CYTOSHRINK: A randomized phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with ipilimumab/nivolumab for metastatic kidney cancer.

416 Background: Patients (pts) presenting with de novo metastatic renal cell carcinoma (mRCC) have a poor prognosis. The role of cytoreductive nephrectomy (CN) is uncertain in these pts. 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. The efficacy and safety of primary SBRT in combination with ipilimumab and nivolumab (I/N) in pts with previously untreated mRCC are unknown. Methods: A randomized phase II trial was conducted at sites in Canada (6) and Australia (1). Inclusion criteria were: previously untreated, biopsy-proven, IMDC intermediate or poor risk de novo clear cell mRCC. Pts with a primary kidney lesion > 20cm, previous abdominal radiation precluding SBRT, or with a contraindication to I/N were excluded. Randomization was 2:1 to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm), versus I/N alone. The primary endpoint was progression free survival (PFS). Target sample size was 78 pts. Secondary objectives included safety, overall survival (OS), objective response rate (ORR), health-related quality of life (QOL), and correlative biomarker analyses. Results: Pts were recruited between February 2020 and July 2024, with accrual paused for 8 months during COVID-19 pandemic. Median follow-up is 23.5 months. A total of 67 pts were randomized: 43 pts to I/N+SBRT, 24 to I/N alone. Median age was 65 years, 73% were male, IMDC risk groups were 58% intermediate and 42% poor. Pts in the experimental arm had larger renal tumours (T3/T4 stage 70% vs 46%), primary target lesion (95 mm vs 87.5 mm), and more likely to have liver sites of metastasis (23% vs 8%) compared to the I/N alone arm. Three pts died prior to any SBRT. PFS rate at 12-months was 35% (95% CI 21-49%) for I/N+SBRT vs 48% (27-66%) for I/N alone (HR 1.29, 0.69-2.40). The ORR was 33% vs 42% and 18-month OS was 59% vs 70%, for I/N+SBRT vs I/N alone. In per protocol analysis of pts who received 4 cycles of I/N +/- SBRT, 12-month PFS was 46% vs 56%, ORR was 50% vs 44%, and 18-month OS was 74% vs 79%, for I/N+SBRT (n = 24) vs I/N alone (n = 16). Grade 3/4 treatment related adverse events were 23% vs 29%, respectively, with no new safety signals related to I/N or SBRT toxicity noted. Conclusions: CYTOSHRINK is the first randomized trial testing the addition of early cytoreductive SBRT to first-line immune checkpoint blockade for patients with de novo mRCC. While 12-month PFS was not improved compared to I/N alone, there were notable baseline imbalances. The addition of SBRT to I/N was considered safe. Further follow up of OS, QOL and correlative biomarker analyses are ongoing. Clinical trial information: NCT04090710 .