MDACC 2018: Debate: What is the Best Front-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma?

Houston, TX ( Dr. Gao defended Nivolumab plus ipilimumab as the best front-line systemic therapy for mRCC.  The argument was centered around the results of Checkmate 214 trial1.  This phase III trial compared Nivolumab (Nivo) plus ipilimumab (Ipi) versus Sunitinib in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate risk and poor-risk patients. 

The overall survival (OS) was not reached with the Nivo/Ipi versus 26 months with Sunitinib.   Progression-free survival (PFS) was 11.6 months for Ipi/Nivo versus 8.4 months with Sunitinib.  Ipi/Nivo versus Sunitinib had an objective response rate (ORR) of 42% versus 27%.  Complete response (CR) was achieved 9% in the Ipi/Nivo group versus 1% in the Sunitinib group. However, in the favorable risk group, Ipi/Nivo had an ORR of 29% versus 52% with Sunitinib.  There were less side effects in the Nivo/Ipi group compared to the Sunitinib group (46% had grade 3 or 4 toxicity for Nivo/Ipi versus 63% grade 3 or 4 toxicity for Sunitinib).   Additionally, Nivo/Ipi scored more favorable in QOL surveys.  However, again for the favorable risk group, the median progression-free survival (PFS) was 15 months with Ipi/Nivo versus 25 months with Sunitinib.  It was noted that the while the favorable risk group had better outcomes for the Sunitinib group, there were only ~1/3 of patients in this risk group compared to the intermediate and high-risk group. 

Dr. Wang supported Cabozantinib as the best tyrosine kinase Inhibitor for front-line systemic therapy for mRCC. The METEOR trial was a large study including 658 patients comparing Cabozantinib versus Everolimus2.  There was a 7.4 versus 3.9 PFS of Cabozantinib over Everolimus and a 21.5 versus 16.5 month OS of Carbozantinib over Everolimus.  This study led to the FDA approval Cabozantinib for advanced RCC for patients who have received previous antiangiogenic therapy. The CABOSUN trial compared Cabozantinib versus Sunitinib3  The primary endpoint was PFS and the secondary endpoints were OS and ORR.  The inclusion criteria were intermediate or poor risk patients with clear cell RCC.  There was a PFS advantage in Cabozantinib over Sunitinib (8.2months versus 5.6 months).  In a subgroup analysis, patients with bone metastases also had a PFS benefit with Cabozantinib.  This study led to FDA approval of Cabozantinib for first-line therapy in patients with advanced RCC.   These trials support Cabozantinib is a viable first-line option for mRCC in patients with IMDC intermediate or poor risk disease, boney metastases, underlying autoimmune disorders and metastases.  Realistically, however, a combination of drugs is likely to give the best outcomes.

Dr. Campbell argued for Sunitinib or Pazopanib as the best front-line systemic therapy for mRCC.  While CABOSUN and Checkmate 214 both showed that Cabozantinib was better than Sunitinib, Dr. Campbell argued that these studies are made up of mostly white men with excellent performance status and therefore cannot apply to every patient and that certainly the patients we see in clinic are far more diverse.  It is also unknown how upfront use of Cabozantinib will affect the efficacy of TKIs later in the disease process.  Is it possible that we are using our best treatment up front and therefore leaving patients without options down the road?  In terms of Nivo/Ipi, this downside of this drug combination is the most expensive treatment and carries the risk of fatal toxicity.  Additionally, the side of Nivo/Ipi are not insignificant as demonstrated in the Checkmate 214 trial.   24% had to come off due to major autoimmune toxicity with 60% requiring steroids.  It was also unclear if OS was purely driven by Nivo/Ipi versus the lack of alternative options for non-responders in the Sunitinib group.  These caveats and downsides support Dr. Campbell’s stance that Sunitinib or Pazopanib should be considered for front-line systemic therapy for mRCC.

Presented by: Jinjun Gao, MD, PhD (Nivolumab plus Ipilimumab), Jennifer Wang, MD (Cabazotinib), and Matthew Campbell, MD (Sunitinib or Pazopanib), Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

Written by Dr. Amy H. Lim, MD, PhD, Urologic Oncology Fellow and Ashish M. Kamat, MD, (@UroDocAsh), Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 13th Update on the Management of Genitourinary Malignancies, The University of Texas (MDACC - MD Anderson Cancer Center) November 9-10, 2018, Dan L. Duncan Building, Houston, TX

1. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-90.
2. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1814-23.
3. Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-25.