Cabozantinib +/− Atezolizumab for Advanced Kidney Cancer
Recruiting in Palo Alto (17 mi)
+203 other locations
Overseen ByBenjamin L Maughan
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial compares the effect of atezolizumab in combination with usual treatment with cabozantinib to cabozantinib alone in patients with papillary renal cell carcinoma that has spread to other places in the body (metastatic). Papillary renal cell carcinoma (PRCC) is a type of kidney cancer that forms in the lining of the tiny tubes in the kidney that return filtered substances that the body needs back to the blood and remove extra fluid and waste as urine. Most papillary tumors look like long, thin finger-like growths under a microscope. It is also called papillary kidney cancer or PRCC. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Cabozantinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply and may also prevent the growth of new blood vessels that tumors need to grow. By these actions it may help slow or stop the spread of cancer cells. Combination therapy with atezolizumab and cabozantinib may shrink the cancer and allow a longer survival time in patients with metastatic renal cell carcinoma.
How does the drug combination of Cabozantinib and Atezolizumab differ from other treatments for advanced kidney cancer?
The combination of Cabozantinib and Atezolizumab is unique because Cabozantinib is a multi-tyrosine kinase inhibitor that targets specific proteins involved in kidney cancer growth, while Atezolizumab is an immunotherapy drug that helps the immune system attack cancer cells. This combination offers a novel approach by combining targeted therapy with immunotherapy, potentially improving outcomes for patients with advanced kidney cancer.
12467Is the combination of Cabozantinib and Atezolizumab safe for humans?
Cabozantinib, when used with other drugs like nivolumab, has shown a manageable safety profile with common side effects such as diarrhea, fatigue, and skin reactions, which can be managed with medical care and dose adjustments. Atezolizumab, used for various cancers, has also been approved with a known safety profile. While specific data on the combination of Cabozantinib and Atezolizumab is not provided, both drugs have been used safely in humans for other conditions.
357910Will I have to stop taking my current medications?
The trial requires that participants do not take certain medications, specifically strong CYP3A4 inhibitors and inducers, within 14 days before starting the trial and during the trial. If you are on these medications, you may need to stop or switch them, but the protocol does not specify about other medications.
What data supports the effectiveness of the drugs Cabozantinib and Atezolizumab for advanced kidney cancer?
Cabozantinib has been shown to help patients with advanced kidney cancer live longer without the disease getting worse compared to another drug, sunitinib. Atezolizumab, when combined with another drug, bevacizumab, has also shown benefits in patients with a specific type of kidney cancer, helping them live longer without disease progression and improving their ability to perform daily activities.
367811Eligibility Criteria
Adults with advanced papillary kidney cancer that has spread, who have not had certain treatments like PD-1/PD-L1 inhibitors in the past 6 months. They must be able to swallow pills, have no major health issues affecting trial participation, and agree to use effective contraception if of reproductive potential.Inclusion Criteria
My cancer can be measured and is not in my brain or spinal cord.
I don't need immediate treatment for brain metastases and don't have leptomeningeal disease.
My blood pressure was below 150/100 mm Hg in the last two weeks.
I have been diagnosed with a type of kidney cancer known as metastatic papillary renal cell carcinoma.
I am 18 years old or older.
I have never had bleeding in my brain or spinal cord.
I have HIV, am on effective treatment, and my viral load is undetectable.
I can take care of myself and am up and about more than 50% of my waking hours.
My recent tests show my urine protein is under control.
Exclusion Criteria
I am not taking, nor will I take, strong medications that affect liver enzymes while on this treatment.
I am not taking warfarin at doses meant to treat conditions. I may be on low dose aspirin or LMWH.
I haven't had major surgery in the last 28 days and have recovered from any surgery effects.
I am not taking, nor plan to take, strong CYP3A4 inducers.
I haven't coughed up a noticeable amount of blood in the last 3 months.
I am not on steroids for a brain condition.
I haven't had PD-1/PD-L1 inhibitors in the last 6 months.
My cancer has not spread to or around any major blood vessels.
My cancer has not spread to my digestive system or airways in the last 28 days.
I haven't had specific brain treatments in the last month before starting the study.
I have never been treated with cabozantinib.
I do not have holes in my lung tissue.
I do not have severe heart failure.
Participant Groups
The PAPMET2 trial is comparing cabozantinib alone versus combining it with atezolizumab in patients with metastatic papillary renal cell carcinoma. The goal is to see if adding the immunotherapy agent improves outcomes compared to just the kinase inhibitor.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm II (cabozantinib S-malate, atezolizumab)Experimental Treatment6 Interventions
Patients receive cabozantinib S-malate PO QD on days 1-21 and atezolizumab IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI and blood and urine sample collection throughout the trial. Patients may also undergo bone scan throughout the trial.
Group II: Arm I (cabozantinib S-malate)Active Control5 Interventions
Patients receive cabozantinib S-malate PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI and blood and urine sample collection throughout the trial. Patients may also undergo bone scan throughout the trial.
Atezolizumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Tecentriq for:
- Melanoma
- Hepatocellular carcinoma
- Small cell lung cancer
- Non-small cell lung cancer
- Urothelial carcinoma
🇪🇺 Approved in European Union as Tecentriq for:
- Melanoma
- Hepatocellular carcinoma
- Small cell lung cancer
- Non-small cell lung cancer
- Urothelial carcinoma
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Northwestern Medicine Lake Forest HospitalLake Forest, IL
Trinity Health Medical Center - CantonCanton, MI
Providence Portland Medical CenterPortland, OR
Saint Luke's Cancer Institute - Twin FallsTwin Falls, ID
More Trial Locations
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Who is running the clinical trial?
National Cancer Institute (NCI)Lead Sponsor
References
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. [2022]Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.
Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. [2022]Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis.
Atezolizumab: First Global Approval. [2019]Atezolizumab (Tecentriq™)-a monoclonal antibody targeting programmed death ligand 1 (PD-L1 or CD274 antigen)-is being developed by Genentech as treatment for a variety of haematological malignancies and solid tumours. It been approved in the US as a second-line therapy for urothelial carcinoma and is awaiting approval as a second-line therapy for non-small cell lung cancer. This article summarizes the milestones in the development of atezolizumab leading to this first approval for urothelial carcinoma.
Cabozantinib for the treatment of kidney cancer. [2020]Cabozantinib is a small molecule tyrosine kinase inhibitor that initially showed activity in medullary thyroid cancer and was recently approved by the Food and Drug Administration for the treatment of metastatic renal cell carcinoma after progression on first line therapy. Areas covered: In the METEOR trial, cabozantinib demonstrated significantly improved efficacy in all three endpoints; response rates, progression free survival and overall survival in a randomized trial with everolimus as an active comparator. Cabozantinib also showed activity in the front line setting in RCC within the CABOSUN trial. The study randomized untreated metastatic RCC patients to either cabozantinib or sunitinib and the former showed improved progression free survival which was the primary endpoint. The future holds promise for indications in other malignancies, given the preliminary efficacy and unique mechanism of action of cabozantinib. In this review we address the mechanism of action, pharmacodynamics and pharmacokinetics of cabozantinib, and also review the development pathway of this agent in the treatment of advanced renal cell carcinoma. The potential benefit in specific patient populations, such as poor risk patients and bone metastases subgroups is also discussed. Expert commentary: The clinical applications of cabozantinib will be addressed within the context of the current competitive therapeutic landscape of RCC.
Cabozantinib use in renal cell carcinoma. [2021]In the last several years, many new drugs have been approved to treat metastatic renal cell carcinoma (RCC). Cabozantinib is a novel multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR), proto-oncogene tyrosine-protein kinase receptor Ret and other kinases that recently joined this impressive list of approved agents. Cabozantinib is an active agent in the preclinical and clinical setting, having recently demonstrated superiority over everolimus in a blinded, randomized phase III study of patients with progressive RCC after at least one prior line of antiangiogenic therapy. This agent's toxicity profile is similar to those of other multikinase inhibitors approved to treat RCC. This review will explore cabozantinib's pharmacologic and safety profile and its preclinical and clinical activity in RCC.
Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma. [2020]Cabozantinib is a multi-tyrosine kinase inhibitor used for the treatment of various solid-organ tumours. It was recently approved as a first- and second-line therapeutic for the management of advanced/metastatic renal cell carcinoma based on the results of two randomised controlled trials. The phase III METEOR trial compared cabozantinib against everolimus as a second- or greater line therapy and found benefits in progression-free and overall survival, and the phase II CABOSUN trial compared cabozantinib against sunitinib as a first-line therapeutic and found benefits in terms of progression-free survival. This review briefly summarises how cabozantinib fits into current treatment paradigms for the management of advanced renal cell carcinoma.
Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. [2020]Oral cabozantinib tablets (Cabometyx®) are an important option for the treatment of advanced renal cell carcinoma (RCC). Cabozantinib is an anti-angiogenic agent and potently inhibits multiple tyrosine kinases, including those implicated in the development of RCC. The previously approved indication of cabozantinib tablets (i.e. treatment of advanced RCC following prior VEGF-targeted therapy) has been extended to include the first-line treatment of advanced RCC in treatment-naïve adults with intermediate or poor risk (EU) and all patients with advanced RCC (USA). These label extensions are based on the results of a randomized, open-label phase 2 trial, in which adults with metastatic RCC of poor or intermediate risk received targeted first-line treatment with cabozantinib or standard-of-care sunitinib. Relative to sunitinib, cabozantinib significantly prolonged median progression-free survival (primary endpoint; investigator and independent assessments), and increased the objective response rate (investigator assessment). The tolerability profile of cabozantinib is comparable to those of other tyrosine kinase inhibitors, with adverse events being manageable with medical intervention, dosage reductions, treatment interruption and/or permanent discontinuation.
Atezolizumab plus Bevacizumab Versus Sunitinib for Patients with Untreated Metastatic Renal Cell Carcinoma and Sarcomatoid Features: A Prespecified Subgroup Analysis of the IMmotion151 Clinical Trial. [2022]Patients with metastatic renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and have shown limited responsiveness to inhibition of the VEGF pathway. We conducted a prespecified analysis of the randomised, phase 3 IMmotion151 trial in previously untreated patients with advanced or metastatic RCC to assess the effectiveness of atezolizumab + bevacizumab versus sunitinib in a subgroup of patients with sarcomatoid features. Patients whose tumour had any component of sarcomatoid features were included and received atezolizumab + bevacizumab (n = 68) or sunitinib (n = 74). Baseline characteristics were similar between the groups. Median progression-free survival was significantly longer in the group receiving atezolizumab + bevacizumab overall (8.3 vs 5.3 mo; hazard ratio [HR] 0.52 95% confidence interval [CI] 0.34-0.79) and in the subset of patients with PD-L1-positive tumours (8.6 vs 5.6 mo; HR 0.45, 95% CI 0.26-0.77). More patients receiving atezolizumab + bevacizumab achieved an objective response (49% vs 14%), including complete responses (10% vs 3%), and reported greater symptom improvements versus sunitinib. Safety was consistent with the known profiles of each drug and with that reported in the overall safety-evaluable population of IMmotion151. This analysis supports enhanced activity of atezolizumab + bevacizumab in patients with sRCC. PATIENT SUMMARY: In this report, we looked at patients with a specific type of kidney cancer (tumours with sarcomatoid features) that has been hard to treat. A treatment with two drugs (atezolizumab and bevacizumab) appeared to help patients live longer without the disease getting worse than another drug (sunitinib) that is often used. Patients who took the two drugs also said they were better able to carry out their everyday activities than patients who took sunitinib. The combination of these two drugs may work better in patients with this type of advanced kidney cancer.
Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. [2022]The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.
Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. [2023]Tyrosine kinase inhibitors have been successfully developed in combination with immune checkpoint inhibitors to treat advanced renal cell carcinoma (RCC), further advancing treatment. While safety profiles are generally manageable with combination regimens, overlapping adverse events (AEs) and immune-related AEs can make treatment more complex. The CheckMate 9ER study evaluated the tyrosine kinase inhibitor cabozantinib in combination with the anti-programmed cell death protein-1 antibody nivolumab in patients with previously untreated advanced RCC. Cabozantinib + nivolumab demonstrated superiority over sunitinib for progression-free survival, overall survival, and objective response rate. These outcomes supported the approval of cabozantinib + nivolumab as a first-line therapy for advanced RCC. The safety profile was manageable with prophylaxis, supportive care, dose holds and reductions for cabozantinib, and dose holds and immunosuppressive therapy for nivolumab. This review discusses the safety results of CheckMate 9ER and provides guidance on managing some of the more clinically relevant AEs with a focus on overlapping AEs, including diarrhea, elevated amylase/lipase, hepatotoxicity, dermatologic reactions, fatigue, endocrine disorders, and nephrotoxicity. We discuss AE management strategies (prophylaxis, supportive care, dose modification, and immunosuppressive therapy), and provide recommendations for identifying the causative agent of overlapping AEs and for consulting specialists about organ-specific immune-related AEs. Optimizing AE management can maintain tolerability and should be a priority with cabozantinib + nivolumab treatment.
Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. [2023]Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment.