EAU 2021: Evolving Landscape of First-Line Systemic Treatment in Metastatic Renal Cell Carcinoma

(UroToday.com) Dr. Laurence Albiges discussed the evolving landscape of first-line systemic treatment in metastatic renal cell carcinoma (mRCC) at the European Association of Urology’s (EAU) 2021 annual meeting’s controversies in onco-urology session. Dr. Albiges started by highlighting the new guidelines adapted from the EAU and ESMO guidelines for RCC, using the IMDC risk classification to select treatment options. A summary of the adapted guidelines are as follows:

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These combination therapies as listed above are either approved or in the process of being approved based on key phase 3 trials:

  1. CheckMate 214 (ESMO 2017): nivolumab + ipilimumab versus sunitinib1
  2. KEYNOTE 426 (GU ASCO 2019): pembrolizumab + axitinib versus sunitinib2
  3. JAVELIN 101 (GU ASCO 2019): avelumab + axitinib versus sunitinib3
  4. CheckMate 9ER (ESMO 2020): nivolumab + cabozantinib versus sunitinib4
  5. CLEAR (GU ASCO 2021): lenvatinib + everolimus versus pembrolizumab + lenvatinib versus sunitinib5

Using the combination of check point inhibitor (nivolumab) + checkpoint inhibitor (ipilimumab), we are able to achieve an overall survival benefit in IMDC intermediate and poor risk patients. The primary data of CheckMate 2141 showed a survival benefit (HR 0.63) for nivolumab + ipilimumab after 17.5 months of follow-up, and this was durable in longer term (48 month) follow-up (HR 0.65) presented at the ESMO 2020 virtual congress:

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Using the combination checkpoint inhibitor plus VEGFR-TKI, there is also prolonged survival advantage with the combination therapy over sunitinib. The KEYNOTE-4262 trial showed a survival benefit for pembrolizumab + axitinib (HR 0.53) in the primary analysis, which was durable with extended follow-up (HR 0.73, 95% CI 0.60-0.88).6 These combination regimens have demonstrated a survival benefit across multiple subgroups, however, Dr. Albiges notes that good risk patients (perhaps with longer follow-up necessary) have not shown a significant survival benefit with these combination therapies. Importantly, the checkpoint inhibitor plus VEGFR-TKI combinations have shown objective response rates of 55%-71% and median progression-free survival data ranging from 15.7-23.9 months.

According to Dr. Albiges, there are several open-ended questions that remain to be answered. First, should we increase treatment intensification in the first-line setting with triplet therapy? Currently, the COSMIC 313 and MK6482-012 trials are accruing patients and will provide further insight into treatment intensification:

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Second, can we incorporate a treatment tailored approach? To assess treatment de-escalation, the TITAN-RCC trial was presented at ESMO 2019 and enrolled 258 first-line and second-line (after TKI) patients with IMDC intermediate and poor-risk, advanced clear cell RCC between October 2016 and December 2018. Patients started with nivolumab 240 mg Q2W induction. Patients with early significant progressive disease at week 8 or either stabile disease or progressive disease at week 16 received 2-4 nivolumab + ipilimumab boost cycles. Responders (defined as either partial response or complete response) to nivolumab monotherapy continued with maintenance with nivolumab + ipilimumab boosts only for progression. Over a median follow-up of 36.2 weeks, the confirmed ORR with first-line nivolumab monotherapy was 28.7 % (95% CI 20 - 38). The best overall response after nivolumab induction ± nivolumab + ipilimumab boosts was 37 % (95 % CI 28 - 47) in the first-line setting. In the second-line setting, the confirmed ORR with first-line nivolumab monotherapy was 18.2% and 28 % (95 % CI 20 - 38) with nivolumab + ipilimumab boosts.

Third, can we utilize biomarkers to select the best upfront combination therapy? The BIONIKK trial was presented at ESMO 2020 and is an open-label, French multicenter randomized phase 2 trial evaluating nivolumab versus nivolumab plus ipilimumab versus TKI in upfront metastatic clear cell RCC according to ccrcc1-4 (35-gene signature). ccrcc1 and ccrcc4 patients were randomized to nivolumab versus nivolumab plus ipilimumab, whereas ccrcc2 and ccrcc3 patients were randomized to receive nivolumab plus ipilimumab versus TKI. The primary endpoint for this study was objective response rate (ORR, RECIST1.1) per treatment and group. Secondary endpoints included progression-free survival, overall survival, and tolerability. A total of 150 patients were expected in target cohort and an additional cohort was included to assess inter-platform variability. After a median follow-up of 16 months the median progression free survival results are as follows:

  • ccrcc1: nivolumab plus ipilimumab 8.0 months vs nivolumab 4.6 months
  • ccrcc4: nivolumab plus ipilimumab 12.2 months vs nivolumab 7.8 months
  • ccrcc2: TKI not reached vs nivolumab plus ipilimumab 10.4 months

Dr. Albiges notes that biomarkers still need to be defined at the patient level and to assess the best combination therapy.

Fourth, what are new agents we can utilize? HIF2alpha inhibition by MK6482 (belzutifan) has recently been tested in the phase I/II setting and presented at GU ASCO 2021. Among 55 patients over a median follow-up of 27 months, the objective response rate was 25%, with a disease control rate of 80%, and median PFS of 14.5 months. A phase 3 study randomizing patients to MK-6482 versus everolimus is ongoing:

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Dr. Albiges concluded with several important take home messages from her presentation:

  • Combination therapy in the first-line setting is standard of care: VEGFR TKI-checkpoint inhibitors for all risk groups, and nivolumab + ipilimumab or VEGFR TKI-checkpoint inhibitors for intermediate/poor risk patients
  • There is no head-to-head comparison data available for checkpoint inhibitor + checkpoint inhibitor versus VEGFR TKI-checkpoint inhibitor

Presenter by: Laurence Albiges, MD, PhD, Goustave Roussy Institute, Villejuif, France

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.


  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
  2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127.
  3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1103-1115.
  4. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841.
  5. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300.
  6. Powles T, Plimack ER, Soulieres D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): Extended follow-up from a randomized, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573.
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