Cabozantinib for Non-Small Cell Lung Cancer

Recruiting in Palo Alto (17 mi)

+6 other locations

Overseen by Alexander Drilon, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anticoagulants, Antiplatelets

Disqualifiers: Uncontrolled hypertension, Brain metastases, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

The purpose of this phase II study is to find out what effects cabozantinib (XL184) has, good and/or bad, in patients whose tumors one of the following gene changes RET, ROS1, or NTRK fusion, or increased MET or AXL activity. A phase II study looks at how effective a medication is at treating a specific type of cancer and collects information on the side effects of the study treatment. RET, ROS1, or NTRK fusion or increased MET or AXL activity gene leads to lung cancer cell growth. Cabozantinib is an oral medicine that inhibits of RET, ROS1, NTRK, MET, and AXL. In addition, this drug interferes with other cell pathways that also cause cancer cells to grow, form new blood vessels, and spread to other organs of the body. The goal of using cabozantinib is to shrink the cancer and to prevent it from growing Cabozantinib has been studied and shown to cause cancer shrinkage in other cancers such as medullary thyroid cancer and prostate cancer. We thus have a good idea of what side-effects it causes and can anticipate them.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you cannot have taken any systemic anticancer agents within 3 weeks of starting the study. If you are on anticoagulants, you may need to adjust your treatment, as only low-dose aspirin and certain types of heparin are allowed.

What data supports the effectiveness of the drug Cabozantinib for treating non-small cell lung cancer?

Cabozantinib has shown effectiveness in treating other cancers, such as advanced hepatocellular carcinoma and thyroid cancer, by targeting specific proteins involved in cancer growth. This suggests it may also be beneficial for non-small cell lung cancer, as it targets similar pathways. ^{1 2 3 4 5}

Is Cabozantinib generally safe for humans?

Cabozantinib, also known as Cabometyx, has been studied for various conditions, and while specific safety data for non-small cell lung cancer isn't provided here, it has been used in other cancers with a known safety profile. Like many cancer treatments, it may have side effects, so it's important to discuss potential risks with your doctor. ^{6 7 8 9 10}

How is the drug Cabozantinib unique for treating non-small cell lung cancer?

Cabozantinib is unique for treating non-small cell lung cancer because it targets the MET gene, which is altered in some patients, making it a potential option for those with specific genetic mutations (MET exon 14 skipping mutations) that drive the cancer. ^{11 12 13 14 15}

Research Team

Alexander Drilon, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with advanced non-small cell lung cancer that is metastatic or unresectable and have specific genetic changes (RET, ROS1, NTRK fusions, MET or AXL overexpression/amplification/mutation). Must be able to perform daily activities well (Karnofsky >70%), have good organ function, not pregnant, agree to use contraception. Excludes those with recent significant illnesses/treatments or known allergies to cabozantinib.

Inclusion Criteria

I understand the study requirements and have signed the consent form.

Your disease can be measured using a specific set of guidelines called RECIST1.1.

I am able to care for myself and engage in normal activities.

Exclusion Criteria

I have had serious bleeding or a tumor affecting major blood vessels in the last 28 days.

I have been treated with cabozantinib before.

I haven't had radiation for bone or brain cancer, or any radiation treatment, in the last 2 to 4 weeks.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib to assess its effects on tumors with RET, ROS1, or NTRK fusion, or increased MET or AXL activity

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Cabozantinib (Tyrosine Kinase Inhibitor)

Trial Overview The trial tests the effects of an oral drug called Cabozantinib on patients with certain gene changes in their lung cancer cells. It's a phase II study which means it focuses on how effective this treatment is and monitors side effects closely.

Participant Groups

Group I: Cabozantinib Experimental Treatment 1 Intervention

This will be a single-institution, open label, two-stage, single agent trial of cabozantinib in patients with advanced NSCLCs.atients in GROUP A will have tumors with a RET fusion. Patients in GROUP B will have tumors with an NTRK fusion, or MET or AXL overexpression, amplication, or mutatation. Patients in GROUP C will have tumors with a ROS1 fusion. Patients in GROUP D will have tumors with a RET fusion and have progressed on a selective RET TKI.

Cabozantinib is already approved in Canada, Japan for the following indications:

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Lisa M. DeAngelis

Memorial Sloan Kettering Cancer Center

Chief Medical Officer since 2021

MD from Columbia University

Selwyn M. Vickers

Memorial Sloan Kettering Cancer Center

Chief Executive Officer since 2022

MD from Johns Hopkins University

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Findings from Research

Cabozantinib demonstrated clinical activity in patients with non-small-cell lung carcinoma (NSCLC), showing a 10% objective response rate and a 38% overall disease-control rate after 12 weeks of treatment, particularly in patients with KRAS mutations.

The treatment was associated with manageable safety concerns, with common grade 3/4 adverse events including fatigue and palmar-plantar erythrodysesthesia, although there was one serious treatment-related adverse event (hemorrhage) reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma. Hellerstedt, BA., Vogelzang, NJ., Kluger, HM., et al.[2019]

Cabozantinib is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, showing potential advantages over single-receptor TKIs.

The article reviews clinical trial data and management strategies for common adverse events associated with cabozantinib, highlighting its expanding use in treating various cancers such as prostate, hepatocellular, and lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. Markowitz, JN., Fancher, KM.[2019]

Cabozantinib (Cabometyx) is an effective treatment for advanced renal cell carcinoma, targeting specific pathways to inhibit tumor growth.

Glycopyrrolate/formoterol fumarate (Bevespi Aerosphere) is used to manage chronic obstructive pulmonary disease (COPD) by relaxing airway muscles and improving breathing, while ephedrine sulfate (Akovaz) is utilized to treat hypotension during anesthesia, helping to stabilize blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Choy, M.[2020]

Osimertinib significantly improves progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation, showing a median PFS of 10.1 months compared to 4.4 months with chemotherapy in a trial of 419 patients.

The safety profile of osimertinib is favorable compared to other EGFR tyrosine kinase inhibitors and chemotherapy, with common side effects including diarrhea and rash, making it a viable treatment option for patients who have progressed on previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. Odogwu, L., Mathieu, L., Goldberg, KB., et al.[2022]

A study of 130 treatment courses in 111 patients revealed that safety monitoring activities (SMAs) for EGFR and ALK inhibitors were inconsistently conducted, with prevalence ranging from 10.0% to 84.6%, and 31.5% of courses had no SMAs performed.

EGFR inhibitors were associated with a higher likelihood of SMAs being conducted compared to ALK inhibitors, highlighting the need for clinicians to closely follow FDA guidelines to ensure patient safety and monitor for serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. Singh, AM., Rubiera-Pebe, R., Ahmad, Y., et al.[2023]

In a study of 15 patients with non-small-cell lung cancer (NSCLC) having MET exon 14 skipping mutations, treatment with MET inhibitors crizotinib and cabozantinib showed promising results, with 50% of treated patients experiencing a partial response.

The presence of METex14 mutations was noted without other actionable mutations, indicating that these mutations can be significant drivers of NSCLC and are responsive to targeted therapies, although some patients experienced side effects requiring treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib. Wang, SXY., Zhang, BM., Wakelee, HA., et al.[2020]

Osimertinib, an EGFR inhibitor, shows promise as an effective treatment for patients with untreated non-small cell lung cancer that has spread to the brain.

In clinical studies, osimertinib demonstrated longer median progression-free survival and higher objective response rates compared to older EGFR inhibitors like gefitinib and erlotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib Treats CNS Metastases in NSCLC. [2022]

Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, was effective for 2.5 years in a 78-year-old woman with T790M-positive lung cancer, but she eventually experienced disease progression due to the emergence of a new resistance mutation (C797G).

The case highlights the potential of liquid biopsy and next-generation sequencing to monitor clonal evolution and identify novel resistance mechanisms in patients treated with osimertinib, which could inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. DE Carlo, E., Schiappacassi, M., Pelizzari, G., et al.[2022]

References

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

Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma. [2019]

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

New Indication for Cabozantinib. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Cabozantinib for the Treatment of Advanced Hepatocellular Carcinoma: Current Data and Future Perspectives. [2021]

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

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. [2019]

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

Pharmaceutical Approval Update. [2020]

6. Ireland pubmed.ncbi.nlm.nih.gov

Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus. [2018]

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

Multiple cardiotoxicities during osimertinib therapy. [2023]

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

Clinical Relevance of High Plasma Trough Levels of the Kinase Inhibitors Crizotinib, Alectinib, Osimertinib, Dabrafenib, and Trametinib in NSCLC Patients. [2023]

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

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. [2022]

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

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. [2023]

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

Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib. [2020]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. [2022]

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

Osimertinib Treats CNS Metastases in NSCLC. [2022]

14. Greece pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. [2022]

15. Singapore pubmed.ncbi.nlm.nih.gov

Early-onset interstitial pneumonitis in a patient with advanced non-small cell lung cancer treated with crizotinib and osimertinib. [2022]