Pembrolizumab + Axitinib for Kidney Cancer

Overseen By Jazlyn Heiligh

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Prior RCC therapy, 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: 3

Duration: 9 weeks

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for metastatic clear cell renal cell carcinoma (a type of advanced kidney cancer) using a combination of two drugs: pembrolizumab (an immunotherapy) and axitinib (a targeted therapy). The main goal is to determine if adjusting doses based on the tumor's response can improve treatment outcomes. This trial might be suitable for those with kidney cancer that cannot be surgically removed and who have not received prior treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or immunosuppressive therapy, you may need to stop them at least 7 days before starting the trial.

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

Research has shown that the combination of pembrolizumab and axitinib is generally well-tolerated by patients with advanced kidney cancer. One study found that the side effects of this combination are manageable, with few severe reactions. Importantly, no new unexpected harmful effects appeared. Most side effects resembled those seen with other kidney cancer treatments, and this combination showed promise in earlier trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab and axitinib for kidney cancer because it offers a novel approach by combining an immune checkpoint inhibitor with a targeted therapy. Pembrolizumab, an immune checkpoint inhibitor, helps the immune system recognize and attack cancer cells, while axitinib, a tyrosine kinase inhibitor, disrupts the blood supply that tumors need to grow. This dual approach is different from traditional treatments, which often rely on either immune modulation or targeted therapy alone. The adaptive dosing strategy also allows for personalized treatment adjustments based on tumor response, potentially improving outcomes for patients.

What evidence suggests that pembrolizumab and axitinib might be an effective treatment for kidney cancer?

In this trial, participants will receive a combination of the drugs pembrolizumab and axitinib, which research has shown may effectively treat kidney cancer, specifically metastatic clear cell renal cell carcinoma (mccRCC). One study found that 73% of patients who had not received prior treatment experienced positive results with this drug combination. Real-world evidence suggests that patients may also experience short-term survival benefits. Although 59.7% of patients reported significant side effects, the overall effectiveness of pembrolizumab and axitinib in treating mccRCC remains promising. ^{1 2 4 6 7}

Who Is on the Research Team?

Jon Chatzkel, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced kidney cancer (mccRCC) who haven't had systemic therapy for it can join this trial. They need to be fairly healthy, able to perform daily activities, and have a tumor that can be measured. People with well-controlled HIV or hepatitis are okay if they use contraception. Those with recent heart issues, uncontrolled infections or blood pressure, severe allergies to the drugs being tested, other active cancers, or major health events like surgery recently cannot participate.

Inclusion Criteria

I have been active and able to care for myself within the last 28 days.

I can provide a sample of my tumor or am willing to have a biopsy.

Measurable disease as defined by Response Evaluation Criteria In Solid Tumors RECIST 1.1 within 28 days prior to registration

Exclusion Criteria

I haven't taken high doses of steroids or have an immunodeficiency within the last week.

I haven't had heart problems in the last 6 months.

I do not have uncontrolled HIV, Hepatitis B, or Hepatitis C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adaptive dosing of pembro-axi, with pembrolizumab given at 200 mg IV every 3 weeks and axitinib 5 mg orally twice daily. Imaging is conducted every 9 weeks to assess response.

9 weeks

3 visits (in-person) for pembrolizumab administration, imaging every 9 weeks

Adaptive Therapy

Therapy cycles on and off based on tumor response, continuing until confirmed progression of disease.

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on progression-free survival and overall survival.

Up to 12 months

What Are the Treatments Tested in This Trial?

Interventions

• Axitinib
• Pembrolizumab

Trial Overview The study is testing how well patients respond when given Pembrolizumab and Axitinib in varying doses for advanced kidney cancer (mccRCC). It's a Phase II trial which means they're looking at effectiveness and side effects of these drugs after seeing some safety data from earlier studies.

How Is the Trial Designed?

Group I: Adaptive Dosing pembro-axi Experimental Treatment 2 Interventions

In therapy naïve mccRCC patients, a standard dose of pembrolizumb will be given at 200 mg iv every 3 weeks, with axitinib given orally 5 mg twice daily. After 9 weeks, subjects will undergo the first response assessment as well as the therapy portion of the trial if they have 20% response per RECIST criteria. During adaptive dosing with pembro-axi, imaging is conducted every 9 weeks. Treatment is held until the tumor has returned to its baseline size or greater per RECIST 1.1, then restarted until a tumor reduction of at least 20% occurs. Therapy cycles on and off in this manner continue as the tumor shrinks and grows until confirmed progression of disease while on therapy.

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Published Research Related to This Trial

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 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 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 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 phase 3 trial with 861 patients suffering from advanced clear-cell renal-cell carcinoma, the combination of pembrolizumab and axitinib significantly improved overall survival (89.9% vs. 78.3% at 12 months) compared to sunitinib, with a hazard ratio for death of 0.53.

Patients receiving pembrolizumab plus axitinib also experienced longer progression-free survival (15.1 months vs. 11.1 months) and a higher objective response rate (59.3% vs. 35.7%), indicating that this combination therapy is more effective than sunitinib for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Rini, BI., Plimack, ER., Stus, V., et al.[2022]

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]

Recent randomized trials have shown that the combination of pembrolizumab and axitinib significantly improves survival in patients with metastatic clear-cell renal cell carcinoma, establishing it as a new standard of care.

This treatment is recommended for all treatment-naïve patients, regardless of their risk group, according to updated guidelines from the European Association of Urology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition Is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma. Albiges, L., Powles, T., Staehler, M., et al.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36681606/

Outcomes With Combination Pembrolizumab and Axitinib ... Combination pembrolizumab/axitinib among previously treated mRCC patients has activity, with AE rates comparable to those reported in the first line.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1816714

Pembrolizumab plus Axitinib versus Sunitinib for Advanced ... In a phase 1b trial involving patients with previously untreated metastatic renal-cell carcinoma, 73% (95% confidence interval [CI], 59 to 84) ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.6_suppl.327

Outcomes for patients in the pembrolizumab+axitinib arm ... 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events.

4. urotoday.com urotoday.com/conference-highlights/asco-2023/asco-2023-kidney-cancer/144812-asco-2023-head-to-head-effectiveness-and-safety-of-pembrolizumab-plus-axitinib-vs-nivolumab-plus-ipilimumab-in-metastatic-renal-cell-carcinoma-in-the-united-states.html

ASCO 2023: Head-to-Head Effectiveness and Safety of ... Real-world analysis from the United States suggests that pembrolizumab + axitinib may be associated with short-term overall survival benefits.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1078143923002855

Real-world clinical outcomes of patients with metastatic ... Our study provides insight into newer mccRCC treatment tolerability and effectiveness in the real-world US community setting.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.6_suppl.688

Safety and tolerability of pembrolizumab/axitinib ... Conclusions: PAXI combination had a tolerable safety profile in mRCC, with few high-grade clinically significant AEs, no new toxicities were ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02853331

NCT02853331 | Study to Evaluate the Efficacy and Safety ... The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib versus sunitinib monotherapy as a ...