August 2020 Edition Vol.11, Issue 8

Metastatic Renal Cell Carcinoma: Combining and Sequencing Novel Agents

By Chase Doyle

The treatment paradigm for advanced and metastatic renal cell carcinoma (RCC) has evolved rapidly since the arrival of targeted agents and immunotherapies, leaving questions about how best to combine and sequence therapies.

During the ASCO20 Virtual Education Program, Jaleh Fallah, MD, Hematology/Oncology Fellow at Cleveland Clinic, in Ohio, reviewed the outcomes of single-agent immunotherapy and immunotherapy-based combinations in the front-line setting and discussed the choice of treatment following disease progression.1

Combination Therapies for Front-Line Management

There are currently three FDA-approved combination therapies for front-line management of metastatic RCC: ipilimumab plus nivolumab, pembrolizumab plus axitinib, and avelumab plus axitinib. These approvals are based on data from three phase III, randomized clinical trials in patients with previously untreated, metastatic, clear-cell RCC.

  • Checkmate-214 evaluated ipilimumab plus nivolumab versus sunitinib.2 The co-primary endpoints for the trial were overall survival (OS), progression-free survival (PFS), and objective responses in intermediate-risk or poor-risk patients. Ipilimumab plus nivolumab was the first FDA-approved combination in this setting and has the longest follow-up data, said Dr. Fallah.
  • KEYNOTE-426 evaluated pembrolizumab plus axitinib versus sunitinib.3 The co-primary endpoints were OS and PFS in the intention-to-treat population. Both CHECKMATE-214 and KEYNOTE-426 regimens demonstrated significantly better OS compared with sunitinib.
  • JAVELIN Renal 101 evaluated avelumab plus axitinib versus sunitinib.4 The co-primary endpoints of this study were OS and PFS in patients with PD-L1-positive tumors. Although PFS was significantly better with the combination therapy, said Dr. Fallah, the OS data are still immature and have not demonstrated any significant differences between treatment arms.

As Dr. Fallah reported, the objective response rate and complete response rate are higher in all three trials with the combination therapies versus sunitinib in the intent-to-treat population, and in patients with intermediate to poor-risk disease, there is also significant OS benefit with combination therapy versus sunitinib.

For patients with favorable-risk disease, however, no statistically significant difference in OS has been observed between treatment arms.

“It will take longer for overall survival data to mature in patients with favorable-risk disease,” said Dr. Fallah, who noted that these studies were not powered to assess the difference in this subgroup.

Dr. Fallah also emphasized that there is no head-to-head comparison of these regimens and that due to differences in patients’ baseline characteristics, data cannot be compared across clinical trials.

Single-Agent Immunotherapy Not Recommended

According to Dr. Fallah, immunotherapy-based combinations have demonstrated better efficacy compared to sunitinib, but these combinations are also associated with significant toxicities. In order to reduce toxicity, investigators have explored giving single-agent nivolumab followed by salvage combination therapy with ipilimumab and nivolumab in several clinical trials.5,6,7

The objective response rate with nivolumab monotherapy ranges from 14% to 31% in this setting, said Dr. Fallah, and the objective response rate after treatment with salvage ipilimumab is only 4% to 15%. In addition, less than 2% of patients achieve complete response, which is lower than the outcomes reported in the CheckMate-214 study.

“Based on the results of these clinical trials, the strategy of treatment with single-agent nivolumab followed by salvage ipilimumab is not recommended due to the limited activity,” said Dr. Fallah.

Role of PD-L1 Expression

As Dr. Fallah reported, checkpoint inhibitors in the front-line setting have frequently shown higher efficacy in patients with PD-L1-positive RCC tumors. However, even in patients with PD-L1-negative tumors, there is a substantial clinical benefit with checkpoint inhibitors compared with sunitinib.

“Considering the inconclusive data on the predictive and prognostic value of PD-L1 expression in renal cell carcinoma, evaluation of PD-L1 expression is currently not recommended in routine clinical practice because it does not affect our decision on how to treat patients with metastatic renal cell carcinoma,” said Dr. Fallah.

Initial Treatment Algorithm

As Dr. Fallah explained, management of newly diagnosed metastatic RCC follows a straightforward algorithm. Clinicians must first determine whether there is a need to start systemic therapy. For example, patients with symptomatic, rapidly progressive, and poor-risk disease with high disease burden need to be started on systemic treatment right away, and the choice of treatment is the combination axitinib plus pembrolizumab or ipilimumab plus nivolumab. If a patient is not a candidate for immunotherapy, then vascular endothelial growth factor (VEGF) tyroskine kinase inhibitors (TKIs) such as sunitinib, pazopanib, or cabozantanib are appropriate options, said Dr. Fallah.

Patients with asymptomatic, favorable-risk disease and low disease burden, on the other hand, do not need to initiate systemic treatment and may be candidates for local therapy. Patients with oligometastatic disease can be considered for local therapy such as surgical metastasectomy or stereotactic body radiation therapy. Initial observation can be considered in patients with asymptomatic, favorable-risk disease with low disease burden who are not candidates for a local therapy. According to Dr. Fallah, this can help maintain a patient’s quality of life by avoiding the potential toxicities associated with systemic treatment.

Treatment after Disease Progression

As Dr. Fallah explained, the choice of treatment for metastatic RCC after disease progression varies depending on the treatment received in the front-line setting. In patients who were initially treated with ipilimumab plus nivolumab, any VEGF-TKI can be used in the second-line setting. Other treatment options include lenvatinib plus everolimus, high-dose interleukin-2, and clinical trials, if available.

In patients who were initially treated with immunotherapy plus a VEGF-TKI (for example, axitinib plus pembrolizumab or axitinib plus avelumab), treatment options in the second-line setting include cabozantinib, lenvatinib plus everolimus, everolimus monotherapy, high-dose interleukin-2, and clinical trials.

In patients who were initially treated with a single-agent VEGF-TKI, treatment options for the second-line setting include nivolumab, ipilimumab plus nivolumab, cabozantinib, axitinib, lenvatinib plus everolimus, and clinical trials. If a patient was initially treated with a VEGF-TKI due to contraindications for immunotherapy, clinicians can use any of those treatment options except for nivolumab or ipilimumab plus nivolumab, said Dr. Fallah.


  1. Fallah, J. Sequencing and Combining Targeted and Immunotherapy. Presented at: 2020 ASCO Virtual Education Program; August 8, 2020.
  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. 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.
  4. 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.
  5. Grimm M, Schmidinger M, Martinez ID, et al. Tailored immunotherapy approach with nivolumab in advanced renal cell carcinoma (TITAN-RCC). Annals of Oncology (2019) 30 (suppl_5): v851-v934.
  6. Atkins MB, Jegede O, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 5006-5006.
  7. McKay RR, Xie W, McGregor BA, et al. Optimized management of nivolumab (nivo) and ipilimumab (ipi) in advanced renal cell carcinoma (RCC): a response-based phase II study (OMNIVORE). J Clin Oncol. 2020;38(suppl 15; abstr 5005).

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