ASCO 2018: Optimizing Systemic Therapy in Advanced Renal Cell Carcinoma

Chicago, IL ( Toni Choueiri, MD, provided a discussion following three Renal Cell Carcinoma (RCC) oral abstracts presented at the 2018 ASCO annual meeting. The first study was results of the KEYNOTE-427 study presented by David F. McDermott, MD. This study evaluated monotherapy pembrolizumab as first-line therapy for patients with mRCC, noting promising antitumor activity for pembrolizumab treating clear cell RCC across IMDC risk groups with an ORR of 38%. There was also encouraging activity of pembrolizumab observed in key subgroups, including IMDC intermediate/poor risk (ORR 42%), and patients with PD-L1-positive tumors (ORR 50%). Furthermore, the safety profile of Cohort A (clear cell RCC patients) was similar to previously described safety profiles of pembrolizumab in other tumor types. Choueiri notes that the landscape for treating mRCC in the first line is changing quickly, as in addition to IO/VEGF trials, there are also ongoing IO/IO combination trials. But, as Choueiri highlights, combination trials have more toxicity than single agent VEGF TKIs and single agent PD-1/PD-L1 inhibitors among untreated patients: treatment-related AE rates for combination therapies are generally 19-22% compared to 3-5% for single agent trials. One of his concerns is the complete response rate of 2.7% noted in KEYNOTE-427, compared to 11% in IMmotion150 with atezolizumab, as well as an increase in treatment-related AEs (10.9% KEYNOTE-427 vs 3% IMmotion150) [1]. According to Choueiri, the “elephant in the room” is the comparison of KEYNOTE-427 to CheckMate 214 (nivolumab + ipilimumab) [2]. Although there were high treatment related AEs for CheckMate 214 (22% vs 10.9%), nivolumab + ipilimumab had higher complete response rates (9.8% vs 2.7%) and median PFS (12.4 vs 8.7 months) compared to KEYNOTE-427.

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
Choueiri thinks that the future will likely encompass a response-based approach to treatment with nivolumab for patients with mRCC. The OMNIVORE trial is starting to accrue at his center (Dana Farber Cancer Institute), where patients will be treated with nivolumab and then triaged to a complete/partial response arm that will receive additional nivolumab (followed by treatment breaks) vs a progressive/stable disease arm that will receive ipilimumab and re-challenged with nivolumab if responses improve.

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 [3], 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
There is optimism that immunotherapy may fair better in the M1 NED setting, and Choueiri notes several phase III trials that are accruing including IMmotion010 (atezolizumab) and KEYNOTE 564 (pembrolizumab). 

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 [4]. 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