IIS support from BMS, BioCanRx
Randomized data from the interferon era demonstrated survival benefits of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN in most IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in mRCC now includes multiple first-line doublet combination immunotherapy approvals. The Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and durable objective responses with ipilimumab and nivolumab (I/N) compared to sunitinib. However, patients with a primary kidney lesion in situ appeared to have less benefit than patients with prior nephrectomy. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an enhanced systemic anti-tumor immune response. We hypothesize that SBRT to the primary kidney mass will enhance the efficacy of I/N compared to standard of care I/N alone in this unique subset of de novo mRCC patients. We also hypothesize that the combination of SBRT and I/N will lead to upregulation of key components of immune modulation as well as unique perturbation of the host gut microbiome compared to I/N alone.
This phase II trial randomizes untreated mRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven mRCC (any histology) and IMDC intermediate/poor risk disease. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include: (1) immune and genomic profiling of liquid biopsies; (2) transcriptional profiling of baseline tumor biopsies; and (3) interrogation of the gut microbiome and bacterial functionality. Blood and fecal samples will be prospectively collected at baseline, prior to cycle 2 of each arm, and at time of disease progression or the 12-month mark, whichever comes first. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α=0.1, power=80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Trial is enrolling in Canada and Australia. Clinical trial information: NCT04090710.