Sequencing and Combining Targeted and Immunotherapy

( The 2020 American Society of Clinical Oncologists (ASCO) virtual education program featured a session on the evolution of renal cell carcinoma (RCC) treatment, including a presentation by Dr. Jaleh Fallah from the Cleveland Clinic discussing sequencing and combining targeted and immunotherapy. Over the last couple of years, trials have utilized combination therapy to continue improving outcomes among patients with metastatic RCC. 

The CheckMate-214 study randomly assigned 1,096 patients 1:1 to receive either nivolumab plus ipilimumab or sunitinib, with co-primary end points of overall survival, objective response rate, and progression-free survival among patients with intermediate or poor prognostic risk metastatic RCC.1 At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% CI 70-78) with nivolumab plus ipilimumab and 60% (95% CI 55-65) with sunitinib. The median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (HR 0.63, p<0.001). The objective response rate was 42% for nivolumab plus ipilimumab versus 27% for sunitinib (p<0.001), and the complete response rate was 9% versus 1%, respectively. Finally, the median progression-free survival was 11.6 months for nivolumab plus ipilimumab and 8.4 months for sunitinib (HR 0.82, p=0.03), which was not significant per a prespecified threshold of p < 0.009. 

The KEYNOTE-426 study randomized 432 to pembrolizumab plus axitinib and 429 patients to sunitinib in the first line setting for metastatic RCC.2 Pembrolizumab plus axitinib significantly improved overall survival (HR 0.53, 95% CI 0.38-0.74, p < 0.0001), progression-free survival (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, progression-free survival 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 progression-free survival (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%).

In the JAVELIN Renal 101 study,3 patients were randomized 1:1 to receive avelumab plus axitinib (n=442) or sunitinib (n=444). Progression-free survival per IRC in the PD-L1 positive group favored avelumab plus axitinib versus sunitinib with a median progression-free survival of 13.8 vs 7.2 months (HR 0.61, 95% CI 0.475-0.790). However, overall survival 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 plus axitinib (HR 0.78, 95% CI 0.554-1.084). In an updated analysis recently published for JAVELIN Renal 101,4 avelumab plus axitinib continued to show a progression-free survival benefit (HR 0.69, 95% CI 0.574-0.825), however overall survival data was still immature (HR 0.80, 95% CI 0.616-1.027).

Dr. Fallah provided the following table summarizing these three trials stratified by International Metastatic RCC Database Consortium (IMDC) risk groups, which has resulted in approval for pembrolizumab plus axitinib for patients in all three risk groups, whereas nivolumab plus ipilimumab is only approved for intermediate and poor risk patients:


Given the toxicity associated with combination nivolumab plus ipilimumab, whether we can give nivolumab monotherapy first followed by salvage ipilimumab if needed has been recently explored. Unfortunately, the strategy of treatment with single agent nivolumab followed by salvage combination therapy with ipilimumab and nivolumab has shown limited activity (low objective response rate and complete response rate) and is currently note recommended based on the data as follows:


Currently, there is inconclusive data on the predictive and prognostic value of PD-L1 expression in RCC, and thus evaluation of PD-L1 expression on RCC tumors is not recommended in routine clinical practice. Dr. Fallah notes that in her practice PD-L1 expression does not affect the decision on how to treat metastatic RCC. The management of newly diagnosed metastatic clear cell RCC is highlighted in the following flow diagram:


A current topic of debate is the management of metastatic clear-cell RCC after disease progression, with the following possible scenarios:

  • Patients who were initially treated with ipilimumab plus nivolumab: options include axitinib, cabozantinib, sunitinib, pazopanib, lenvatinib plus everolimus, high-dose IL-2, or a clinical trial
  • Patients who were initially treated with immunotherapy plus a VEGF-TKI (pembrolizumab plus axitinib or avelumab plus axitinib): options include cabozantinib, lenvatinib plus everolimus, everolimus, high-dose IL-2 or a clinical trial
  • Patients initially treated with VEGF-receptor directed TKI monotherapy: options include nivolumab, cabozantinib, nivolumab plus ipilimumab, axitinib, lenvatinib plus everolimus or a clinical trial
  • Patients initially treated with VEGF-receptor directed TKI monotherapy and are not eligible for immunotherapy: options include cabozantinib, axitinib, lenvatinib plus everolimus, or a clinical trial

Dr. Fallah conclude this presentation of sequencing and combining targeted and immunotherapy presentation with the following take home points:

  • Patients with newly diagnosed metastatic RCC should be offered an immunotherapy-based combination therapy
  • The strategy of treatment with single agent nivolumab followed by salvage ipilimumab has shown limited activity and is not recommended
  • Measurement of PD-L1 expression is currently not recommended in routine clinical practice
  • The choice of treatment for metastatic RCC after disease progression varies depending on the treatment received in the frontline setting

Presented by: Jaleh Fallah, MD, Hematology and Oncology Fellow, Cleveland Clinic Foundation, Cleveland, Ohio

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, GA, USA, Twitter: @zklaassen_md, at the ASCO20 Virtual Education Program, #ASCO20, August 8-10, 2020. 

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med2018;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 Med2019;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 Med2019;380(12):1103-1115.
4. 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 Oncol2020 Apr 25;S0923-7534.

Related Content:
Read: ASCO GU 2020: Overall Survival and Independent Review of Response in CheckMate 214 with 42-month Follow-up: First-line Nivolumab + Ipilimumab versus Sunitinib in Patients with Advanced Renal Cell Carcinoma
Watch: KEYNOTE-426: Pembrolizumab plus Axitinib versus Sunitinib as First-Line Therapy for Advanced Renal Cell Carcinoma (RCC) - Brian Rini