination is promising for lung cancer. Nivolumab, one of the drugs in the combination, has shown to improve survival rates in lung cancer patients, especially when used with other treatments. It helps the immune system fight cancer more effectively, which can lead to better outcomes for patients. ^{4 5 9 10 11}

Eligibility Criteria

This trial is for patients with advanced non-small cell lung cancer that has LKB1 mutation and hasn't responded to anti-PD1 treatments. It's aimed at those whose cancer may have spread, and who are looking for new treatment options.

Inclusion Criteria

My cancer has a known LKB1 mutation.

My lung cancer is specifically diagnosed as adenocarcinoma.

Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 umole/L)

Exclusion Criteria

I had a severe allergic reaction to previous immunotherapy.

I have had a skin condition treated with medication in the past year, but early stage skin cancers removed by surgery are okay.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to avutometinib or defactinib

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive defactinib orally twice daily, avutometinib twice weekly, and nivolumab intravenously on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

6 months

Monthly visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for up to 5 years.

5 years

Quarterly visits (in-person)

Treatment Details

Interventions

• Avutometinib (Kinase Inhibitor)
• Defactinib (Kinase Inhibitor)
• Nivolumab (Checkpoint Inhibitor)

Trial Overview The trial tests a combination of defactinib and avutometinib (kinase inhibitors) with nivolumab (an immunotherapy drug). The goal is to see if this mix can better kill tumor cells in patients resistant to previous anti-PD1 therapy.

Participant Groups

Group I: Treatment (defactinib, avutometinib, nivolumab) Experimental Treatment 7 Interventions

Patients receive defactinib PO BID on days 1-21, avutometinib PO twice weekly on Monday and Thursday, Tuesday and Friday or Wednesday and Saturday for 21 days and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, blood sample collection, CT or PET on study.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Emory University Hospital Midtown Atlanta, GA

Emory University Hospital/Winship Cancer Institute Atlanta, GA

Emory Saint Joseph's Hospital Atlanta, GA

Who Is Running the Clinical Trial?

Emory University Lead Sponsor

National Cancer Institute (NCI) Collaborator

References

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021] Frontline treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) induced durable and long-term efficacy, compared with chemotherapy, in patients with advanced non-small cell lung cancer (NSCLC) and tumor PD-L1 expression greater than 1% or less than 1%, according to updated results from part 1 of the phase 3 CheckMate 227 (NCT02477826)trial presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.

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

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib. [2018] In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non-small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib.

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

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. [2023] First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival.

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

Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. [2018] Progress in the treatment of patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) has been limited. An improvement in the understanding of tumor immunosurveillance has resulted in the development of the immune checkpoint inhibitors such as nivolumab. Nivolumab (Opdivo(®)), a human immunoglobulin (Ig)G4 anti-programmed death (PD)-1 monoclonal antibody, was the first PD-1 inhibitor approved in the treatment of patients with advanced stage squamous cell NSCLC following platinum-based chemotherapy. CHECKMATE 017, a randomized phase III study of second-line nivolumab versus docetaxel, significantly improved overall survival (OS), progression-free survival (PFS), patient reported outcomes and the safety and tolerability favored patients treated with nivolumab. The ligand (PD-L1) expression did not predict for outcome. In this paper, we review the role of nivolumab in the treatment of NSCLC with particular attention on recent studies, ongoing combination studies, toxicity profile, current and potential predictive biomarkers.

5. Georgia (Republic) pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. [2021] The case was analyzed for response to nivolumab (Opdivo) monotherapy in a patient with recurrent skin melanoma (10x6x6 cm) and disease dissemination (with multiple lung metastasis), positive for BRAF mutation that followed upon the local therapy (surgical excision) and 6 cycles of adjuvant chemotherapy (at CVD regimen - cisplatin, vinblastine, dacarbazine). Histological results: melanoma. Immunohystochemical: S 100-positive; Melan A - positive; HMB45 - positive, AE1/AE3 - negative, p53 - positive in most cells, vim - positive, ɑ sma - weak in most cells, Ki67 - positive in 20%, BRAFmut, ECOG performance status 1, LDH - 1320 U/L (N

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

FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-small Cell Lung Cancer, A Collaborative Project Orbis Review. [2022] On May 26, 2020, the FDA approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n = 361) or four cycles of platinum-doublet chemotherapy (n = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months [95% confidence interval (CI), 13.2-16.2] compared with 10.7 months (95% CI, 9.5-12.5) for patients who received chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; P = 0.0006). Progression-free survival and overall response rate per blinded independent central review were also statistically significant. This was the first NSCLC application reviewed under FDA's Project Orbis, in collaboration with Singapore's Health Sciences Authority, Australia's Therapeutic Goods Administration, and Health Canada. The benefit-risk analysis supports FDA's approval of nivolumab with ipilimumab and chemotherapy.

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

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. [2022] Nivolumab plus ipilimumab demonstrated clinically meaningful improvement in efficacy versus chemotherapy with a manageable safety profile in patients with advanced non-small cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% or

8. Switzerland pubmed.ncbi.nlm.nih.gov

Focus on Nivolumab in NSCLC. [2021] Immunotherapy is changing the treatment of non-small cell lung cancer (NSCLC). The PD-1 inhibitor nivolumab has demonstrated meaningful results in terms of efficacy with a good safety profile. The novel approach to treating NSCLC using immunotherapy still has unsolved questions and challenging issues. The main doubts regarding the optimal selection of the patient are the role of this drug in first line of treatment, the individualization of the correct methodology of radiologic assessment and efficacy analysis, the best management of immune-mediated adverse events, and how to overcome the immunoresistance. The aim of this review is to analyze literature data on nivolumab in lung cancer with a focus on critical aspects related to the drug in terms of safety, the use in clinical practice, and possible placement in the treatment algorithm.

9. Greece pubmed.ncbi.nlm.nih.gov

Comparison of PD-L1 Assays in Non-small Cell Lung Cancer: 22C3 pharmDx and SP263. [2019] While the PD-L1 22C3 pharmDx assay is an FDA-approved diagnostic assay for pembrolizumab use, not every pathology laboratory has the Dako Autostainer to use this assay. Since Ventana BenchMark platforms are more common, the Ventana SP263 assay can be used to inform treatment decisions involving nivolumab and pembrolizumab in non-small cell lung cancer (NSCLC). However, some studies have shown discordant results between the two assays. This study aimed was to compare PD-L1 expression using these two assays.

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

High TMB Predicts Immunotherapy Benefit. [2019] The first data from the phase III CheckMate-227 trial of ipilimumab plus nivolumab for the treatment of non-small cell lung cancer suggests that the two drugs boost progression-free survival in patients with a high tumor mutation burden. After 1 year, progression-free survival was 43% for patients treated with the checkpoint inhibitor combination, compared with 13% for patients treated with chemotherapy.

11. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in non-small-cell lung cancer. [2019] Nivolumab and ipilimumab, two therapeutic immune checkpoint inhibitor antibodies that block PD-1 and CTLA-4, respectively, have indications in cancer as single agents and in combination. In this Review, we examine the potential role of dual immune checkpoint inhibition with nivolumab plus ipilimumab in the management of patients with previously untreated advanced non-small-cell lung cancer, based on results from the Phase III CheckMate 227 study. Immunotherapies with indications in the first-line treatment of non-small-cell lung cancer include pembrolizumab alone and combined with chemotherapy, and atezolizumab combined with bevacizumab and chemotherapy. CheckMate 227 is the first Phase III study evaluating first-line chemotherapy-sparing combination immunotherapy and including tumor mutational burden as a biomarker for patient selection.