Pembrolizumab +/− Axitinib for Renal Cell Carcinoma

Overseen By UCSF HDFCCC Cancer Immunotherapy Program (CIP)

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Non-clear cell RCC, Immunodeficiency, Active infection, 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

Compensation: Varies

Number of Visits: 57

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies how well pembrolizumab with or without standard of care axitinib works in treating patients with clear cell kidney cancer that has spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic) who are undergoing surgery. Pembrolizumab is an antibody that is designed to bind to and block the activity of PD-1, a molecule in the body that may be responsible for inhibiting the body's immune response against cancer cells. Axitinib is a type of drug known as a tyrosine kinase inhibitor. Tyrosine kinase inhibitors work by blocking enzymes called tyrosine kinases. These enzymes may be too active or found at high levels in some types of cancer cells and blocking them may help keep cancer cells from growing. Giving pembrolizumab with or without axitinib may work better in controlling the cancer and decrease the likelihood of it coming back following surgery in patients with kidney cancer compared to usual treatment (surgery followed by chemotherapy and/or radiation 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, if you are on certain treatments like systemic steroids or have had recent cancer therapies, you may need to stop or adjust them before joining the trial. It's best to discuss your specific medications with the trial team.

Is the combination of Pembrolizumab and Axitinib safe for humans?

The combination of Pembrolizumab and Axitinib has been studied for safety in patients with advanced renal cell carcinoma. While it has shown improved effectiveness over other treatments, there is a relatively high occurrence of liver-related side effects, such as elevated liver enzymes, which indicates some risk of liver toxicity. ^{1 2 3 4 5}

How is the drug combination of Pembrolizumab and Axitinib unique for treating renal cell carcinoma?

The combination of Pembrolizumab and Axitinib is unique because it is a first-line treatment for advanced renal cell carcinoma that combines an immune checkpoint inhibitor (Pembrolizumab) with a VEGF-R-TKI (Axitinib), leading to better outcomes like longer survival and higher response rates compared to the standard treatment with sunitinib. ^{3 4 6 7 8}

What data supports the effectiveness of the drug combination of pembrolizumab and axitinib for renal cell carcinoma?

Research shows that the combination of pembrolizumab and axitinib is effective for advanced renal cell carcinoma, with a 73% response rate in untreated patients and improved survival outcomes compared to another drug, sunitinib. ^{4 6 9 10 11}

Who Is on the Research Team?

David Y Oh, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adults with advanced or metastatic clear cell kidney cancer who are undergoing surgery may join this trial. They should be in good physical condition, have a tumor that can be biopsied, and agree to use contraception if of childbearing potential. Exclusions include recent anti-cancer treatments, active infections, serious wounds, psychiatric issues affecting participation, pregnancy/breastfeeding intentions within 120 days post-treatment, prior PD-1/PD-L1 therapy or certain autoimmune diseases.

Inclusion Criteria

Subject (or legally acceptable representative if applicable) must provide written informed consent for the trial

My kidney cancer has been confirmed to have clear cells.

My recent tests show my organs are functioning well.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

I am a woman who can have children and I had a positive pregnancy test recently.

I have received an organ or tissue transplant from another person.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preoperative Treatment

Patients receive pembrolizumab with or without axitinib for 3 cycles before surgery

9 weeks

3 visits (in-person)

Surgery

Patients undergo cytoreductive nephrectomy or metastasectomy

2-3 weeks post-treatment

Postoperative Treatment

Patients receive pembrolizumab with or without axitinib based on resection status for up to 1-2 years

1-2 years

Every 42 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Axitinib
• Cytoreductive Nephrectomy (CN)
• Metastasectomy (MET)
• Pembrolizumab

Trial Overview The study is testing the effectiveness of pembrolizumab (an immune system booster) alone or combined with axitinib (a drug blocking enzymes promoting cancer growth) compared to standard care involving surgery followed by chemotherapy/radiation. The goal is to see if these drugs better control kidney cancer and reduce its return after surgery.

How Is the Trial Designed?

Group I: Cohort B (Pembrolizumab + VEGF-TKI) Experimental Treatment 4 Interventions

Preoperative treatment consists of 200 mg pembrolizumab IV on day 1 of each cycle, and 5mg axitinib (a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI)) PO BID on days 1-42 of each cycle. Axitinib maybe titered in select patients after cycle 1. Treatment repeats every 21 days for up to 3 cycles (9 weeks). Within 14-21 days following the end of pre-operative treatment, patients undergo standard of care CN or MET. Patients with PD may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients with an R0 or R1 resection receive 400 mg pembrolizumab and 1, 3, 5, 7 or 10 mg axitinib PO BID every 42 days for up to 9 cycles (1 year), and patients with an R2 resection receive pembrolizumab IV and axitinib PO BID every 42 days for up to 18 cycles (2 years) in the absence of disease progression or unacceptable toxicity.

Group II: Cohort A (Pembrolizumab monotherapy) Experimental Treatment 3 Interventions

Preoperative treatment consists of 200mg pembrolizumab IV on day 1 of each cycle. Treatment repeats every 21 days for up to 3 cycles (9 weeks). Within 14-21 days following the end of treatment, patients undergo standard of care CN or MET. Patients with PD may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients with R0 resection or R1 resection receive 400 mg pembrolizumab every 42 days for up to 9 cycles (1 year) and patients with R2 resection receive pembrolizumab every 42 days for up to 18 cycles (2 years) in the absence of disease progression or unacceptable toxicity.

Axitinib is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Inlyta for:

• Renal cell carcinoma

Approved in United States as Inlyta for:

• Advanced renal cell carcinoma

Approved in United Kingdom as Inlyta for:

• Advanced renal cell carcinoma

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

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 the phase 3 KEYNOTE-426 trial involving 861 patients, the combination of pembrolizumab and axitinib significantly improved overall survival and progression-free survival compared to sunitinib for advanced renal cell carcinoma.

While both treatment groups showed similar health-related quality of life outcomes, the time to confirmed deterioration favored sunitinib, indicating that while pembrolizumab + axitinib is more effective in extending survival, it does not significantly enhance quality of life compared to sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. Bedke, J., Rini, BI., Plimack, ER., et al.[2022]

In a real-world study of 355 patients with advanced clear cell renal cell carcinoma, the combination of axitinib and pembrolizumab showed a best overall response rate of 47.9% and a one-year overall survival rate of 73.5%.

Treatment-related toxicity was the primary reason for dose adjustments, but over 80% of patients who experienced treatment management events were able to continue their therapy, suggesting that dose holds can be an effective strategy to manage side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Therapy Management and Outcomes of First-Line Axitinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma in the United States. Zakharia, Y., Thomaidou, D., Li, B., et al.[2022]

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]

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 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 a study involving 861 patients with advanced renal cell carcinoma, pembrolizumab plus axitinib demonstrated significantly better overall survival and progression-free survival compared to sunitinib monotherapy, with a median follow-up of 30.6 months.

The combination treatment was associated with manageable adverse events, with no new treatment-related deaths reported, reinforcing its safety profile as a first-line therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Powles, T., Plimack, ER., Soulières, D., et al.[2021]

Patients with advanced renal cell carcinoma treated with pembrolizumab plus axitinib experienced a higher incidence of grade 3/4 aminotransferase elevations (22%) compared to those treated with sunitinib (7%), indicating a need for careful monitoring of liver function during treatment.

Despite the higher rates of liver enzyme elevations, most patients (96%) with significant alanine aminotransferase (ALT) increases recovered after treatment interruption, suggesting that with proper management, the adverse effects can be effectively controlled.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial. Rini, BI., Atkins, MB., Plimack, ER., et al.[2022]

The combination of axitinib and pembrolizumab is tolerable and shows promising antitumor activity in patients with treatment-naive advanced renal cell carcinoma, with 73% of patients achieving an objective response.

In a study involving 52 patients, no unexpected toxicities were observed, although 65% experienced grade 3 or worse treatment-related adverse events, indicating that while the treatment is effective, it does carry some risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Atkins, MB., Plimack, ER., Puzanov, I., et al.[2023]

In a study of 52 treatment-naïve patients with advanced renal cell carcinoma receiving axitinib and pembrolizumab, higher baseline levels of immune-related biomarkers like CD8 and CXCL10 were associated with longer progression-free survival and better response rates.

The presence of IL6 at baseline was linked to shorter progression-free survival, suggesting that certain biomarkers could help predict treatment outcomes and warrant further investigation in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma. Martini, JF., Plimack, ER., Choueiri, TK., et al.[2023]

In a study of 38 patients with metastatic renal cell carcinoma (mRCC) receiving pembrolizumab/axitinib as second-line or later therapy, the treatment showed a median progression-free survival (PFS) of 9.7 months and an objective response rate (ORR) of 25%, indicating its effectiveness even after prior treatments.

The safety profile of pembrolizumab/axitinib was consistent with earlier studies, with 86.8% of patients experiencing adverse events, but no grade 5 adverse events were reported, suggesting it is a relatively safe option for patients who have already undergone other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. Dizman, N., Austin, M., Considine, B., et al.[2023]

Citations

1. 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]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Therapy Management and Outcomes of First-Line Axitinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma in the United States. [2022]

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

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

5. 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]

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

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. [2023]

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

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma. [2023]

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

Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. [2023]