1. Fuerst, Mark L.

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SAN FRANCISCO-A combination of pembrolizumab plus axitinib is set to become the standard of care for metastatic renal cell carcinoma.

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First-line therapy with a combination of the PD-1 targeted immunotherapy pembrolizumab and VEGF-targeted tyrosine kinase inhibitor axitinib extended both overall survival and progression-free survival (PFS) for patients with clear-cell metastatic renal cell carcinoma when compared with sunitinib, the current standard of care.


"These results are exciting. By adding pembrolizumab to a VEGF-targeted therapy, we are seeing powerful anti-cancer responses, including improved survival-and importantly, the results are seen across broad subgroups of patients," said co-lead study author Thomas Powles, MD, Professor of Urology Oncology at Barts Cancer Institute in London. "These data suggest that pembrolizumab plus axitinib should be a new standard therapy for first-line treatment of patients with metastatic renal cell carcinoma."


Powles presented the findings from this international study at the 2019 Genitourinary Cancers Symposium (Abstract 543).


Research Findings

Pembrolizumab is an immune checkpoint inhibitor that blocks the PD-1 protein on the surface of immune cells, which allows the immune system to then recognize and attack tumor cells. Axitinib and sunitinib are antiangiogenic agents that can block the growth of blood vessels to the tumor, therefore limiting its growth.


"Antiangiogenic therapy such as axitinib facilitates immune T-cell infiltration. When given by themselves, pembrolizumab and axitinib have shown efficacy in treating patients with metastatic renal cell carcinoma who have received no other therapy," explained Powles at a presscast before the meeting.


A phase 1b study showed that pembrolizumab and axitinib given together showed manageable safety and a high response rate (73%) in this disease. According to Powles, the phase Ib study results indicated that axitinib was easier to combine with pembrolizumab than some other antiangiogenic drugs in the same class as sunitinib. Following these positive results, investigators proceeded directly to a phase III trial.


In the phase III KEYNOTE-426 clinical trial, 861 patients, median age 62 years, with untreated clear-cell metastatic renal cell carcinoma were randomly assigned to oral sunitinib once daily or to combination therapy, with pembrolizumab given intravenously every 3 weeks along with oral axitinib twice daily. Treatment continued until the disease progressed, patients developed high toxicity, or they dropped out of the study. They received 200 mg pembrolizumab intravenously every 3 weeks up to 35 cycles plus axitinib 5 mg orally twice daily, or to sunitinib 50 mg orally once daily for the first 4 weeks of each 6-week cycle.


At a median follow-up of 12.8 months, patients who received the combination therapy had a 47 percent reduction in the risk of death as compared with sunitinib. The 12-month overall survival rate was 89.9 percent in the combination group versus 78.3 percent in the sunitinib group. These benefits were seen irrespective of risk group or PD-L1 status, Powles noted.


The combination reduced the risk of PFS events by a relative 31 percent, with patients living a median of 15.1 months without disease progression with pembrolizumab plus axitinib versus 11.1 months with sunitinib. Similarly, the overall response rate was higher with the combination (59.3%) than with sunitinib (35.7%). Also, the duration of response was longer in patients treated with combination therapy (median not yet reached) than with sunitinib (15.2 months). Some 59 percent of patients continue to be treated with the combination versus 43.1 percent with sunitinib.


Powles noted the 11.1 months PFS "is quite long for a control arm, so there's nothing from these data to suggest that sunitinib underperformed in this trial."


Pembrolizumab plus axitinib had a manageable safety profile, he said. Serious treatment-related side effects were seen in 62.9 percent of patient taking pembrolizumab plus axitinib as compared to 58.1 percent who were taking sunitinib. These side effects led to discontinuation of all treatment in 8.2 percent of the combination group versus 10.1 percent of the sunitinib group.


Study Commentary

"We have a number of unanswered questions at this point, particularly the absence of biomarkers to predict response. PD-L1 levels, which have been markers for immunotherapy success in other cancers, remain unproven in renal cancer. It is possible that by combining pembrolizumab with axitinib, the predictive value of PD-L1 is being masked," stated Powles. "Overall, we have not previously seen a renal cancer study which has improved response, PFS, and overall survival. This is therefore a major step forward in renal cancer."


ASCO expert and presscast moderator Robert Dreicer, MD, MS, Deputy Director and Associate Director of Clinical Research at the University of Virginia Cancer Center and Professor of Medicine and Urology at the University of Virginia, Charlottesville, commented: "This is a very significant trial, and it's going to impact on patient management going forward as it works through the regulatory process. Metastatic kidney cancer has very low survival rates and there have been few significant advances in treating this advanced form of the disease. These findings may help provide an important new option for patients."


Mark L. Fuerst is a contributing writer.