Comparison of nivolumab drug combination versus immunotherapy‑TKI sequence in patients with metastatic renal cell carcinoma

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What is this study about?

The study focuses on metastatic renal cell carcinoma, a type of kidney cancer that has spread to other parts of the body. Treatment options being examined include oral tablets of axitinib, cabozantinib, sorafenib, sunitinib, and lenvatinib mesilate, as well as intravenous infusions of nivolumab, pembrolizumab, and ipilimumab. These medicines belong to two main classes: immune‑based therapies, referred to as immuneoncology (IO-IO), and drugs that block specific cell signals, called tyrosine kinase inhibitors (TKI).

The purpose of the study is to compare how well the two different treatment sequences work in slowing disease and extending survival. Participants are randomly assigned to receive either a combination of two immune drugs together, or an immune drug followed by a TKI, with a second TKI given if the cancer progresses. The study follows each person from the start of treatment, includes regular doctor visits, imaging scans evaluated by RECIST criteria, and blood tests, and continues until the disease gets worse or side effects require stopping the medication.

Throughout the trial, researchers record any side effects using the standard grading system called CTCAE, and also track overall health and quality of life. Key outcomes that will be measured are the time until the cancer progresses a second time, known as PFS-2, and overall survival, referred to as OS. The collected information helps determine which treatment approach may be more beneficial for patients with this advanced kidney cancer.

1 randomization to treatment group

after joining the study you will be assigned to one of two treatment strategies. the assignment is made by the study system and you will not choose the group yourself.

2 first‑line therapy

you will start the first set of study medicines according to the group you were assigned to.

if your group uses oral medication, you will take a tablet each day at the dose shown for that drug:

– axitinib 10 mg daily

– cabozantinib 60 mg daily

– sorafenib 400 mg daily

– sunitinib 50 mg daily

– lenvatinib 20 mg daily

if your group uses intravenous infusion, the medicine will be given through a vein at the clinic:

– nivolumab 480 mg per infusion

– pembrolizumab 200 mg per infusion

– ipilimumab 1 mg per kilogram of body weight per infusion

the exact schedule for the infusions (for example, every 2 or 3 weeks) follows the study protocol and will be explained by the study staff.

3 regular monitoring visits

throughout the first‑line therapy you will attend clinic visits at regular intervals. during each visit you will:

– have blood drawn to check how your body is responding

– undergo imaging tests such as scans to look for changes in the cancer

– answer questionnaires that measure symptoms and quality of life

any side effects you experience will be recorded and managed according to the study safety guidelines.

4 assessment for disease progression

the study team will evaluate the scan results and other tests to determine if the cancer has grown or spread. this assessment is called progression.

if progression is confirmed, the next step of the study protocol will be started.

5 second‑line tyrosine‑kinase inhibitor (TKI) therapy

after progression you will receive a tyrosine‑kinase inhibitor (TKI) as the second line of treatment. the TKI may be one of the oral drugs listed above, taken at the same daily dose:

– axitinib 10 mg daily

– cabozantinib 60 mg daily

– sorafenib 400 mg daily

– sunitinib 50 mg daily

– lenvatinib 20 mg daily

you will continue to take the medication each day until the study ends, until further progression is observed, or until a safety reason requires stopping the drug.

6 continued monitoring during second‑line therapy

the same type of clinic visits described in step 3 will be continued while you are on the second‑line TKI. the visits will include blood tests, imaging, and questionnaires.

any new side effects will be recorded and managed.

7 study completion and final follow‑up

the study will end for you after the planned follow‑up period or if you stop treatment because of side effects or disease progression.

a final assessment will be performed to collect the last set of data required by the study.

Who Can Join the Study?

Be at least 18 years old.
If you are already taking medicines that help keep your bones strong (called bone resorptive therapy), you can join the study.
You must have a stored sample of your tumor tissue (an archival tumor tissue sample) that can be used for testing.
Your recent blood test must show:
- Enough white blood cells, measured as an absolute neutrophil count (ANC) greater than 1,000 per microliter,
- Enough platelets (more than 100,000 per microliter), and
- Enough hemoglobin (the protein that carries oxygen) greater than 8 g/dL.
These numbers must be taken without needing special medicines that boost blood‑cell production (myeloid growth factor) or a platelet transfusion in the two weeks before you are randomly assigned to a treatment group.
Your liver function tests must be within safe limits:
- Total bilirubin must be 1.5 times or less the normal upper limit (upper limit of normal, ULN),
- The enzymes called AST and ALT must be 2.5 times or less the ULN (they may be up to 5 × ULN if you have known cancer spread to the liver).
If you have received palliative radiation therapy (radiation given to relieve symptoms rather than to cure), at least 7 days must pass between your last radiation session and the day you are randomly assigned to a treatment.
You must be able to come to the clinic for treatment and follow‑up visits, and be willing and able to follow the study requirements.
If you are a woman, you must be either:
- post‑menopausal (no periods for at least one year),
- have had a surgical procedure that makes you unable to have children (surgically sterilized), or
- agree to use a reliable birth‑control method (such as hormonal contraception, an intra‑uterine device, a diaphragm with spermicide, a condom with spermicide, or abstinence) during treatment and for up to 5 months after the last dose.
If you are a man, even if you have had a vasectomy (surgical sterilization), you must agree to use a reliable birth‑control method during treatment and for 7 months after the last dose.
You must sign a voluntary written informed consent before any study procedures that are not part of your regular medical care. You can withdraw this consent at any time without affecting your future medical care.
Your cancer must be histologically confirmed as renal cell carcinoma (RCC). Both clear‑cell and non‑clear‑cell types are allowed, except for two rare types called collecting duct carcinoma and renal medullary carcinoma. The tumor may have sarcomatoid features, which are also allowed.
Your disease must be classified as locally advanced or metastatic (cancer that has spread beyond the kidney) according to the American Joint Committee on Cancer (AJCC) version VIII staging system.
You must not have received any systemic therapy (treatment that affects the whole body) for advanced kidney cancer before. If you had adjuvant immunotherapy after surgery, it is allowed only if it finished more than 6 months before you are randomly assigned.
You need to have at least one tumor that can be measured on imaging scans, defined as a measurable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
Your disease must be classified as intermediate‑risk or poor‑risk according to the International Metastatic RCC Database Consortium (IMDC) criteria. Patients with favorable risk may join a separate observational group.
Your overall health must be good enough to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (meaning you are fully active, able to do light work, or able to care for yourself but unable to work).
Your Karnofsky Performance Status (KPS) must be greater than 50 % (you are able to care for most personal needs).

Who Cannot Join the Study?

Age: You are younger than 18 years old.
Experimental drug: You have taken any other investigational medication within the past 28 days.
Tissue transplant: You have received a transplant of tissue or an organ from another person.
Serious heart problems: Within the last 6 months you have had any of the following – advanced heart failure (New York Heart Association Class III or IV), unstable chest pain (angina), heart attack (myocardial infarction), stroke (cerebral vascular accident), or an uncontrolled irregular heartbeat (arrhythmia). Controlled irregular heartbeat is allowed.
Other recent cancer: You have been diagnosed with or treated for another cancer in the past 3 years, except for completely removed skin cancers (basal cell or squamous cell), very early skin cancer (in‑situ), or low‑grade prostate cancer (Gleason 6).
Recent significant bleeding: You have had noticeable blood in your urine (hematuria), vomit (hematemesis), or cough (hemoptysis) within the past 3 weeks.
Bleeding episode: You experienced a major bleeding event in the past 3 months.
Major surgery: You had a large operation within the past 3 weeks.
Untreated brain metastasis: Cancer that has spread to the brain or spinal cord and has not been treated. Treated brain metastases are allowed only if they are stable and you are taking a low dose of steroids (≤10 mg prednisone‑equivalent).
Unstable medical condition: Any health problem that is not stable and could put your safety at risk or make it hard to follow the study schedule.
Active infection: You have an infection that requires medication such as antibiotics, antivirals, or antifungals.
Contraindication to immunotherapy: You have an active autoimmune disease that needs systemic treatment (low‑dose prednisone ≤10 mg/day is allowed).
Non‑infection pneumonitis: Lung inflammation not caused by infection that requires medication.
History of interstitial lung disease: Past diagnosis of a group of lung disorders that cause scarring.
Pregnancy or breastfeeding: You are pregnant or nursing. Pregnancy must be ruled out with a negative blood test for β‑hCG within 14 days (not required for post‑menopausal or surgically sterile women).
Incapacitated participant: You are unable to give informed consent because of mental or legal incapacity.
Serious medical or psychiatric illness: A severe health or mental condition that would likely interfere with participation.
Other severe conditions: Includes uncontrolled diabetes, problems absorbing nutrients (malabsorption), removal of the pancreas or upper small intestine, need for pancreatic enzymes, or any lab abnormality that raises risk or could affect study results.
Prior radiation therapy: You have received radiation to the tumor sites (except for palliative radiation, which is allowed).
Prior immunotherapy: You have had immunotherapy before, except for adjuvant immunotherapy completed more than 6 months ago.
Prior systemic treatment for advanced kidney cancer: You have received any whole‑body therapy for locally advanced or metastatic renal cell carcinoma.
Abnormal ECG: At screening, your heart’s electrical test (ECG) shows an abnormality that the doctor cannot confirm as not clinically important.
Abnormal heart imaging: At screening, an abnormal heart ultrasound (ECHO) or MUGA scan is found that the doctor cannot confirm as not clinically important.

Where you can join this trial?

Verified and Recommended Sites

No sites found in this category

Verified Sites

Site Name	City	Country	Status
Azienda Ospedaliero Universitaria Careggi	Florence	Italy

Other Sites

Site Name	City	Country
Azienda Sanitaria Locale Cn2 Alba-Bra	Alba	Italy
Centro Di Riferimento Oncologico Di Aviano	Aviano	Italy
Istituto Europeo Di Oncologia S.r.l.	Milan	Italy
Azienda Ospedaliero Universitaria Di Modena	Modena	Italy
Azienda Unita Sanitaria Locale Di Modena	Carpi	Italy
ARNAS Civico Di Cristina Benfratelli	Palermo	Italy
Azienda Universitaria Ospedaliera Consorziale Policlinico Bari	Bari	Italy
Ihgpvjdf Ocggeaazbi Vtsdeu	Padua	Italy
Ontfvjwq Vymf Fmksr Loxnm	Lecce	Italy
Aqc Dq Lwkjzs	Latina	Italy
Acxmbhp Uewf 6 Eameecd	Padua	Italy
Aogawvu Omjycbfzgozkwexnfpsopkuyd Sub Lihgi Grlqgar	Orbassano	Italy
Iftmgpoi Rsoadxgre Pfc Lt Svjfos Deu Traacd Dixe Arftgdh Iijj Sjvfsx	Meldola	Italy
Afebaxi Oxubbmapzjs Udtbetoyrxwtr Ccanjkemqlby Dvpld Sxiaxs E Dwqfo Slcyccz Dg Tesvxd	Turin	Italy
Ayfandu Ondvoebltax Usxraoylzqzdu Fwbjtdag Io Dr Nylylr	Naples	Italy
Acofzpl Ohzbbffpwteovuulnpfhzrlrm Mynrsugk Dimao Ciljqp	Novara	Italy
Adpokpe Uwf Tubuwnc Sjm Efm	Arezzo	Italy
Apicimz Otfpyetcnvv Ucnxyqwhoggnk Pweij	Parma	Italy
Ambghui Spvpm Sfrcknbrj Tmobukewcjuu Dr Cuvpldd	Cremona	Italy
Crzd Sgbniprl Dssoj Sdeovrvbgl	San Giovanni Rotondo	Italy
Agqubxq Skqpk Saujpvaov Tianlwzcoojv Dqv Swxdg Ljoxy	Varese	Italy
Avdzjxo Ssjrh Skjzziwez Tdgchpsoffmm Oxruw Mfzmayoa	Legnano	Italy
Fafjzwyohh Iyopflbsdu Ipybarag Njfsncfwkhe Bdufv	Milan	Italy

Trial status

Country	Status	Recruitment Start
Italy	Not yet recruiting	30.09.2026

Trial locations

Investigated Drugs:

Axitinib is a pill taken by mouth that blocks certain signals that help cancer cells grow new blood vessels. In this study it is used as a tyrosine kinase inhibitor (TKI) to see how well it works after the initial treatment stops working.

Nivolumab is given through an IV infusion and belongs to a group of medicines called checkpoint inhibitors. It helps the body’s immune system recognize and attack kidney cancer cells. In the trial it is part of the immunotherapy (IO) combination tested at the start of treatment.

Cabozantinib is an oral medication that blocks several pathways that cancer cells use to grow and spread. It is another TKI that is tested either after progression on the first therapy or as part of the combination with immunotherapy.

Pembrolizumab is an IV infusion that also works as a checkpoint inhibitor, encouraging the immune system to target cancer cells. It is used together with another immunotherapy drug at the beginning of the study to evaluate the IO‑IO approach.

Sorafenib is a pill taken by mouth that interferes with signals that promote tumor blood vessel formation and cell growth. It serves as a TKI option in the trial, used after the initial treatment if the disease gets worse.

Sunitinib is an oral TKI that blocks multiple proteins involved in tumor growth and blood vessel formation. In this study it is one of the drugs examined for use after disease progression on the first line of therapy.

Ipilimumab is delivered by IV infusion and is a checkpoint inhibitor that activates immune cells to fight cancer. It is combined with another immunotherapy drug at the start of the trial to test the effectiveness of the IO‑IO strategy.

Lenvatinib (lenvatinib mesilate) is a pill taken by mouth that blocks several pathways cancers use to grow and develop new blood vessels. It is used as a TKI in the study, either after the first treatment stops working or as part of a combination with immunotherapy.

Investigated Diseases:

Metastatic renal cell carcinoma

Metastatic renal cell carcinoma – Metastatic renal cell carcinoma is kidney cancer that has spread from the original kidney tumor to distant sites. The disease starts with a primary tumor in the kidney that can invade nearby tissue. Cancer cells travel through the blood or lymphatic system to organs such as the lungs, bones, liver, and brain. As metastatic lesions grow, they can cause new symptoms related to the affected organ, such as cough, bone pain, or abdominal discomfort. The disease typically follows a pattern of gradual increase in tumor burden, with each site potentially expanding over time.

Trial ID:

2025-523903-31-00

Trial Phase:

Therapeutic confirmatory (Phase III)

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Comparison of nivolumab drug combination versus immunotherapy‑TKI sequence in patients with metastatic renal cell carcinoma

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?