Immunotherapy With or Without Surgery for Kidney Cancer

(PROBE Trial)

Recruiting at 389 trial locations

Overseen By Sandeep Mashru

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Southwest Oncology Group

Must be taking: Immunotherapy

Disqualifiers: Active brain metastases, Solitary kidney, 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: 7

364 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding kidney removal surgery to standard immunotherapy is more effective for kidney cancer that has spread. Immunotherapy uses medications to help the immune system fight cancer, while surgery involves removing the kidney to potentially manage the disease. The trial targets individuals with kidney cancer, confirmed by scans to have spread, who can undergo surgery. Participants may receive treatments such as nivolumab, ipilimumab, pembrolizumab, avelumab (Bavencio), and axitinib, which aim to halt cancer growth and help the immune system target cancer cells. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor to get specific guidance based on your situation.

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

Previous studies have well-documented the safety of these treatments, but risks remain. For example, Nivolumab can cause serious side effects like lung inflammation and diarrhea in some patients. Pembrolizumab also has immune-related side effects, though it is generally safe for many. When combined with axitinib, Avelumab led to significant side effects in about 20% of patients, but these were manageable. Axitinib alone causes side effects in most patients, though often mild.

These drugs have been used in patients with advanced kidney cancer, aiding researchers in understanding expectations. While these treatments are generally safe, individual experiences can vary. Participating in a clinical trial ensures careful monitoring to manage any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores the potential benefits of combining immunotherapy with surgery for kidney cancer, in contrast to relying solely on systemic therapy. Unlike standard treatments that typically involve either surgery or medication, this approach investigates whether combining these methods can enhance outcomes. The trial includes innovative immunotherapies like Nivolumab, Pembrolizumab, and Avelumab, which work by boosting the body's immune system to attack cancer cells more effectively. By comparing these strategies, researchers hope to determine if surgery in addition to immunotherapy can improve survival rates or quality of life for patients.

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

Research has shown that certain immunotherapy drugs, such as nivolumab, ipilimumab, pembrolizumab, and avelumab, hold promise for treating advanced kidney cancer. In this trial, participants in Arm 1 will receive continued systemic therapy, which may include nivolumab, pembrolizumab, or avelumab, potentially combined with axitinib. For instance, using nivolumab with ipilimumab can reduce the risk of death by up to 28% in patients with advanced kidney cancer. Pembrolizumab has improved survival rates after kidney surgery. Avelumab, when combined with axitinib, can delay cancer progression. Axitinib alone has effectively shrunk tumors in many patients. These treatments enhance the immune system's ability to fight cancer and block enzymes that promote tumor growth. Meanwhile, participants in Arm 2 will undergo nephrectomy in addition to receiving continued systemic therapy. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for patients with metastatic kidney cancer who have already started immunotherapy. They must have had certain minimum treatments, be able to continue immunotherapy, and be fit for surgery to remove the kidney. People can't join if they've had too much pre-trial treatment, other cancers (with some exceptions), active brain metastases, or conditions that rule out immunotherapy or surgery.

Inclusion Criteria

My primary cancer tumor has not been removed.

Your recent lab test results need to meet specific requirements.

I have scans from the last 3 months showing my cancer has spread.

Exclusion Criteria

I do not have active brain cancer, and if I had it before, I currently show no symptoms.

My primary cancer has not worsened.

I have no medical conditions that prevent me from receiving immune therapy or kidney removal.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-randomization Treatment

Treatment naive patients receive one of three immunotherapy-based regimens per standard of care

10-14 weeks

Every 2-3 weeks (in-person)

Randomization Treatment

Patients are randomized to receive continued systemic therapy with or without nephrectomy

Up to 8 weeks for surgery post-randomization

Every 2-4 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 7 years

Every 3 months for the first year, every 6 months for years 2 and 3, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• Axitinib
• Cytoreductive Nephrectomy
• Ipilimumab
• Nivolumab
• Pembrolizumab

Trial Overview The PROBE Trial is testing whether adding a surgical procedure called cytoreductive nephrectomy (kidney removal) to standard care immunotherapies like nivolumab, ipilimumab, pembrolizumab, and avelumab improves outcomes in metastatic kidney cancer compared to just the drug combination alone.

How Is the Trial Designed?

Group I: Arm 2: Nephrectomy and Continued Systemic Therapy Experimental Treatment 1 Intervention

Continued systemic therapy as above, plus: Radical or partial nephrectomy may be performed using laparoscopic, open, or robotic approaches. Surgery should be performed within 8 weeks of randomization.

Group II: Arm 1: Continued Systemic Therapy Only Active Control 2 Interventions

Nivolumab 240 mg IV 1 q 2 weeks OR Nivolumab 480 mg IV 1 q 4 weeks OR Pembrolizumab 200 mg IV 1 q 3 weeks Axitinib 5 mg oral Daily BID OR Avelumab 10 mg/kg IV 1 q 2 weeks Axitinib 5 mg oral Daily BID

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

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of axitinib and pembrolizumab shows a high response rate of 73% in patients with previously untreated advanced renal cell carcinoma, indicating strong efficacy for this treatment regimen.

This finding suggests that the dual approach of targeting both tumor growth and immune response may be effective in managing advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

Pembrolizumab or avelumab combined with axitinib showed improved progression-free survival in patients with clear-cell advanced renal cell carcinoma compared to sunitinib, based on results from phase III trials.

The combination treatments were associated with relatively manageable side effects, suggesting a favorable safety profile for these first-line therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint Inhibitor-TKI Combos Effective in RCC. [2020]

The combination of ipilimumab and nivolumab is considered a feasible first-line treatment for metastatic renal cell carcinoma, showing an acceptable safety profile compared to sunitinib monotherapy, based on a systematic review and meta-analysis of four randomized controlled trials.

Different immune-based combinations, including nivolumab plus ipilimumab and pembrolizumab plus axitinib, exhibit varying toxicity profiles, highlighting the importance of personalized treatment choices and the need for improved management of immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma: a systematic review and meta-analysis. Massari, F., Mollica, V., Rizzo, A., et al.[2022]

In a subgroup analysis of 94 Japanese patients with metastatic renal cell carcinoma, the combination of pembrolizumab and axitinib showed improved overall survival and progression-free survival compared to sunitinib, consistent with results from the larger global study.

The safety profile was also favorable, with fewer grade ≥3 treatment-related adverse events in the pembrolizumab-axitinib group (70%) compared to sunitinib (78%), and no deaths from treatment-related adverse events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study. Tamada, S., Kondoh, C., Matsubara, N., et al.[2022]

In a study of 91 patients with metastatic renal cell carcinoma (mRCC), nivolumab showed significant improvements in overall survival, with a median survival of 25.2 months for the highest dose (10 mg/kg) and not reached for treatment-naïve patients.

Nivolumab treatment led to substantial increases in tumor-associated lymphocytes and changes in chemokine levels, indicating its immunomodulatory effects, while no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma. Choueiri, TK., Fishman, MN., Escudier, B., et al.[2022]

Adjuvant pembrolizumab significantly improves disease-free survival in patients with high-risk renal cell carcinoma (RCC) after surgery, as shown in the KEYNOTE 564 trial.

Pembrolizumab is an effective and well-tolerated treatment option for patients with surgically resected RCC, paving the way for future research on patient selection and biomarkers for therapy response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy for patients with renal cell carcinoma following surgery: a focus on pembrolizumab. Serzan, M., Atkins, MB.[2022]

Nivolumab-ipilimumab is the most cost-effective first-line treatment for metastatic clear-cell renal cell carcinoma (mRCC), with an incremental cost-effectiveness ratio (ICER) of $34,190 per quality-adjusted life year (QALY) compared to sunitinib.

In contrast, pembrolizumab-axitinib was found to be not cost-effective, with an ICER of $12,630,828 per QALY, and resulted in shorter QALY gains (1.99) compared to nivolumab-ipilimumab (3.23 QALY).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cost-effectiveness Analysis Comparing Pembrolizumab-Axitinib, Nivolumab-Ipilimumab, and Sunitinib for Treatment of Advanced Renal Cell Carcinoma. Chan, A., Dang, C., Wisniewski, J., et al.[2023]

The combination of nivolumab and ipilimumab, which targets PD-1 and CTLA-4 pathways, is an approved frontline therapy for metastatic clear-cell renal cell carcinoma (mccRCC).

This case study demonstrates the safe and effective use of this combination therapy in a 53-year-old patient with mccRCC and end-stage renal disease (ESRD) on hemodialysis, highlighting its potential applicability in populations often excluded from clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safe and effective use of nivolumab plus ipilimumab in a patient with metastatic clear-cell renal cell carcinoma with sarcomatoid dedifferentiation and end stage renal disease on hemodialysis. Shaw, LK., Wiele, AJ., Sircar, K., et al.[2022]

Axitinib combined with immune checkpoint inhibitors (ICI) like pembrolizumab or avelumab is now approved for treating advanced renal cell carcinoma, but distinguishing between adverse events (AEs) caused by each treatment is crucial for optimizing therapy.

Experts identified specific AEs such as diarrhea, hepatic toxicity, fatigue, and cardiovascular issues that require unique management strategies when using axitinib-ICI combinations, emphasizing the need for careful clinical monitoring and tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. Grünwald, V., Voss, MH., Rini, BI., et al.[2021]

In a long-term study of 52 patients with advanced renal-cell carcinoma, the combination of axitinib and pembrolizumab showed promising efficacy, with a median progression-free survival of 23.5 months and an overall response rate of 73.1%.

After nearly 4 years of follow-up, the treatment was associated with significant clinical benefits and no new safety concerns, although 73.1% of patients experienced grade III/IV adverse events, leading to treatment discontinuation in 38.5% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial. Atkins, MB., Plimack, ER., Puzanov, I., et al.[2021]

In the phase III JAVELIN Renal 101 trial, avelumab plus axitinib demonstrated significantly improved progression-free survival (PFS) of 13.9 months compared to 8.5 months for sunitinib, indicating better efficacy in treating advanced renal cell carcinoma.

The overall survival (OS) trend also favored avelumab plus axitinib, with a hazard ratio of 0.79 compared to sunitinib, although the data is still immature and requires further follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. Haanen, JBAG., Larkin, J., Choueiri, TK., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11700049/

Real-world outcomes of avelumab plus axitinib in patients ... Avelumab + axitinib was approved for advanced renal cell carcinoma (aRCC) in Japan in December 2019. We report long-term real-world outcomes with first-line ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.474

Real-world effectiveness and safety of first-line (1L) ... Background: In the JAVELIN Renal 101 phase 3 trial, 1L avelumab + axitinib resulted in significantly longer progression-free survival (PFS) ...

3. urotoday.com urotoday.com/conference-highlights/esmo-2019/esmo-2019-kidney-cancer/115203-new-data-for-bavencio-avelumab-for-advanced-cancers-to-be-presented-at-esmo-2019.html

New Data for BAVENCIO® (avelumab) for Advanced ... ESMO 2019 JAVELIN Renal 101 study support efficacy of BAVENCIO plus axitinib across multiple subgroups of patients with advanced renal cell carcinoma (RCC)

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1816047

Avelumab plus Axitinib versus Sunitinib for Advanced ... In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma.

5. pfizer.com pfizer.com/news/press-release/press-release-detail/pivotal_phase_iii_data_for_bavencio_avelumab_plus_inlyta_axitinib_in_advanced_renal_cell_carcinoma_published_in_the_new_england_journal_of_medicine

Pivotal Phase III Data for BAVENCIO® (avelumab) Plus ... JAVELIN Renal 101 shows significant improvement in progression-free survival with a hazard ratio of 0.69 in patients regardless of PD-L1 ...

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/06/NCT02684006/Prot_000.pdf

MSB0010718C, AG-013736 B9991003 Final Protocol ... safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015 Mar 30. 52. Motzer RJ, Rini BI, McDermott ...

7. ema.europa.eu ema.europa.eu/en/documents/product-information/bavencio-epar-product-information_en.pdf

Bavencio, INN-avelumab - EMA Renal cell carcinoma. Summary of the safety profile. The safety of avelumab in combination with axitinib has been evaluated in 489 patients with advanced. RCC ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10078905/

Avelumab Plus Axitinib as First-Line Therapy for Advanced ... We report long-term safety and efficacy of avelumab plus axitinib as first-line treatment for patients with aRCC from the JAVELIN Renal 100 phase Ib trial.

9. bavencio.com bavencio.com/en_US/patients-and-caregivers/uc-home.html

UC Home BAVENCIO® (avelumab) is a medicine that may treat certain cancers by working with your immune system. BAVENCIO can cause your immune system to attack normal ...