ASCO GU 2020: Best of the Journals – Renal Cell Carcinoma: Medical Oncology Perspective

San Francisco, California (UroToday.com) As part of the Best of the Journals series at GU ASCO, Dr. Aly-Khan Lalani discussed the impactful studies in renal cell carcinoma (RCC) from the medical oncology perspective. The theme for his talk is the advancements in front-line treatment options for RCC; in 2019 alone we have seen several major trials published that have once again changed the current landscape of first-line treatment.


JAVELIN Renal 101 evaluated avelumab plus axitinib versus sunitinib in patients with previously untreated advanced/metastatic RCC.1 Patients in this phase III study 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). JAVELIN Renal 101 had a total of 886 patients were randomized, this included 560 patients (63%) that had PD-L1+ tumors (avelumab + axitinib, n=270; sunitinib, n=290). In the overall population, there were 64%/12% IMDC intermediate/poor risk patients treated with avelumab + axitinib compared to 66%/10% treated with sunitinib. The median follow-up for this analysis was 12.0 vs 11.5 months for avelumab + axitinib vs sunitinib groups. Stratified by IMDC prognostic group, avelumab + axitinib outperformed sunitinib in all risk groups: favorable (HR 0.54, 95%CI 0.321-0.907), intermediate (HR 0.74, 95%CI 0.570-0.950), and poor (HR 0.57, 95%CI 0.375-0.880). Similar results for prognostic risk were seen in patients with PD-L1+ tumors. 22.6% of patients on avelumab + axitinib had ≥1 type of follow-up anticancer therapy compared to 40.5% for patients on sunitinib; patients on avelumab + axitinib also outperformed sunitinib with PFS2 as an endpoint (HR 0.56, 95%CI 0.421-0.735). For all subgroups assessed, ORR favored avelumab + axitinib.

Concomitantly published in the New England Journal of Medicine was the KEYNOTE-426 assessing pembrolizumab plus axitinib versus sunitinib in advanced RCC.2 In this phase III trial, pembrolizumab plus axitinib significantly improved overall survival (OS) (HR 0.53, 95% CI 0.38-0.74, p < 0.0001), progression free survival (PFS) (HR 0.69, 95% CI 0.57-0.84, p = 0.0001), and objective response rate (ORR) (59.3% vs 35.7%, p < 0.0001) vs sunitinib. Additionally, there were 592 (68.8%) of all randomized patients that were of IMDC intermediate/poor risk — 294 in the pembrolizumab plus axitinib arm and 298 in the sunitinib arm. Pembrolizumab plus axitinib improved OS (HR 0.52, 95% CI 0.37-0.74; 12-month rate 87.3% vs 71.3%), PFS (HR 0.67, 95% CI 0.53-0.85; median 12.6 vs 8.2 months), and ORR (55.8% vs 29.5%) in patients with intermediate/poor risk. Of the 578 patients with known status, 105 (18.2%) had sarcomatoid features — 51 in the pembrolizumab plus axitinib arm and 54 in the sunitinib arm. Pembrolizumab plus axitinib favored OS (HR 0.58, 95% CI 0.21-1.59; 12-month rate 83.4% vs 79.5%), PFS (HR 0.54, 95% CI 0.29-1.00; median not reached vs 8.4 months), and ORR (58.8% vs 31.5%) in patients with sarcomatoid features.

There were two updates for the CheckMate 214 trial (nivolumab plus ipilimumab vs sunitinib) published in 2019, which Dr. Lalani highlighted. With extended follow-up of median 32.4 months (IQR 13.4-36.3 months), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of OS (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; HR 0.66 [95% CI 0.54-0.80], p<0.0001), PFS (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (42% vs 29%; p=0.0001).3 Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy across all three endpoints. The most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (10%), increased amylase (6%), and increased alanine aminotransferase (5%), whereas in the sunitinib group they were hypertension (17%), fatigue (10%), and palmar-plantar erythrodysesthesia (9%). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. In a post hoc analysis (n = 1,051) of efficacy by the number of IMDC risk factors, ORR with nivolumab plus ipilimumab was consistent across zero to six IMDC risk factors, whereas with sunitinib it decreased with an increasing number of risk factors.4 Benefits of nivolumab plus ipilimumab over sunitinib in terms of ORR (40-44% vs 16-38%), OS (HR 0.50-0.72), and PFS (HR 0.44-0.86) were consistently observed in subgroups with one, two, three, or four to six IMDC risk factors.

As follows is a summary of first-line combination strategies for RCC as of February 14, 2020:


UROTODAY_ASCO_GU_2020_RCCjournals_medonc.png

Looking closer at advancements for patients with variant histologies, Dr. Lalani discussed the very recently published phase 2 trial assessing atezolizumab and bevacizumab for patients with metastatic renal cell carcinoma with variant histology and/or sarcomatoid features [5]. There were 60 patients that received at least one dose of either medication and the majority (65%) of patients were treatment naïve. The ORR for the overall population was 33%. ORR was 50% in patients with clear cell RCC with sarcomatoid differentiation, and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7-10.9 months). Eight patients (13%) developed treatment-related grade 3 toxicities and there were no treatment-related grade 4-5 toxicities. ‘

There are several key studies ongoing among patients with variant histologies:

UROTODAY_ASCO_GU_2020_RCCjournals_medonc_2.png

Dr. Lalani concluded his medical oncology perspective of the best of the journals for RCC with the following conclusions:

  • There are multiple combination options for first-line therapy for aRCC, however there are no head-to-head comparisons, which complicates decisions in the clinic. Furthermore, there is anticipated data from CheckMate 9ER and CLEAR in 2020
  • Triplet strategies are under evaluation and it remains to be seen if these studies raise bar
  • Novel targets may be promising in a post IO/VEGF landscape
  • Non-clear cell (variant) histology remains an area of dire need

Presented by: Aly-Khan A. Lalani, Assistant Professor at McMaster University and a Medical Oncologist at the Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:

  1. 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.
  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, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomized, controlled, phase 3 trial. Lancet Oncol 2019 Oct;20(10):1370-1385.
  4. Escudier B, Motzer RJ, Tannir NM, et al. Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214. Eur Urol 2019 Nov 13 [Epub ahead of print].
  5. McGregor BA, McKay RR, Braun DA, et al. Results of a multicenter phase II study of atezolizumab and bevacizumab for patients with metastatic renal cell carcinoma with variant histology and/or sarcomatoid features. J Clin Oncol 2020 Jan 1;38(1):63-70.

email news signup