177Lu Girentuximab + Cabozantinib + Nivolumab for Advanced Renal Cell Carcinoma

Overseen By Eric Jonasch, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Autoimmune disease, Hypertension, Cardiovascular events, others

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

Compensation: Varies

Number of Visits: 2

Duration: 20 months

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of three treatments—177Lu girentuximab (a radiolabeled antibody therapy), cabozantinib, and nivolumab—can help control advanced clear cell renal cell carcinoma, a type of kidney cancer. The researchers aim to determine if these treatments can slow the cancer's progression. Suitable candidates for this trial include those diagnosed with advanced or metastatic renal cell carcinoma that hasn't been treated with other systemic therapies and have at least one measurable tumor. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this novel combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are receiving chronic treatment with strong CYP3A4 inducers or inhibitors, as these can affect how the trial drugs work.

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

Research has shown that cabozantinib and nivolumab are well-known treatments for advanced kidney cancer and have received FDA approval. Studies indicate that cabozantinib does not present any new or unexpected safety issues. It can cause side effects such as diarrhea, tiredness, and changes in liver function tests, but these are usually manageable.

Nivolumab is also a trusted treatment with a well-established safety record. Most people tolerate it well, though some may experience tiredness or a skin rash.

Regarding 177Lu girentuximab, less information is available because it remains under study. Early research suggests it may be well-tolerated when used with nivolumab. However, since this treatment is still in early testing, not all possible side effects are known. Researchers are studying the combination of these treatments to ensure safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced renal cell carcinoma because they combine innovative approaches to target cancer cells more effectively. Unlike traditional treatments, which often rely on either surgical removal or broad-spectrum chemotherapies, 177Lu girentuximab is a radio-labeled antibody that directly targets kidney cancer cells, delivering radiation precisely where it’s needed. Cabozantinib adds another layer by inhibiting pathways that tumors use to grow and spread. Meanwhile, Nivolumab is an immunotherapy that empowers the body’s own immune system to better recognize and attack cancer cells. This multi-faceted approach aims to enhance treatment effectiveness and improve patient outcomes beyond what current standard treatments can achieve.

What evidence suggests that this trial's treatments could be effective for advanced renal cell carcinoma?

Previous studies have shown promising results for the combination of cabozantinib and nivolumab in treating advanced kidney cancer. Cabozantinib slowed the disease by 34% and improved tumor response to treatment. When combined with another drug, nivolumab reduced the risk of death by 28% in people with untreated advanced kidney cancer. This trial explores the new addition of 177Lu girentuximab, a targeted therapy, for its potential to enhance treatment effectiveness by directly attacking cancer cells. Together, these treatments in various cohorts aim to improve survival and control the disease more effectively. ^{1 4 6 7 8}

Who Is on the Research Team?

Eric Jonasch, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced clear cell renal cell carcinoma who haven't had systemic therapy for metastatic RCC. They must be able to swallow pills, have good organ function, and no major health issues that could affect the trial. Women of childbearing age need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

Women who could become pregnant must have a negative pregnancy test within 7 days before starting the study drug.

My brain cancer is under control and not life-threatening, with other measurable disease present.

Your blood counts and organ function are within certain levels and have not required specific treatments within the past 2 weeks.

Exclusion Criteria

I have nutrient absorption issues due to past GI surgery or disease.

Is participating in another therapeutic clinical trial

I am on long-term medication that affects how drugs are broken down in my body.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 177Lu girentuximab in combination with cabozantinib and nivolumab

20 months

Biopsy within 2 weeks of starting treatment and at Cycle 4

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 177Lu girentuximab
• Cabozantinib
• Nivolumab

Trial Overview The study tests if combining 177Lu girentuximab with cabozantinib and nivolumab can control advanced kidney cancer. It's in early stages (Phase 1b/2) to see how well patients respond and what doses are safe.

How Is the Trial Designed?

Group I: Cohort 3 (Biopsy) Experimental Treatment 4 Interventions

Participants at the time of progression or at 20 months post treatment

Group II: Cohort 2 (Biopsy) Experimental Treatment 4 Interventions

Participants within 2 weeks of Cycle 4

Group III: Cohort 1 (Biopsy) Experimental Treatment 4 Interventions

Participants within 2 weeks of starting the first dose of 177Lu-girentuximab

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Telix Pharmaceuticals Limited

Collaborator

Trials

1

Recruited

100+

Published Research Related to This Trial

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]

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]

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]

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]

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]

A 52-year-old male with a large inoperable tumor in a horseshoe kidney achieved a major partial response to neoadjuvant therapy with nivolumab and cabozantinib, allowing for successful radical tumor resection and maintaining mild renal function post-treatment.

Despite experiencing hepatotoxicity that led to early withdrawal of nivolumab, the combination of immune checkpoint inhibitors and tyrosine kinase inhibitors shows promise as a neoadjuvant treatment strategy for advanced renal cell carcinoma, particularly in challenging cases like horseshoe kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab and cabozantinib in advanced renal cell carcinoma in a horseshoe kidney - how to achieve a safe and radical resection? a case report and review of the literature. Zemankova, A., Studentova, H., Kopova, A., et al.[2023]

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]

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]

Citations

1. urotoday.com urotoday.com/conference-highlights/asco-2025/asco-2025-kidney-cancer/161088-asco-2025-starlite-1-phase-1b-2-study-of-combination-177lu-girentuximab-plus-cabozantinib-and-nivolumab-in-treatment-naive-patients-with-advanced-clear-cell-rcc.html

STARLITE-1: Phase 1b/2 Study of Combination 177Lu ... A phase 1b/2, single-arm clinical trial evaluating the safety and efficacy of the combination of 177Lu-girentuximab, cabozantinib, and nivolumab in patients ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS4611

STARLITE-1: Phase 1b/2 study of combination 177 Lu ... The combination of nivolumab plus cabozantinib was approved for first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S240545692500077X

Phase 1b/2 Study of Combined 177Lu-Girentuximab plus ... The combination of 177 Lu-girentuximab with nivolumab and cabozantinib represents a novel approach to improving CR rates in advanced ccRCC.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT07197580

Study of 177Lu-TLX250 in Advanced Relapsed or ... This is a randomized, open-label, multi-center 3 study evaluating the safety and efficacy of 177Lu-TLX250, a CAIX-targeting radioligand therapy, in adult ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/22980441/

Phase 1 radioimmunotherapy study with lutetium 177- ... (177)Lu-cG250 radioimmunotherapy in metastatic ccRCC patients is well tolerated at an activity dose level as high as 2405 MBq/m(2) (MTD).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02002312

Phase II Study of Lutetium-177 Labeled Girentuximab in ... This is a Phase II study using Lu-177-DOTA-girentuximab for treatment of patients with advanced clear cell renal cell carcinoma. The trial requires 14 patients.

7. urotoday.com urotoday.com/conference-highlights/asco-gu-2025/asco-gu-2025-kidney-cancer/158315-asco-gu-2025-starlite-2-phase-2-study-of-nivolumab-plus-177lutetium-labeled-anti-carbonic-anhydrase-ix-caix-monoclonal-antibody-girentuximab-177lu-girentuximab-in-patients-with-advanced-clear-cell-renal-cell-carcinoma-ccrcc.html

ASCO GU 2025: STARLITE 2: Phase 2 Study of Nivolumab ... The STARLITE 2 trial is a phase 2, open-label, single-arm study evaluating the combination of lutetium-177 (¹⁷⁷Lu)-girentuximab and nivolumab in ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4610

Phase 1b/2 study of combination 177 Lu girentuximab plus ... The combination of nivolumab plus cabozantinib was recently approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study.