Cabozantinib + Immunotherapy for Kidney Cancer

(COSMIC-313 Trial)

Not currently recruiting at 194 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Exelixis

Must not be taking: Anticoagulants, Immunosuppressants, Corticosteroids, others

Disqualifiers: Brain metastases, Autoimmune disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 4

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for advanced kidney cancer. Researchers compare a combination of three drugs—cabozantinib (a type of cancer medication), nivolumab, and ipilimumab—against a combination of just nivolumab and ipilimumab. The goal is to determine if adding cabozantinib improves outcomes for patients with specific types of advanced kidney cancer. Individuals with advanced or metastatic kidney cancer with a clear-cell component who meet certain health criteria might be suitable for this study. The trial involves two groups: one receiving the experimental drug combination and the other receiving a placebo with the standard drugs. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering patients a chance to contribute to a treatment that could soon become widely available.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on certain treatments like systemic anticancer therapy, oral anticoagulants, or immunosuppressive medications. It's best to discuss your specific medications with the trial team.

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

Research has shown that combining the drugs cabozantinib, nivolumab, and ipilimumab can effectively treat kidney cancer. One study found that this combination helped people live longer without their cancer worsening, compared to using just nivolumab and ipilimumab.

Regarding safety, data from past patients suggest that starting with a lower dose of cabozantinib, specifically 20 mg per day, results in fewer severe side effects than a higher dose. While side effects can still occur, they might be less severe at this lower dose.

Nivolumab and ipilimumab have been used together for a long time and are generally considered safe. Many patients have experienced a reduced risk of death when using these drugs for similar conditions.

Overall, this combination treatment has shown promise in other studies. However, like any medical treatment, it's important to consider the potential benefits and possible side effects. Consulting a healthcare professional is essential to understand what this might mean for individual patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for kidney cancer?

Researchers are excited about the combination of cabozantinib, nivolumab, and ipilimumab for kidney cancer because it offers a unique multi-faceted approach. Unlike standard treatments such as sunitinib or pazopanib, which primarily target tumor blood vessels, this combination leverages both targeted therapy and immunotherapy. Cabozantinib inhibits the growth of blood vessels that feed tumors, while nivolumab and ipilimumab help activate the immune system to recognize and attack cancer cells. This dual-action strategy not only aims to shrink tumors but also bolsters the body's natural defenses, potentially leading to more durable responses.

What evidence suggests that this trial's treatments could be effective for kidney cancer?

Research shows that combining cabozantinib, nivolumab, and ipilimumab may help treat advanced kidney cancer. In this trial, participants in the experimental arm will receive this combination, which studies have shown significantly reduces the risk of death compared to some standard treatments. For example, one study found that people taking these three drugs had a 40% lower risk of dying than those taking another common treatment called SUTENT. Another study demonstrated that using this combination as the first treatment reduced the risk of death by 23% in people with advanced kidney cancer. These treatments work by stopping cancer growth and boosting the body's immune system, offering hope for better outcomes. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic kidney cancer that hasn't been treated before. They should have a certain level of fitness (KPS ≥ 70%) and measurable disease. People can't join if they've had recent surgeries, live vaccines, other cancers within 3 years, autoimmune diseases needing treatment in the last two years, or are on high-dose steroids.

Inclusion Criteria

My kidney cancer cannot be cured with surgery or radiation and has spread.

My cancer can be measured and is not in an area treated by radiation.

My organs and bone marrow are working well.

Exclusion Criteria

My brain metastases have been treated and stable for at least 4 weeks.

I have had treatment for advanced kidney cancer that couldn't be surgically removed.

I do not have any active infections needing treatment, including hepatitis, HIV/AIDS, or tuberculosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib in combination with nivolumab and ipilimumab or nivolumab and ipilimumab with placebo

16 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab
• Nivolumab

Trial Overview The study tests Cabozantinib combined with Nivolumab and Ipilimumab against a placebo plus Nivolumab and Ipilimumab in patients with kidney cancer. It's randomized and double-blinded, meaning neither doctors nor patients know who gets the real drug versus placebo.

How Is the Trial Designed?

Group I: Experimental Arm Experimental Treatment 3 Interventions

Cabozantinib + nivolumab + ipilimumab (4 doses) followed by cabozantinib + nivolumab

Group II: Control Arm Active Control 3 Interventions

Cabozantinib-matched placebo + nivolumab + ipilimumab (4 doses) followed by cabozantinib-matched placebo + nivolumab

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?

Exelixis

Lead 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

Published Research Related to This Trial

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]

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 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 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]

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 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]

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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2212851

Cabozantinib plus Nivolumab and Ipilimumab in Renal- ... The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated ...

2. opdivo.com opdivo.com/advanced-kidney-cancer/clinical-trial-results/opdivo-cabometyx-immunotherapy-combination

Clinical trial results for advanced kidney cancer (renal cell ... In a clinical trial, people given OPDIVO + CABOMETYX had a 40% lower risk of dying than those given SUTENT. Words to know.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4539

Analysis of phase II study of cabozantinib (Cabo) with ... Reduction of the starting dose of Cabo to 20 mg/d in combination with Nivo/Ipi results in numerically lower ≥ grade 3 TrAEs than starting at 40 mg/d.

4. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/n/tr826967112990312/

Cabozantinib (Cabometyx) - NCBI Bookshelf - NIH After 10 years' predictive time horizon, the results favoured ipilimumab plus nivolumab followed by cabozantinib plus nivolumab. ... renal cell carcinoma.

5. news.bms.com news.bms.com/news/details/2024/Opdivo-nivolumab-in-Combination-with-CABOMETYX-cabozantinib-Demonstrates-Long-Term-Survival-Benefits-After-Four-Years-of-Follow-Up-in-the-CheckMate--9ER-Trial-in-First-Line-Advanced-Renal-Cell-Carcinoma/default.aspx

9ER Trial in First-Line Advanced Renal Cell Carcinoma Opdivo in combination with CABOMETYX reduced the risk of death by 23% in the first-line treatment of advanced renal cell carcinoma vs.

6. urotoday.com urotoday.com/conference-highlights/asco-gu-2025/asco-gu-2025-kidney-cancer/158340-asco-gu-2025-cabozantinib-in-combination-with-nivolumab-and-ipilimumab-in-previously-untreated-advanced-renal-cell-carcinoma-arcc-final-results-of-cosmic-313.html

Final Results of COSMIC-313 Dr. Laurence Albiges presented the final results of COSMIC-313 of cabozantinib (cabo) in combination with nivolumab (nivo) plus ipilimumab (ipi) in previously ...

7. news.bms.com news.bms.com/news/details/2024/Eight-Year-Data-for-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Continue-to-Demonstrate-Longest-Survival-Benefit-vs.-Sunitinib-Reported-in-Patients-with-Previously-Untreated-Advanced-or-Metastatic-Renal-Cell-Carcinoma/default.aspx

Eight-Year Data for Opdivo (nivolumab) Plus Yervoy ... Patients with previously untreated advanced or metastatic renal cell carcinoma treated with Opdivo plus Yervoy experienced a 28% reduction in the risk of death ...