A landslide trial for patients with metastatic RCC

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Fern Anari, MD

Alexander Kutikov, MD

Dr. Anari is a hematology/oncology fellow, and Dr. Kutikov is chief of urology and urologic oncology and professor of surgical oncology, Fox Chase Cancer Center, Philadelphia.

Nearly 15 years have passed since the seismic shift to anti-VEGF therapy from first-generation immunotherapy agents in patients with metastatic renal cell carcinoma (mRCC). With the advent of modern immunotherapy, tectonic plates of mRCC therapy continue to shift.

Indeed, several recent studies have sent significant tremors through the mRCC space. These studies compared combinations of therapies such as dual immunotherapy (PD-1/PD-L1 inhibitor + CTLA-4 inhibitor) and checkpoint inhibitor + VEGF-targeted tyrosine kinase inhibitor (TKI), to sunitinib monotherapy as first-line treatment.

The first interim analysis of the KEYNOTE-426 study was recently presented. This study compared efficacy of pembrolizumab (Keytruda), a PD-1 inhibitor, plus axitinib (Inlyta), an anti-VEGF TKI, against sunitinib (Sutent) monotherapy as front-line treatment for mRCC. The study met its two primary endpoints of improved overall survival (OS) and progression-free survival (PFS). Impressively, combination therapy reduced the risk of death by 47% (HR: 0.53; p<.0001) and risk for progression versus sunitinib by 31% (HR: 0.69; p=.0001).

The benefit from combination therapy was observed in all subgroups tested, including (International Metastatic RCC Database Consortium) IMDC risk and PD-L1 expression subgroups. One of the study’s strengths is its diverse patient population in terms of IMDC risk and PD-L1 expression. In addition, approximately 60% of patients in each arm had a PD-L1 combined positive score ≥1.

Related: Pembro plus axitinib is new standard in advanced RCC

While the study data point to a new standard of care for advanced RCC, many questions remain. It is still unclear which treatment is best for intermediate- and poor-risk patients due to very promising results from the CheckMate 214 trial. This trial evaluated nivolumab (Opdivo [PD-1 inhibitor]) plus ipilimumab (Yervoy [CTLA-4 inhibitor]) versus sunitinib and showed an OS benefit with dual immunotherapy in patients with previously untreated intermediate- and poor-risk advanced RCC.

In patients with intermediate- or poor-risk disease, shared decision-making between the provider and patient is essential to determine if dual immunotherapy or checkpoint inhibitor plus anti-VEGF TKI is the best treatment option. Overall response rate (ORR) was higher with pembrolizumab + axitinib compared with nivolumab + ipilimumab (59.3% vs. 42%). Another consideration when choosing between treatments is the complete response (CR) rate, which was higher in CheckMate 214 versus KEYNOTE-426 (9% vs 5.8%, respectively).

Overall, KEYNOTE-426 marks an exciting breakthrough in the management of advanced and metastatic RCC. Indeed, the study’s aftershocks are sure to be felt in the mRCC space for years.