Choosing Frontline Regimens in Different RCC Patient Populations and Future Promise of Novel Therapies

Cytotoxic chemotherapy has shown limited efficacy in metastatic RCC, but immunotherapeutic and antiangiogenic approaches have introduced promising treatment modalities. The use of immunotherapy has made a significant impact on the treatment of patients with RCC, first with single agents and then with combination regimens.

Daniel C. Cho, MD

With new immunotherapycombinations approved this year and more under investigation, optimizing therapy selection for each patient’s unique disease characteristics and needs is becoming increasingly important.

Worldwide, incidence of renal cell carcinoma (RCC) is increasing. In the United States, there were 73,820 estimated new cases in 2019.1 Cytotoxic chemotherapy has shown limited efficacy in metastatic RCC, but immunotherapeutic and antiangiogenic approaches have introduced promising treatment modalities.2The use of immunotherapy has made a significant impact on the treatment of patients with RCC, first with single agents and then with combination regimens.

“Immunotherapy is now considered largely [a] standard of care,” explainedDaniel C. Cho, MD. “There are 3 combinational regimens approved for the first line in kidney cancer.”

Cho, an associate professor in the Department of Medicine and director of the Phase I Drug Development Program at NYU Langone Health in New York, New York, will speak during his presentation, “Next-Generation Immunotherapy in Renal Cell Carcinoma,” as part of the Genitourinary Cancer track during the afternoon session of today’s meeting.

Current Frontline Treatment Options

First- and second-line therapeutic options for patients with RCC include targeted therapy using tyrosine kinase inhibitors (TKIs) and/ or antivascular endothelial growth factor antibodies. Additional agents targeting the mammalian target of rapamycin are also options in this setting. FDA-approved agents for advanced RCC treatment in the first line and/or subsequent lines of therapy include sunitinib (Sutent), sorafenib (Nexavar), pazopanib (Votrient), axitinib (Inlyta), temsirolimus (Torisel), everolimus (Afinitor), bevacizumab (Avastin) in combination with interferon, cabozantinib (Cabometyx), and lenvatinib (Lenvima) plus everolimus.3

The current National Comprehensive Cancer Network Guidelines outline preferred and other recommendations for patients with clear cell RCC, and these include combinations of PD-1 inhibitors with axitinib and inhibitors of CTLA-4 and PD-1 (TABLE).3

The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) was approved by the FDA for use in the frontline setting in April 2018 based on findings from the phase III CheckMate 214 trial.4In this trial, 1096 patients with previously untreated clear cell advanced RCC were randomized to nivolumab (3 mg/kg body weight) plus ipilimumab (1 mg/kg) every 3 weeks for 4 doses, followed by nivolumab every 2 weeks or sunitinib (50 mg) once daily for 4 weeks.5After a median follow-up of 25 months, the 18-month overall survival (OS) rate was 75% with nivolumab plus ipilimumab and 60% with sunitinib.

Median progression-free survival (PFS) was also significantly prolonged with ipilimumab plus nivolumab. The objective response rate (ORR) was significantly higher with the combination compared with sunitinib (42% vs 27%), with complete response (CR) rates of 9% and 1%, respectively. Grade 3/4 adverse events (AEs) occurred in 46% of patients treated with ipilimumab plus nivolumab and 63% of patients treated with sunitinib.5

“This trial showed an efficacy and OS benefit of nivolumab plus ipilimumab over sunitinib in the first-line treatment of intermediate- or poor-risk advanced clear cell RCC,” noted Robert J. Motzer, MD, kidney cancer section head of the Genitourinary Oncology Service and the Jack and Dorothy Byrne Chair in Clinical Oncology, at Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues in theNew England Journal of Medicine.6 Motzer will also be speaking today during the session, “First-Line Metastatic Renal Cell Carcinoma: What Is the Right Choice?”

Axitinib in combination with pembrolizumab (Keytruda) was approved by the FDA in April 2019 for the first-line treatment of patients with advanced RCC, a decision that was supported by data from the phase III KEYNOTE-426 trial.6,7In this trial, 861 patients with previously untreated advanced clear cell RCC were randomized to receive pembrolizumab (200 mg) once every 3 weeks plus axitinib (5 mg) twice daily or sunitinib (50 mg) once daily for the first 4 weeks of each 6-week cycle. At 12 months, the estimated percentage of patients remaining alive was significantly higher in the pembrolizumab/axitinib group compared with the sunitinib group (89.9% vs 78.3%;P<.0001). The median PFS (15.1 vs 11.1 months) and ORR (59.3% vs 35.7%) both increased in patients treated with pembrolizumab/axitinib compared with sunitinib.

Importantly, the benefit of the combination regimen was observed in patients with favorable-, intermediate-, and poor-risk disease, regardless of PD-L1 expression. Similar rates of grade ≥3 AEs were reported in both groups.

“TKIs and checkpoint blockers like avelumab [Bavencio] both may have potential immune-modulating functions that, when combined, may provide clinical benefit in patients with advanced RCC that exceeds the effects of the respective drugs alone, without compromising toxicity,” Motzer noted in a press release.

The combination of avelumab plus axitinib was also approved this year in May for the frontline treatment of patients with advanced RCC based on results from the phase III JAVELIN Renal 101 trial.8In this study, 886 patients with previously untreated advanced RCC were randomized to receive avelumab (10 mg/kg) every 2 weeks plus axitinib (5 mg) twice daily or sunitinib (50 mg) once daily for 4 weeks. Compared with patients treated with sunitinib, those treated with avelumab/axitinib had a greater median PFS overall (13.8 vs 8.4 months;P<.001) and among the 560 patients with PD-L1—positive tumors (13.8 months vs 7.2 months;P<.001). The ORR was significantly higher in patients with PD-L1—positive tumors treated with the combination compared with sunitinib (55.2% vs 25.5%). AEs were reported in most patients in both groups, with grade ≥3 AEs in 71.2% of patients treated with avelumab/axitinib and 71.5% treated with sunitinib.9

“JAVELIN Renal 101 is the first positive phase III study combining an immune checkpoint blocker with a TKI compared with TKI alone in the first-line treatment of advanced RCC,” Motzer noted in a press release. “The findings support the potential of avelumab plus axitinib as a new treatment approach for patients with advanced RCC. The combination benefit was shown in all subgroups of patients, by independent review as well as by investigators, and whether tumor cells stained positive for PD-L1 or not,” he explained.

When it comes to deciding which therapy to choose for individual patients, Cho explained that it depends on the urgency with which you need a response. “I think one of the shortcomings of immunotherapy is that the response kinetics are unpredictable, meaning we don’t know how quickly patients will respond,” he said. He also noted that for some patients, tumors may grow before any tumor growth inhibition effects are seen, which suggests that immunotherapy may not be the best choice for patients with a large tumor burden or quickly growing cancer or for those who are symptomatic.

Emerging Immunotherapy Regimens

“The way I choose between them is I make an assessment for how quickly I need that patient to respond,” Cho said. “If they need to respond quickly, I prefer to use a TKI-based regimen, which [includes] 1 of the 2 combinations of axitinib and either pembrolizumab or avelumab, mainly because I feel that the response with the TKI is just much more reliable in terms of onset of response.”There are other combinations of TKI and PD-1 agents under investigation, including cabozantinib with nivolumab, lenvatinib with pembrolizumab, and bevacizumab plus atezolizumab, which have already been studied. “They are similar to the existing combinations that are available, so it’s going to be a matter of physician preference as to which of those combinations you use,” explained Cho.

In addition to the many FDA-approved regimens for use in this patient population, emerging immunotherapy combinations have potential to contribute to future change in the treatment paradigm of RCC.

Results from a phase I/II trial designed to evaluate the safety and efficacy of pembrolizumab plus cabozantinib in 8 patients with metastatic RCC were reported at the 2019 Genitourinary Cancers Symposium. No dose-limiting toxicities were reported with grade 1/2 drug-related AEs that included fatigue, weight loss, anorexia, diarrhea, dysgeusia, and abnormal liver function tests. A single case of grade 3 reversible posterior leukoencephalopathy syndrome attributed to cabozantinib was reported. No patients receiving cabozantinib at 40 mg required dose reductions; 1 patient at 60 mg did. The clinical benefit rate was 87.5%, including 2 partial responses (PRs) and 5 patients with stable disease. No correlation was seen between response and PD-L1 status. Based on these encouraging preliminary efficacy results, the dose-expansion phase of the phase II trial is currently enrolling patients.10

Promising antitumor activity has also been reported with first-line, single-agent pembrolizumab in key patient subgroups with clear cell RCC in cohort A of KEYNOTE-427 and was reported at the 2018 American Society of Clinical Oncology Annual Meeting. In patients with International Metastatic Renal Cell Carcinoma Database Consortium favorable risk, the ORR was 32%.11

Cohort B of KEYNOTE-427, which was reported at this year’s Genitourinary Cancers Symposium, included 165 patients with non— clear cell RCC treated with pembrolizumab monotherapy. The ORR was 24.8%, consisting of 8 CRs and 33 PRs. Overall, 55.2% of patients experienced a reduction in tumor burden, including 4.2% who experienced 100% tumor burden reduction. The median PFS was 4.1 months, and the median OS was not reached. Overall, 64% of patients reported treatment-related AEs, including grade ≥3 colitis, hepatitis, fatigue, and type 1 diabetes.

Discontinuation due to treatment-related AEs was reported in 6% of patients. The safety profile was generally as expected, based on reports in other tumor types. These results support continued investigation of single-agent pembrolizumab in this patient population.12

Nivolumab and tivozanib, a vascular endothelial growth factor receptor TKI, was investigated in the phase II portion of a dose-escalation and -expansion trial involving 25 patients with metastatic RCC and was recently reported at the European Society for Medical Oncology 2019 Congress. Among these, 8 patients had favorable-risk disease, 19 had intermediate-risk disease, and 1 had poor-risk disease; clear cell histology was reported in 22 patients. For previously untreated patients, the median PFS was 18.5 months. The median was not reached in previously treated patients. The disease control rate was 96%, and the ORR was 56%, including 1 CR and 1 unconfirmed PR. The most frequently reported treatment-related grade 3/4 AE was hypertension (44%). According to the authors, this combination compares well with other combinations of TKIs and immunotherapy, warranting additional studies.13

Ilixadencel, an off-the-shelf cancer immune primer developed for the treatment of solid tumors, has also been investigated in combination with sunitinib in patients with newly diagnosed intermediate- and poor-risk metastatic RCC.14The agent is a cell-based product that consists of pro-inflammatory allogeneic dendritic cells that secrete high amounts of proinflammatory cytokines and chemokines when administered intratumorally.15

In an open-label, phase II study, 88 patients were treated with 2 intratumoral doses of ilixadencel before nephrectomy and subsequent treatment with sunitinib or sunitinib therapy alone post nephrectomy. Among 70 evaluable patients, complete tumor responses were observed in 11% who received ilixadencel compared with 4% who received sunitinib alone. The corresponding 18-month survival rates were similar in both groups (63% vs 66%).

Safety and tolerability were also similar in both groups, and they were consistent with previously reported safety data for ilixadencel.

“There’s another drug in assessment, NKTR-214, which is a pegylated version of interleukin [IL]-2, which is being studied in a phase III trial in combination with nivolumab [NCT03729245],” Cho said. “That is also a pure immunotherapy, unlike the TKI combinations, so that is something that has the chance of potentially shifting things if the efficacy data are promising.”

Future Considerations

When thinking about unanswered questions regarding the treatment of RCC, it is important to consider ways to improve the quality of response, which is measured in patients who are complete responders or in those who have durable CRs. “The biggest question is, can we cure more patients with kidney cancer and how do we do that,” explained Cho. “I think the novel immunotherapies are the only way to get there because we know from our past experience with high-dose IL-2 that we can actually cure patients with kidney cancer using immunotherapy.”

Another important concern is identifying therapies to use in the second line following the use of the most effective drugs in combination in the first line. “We are going to be seeing a lot of that with patients who get a combination of a TKI plus a PD-1 [inhibitor] in the frontline,” Cho said. “I think what happens in the second line is going to become a much more interesting situation.”

Overall, it is important to remember that RCC is curable, which should be the ultimate goal. “We shouldn’t be too consumed with increasing response rates and other metrics of response,” noted Cho. “I think we need to be focused on what is the most important thing, which is curing patients with kidney cancer.”


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