Cabozantinib + Nivolumab for Kidney Cancer

Overseen by Tian Zhang, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Cabozantinib

Must not be taking: Warfarin, Dabigatran, Clopidogrel

Disqualifiers: Brain metastases, Uncontrolled hypertension, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing higher doses of cabozantinib or a combination of cabozantinib with nivolumab in patients with advanced kidney cancer who did not respond to previous treatment. Cabozantinib stops cancer growth, while nivolumab helps the immune system fight the cancer. Cabozantinib and nivolumab have been used together to treat advanced renal cell carcinoma, showing benefits in disease control and survival.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but there is no washout period required for cabozantinib. For other cancer treatments, a washout period of 4 weeks or 4 half-lives, whichever is shorter, is needed. Some anticoagulants are not allowed, so check with the trial team about your specific medications.

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

The combination of Cabozantinib and Nivolumab has been shown to be effective as a first-line treatment for advanced renal cell carcinoma (RCC), with studies indicating longer progression-free survival and improved overall survival compared to the drug Sunitinib. Patients also reported better quality of life with this combination. ^{1 2 3 4 5}

Is the combination of Cabozantinib and Nivolumab safe for treating kidney cancer?

The combination of Cabozantinib and Nivolumab has been studied for safety in treating advanced kidney cancer. While the safety profile is generally manageable, some side effects like diarrhea, liver issues, skin reactions, fatigue, and kidney problems can occur. These side effects can often be managed with supportive care and dose adjustments. ^{1 2 4 6 7}

How is the drug combination of Cabozantinib and Nivolumab unique for treating advanced kidney cancer?

The combination of Cabozantinib and Nivolumab is unique because it pairs a tyrosine kinase inhibitor (Cabozantinib) with an immune checkpoint inhibitor (Nivolumab), offering improved progression-free survival and overall survival compared to traditional treatments like sunitinib. This combination is recommended as a first-line treatment for advanced renal cell carcinoma in both European and American guidelines. ^{1 2 4 5 8}

Research Team

Tian Zhang, MD

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

Adults with advanced kidney cancer who've seen their disease progress after cabozantinib treatment can join. They must have used cabozantinib for over 6 months, be able to take it without severe side effects, and not be on certain medications or have specific health conditions. Participants need measurable cancer growth, good organ function, and a performance status indicating they can walk and care for themselves.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

My advanced kidney cancer responded to cabozantinib treatment for over 6 months.

Capable of understanding and complying with the protocol requirements and must have signed the informed consent document

Exclusion Criteria

I don't have another cancer needing treatment right now, except for certain exceptions.

I haven't had radiation for bone metastasis in the last 2 weeks or any radiation in the last 4 weeks.

My brain metastases are treated and have been stable.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib 80mg PO daily for dose escalation after progression on cabozantinib monotherapy

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

Treatment Details

Interventions

• Cabozantinib (Tyrosine Kinase Inhibitor)
• Nivolumab (Checkpoint Inhibitor)

Trial Overview The trial is testing two approaches in patients whose kidney cancer has worsened despite previous treatment: one group will receive a high dose of cabozantinib alone, while the other will get a lower dose combined with nivolumab. The choice between these options depends on what dosage participants tolerated before.

Participant Groups

Group I: Cabozantinib Dose Escalation Experimental Treatment 1 Intervention

cabozantinib 80mg PO daily

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?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

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

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 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]

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 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]

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 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 combined with nivolumab is shown to be superior in terms of progression-free survival (PFS) compared to axitinib + pembrolizumab and nivolumab + ipilimumab for the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC), based on a systematic review of four randomized controlled trials involving treatment-naïve patients.

While cabozantinib + nivolumab demonstrated effectiveness, the combination of lenvatinib + pembrolizumab showed numerical superiority in overall survival, indicating that while cabozantinib + nivolumab is a strong option, other combinations may also be effective and warrant consideration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab. Niewada, M., Macioch, T., Konarska, M., et al.[2023]

References

1. 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]

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

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

3. 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]

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

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

5. France pubmed.ncbi.nlm.nih.gov

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

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

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

7. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab. [2023]