Immunotherapy With or Without Surgery for Kidney Cancer

(PROBE Trial)

Recruiting at 384 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

Trial Summary

What is the purpose of this trial?

This phase III trial compares the effect of adding surgery to a standard of care immunotherapy-based drug combination versus a standard of care immunotherapy-based drug combination alone in treating patients with kidney cancer that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, pembrolizumab, and avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Surgery to remove the kidney, called a nephrectomy, is also considered standard of care; however, doctors who treat kidney cancer do not agree on its benefits. It is not yet known if the addition of surgery to an immunotherapy-based drug combination works better than an immunotherapy-based drug combination alone in treating patients with kidney cancer.

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.

What data supports the effectiveness of the drug combination used in the clinical trial for kidney cancer?

Research shows that combining axitinib and pembrolizumab has a 73% response rate in advanced kidney cancer, and pembrolizumab alone significantly improves disease-free survival after kidney surgery. Additionally, avelumab combined with axitinib has shown positive results in advanced kidney cancer. ^{1 2 3 4 5}

Is the combination of immunotherapy and axitinib generally safe for kidney cancer patients?

The combination of axitinib with immune checkpoint inhibitors like pembrolizumab or avelumab has been studied for safety in kidney cancer patients. Common side effects include diarrhea, liver issues, fatigue, and heart-related problems, but these can be managed with proper medical care. ^{1 3 6 7 8}

How is the drug combination of Avelumab, Axitinib, Ipilimumab, Nivolumab, and Pembrolizumab unique for kidney cancer?

This drug combination is unique because it combines immune checkpoint inhibitors (drugs that help the immune system attack cancer cells) like pembrolizumab and nivolumab with tyrosine kinase inhibitors (drugs that block signals that tumors use to grow) like axitinib, offering a new approach that has shown effectiveness in extending progression-free survival in advanced kidney cancer. ^{1 2 9 10 11}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Adjuvant therapy for patients with renal cell carcinoma following surgery: a focus on pembrolizumab. [2022]

3. England 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. [2023]

4. Japan 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. [2022]

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

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma. [2022]

6. England 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. [2021]

7. England 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. [2021]

8. England 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. [2022]

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

A Cost-effectiveness Analysis Comparing Pembrolizumab-Axitinib, Nivolumab-Ipilimumab, and Sunitinib for Treatment of Advanced Renal Cell Carcinoma. [2023]

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

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

11. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma: a systematic review and meta-analysis. [2022]