During the past few years, multi-target TKIs and checkpoint inhibitors have reshaped the landscape of both front line and second therapy of mRCC. With respect to multi-target TKIs, METEOR and CABOSUN established the role of cabozantinib, a VEGF, MET, and AXL inhibitor, both in the second line setting and in the front-line setting for patients with intermediate or high-risk metastatic RCC2,3.
With respect to immunotherapy, in the second line setting, Checkmate 025 demonstrated that patients treated nivolumab had improved median overall survival when compared against everolimus (25.0 vs 19.6 months, HR 0.73, p=0.002)4. Checkmate 214 moved immunotherapy to the front line for IMDC intermediate or poor risk disease, combining PD-1 blockade with anti-CTLA-4 blockade, and showed a significantly improved OS with nivolumab plus ipilimumab compared against sunitinib (median not reached versus 32.9 months, HR 0.68, 99.8% CI 0.49-0.95)5. Various duos of TKI or VEGF blockade combined with checkpoint inhibitors are also being investigated6,7.
To provide a comprehensive review of the current treatment paradigm, Dr. Vaishampayan referenced the updated EAU guidelines8. While the guidelines are helpful, the treatment choices are nuanced by both patient factors (patient age, organ function, immune status, comorbid conditions, IMDC risk, urgency of response) as well as disease factors (histology, synchronous vs metachronous, PDL-1 status, tumor genomic mutations).
Powles T, Albiges L, Staehler M, et al. Updated European Association of Urology Guidelines
While we may be entering the “golden age” with new drugs, drug combinations, and precision therapy, several challenges still exist. For example, for brain metastases, surgery and radiation therapy remain mainstays of therapy and this is an area where we still have a great unmet need. Additionally, given the inter and intra tumor heterogeneity of RCC, it is unlikely that we will have a single biomarker that will guide us in therapy and we still need more research into patterns of genomic biomarkers for RCC. As the speakers mentioned in the session “Have we found the Philadelphia Chromosome of kidney cancer? Unlikely that it is a single biomarker!”
Dr. Heng spoke next regarding prognostic factors for mRCC, and how he uses prognostic factors, specifically for patient counseling, clinical trial stratification, and most importantly, for patient treatment. In a slide titled “The Future”, Dr. Heng suggests that rather than using only one criteria, we should use a collection of “composite treatment selection biomarkers”, of which may include PDL1 status, IMDC risk score, as well as genomic mutations including PRBM1, mTOR, TSC1, and TSC2. However, he notes none of these are perfect (i.e. he currently does not check PDL1 status as it has a poor negative predictive value for RCC) but as a GU community, we should take further steps to develop composite biomarkers, which may be helpful in guiding therapy for our patients in the future.
Presented By: Ulka N. Vaishampayan, MD and Daniel Heng, MD
Written by: Jason Zhu, MD Fellow, Division of Hematology and Oncology Duke University Medical Center, Twitter: @TheRealJasonZhu at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
1.Motzer RJ, Hutson TE, Tomczak P, et al. Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology 2009;27:3584-90.
2.Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017;35:591-7.
3.Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. The Lancet Oncology 2016;17:917-27.
4.Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. New England Journal of Medicine 2015;373:1803-13.
5.Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2018;378:1277-90.
6.Atkins MB, Plimack ER, Puzanov I, et al. Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients (pts) with advanced renal cell cancer (aRCC). Journal of Clinical Oncology 2018;36:579-.
7.Escudier B, Barthelemy P, Ravaud A, Negrier S, Needle MN, Albiges L. Tivozanib combined with nivolumab: Phase Ib/II study in metastatic renal cell carcinoma (mRCC). Journal of Clinical Oncology 2018;36:618-.
8.Powles T, Albiges L, Staehler M, et al. Updated European Association of Urology Guidelines: Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer. European Urology 2018;73:311-5.