This phase II trial tests whether the addition of radiation to the primary tumor, typically given with stereotactic ablative radiation therapy (SABR), in combination with standard of care immunotherapy improves outcomes in patients with renal cell cancer that is not recommended for surgery and has spread from where it first started (primary site) to other places in the body (metastatic). Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses of radiation over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, avelumab, and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are in a class of medications called antiangiogenic agents. They work by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving SABR in combination with standard of care immunotherapy may help shrink or stabilize the cancer in patients with renal cell cancer.
Pathologically (histologically or cytologically) proven diagnosis of renal cell carcinoma prior to registration
History/physical examination within 45 days prior to registration
CT/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 45 days prior to registration
Patients must have IMDC intermediate (1-2 factors) or poor risk disease (>= 3 factors)
Patients with planned treatment of all metastatic disease with definitive therapy including either surgery, ablative (non-palliative) doses of radiation, or intervention of some type (definitive interventional radiology techniques) to ALL metastatic sites rendering the patient without extra-renal measurable disease. Patients NOT planned for definitive treatment of all metastatic sites are eligible. Lesions radiated palliatively are not eligible for response assessment
Patients with untreated or unstable brain metastases or cranial epidural disease
Note: Patients who have been adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator are eligible. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator
Prior radiotherapy to the kidney that would result in overlap of radiation therapy fields treatment of the primary tumor
Parallel
Avelumab
Biological/VaccineGiven IV
Axitinib
DrugGiven PO
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood
Bone Scan
Procedure/SurgeryUndergo bone scan
Cabozantinib
DrugGiven PO
Computed Tomography
Procedure/SurgeryUndergo CT
Ipilimumab
Biological/VaccineGiven IV
Lenvatinib
DrugGiven PO
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Nivolumab
Biological/VaccineGiven IV
Pembrolizumab
Biological/VaccineGiven IV
Stereotactic Ablative Radiotherapy
Radiation42 Gy in 3 fractions
Nephrectomy and radiographic progression-free survival (nrPFS)
Nephrectomy and radiographic progression-free survival time is defined as time from randomization to the date of first radiographic progression, nephrectomy, death, or last negative evaluation (censored). nrPFS rates are estimated using the Kaplan-Meier method. Progression is determined by the Response Evaluation Criteria in Solid Tumors version 1.1 criteria modified for immunotherapy trials (iRECIST).
Percentage of participants with complete or partial response
Best overall response is determined by the iRECIST version 1.1.
Percentage of participants with complete or partial response in the primary renal mass
Best overall response is determined by the iRECIST version 1.1.
Radiographic progression-free survival (rPFS)
Radiographic progression-free survival time is defined as time from randomization to the date of first radiographic progression, death, or last negative evaluation (censored). rPFS rates are estimated using the Kaplan-Meier method. Radiographic progression is determined by the iRECIST version 1.1.
Nephrectomy and radiographic progression-free survival excluding nephrectomies that were performed for non-protocol specified reasons (nrPFS2)
Nephrectomy and radiographic progression-free survival time (excluding nephrectomies that were performed for non-protocol specified reasons) is defined as time from randomization to the date of first radiographic progression, nephrectomy performed for protocol-stated reasons, death, or last negative evaluation (censored). nrPFS2 rates are estimated using the Kaplan-Meier method. Progression is determined by the iRECIST version 1.1.
nrPFS and overall survival
Exploratory analyses will compare nrPFS and overall survival in four pre-defined subgroups: clear cell versus (vs.) non-clear cell histology, intermediate vs. poor International Metastatic RCC database consortium risk group, treatment with immuno-oncology (IO)-IO vs. IO-vascular endothelial growth factor, and sarcomatoid vs. non sarcomatoid variant. Forest plots will be constructed showing estimated hazard ratios from Cox models and 90% confidence intervals generated within each subgroup. Treatment-by-subgroup interaction terms will be incorporated into the Cox modelling to assess whether the effect of stereotactic ablative radiotherapy (SABR) varies significantly by subgroup; however, these analyses will be considered hypothesis-generating only.
Prognostic and predictive biomarkers
Will be accomplished by including the biomarkers in Cox time-to-event regression models for the evaluation of prognostic factors. Treatment-by-biomarker interaction terms will be incorporated into the modelling process to assess for potential predictive markers.
Abscopal effect of SABR with systemic therapy
These analyses will include only patients in the control arm who have not received any palliative radiation therapy and those in the experimental arm who have received protocol defined stereotactic body radiation therapy only without additional radiation therapy. Response rates among lesions outside the renal mass will be determined based in iRECIST criteria and compared using a chi-square test.
Impact of treatment on the level of inferior vena cava (IVC) thrombus
Will be assessed by comparing the rates of IVC thromboembolism using Fisher's exact test. Cumulative incidence curves with death as a competing risk will also be generated and compared using the Fine-Gray test.
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NRG Oncology
Lead sponsor
National Cancer Institute (NCI)
Collaborator
