Cabozantinib + Nivolumab + Radiation for Metastatic Kidney Cancer

Recruiting at 6 trial locations

Overseen By Luke Pike, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anticoagulants, Steroids, Kinase inhibitors, others

Disqualifiers: Cardiovascular disease, Autoimmune disease, Infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

20 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether the combination of cabozantinib, nivolumab, and radiation therapy is a safe and effective treatment that causes few or mild side effects in people with renal cell cancer that has spread to the brain. The researches will also look at how the study treatment affects the quality of life of participants. They will measure the quality of life by having participants complete questionnaires.

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

The trial requires a 2-week period without taking any small molecule kinase inhibitors or VEGF-targeted therapies before starting the study treatment. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination of Cabozantinib and Nivolumab for metastatic kidney cancer?

The combination of Cabozantinib and Nivolumab has been shown to improve progression-free survival and overall survival compared to another drug, Sunitinib, in the treatment of advanced kidney cancer, according to the CheckMate 9ER study. This combination is also approved as a first-line treatment for advanced kidney cancer in several countries, indicating its effectiveness. ^{1 2 3 4 5}

Is the combination of Cabozantinib and Nivolumab safe for humans?

The combination of Cabozantinib and Nivolumab has been studied for safety in treating advanced kidney cancer. While the treatment can have side effects like diarrhea, fatigue, and skin reactions, these are generally manageable with proper care and dose adjustments. ^{2 3 6 7 8}

What makes the drug combination of Cabozantinib and Nivolumab unique for treating metastatic kidney cancer?

The combination of Cabozantinib and Nivolumab is unique because it pairs a multi-targeted tyrosine kinase inhibitor (Cabozantinib) with an immune checkpoint inhibitor (Nivolumab), which has shown to improve progression-free survival and overall survival compared to standard treatments like sunitinib for advanced renal cell carcinoma. This combination is also associated with better health-related quality of life for patients. ^{1 2 3 6 9}

Research Team

Ritesh R Kotecha

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with renal cell carcinoma that has spread to the brain. Participants must be over 18, have a good performance status (able to carry out daily activities), and agree to use effective contraception if necessary. They should not have had certain treatments recently, like whole brain radiotherapy or experimental drugs within the last month, and should not need major surgery during the study.

Inclusion Criteria

My blood and organ tests meet the required health standards.

I have recovered from any serious side effects of my previous treatments.

I can provide a tissue sample for my kidney cancer diagnosis.

Exclusion Criteria

Previously identified allergy or hypersensitivity to components of the treatment

I am on steroids or immunosuppressants for an autoimmune disease, with some exceptions.

I have not had significant blood vessel problems in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib and nivolumab with radiation therapy. Cabozantinib is administered at 40 mg PO daily and nivolumab at 480 mg IV every 4 weeks. Radiation is delivered as stereotactic radiosurgery over 1-5 fractions.

8 weeks

Safety Monitoring

Participants are monitored for safety, specifically for CNS toxicity, over a 56-day period.

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including quality of life assessments through questionnaires.

1 year

Treatment Details

Interventions

• Cabozantinib
• Nivolumab
• Stereotactic Radiosurgery (SRS)

Trial Overview The study tests a combination of cabozantinib and nivolumab with stereotactic radiosurgery on patients with kidney cancer in the brain. It aims to assess safety, effectiveness, and impact on quality of life through questionnaires.

Participant Groups

Group I: Cabozantinib and Nivolumab With Radiation Therapy Experimental Treatment 3 Interventions

Patients being newly initiated on cabo/nivo will be started on with cabozantinib 40 mg PO daily and nivolumab 480 mg IV day Q4 weeks o Dose de-escalation of cabozantinib for toxicity will be allowed per prespecified toxicity dose levels Radiation will be stereotactic radiosurgery, delivered over 1-5 fractions with a total dose of 18-30Gy depending on fractionation schedule per the discretion of the treating radiation oncologist. Standard institutional regimens such as 18-24 Gy in a single fraction, 24-27 Gy in three fractions, and 25-30 Gy in five fractions are permissible.

Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

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+

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

The combination of cabozantinib (a TKI) and nivolumab (an anti-PD-1 antibody) is an effective first-line treatment for previously-untreated advanced renal cell carcinoma (RCC), showing significantly longer progression-free and overall survival compared to sunitinib monotherapy in the CheckMate 9ER trial.

Patients receiving cabozantinib plus nivolumab reported better health-related quality of life, although the combination therapy had a higher incidence of serious adverse events compared to sunitinib, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma. Markham, A.[2022]

In a phase 3 trial involving 855 patients with untreated advanced renal-cell carcinoma, the combination of cabozantinib with nivolumab and ipilimumab significantly improved progression-free survival compared to nivolumab and ipilimumab alone, with a 12-month progression-free survival rate of 57% versus 49%.

However, the experimental group experienced a higher incidence of severe adverse events (grade 3 or 4) at 79%, compared to 56% in the control group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Albiges, L., et al.[2023]

In a phase 3 trial involving 651 patients with untreated advanced renal-cell carcinoma, the combination of nivolumab and cabozantinib significantly improved progression-free survival (16.6 months) compared to sunitinib (8.3 months), with a hazard ratio of 0.51, indicating a 49% reduction in the risk of disease progression or death.

Patients receiving nivolumab plus cabozantinib also had a higher overall survival rate at 12 months (85.7%) compared to those on sunitinib (75.6%), and a greater objective response rate (55.7% vs. 27.1%), although adverse events were common in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Burotto, M., et al.[2022]

Nivolumab plus cabozantinib significantly improved progression-free survival and overall survival compared to sunitinib in advanced renal cell carcinoma, as shown in the CheckMate 9ER study.

However, the combination treatment was found to be not cost-effective, with an incremental cost-effectiveness ratio of $863,720 per quality-adjusted life-year (QALY) gained, far exceeding the commonly accepted threshold of $150,000.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States. Liao, W., Lei, W., Feng, M., et al.[2021]

A 77-year-old male with metastatic papillary renal cell carcinoma and inferior vena cava tumor thrombus was successfully treated with nivolumab plus cabozantinib, leading to significant regression of all lesions.

Following treatment, the patient underwent radical nephrectomy and other surgeries, with no viable cancer cells found and no recurrence of the disease for 9 months, indicating the potential efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib. Hayashida, M., Miura, Y., Yamaguchi, T., et al.[2023]

In a phase II trial involving 47 patients with advanced non-clear-cell renal cell carcinoma, the combination of cabozantinib and nivolumab showed a promising objective response rate of 47.5% in patients with papillary, unclassified, or translocation-associated RCC, along with a median progression-free survival of 12.5 months.

The treatment was less effective in chromophobe RCC, with no objective responses observed, highlighting the need for further research into genomic predictors of response, particularly mutations like NF2 and FH that were associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Lee, CH., Voss, MH., Carlo, MI., et al.[2023]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

The combination of cabozantinib (a tyrosine kinase inhibitor) and nivolumab (an immune checkpoint inhibitor) significantly improved progression-free survival, overall survival, and objective response rates in patients with untreated advanced renal cell carcinoma compared to sunitinib, supporting its approval as a first-line therapy.

While the safety profile of the combination treatment is generally manageable, it requires careful monitoring and management of overlapping adverse events, such as diarrhea and hepatotoxicity, to maintain patient tolerability and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. McGregor, B., Mortazavi, A., Cordes, L., et al.[2023]

Cabozantinib (CAB) has shown significant improvements in overall survival and progression-free survival in phase-III studies for patients with advanced renal cell carcinoma and hepatocellular carcinoma, leading to its approval in Japan for these conditions.

CAB may enhance antitumor immunity and, when combined with PD-1 checkpoint inhibitors like nivolumab, has demonstrated increased progression-free survival compared to standard treatments, indicating a potential synergistic effect in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX®)]. Osaka, T., Yamaguchi, N., Hara, T.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma. [2022]

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

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. [2023]

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

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. [2022]

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

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States. [2021]

5. Australia pubmed.ncbi.nlm.nih.gov

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib. [2023]

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

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. [2023]

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

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. [2023]

9. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX®)]. [2022]