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First-Line Combinations Show Promise in the Treatment of Advanced Renal-Cell Carcinoma

TOP - January 2021 Vol 14, No 1

The treatment of renal-cell carcinoma (RCC) continues to evolve with the development of more effective front-line regimens. During the virtual 2020 International Kidney Cancer Symposium, experts discussed the expanding role of several of these therapies, including tyrosine kinase inhibitors (TKIs) and immunotherapies, which are being evaluated in various combinations to improve outcomes for patients with advanced and high-risk disease.

Treatment with a combination of the CTLA-4 inhibitor ipilimumab (Yervoy) plus the PD-1 inhibitor nivolumab (Opdivo) led to a 56.7% response rate in a high-risk subgroup of patients with sarcomatoid RCC, with 18.3% of patients achieving a complete response. The median overall survival (OS) rate in patients in this subgroup who were treated with ipilimumab plus nivolumab was 31.2 months. In patients with primary RCC with synchronous metastases—another high-risk group—the median OS was 26 months in those who received this combination therapy.

“PD-1 inhibition is now considered the backbone of future combinations in RCC, and that is a position well-earned with all of the frontline studies to date,” said Ulka Vaishampayan, MD, FAB, Director, Phase I Program, Rogel Cancer Center, the University of Michigan, Ann Arbor.

Promising Drug Combinations

NKTR-214 is an investigational CD122-biased agonist designed to stimulate T-cell production. The CD122 bias eliminates overactivation of the interleukin (IL)-2 pathway, which can result in serious safety issues, specifically capillary release syndrome, Dr Vaishampayan said. NKTR-214 is currently being studied in combination with nivolumab in a phase 3 clinical trial of treatment-naive patients with advanced RCC.

ALKS 4230 is a novel engineered cytokine that selectively binds the intermediate-affinity IL-2α receptor expressed on CD8+ T-cells and natural killer cells, thereby mitigating the side effects of IL-2 therapy. ALKS 4230 has been shown to induce durable and deep responses in patients with melanoma who were previously treated with immunotherapies and in heavily pretreated patients with ovarian cancer. A subcutaneous formulation of ALKS 4230 in combination with pembrolizumab is being considered for evaluation in clinical trials in patients with RCC.

Also under active investigation are macrophage immune checkpoint inhibitors in combination with PD-1 inhibitors, bispecific antibodies with targets such as cytotoxic T-lymphocyte–associated protein 4 and PD-1, and antibody-armed activated T-cells.

“For the first time, there is a comprehensive database for checkpoint targets and modulators [Checkpoint Therapeutic Target Database] in cancer immunotherapy with an efficacy score that helps you determine where things are in development,” said Dr Vaishampayan.

Improved OS and PFS

Results from recent trials have shown significantly improved OS and progression-free survival (PFS) with the use of immune checkpoint inhibitor plus TKI regimens compared with TKI monotherapy as first-line treatment in patients with advanced RCC. These drug combinations include pembrolizumab (Keytruda) plus axitinib (Inlyta), avelumab (Bavencio) plus axitinib, and most recently, nivolumab plus cabozantinib (Cabometyx).

With the combination of nivolumab and cabozantinib, which is still awaiting approval by the FDA, “at the 18-month mark, we are seeing a 40% risk reduction in death compared with sunitinib alone, and so this has received a priority review by the FDA, and we’re hoping that this will receive approval within the next year,” said Suzanne Cole, MD, FACP, Medical Director, University Hospital Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Richardson/Plano.

The 12-month OS rates seen with TKI plus immune checkpoint inhibitor combinations as first-line therapy in patients with advanced RCC are 6% to 10% higher than those reported in patients receiving the ipilimumab plus nivolumab combination, Dr Cole noted. Higher rates of response and median PFS have also been achieved with TKI plus immune checkpoint inhibitor combinations, although direct comparisons are lacking. Responses appear to be long-lasting with the combination of ipilimumab and nivolumab, “and it’s not clear in the immune-oncology [and] TKI fraction whether that’s happening,” said Dr Cole. In addition, the added toxicity that occurs with the TKI “is not trivial,” she noted.

Financial Toxicity Remains an Issue

Dr Cole addressed concerns associated with the financial toxicity of these newer regimens. Cost estimates for 1 year of treatment with an immunotherapy/TKI regimen range between $300,000 and $500,000, depending on the treatment. Although some health insurances may cover these costs, she noted that high copays and deductibles frequently put the financial burden on patients who may not be able to work because of their disease. Even with health insurance, out-of-pocket costs for these drugs can be as high as $25,000 per year, she said.

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