Treating the main kidney tumor in metastatic kidney cancer during immunotherapy

Clinical and Humoral Impact of Primary Tumor Ablation in Metastatic Renal Cell Carcinoma Treated With Immunotherapy. The ITALIC-RCC Randomized Study.

This trial will see if adding surgery or radiotherapy to the main kidney tumor helps people with metastatic clear‑cell kidney cancer who are already benefiting from anti‑PD1–based therapy live longer.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 409 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Academic / other)
• Drugs / interventions: pembrolizumab, nivolumab, ipilimumab, axitinib, cabozantinib, lenvatinib
• Locations: 1 site (Roma)
• Trial ID: NCT06903312 on ClinicalTrials.gov

What this trial studies

This is a phase IV, randomized, multicenter, low‑interventional trial enrolling patients with predominantly clear‑cell metastatic renal cell carcinoma who have had initial benefit from anti‑PD1–based therapy. Patients are stratified by primary tumor size: those with tumors ≤4 cm are randomized 1:1:1 to cytoreductive nephrectomy plus continued standard immunotherapy, single‑fraction radiotherapy to the primary tumor plus continued immunotherapy, or continued immunotherapy alone. Patients with tumors >4 cm are randomized 1:1 to deferred cytoreductive nephrectomy plus continued immunotherapy or continued immunotherapy alone, with surgical options including radical nephrectomy, partial nephrectomy, or lumpectomy. The primary outcome is overall survival, and radiotherapy is delivered as a single 25 Gy dose (or an equivalent fractionation) while systemic treatment follows specified anti‑PD1 combination regimens.

Who should consider this trial

Good fit: Adults (≥18) with predominantly clear‑cell metastatic renal cell carcinoma who have been on specified anti‑PD1–based regimens for 24–52 weeks without progression, have ECOG performance status ≤1, and a life expectancy of at least 9 months.

Not a fit: Patients with progressive disease on anti‑PD1 therapy, non–clear‑cell histology, ECOG >1, or those unable to undergo or travel for surgery/radiotherapy are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this could help some patients live longer by showing when adding surgery or radiotherapy to ongoing immunotherapy is beneficial.

How similar studies have performed: Previous randomized work in the targeted‑therapy era (for example, CARMENA) questioned routine cytoreductive nephrectomy, and prospective evidence specifically in patients responding to modern anti‑PD1 combinations is limited, so this approach remains incompletely tested.

Eligibility criteria

Inclusion Criteria:

1. Informed consent obtained before any study-specific procedures. Patients must be able to understand and be willing to sign a written informed consent.
2. Male or female patient ≥18 years of age.
3. Histological or cytological documentation of renal cell carcinoma with predominantly clear cell histology.
4. Evidence of primary renal cancer.
5. Measurable or not measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors criteria, version 1.1 \[22\].
6. Eastern Cooperative Oncology Group performance status of ≤1.
7. Life expectancy of at least 9 months.
8. Under treatment with one anti-PD1 based therapy (SOC) among axitinib + pembrolizumab or cabozantinib + nivolumab or lenvatinib + pembrolizumab or nivolumab alone after nivolumab + ipilimumab for at least 24 but not more than 52 weeks at the time of the signed informed consent and without evidence of progressive disease based on RECIST criteria v 1.1 \[21\].
9. Eligible to continue the combination of therapies for mRCC (or nivolumab alone in case of nivolumab + ipilimumab).
10. Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.
11. Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting to study treatment:

    1. Creatinine value \<2.5 mg/dl and creatinine clearance \> 30 ml/min evaluated by the Cockcroft-Gault Formula.
    2. Total bilirubin ≤1∙5 × the upper limit of normal (ULN);
    3. Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of their cancer);
    4. International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1∙5 × ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate if no prior evidence of an underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care;
    5. Platelet count ≥100 000/mm3, hemoglobin \>9 g/dl, absolute neutrophil count \>1,500/mm3;
    6. Alkaline phosphatase limit ≤2∙5 × ULN (≤5 × ULN for patients with liver involvement of their cancer).

Exclusion Criteria:

1. More than one treatment for metastatic or locally advanced renal cell carcinoma.
2. Solitary kidney
3. Any contraindication to surgery or radiotherapy on primary renal tumor.
4. Discontinuation (definitive) of one of the therapies for mRCC due to toxicity (previous discontinuation of ipilimumab in the ipilimumab + nivolumab combo is allowed).
5. Concurrent or previous cancer within 3 years before enrolment EXCEPT curatively treated cervical cancer in situ, non-melanoma skin cancer and pT2 prostate cancer with PSA\<0.01 or non-muscle invasive bladder cancer.
6. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before the signed informed consent.
7. Pregnancy or breast-feeding. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before surgery or radiotherapy on primary tumor, and a negative result must be documented before start of treatment.
8. Any cardiological condition among:

   1. Congestive heart failure of New York Heart Association class 3 or worse.
   2. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of study drug.
   3. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted).
   4. Uncontrolled hypertension (systolic blood pressure \>150 mmHg or diastolic pressure \>90 mmHg despite optimal medical management).
   5. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), pulmonary embolism within the 4 months before start of study.
9. Ongoing infection higher than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 6.0 grade 2.
10. Known history of human immunodeficiency (HIV) virus infection or known history of chronic hepatitis B or C.
11. Any autoimmune reaction or toxicity that contraindicates the use of anti-PD1 therapy.
12. Seizure disorder requiring medication.
13. Symptomatic metastatic brain or meningeal tumors unless the patient is \>2 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or tapering (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before and after screening radiographic studies).
14. History of organ allograft.
15. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event of CTCAE grade 3 or higher within 4 weeks of start of study medication.
16. Non-healing wound, ulcer, or bone fracture.
17. Renal failure requiring hemodialysis or peritoneal dialysis.
18. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study.

Where this trial is running

Roma

• Fondazione Policlinico Universitario A. Gemelli IRCCS — Roma, Italy (Recruiting)

Study contacts

• Principal investigator: Roberto Iacovelli, M.D.; Ph.D. — Catholic University of Rome, Italy
• Study coordinator: Roberto Iacovelli, M.D.; Ph.D.

Conditions Renal Cell Cancer; Kidney Neoplasm; Immunotherapy; Kidney Cancer; Surgery Programmed; Radiotherapy; renal cancer; primary tumor