This was an open-label, pilot randomized trial of patients with mRCC without prior immune checkpoint therapy and anti-VEGF therapy. Patients were randomized 2:3:2 to receive nivolumab (3mg/kg every two weeks for 3 cycles), nivolumab plus bevacizumab (10mg/kg every two weeks for 3 cycles) or nivolumab + ipilimumab (1mg/kg every three weeks for 2 cycles), followed by cytoreductive surgery or biopsy, and then nivolumab maintenance therapy up to 2 years. Clinical response per RECIST criteria was assessed at ≥12 wks. Pre- and post-treatment blood and tumors were obtained for correlative studies. The primary endpoint for the study was safety and the trial was not designed to compare clinical outcomes between arms. The schema for this trial is as follows:
There have been 105 patients accrued and 104 evaluable for response (median follow-up of 29 months): 29 to nivolumab, 45 to nivolumab + bevacizumab, and 30 to nivolumab + ipilimumab. Baseline characteristics were balanced between groups, and >90% of patients had not received prior systemic therapy. Grade 3 or higher toxicities related to therapy were 28% for nivolumab, 38% for nivolumab + bevacizumab (including 18% hypertension), and 43% for nivolumab + ipilimumab. For all patients, best overall response (equal to complete response + partial response) including surgery effect was 59% nivolumab, 44% nivolumab + bevacizumab, and 43% nivolumab + ipilimumab. The median progression-free survival (PFS) was 14.5 months (95% CI 5.5 to not reached) for nivolumab, 7.6 months (95% CI 4.8 to 8.9) months for nivolumab + bevacizumab, and 7.5 (95% CI 2.0 to 12.4) months for nivolumab + ipilimumab. Overall survival (OS) at two years was 72% for nivolumab, 60% for nivolumab + bevacizumab, and 56% nivolumab + ipilimumab.
For patients with cytoreductive surgery, best overall response including surgery effect was: 86% for nivolumab, 82% for nivolumab + bevacizumab, and 69% for nivolumab + ipilimumab. Median PFS was 17.3 months (95%CI 6.1 to not reached) for nivolumab, 7.6 (95% CI 5.7 to 10.3) months for nivolumab + bevacizumab, 8.9 (95% CI 2.9 to 23.0) months for nivolumab + ipilimumab. OS at one year was 100% for nivolumab, 94% for nivolumab + bevacizumab, 92% for nivolumab + ipilimumab. Median OS has not yet reached with a median follow-up of 24.6 months.
For non-surgical patients, best overall response was 33% for nivolumab, 21% for nivolumab + bevacizumab, and 24% for nivolumab + ipilimumab.
Immune and gene profiling analyses demonstrate:
- Tumor-infiltrating CD8 T cells correlate with clinical responses to nivolumab or nivolumab + bevacizumab, but not to nivolumab + ipilimumab
- Tumor IFN pathway gene expression correlates with responses
- PD-L1 status, tumor mutation or mutation burden, neoantigens did not correlate with response.
- Nivolumab +/- bevacizumab or ipilimumab with cytoreductive surgery were safe and showed promising clinical activities in patients with mRCC
- Correlative studies identified biomarkers in pre-treatment tumor tissues that may be used to predict clinical outcomes for RCC patients receiving immune checkpoint therapy
- This data suggests that immune checkpoint therapy plus cytoreductive surgery improved clinical outcomes for patients with mRCC and this strategy should be tested in a larger randomized clinical trial.
Presented by: Jianjun Gao, MD, The University of Texas MD Anderson Cancer Center, Houston, TX
Co-Authors: Jose A. Karam, Nizar M. Tannir, Matthew T Campbell, Rebecca Slack Tidwell, Kamran Ahrar, Priya Rao, Chaan S. Ng, Eric Jonasch, Surena F. Matin, Amado J. Zurita, Amishi Yogesh Shah, Yu Shen, Jorge M. Blando, Luis M. Vence, Sreyashi Basu, Hao Zhao, James Patrick Allison, Christopher G. Wood, Padmanee Sharma; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Texas MD Anderson Cancer Center, Houston, TX; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA