Immunotherapy Plus Targeted Therapy, a New Strategy for Advanced RCC

For years, the standard of care for previously untreated patients with advanced renal cell carcinoma (RCC) was single-agent treatment with a vascular endothelial growth factor recepto(VEGFR)-targeting tyrosine kinase inhibitors (TKIs), most commonly sunitinib. However, in the past year, combination immunotherapy with the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab showed improved survival compared to sunitinib for newly diagnosed patients with intermediate- or poor-risk RCC and became standard option for these patients. Recently, much investigation in RCC has focused on the potential of combining immune checkpoint inhibitor immunotherapy with VEGFR TKIs. In phase I trials, combination of either the PD-1 inhibitor pembrolizumab or the PD-L1 inhibitor avelumab with axitinib were tolerable and yielded high and durable responses in the frontline management of advanced RCC. These combinations were further evaluated in phase III trials.

In the open-label phase III KEYNOTE-426 trial (N = 861), the combination of the pembrolizumab and the VEGFR TKI axitinib was compared to single-agent sunitinib in previously untreated patients with advanced RCC. The combination of pembrolizumab and axitinib was associated with significant improvements in both overall survival (OS) and progression-free survival (PFS), compared to sunitinib. The 12-month rate of OS was 89.9% in patients receiving pembrolizumab plus axitinib, compared to 78.3% in patients receiving sunitinib, corresponding to a 47% reduction in the risk of death (HR 0.53, P<.0001). The median PFS in the two treatment groups was 15.1 months and 11.1 months, respectively (HR 0.69, P<.001). Pembrolizumab plus axitinib resulted in an increase in the objective response rate (ORR) compared to sunitinib (59.3% vs 35.7%; P<.001). The benefit of pembrolizumab plus axitinib over sunitinib was consistent, regardless of patient risk group or PD-L1 status.

The combination of pembrolizumab and axitinib was associated with a manageable adverse event (AE) profile. Grade 3 or higher AEs occurred in 75.8% of patients receiving pembrolizumab plus axitinib and 70.6% of patients receiving sunitinib. The most common AEs in both treatment arms were diarrhea and hypertension. Deaths due to AEs occurred in 11 patients receiving pembrolizumab plus axitinib and 15 patients receiving sunitinib.

Another phase III trial, JAVELIN Renal 101 (N = 886) compared avelumab plus axitinib to sunitinib and was published simultaneously with KEYNOTE-426. In this trial, the combination of avelumab and axitinib resulted in a significant improvement in median PFS over single-agent sunitinib in both PD-L1-positive patients (13.8 months vs 7.2 months; HR 0.61, P<.001) and the overall trial population (13.8 months vs 8.4 months; HR 0.69, P<.001), with a manageable safety profile. OS data from this trial are not yet mature. The ORR doubled with combination treatment in both PD-L1-positive patients (55.2% vs 25.5%) and in the overall population (51.4% vs 25.7%).

In the editorial accompanying these two studies, Bernard Escudier, MD (Gustave Roussy, Villejuif, France), highlighted that, including the phase III study of nivolumab plus ipilimumab, there are now three phase III trials showing the superiority of immunotherapy-based combinations over single-agent sunitinib in newly diagnosed RCC, and that all combinations will likely be considered the standard of care in this population. Dr Escudier discussed the differences between the three trials, including the higher percentage of favorable-risk patients in the KEYNOTE-426 trial, and commented that longer follow-up and thorough subgroup analyses may be helpful to determine the best combination. Selection of treatment in this setting will likely depend on a combination of factors, including survival benefit, patient risk status, potential predictive biomarkers, and physician and patient preference.

N Engl J Med. 2019 Feb 16. [Epub ahead of print.]

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