EAU 2020: Immunotherapy Combinations for Intermediate-Poor Risk mRCC: IO + TKI

(UroToday.com) The virtual EAU 2020 meeting featured a thematic session discussing immunotherapy combinations for intermediate-poor risk metastatic renal cell carcinoma (mRCC). Axel Merseburger, MD, PhD, discussed the utility of combining Immuno-Oncology (IO) treatment with TKIs. Dr. Merseburger notes that according to older versions of the EAU guidelines, the first-line treatment for IMDC intermediate-poor risk patients is ipilimumab plus nivolumab. Additional options (without a strong recommendation) are cabozantinib, sunitinib or pazopanib. In an update of these guidelines (with new data reported recently), the current recommendations for intermediate-poor risk patients is pembrolizumab plus axitinib or ipilimumab plus nivolumab.1 Currently, Dr. Merseburger notes that we have new first-line combination treatments with phase 3 data, including nivolumab plus ipilimumab, axitinib plus pembrolizumab, and axitinib plus avelumab.

Based on the CheckMate-214, nivolumab + ipilimumab showed an improved objective response rate and overall survival, but only for patients with intermediate and poor prognosis patients, for which it is approved (not approved favorable risk).2 Subsequently, the JAVELIN Renal 101 study of avelumab plus axitinib showed improved PFS in the first-line setting,3 and KEYNOTE-426 of pembrolizumab plus axitinib showed both improved PFS and overall survival.4 

In the JAVELIN Renal 101 study,3 patients were randomized 1:1 to receive avelumab (10 mg/kg) IV every 2 weeks + axitinib (5 mg) PO twice daily (n=442) or sunitinib (50 mg) PO once daily for 4 weeks (6-wk cycle) (n=444). The primary and key secondary endpoints were PFS per independent review committee (IRC; RECIST v1.1) and OS in patients with PD-L1+ tumors (≥1% of immune cells) and in patients irrespective of PD-L1 expression. Additional secondary endpoints included objective response per IRC (RECIST v1.1). All subgroup analyses were prespecified in the analysis plan, except for body mass index, and smoking status, which were post-hoc exploratory analyses. The trial design is as follows:

JAVELIN_Renal101.png

PFS per IRC in the PD-L1 positive group favored avelumab + axitinib vs sunitinib with a median PFS of 13.8 vs 7.2 months (HR 0.61, 95% CI 0.475-0.790). OS data is currently immature (14% of patients with an event in the avelumab plus axitinib arm; 17% of patients with an event in the sunitinib arm), but is showing a signal for benefiting patients receiving avelumab + axitinib (HR 0.78, 95% CI 0.554-1.084). In an updated analysis recently published for JAVELIN Renal 101,5 avelumab plus axitinib continued to show a PFS benefit (HR 0.69, 95% CI 0.574-0.825), however, OS data was still immature (HR 0.80, 95% CI 0.616-1.027):
OSdata_JAVELIN.png

The KEYNOTE-426 study randomized 432 to pembrolizumab (200 mg IV Q3W for up to 35 doses) plus axitinib (5 mg orally BID) and 429 patients to sunitinib (50 mg orally QD on a 4-wk on/2-wk off schedule) in the first-line setting for mRCC [4]. The trial design is as follows:
KEYNOTE426.png

Pembrolizumab plus axitinib significantly improved overall survival (HR 0.53, 95% CI 0.38-0.74, p < 0.0001), PFS (HR 0.69, 95% CI 0.57-0.84, p = 0.0001), and objective response rate (59.3% vs 35.7%, p < 0.0001) compared to sunitinib. In an updated analysis presented at ASCO 2020, PFS remained durable (HR 0.71, 95% CI 0.60-0.84), as did overall survival (HR 0.68, 95% CI 0.55-0.85). In this updated analysis, among patients with intermediate-poor risk disease, patients treated with pembrolizumab plus axitinib had improved PFS (HR 0.69, 95% CI 0.56-0.84), overall survival (HR 0.63, 95% CI 0.50-0.81), and superior objective response rate (55.8% vs 35.2%). 

When comparing KEYNOTE-426 to CheckMate-214 with regards to PFS, Dr. Merseburger notes that median PFS for pembrolizumab plus axitinib is 4.2 months (95% CI 3.7-5.4) compared to 8.2 months (95% CI 6.9-10.0) for nivolumab plus ipilimumab. However, what is important to note, is that these disparate outcomes may be secondary to a difference in follow-up time: 12 months for KEYNOTE-426 compared to 30 months for CheckMate-214. 

According to Dr. Merseburger, there are several pros and cons for the IO + TKI combo. Pros include (i) an OS advantage, (ii) longer PFS, (iii) higher objective response rate, and (iv) lower immune-related adverse events (15%). Several cons include (i) whether it is unclear if/when to stop therapy, (ii) shorter follow-up as compared to the IO-IO combinations, (iii) lower quality of life, and (iv) chronic toxicity associated with TKIs. Additionally, there are pros and cons with IO/IO combinations. Pros include (i) an OS advantage, (ii) mature follow-up, and (iii) improved quality of life. Cons include a lower PFS, and an unpredictable and higher immune-related adverse event rate. Additionally, there has been recent data presented highlighting nivolumab and ipilimumab in different settings (ie. salvage/rescue) as depicted in the following figure:
nivolumab_ipilumab.png

Dr. Merseburger concluded with the following take-home messages from his talk on IO + TKI combination therapy for first-line mRCC:

  • PD-1 immune-checkpoint inhibition is the backbone of first-line therapy
  • Pembrolizumab or avelumab plus axitinib is approved for all risk groups
  • Nivolumab plus ipilimumab is only approved for intermediate-poor risk groups
  • The major differences between IO-IO vs IO-TKI include: maturity of data, efficacy endpoints, the side effect profile, quality of life, and possible differences with regards to histology
Presented by: Axel S. Merseburger, MD, PhD, University Medical Center Schleswig-Holstein, Lubeck, Germany

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020.

References: 
  1. Albiges L, Powles T, Staehler M, et al. Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma. Eur Urol 2019 Aug;76(2):151-156.
  2. 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.
  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. 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.
  5. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol 2020 Apr 25;S0923-7534.
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