Choueiri noted several points of consideration regarding KEYNOTE-427:
- This is a single arm study with only 15.5% IMDC poor-risk patients
- There was a low rate of complete response (2.7%) with a short follow-up of 12.1 months compared to 20.7 months in IMmotion150 and 25.2 months in CheckMate 214, noting that some partial responses may become complete responses with longer follow-up
The second study was the RESORT trial presented by Giuseppe Procopio, MD, randomizing patients undergoing radical metastasectomy to sorafenib vs observation after surgery. The study was prematurely terminated and did not meet its primary endpoint of improving RFS with sorafenib vs observation. There was poor compliance/tolerability of patients to the full dose of sorafenib, which may partially explain the negative results. Choueiri notes that data for the M1 NED population may potentially be extrapolated from the high-risk localized setting. In a paper by his group recently published using a pooled analysis of all of the adjuvant therapy trials , the disease-free survival HR was 0.92 (95%CI 0.82-1.03) and the OS HR was 0.98 (95%CI 0.84-1.15). Not surprisingly, patients treated with adjuvant therapy had significantly worse AEs: OR 5.9, 95%CI 4.8-7.1. Also, Choueiri notes that a recent Business Wire news briefing released April 18, 2018 stated that the phase III ATLAS trial evaluating adjuvant axitinib was recommended to be stopped by the trial DMC for futility, noting another failed trial in the adjuvant setting.
Choueiri highlighted several points of consideration regarding RESORT:
- This trial struggled with a very small sample size, despite randomization
- The confidence intervals were very wide, secondary to <50% event rate in either arm
- Three planned stratifications and one unplanned analysis for a small trial is problematic
- There were 19% of patients that discontinued treatment secondary to AEs, in addition to 69% with dose modifications
The third study was the PRO reporting from the IMmotion151 trial presented by Bernard Escudier, MD, IMmotion151 was a randomized, open-label phase III study assessing atezolizumab + bevacizumab vs sunitinib in treatment naive mRCC patients . IMmotion151 met its co-primary endpoint in PD-L1+ patients with improvement in investigator-assessed PFS for patients receiving atezolizumab + bevacizumab compared to sunitinib (HR 0.74, 95%CI 0.57-0.96; median PFS 11.2 vs 7.7 months). In addition to IMmotion151 meeting its co-primary endpoint, all PROs favored atezolizumab + bevacizumab vs sunitinib including: milder symptoms, less functional impairment, delay in meaningful deterioration of patient’s daily functioning, less treatment-related side effects, and better HRQoL.
According to Chouieri, this is one of the most complete QoL/PRO studies for IO combinations for RCC, which included assessment of 17 disease/treatment-related symptoms. Even with the 2 week sunitinib break, patients receiving atezolizumab + bevacizumab had a less meaningful functional impairment. Choueiri ponders whether a different sunitinib schedule (ie. 50 mg two weeks on/one week off) may be associated with fewer side effects? One cautionary note is that there was one death related to atezolizumab every 90 patients (1.1%) compared to 1 death every 446 patients for sunitinib (0.2%). Ultimately, according to Choueiri, this confirms the experience amongst most trialist that atezolizumab + bevacizumab is a well-tolerated regimen.
1. Atkins MB, McDermott DF, Powles T, et al. IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol 2017;35(15 Suppl 1).
2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.
3. Sun M, Marconi L, Eisen T, et al. Adjuvant vascular endothelial growth factor-targeted therapy in renal cell carcinoma: A systematic review and pooled analysis. Eur Urol 2018 May 18 [Epub ahead of print].
4. Motzer RJ, Powles T, Atkins MB, et al. IMmotion 151: A randomized Phase III Study of Atezolizumab plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). J Clin Oncol 2018;36(suppl 6S; abstr 578).
Presented by: Toni Choueiri, MD, Dana-Farber Cancer Institute, Boston, MA
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA