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Advanced Renal-Cell Carcinoma: Potential First-Line Treatment

Renal clear cell carcinoma.

A phase 3 clinical trial has found that in previously untreated patients with advanced renal-cell carcinoma (RCC), avelumab plus axitinib improves progression-free survival and objective response compared with sunitinib.

Sunitinib is an antiangiogenic drug, meaning that it prevents tumors from growing their own blood vessels. It is considered standard of care as a first-line therapy for patients with advanced RCC. However, many patients either have inherent resistance to antiangiogenic drugs or else continue to progress while on treatment.

Avelumab is an anti–programmed death ligand 1 (anti–PD-L1) antibody, which is a type of immune checkpoint inhibitor. Previously, anti–PD-L1 therapies have demonstrated acceptable safety and lasting antitumor activity as first- and second-line treatments for multiple tumor types, including advanced RCC.

Axitinib is a VEGF receptor inhibitor. This class of drugs enhances immune cells' ability to infiltrate tumors and reduces cancer-related immunosuppressive effects. Axitinib also has antiangiogenic activity.

The researchers hypothesized that combining an immune checkpoint inhibitor (such as avelumab) with a VEGF-targeted antiangiogenic therapy (such as axitinib) could provide enhanced tumor-fighting power as a result of the two drug classes' complementary mechanisms of action. Preliminary data from a single-group, nonrandomized phase 1b trial enrolling 55 patients with advanced RCC showed the promise of the avelumab/axitinib combination. The current trial showed its effectiveness in a much larger group.

"This [combination] is certainly better than sunitinib—hopefully this will lead to Food and Drug Administration approval soon," commented Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and co-corresponding author of the study, which was published in The New England Journal of Medicine. "Interestingly, the analysis showed that all subgroups—good, intermediate, and poor-risk patient[s]—benefited from the combination treatment."

For the study (the JAVELIN Renal 101 trial, NCT02684006), 886 patients with previously untreated advanced RCC were randomly assigned in a 1:1 ratio to receive either avelumab 10 mg per kg of body weight intravenously every 2 weeks plus axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for 4 weeks of a 6-week cycle.

The study's two independent primary end points were progression-free survival and overall survival in the subset of 560 patients (63.2% of the study population) with PD-L1–positive tumors. Progression-free survival in the overall population was a key secondary end point. Other study end points included objective response and safety in the overall population.

For the patients with PD-L1–positive tumors, avelumab/axitinib produced a median progression-free survival of 13.8 months, compared with 7.2 months for sunitinib. Avelumab/axitinib also demonstrated a higher objective response rate (55.2% vs 25.5% for sunitinib) with fewer deaths: at a median follow-up for overall survival of 11.6 months, 37 patients had died in the avelumab/axitinib group, compared with 44 patients who had died in the sunitinib group at a median follow-up of 10.7 months.

In the overall study population, avelumab/axitinib also increased median progression-free survival compared with sunitinib (13.8 vs 8.4 months) and objective response rate (51.4% vs 25.7%).

The two treatments demonstrated similar safety profiles, with adverse events occurring during treatment in 99.5% of patients in the avelumab/axitinib arm compared with 99.3% of patients in the sunitinib arm. Grade 3 or higher adverse events occurred in 71.2% of patients receiving avelumab/axitinib and in 71.5% of patients receiving sunitinib.

Dr. Choueiri emphasized the importance of avelumab/axitinib as a potential treatment for advanced RCC: "This is an important option. What we're doing in advanced kidney cancers is pushing the envelope. These treatments may not be curative, but patients are living longer, and the disease is becoming more chronic."

For More Information

Motzer RJ, Penkov K, Haanen J, et al (2019). Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. [Epub ahead of print] DOI:10.1056/NEJMoa1816047

Image credit: KGH

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