Nivolumab + Cabozantinib for Kidney Cancer

Not currently recruiting at 9 trial locations

Overseen By Robert Motzer, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

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

Disqualifiers: Brain malignancies, HIV, Hepatitis, others

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

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: Unknown

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of nivolumab (an immunotherapy drug) and cabozantinib (a targeted therapy) to evaluate its effectiveness for individuals with advanced kidney cancer that has spread. Researchers aim to determine the positive and negative effects of this combination on cancer that cannot be surgically removed. Eligible participants have been diagnosed with metastatic kidney cancer and have undergone 0 or 1 prior treatments. The trial includes several arms, each focusing on different types of kidney cancer to collect a broad range of data. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received certain cancer treatments or immunotherapy recently, and if you are on pain medication, it must be stable. 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 the combination of nivolumab and cabozantinib has been tested for safety in people with advanced kidney cancer. A study comparing this combination to sunitinib provided important safety information. Most patients tolerated the treatment well, though some side effects occurred.

Common side effects included diarrhea, tiredness, and changes in liver function tests, which were mostly mild to moderate. More serious side effects, such as high blood pressure and severe diarrhea, were less common.

Nivolumab, an FDA-approved treatment for kidney cancer, has a well-understood safety profile. Cabozantinib is also used for advanced kidney cancer, either alone or with nivolumab, indicating it is generally safe when used correctly. Patients should consult their healthcare provider about possible side effects and safety concerns before deciding to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Nivolumab and Cabozantinib for kidney cancer because of their unique mechanisms of action. Most treatments for kidney cancer, like traditional targeted therapies and immunotherapies, work separately. However, Nivolumab boosts the immune system by inhibiting the PD-1 pathway, allowing the body to better attack cancer cells, while Cabozantinib targets multiple pathways involved in tumor growth and blood vessel development. This combination has the potential to be more effective than current options by attacking the cancer from multiple angles, offering hope for improved outcomes in patients with specific kidney cancer subtypes.

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

Research has shown that using cabozantinib and nivolumab together holds promise for treating advanced kidney cancer. Participants in this trial will receive this combination treatment. One study found that patients taking this combination had a 40% lower risk of dying compared to those taking sunitinib, another cancer drug. Another study indicated that this treatment helped patients live longer without their cancer worsening. Specifically, the period during which the cancer did not worsen was longer with cabozantinib and nivolumab than with sunitinib. Overall, evidence suggests that this combination may be more effective than some current treatments for kidney cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Darren R. Feldman

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults (18+) with advanced or metastatic non-clear cell renal cell carcinoma who've had 0 or 1 prior treatments. They must be able to understand the study, consent to it, and agree to use contraception if fertile. Excluded are those on certain medications, with severe allergies, HIV/hepatitis B/C infections, uncontrolled conditions like hypertension or thyroid issues, recent major surgery, brain/spinal cancer history or significant cardiovascular disease.

Inclusion Criteria

Signed and dated IRB-approved Informed Consent Form

I can provide a tissue sample from my cancer for testing.

My recent blood and organ tests meet the study's requirements.

Exclusion Criteria

I have a serious wound, ulcer, or bone fracture that is not healing.

My heart's electrical activity (QTcF) is not over 500 ms.

I have lung lesions or disease in my airways.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of nivolumab and cabozantinib for metastatic kidney cancer

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Nivolumab

Trial Overview The study tests a combination of two drugs: Nivolumab (Opdivo®) and Cabozantinib (Cabometyx®), in patients with metastatic kidney cancer. It aims to assess the benefits and adverse effects compared to current standard treatments.

How Is the Trial Designed?

Group I: Cohort 4: Unclassified, papillary, and HL RCC Experimental Treatment 2 Interventions

Cohort 4 is an expansion of Cohorts 1+3, which will accure an additional 40 patients

Group II: Cohort 3: Unclassified, papillary, and HL RCC Experimental Treatment 2 Interventions

Cohort 3 is designed as an expansion cohort of Cohort 1 with 20 additional patients to obtain a more precise estimate of the ORR and clinical outcomes

Group III: Cohort 2: Chromophobe RCC Experimental Treatment 2 Interventions

Cohort 2 is designed as a Simon's optimal two-stage design with a total possible sample size of 17. This design discriminates between ORR rates of 5 and 25%.

Group IV: Cohort 1: Unclassified, papillary, and HL RCC Experimental Treatment 2 Interventions

Cohort 1 is designed as a single stage study with a total sample size of 20. This design discriminates between ORR rates of 10 and 35%.

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+

Published Research Related to This Trial

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]

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]

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]

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]

The European Association of Urology now recommends nivolumab and cabozantinib as preferred treatments for patients with renal cancer who have not responded to previous vascular endothelial growth factor-targeted therapies.

Recent data indicate that cabozantinib offers a survival benefit, reinforcing its efficacy as a treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy. Powles, T., Staehler, M., Ljungberg, B., et al.[2018]

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]

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 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]

Citations

1. urotoday.com urotoday.com/conference-highlights/esmo-2025/esmo-2025-kidney-cancer/164062-esmo-2025-efficacy-of-cabozantinib-and-nivolumab-in-cluster-1-2-metastatic-clear-cell-renal-cell-carcinoma-results-from-optic-rcc-a-phase-ii-trial-of-a-novel-rnaseq-based-biomarker.html

ESMO 2025: Efficacy of Cabozantinib and Nivolumab in ... ESMO 2025: Efficacy of Cabozantinib and Nivolumab in Cluster 1/2 Metastatic Clear Cell Renal Cell Carcinoma: Results from OPTIC RCC, a Phase II ...

2. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-final-five-year-follow-results-checkmate-9er

9ER Trial Evaluating CABOMETYX® (cabozantinib ... - Exelixis At a median follow-up of 67.6 months, CABOMETYX in combination with Opdivo improved progression-free survival (PFS; hazard ratio [HR]: 0.58; 95% ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38642472/

Nivolumab plus cabozantinib versus sunitinib for first-line ... Results: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus ...

4. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/combo/efficacy

1L aRCC Efficacy & Safety for CABOMETYX® ... CABOMETYX + OPDIVO had a median OS of 46.5 months vs 35.5 months with sunitinib3. No formal statistical testing was conducted at the time of the updated ...

5. 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.

6. opdivohcp.com opdivohcp.com/efficacy/rcc/opdivo-cabometyx

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib ... Safety Data. View a selected safety profile of adverse reactions seen in ... Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9590624/

Management of Adverse Events Associated with Cabozantinib ... This review discusses the safety results of CheckMate 9ER and provides guidance on managing some of the more clinically relevant AEs with a focus on ...

8. opdivo.com opdivo.com/advanced-kidney-cancer

Advanced Kidney Cancer (RCC) Cancer Treatment OPDIVO® (nivolumab) is an FDA-approved immunotherapy. This cancer treatment is the foundation for three different treatments to fight against RCC.

9. cabometyx.com cabometyx.com/kidney-cancer

Advanced Kidney Cancer Treatment Option| CABOMETYX ... CABOMETYX is used to treat certain people with advanced kidney cancer (RCC) alone or in combination with OPDIVO. See indication and important safety information