SAN FRANCISCO—New findings presented at the 2019 Genitourinary Cancers Symposium add to a growing body of data that could lead to a new standard of care for the first-line treatment of metastatic renal cell carcinoma (mRCC).

These data, from the KEYNOTE-426 phase 3 trial and the JAVELIN Renal 101 trial, support the use of an immunotherapy-based combination regimen rather than monotherapy with a tyrosine kinase inhibitor (TKI) such as sunitinib for previously untreated advanced kidney cancer.

“We’re heading towards a time very quickly when every new metastatic kidney cancer patient is going to get an immunotherapy-based combination regimen,” Brian I. Rini, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, in Cleveland, told Renal & Urology News.

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Dr Rini was an investigator with the KEYNOTE-426 trial, the findings of which, he said, “are top line phase 3 results showing the best overall survival that’s ever been shown in a phase 3 [trial] in kidney cancer.”

If pembrolizumab and axitinib receive FDA approval as first-line therapy for advanced kidney cancer, he said, the combination will be a new standard of care.

In the KEYNOTE-426 trial, treatment with a dual regimen of pembrolizumab, an immunotherapeutic agent that inhibits programmed death-ligand 1 (PD-L1), and axitinib, a TKI, was associated with significantly longer overall and progression-free survival (PFS) compared with sunitinib in untreated locally advanced or metastatic renal cell carcinoma (RCC).

The JAVELIN trial, which is ongoing, demonstrated that combined treatment with avelumab, also a PD-LI inhibitor, and axitinib was associated with superior PFS compared with sunitinib in patients with advanced RCC.


The KEYNOTE-426 trial included 861 patients randomly assigned to receive either pembrolizumab plus axitinib (432 patients) or sunitinib (429 patients). After a median follow-up of 12.8-months, 59% of patients in the combined treatment arm remained on treatment compared with 43.1% of the sunitinib arm, Thomas Powles, MD, PhD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London, London, UK, reported at the conference. The 12-month survival rate was 89.9% in the pembrolizumab-axitinib arm compared with 78.3% in the sunitinib-treated patients. Median PFS was 15.1 months in the combined therapy arm compared with 11.1 months among sunitinib-treated patients. Recipients of the combined therapy had a significant 47% decreased risk of death and 31% decreased risk of disease progression compared with the sunitinib arm. The ORR was significantly higher in the pembrolizumab-axitinib group than the sunitinib group (59.3% vs 35.7%).

All of the subgroups examined, including all IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) risk and PD-Ll expression subgroups, benefited from the dual regimen, Dr Powles said.

Treatment-related adverse events (AEs) were grade 3–5 in 62.9% of patients in the pembrolizumab-axitinib group and 58.1% in the sunitinib arm. These events led to discontinuation of treatment with both pembrolizumab and axitinib in the combined treatment group (8.2% of patients), but no patient in the sunitinib arm discontinued treatment due to treatment-related AEs, according to investigators.

JAVELIN Renal 101

The JAVELIN trial previously had demonstrated longer PFS (median 13.8 vs 8.4 months) and objective response rate (ORR, 51% vs 26%) with avelumab plus axitinib compared with sunitinib. Of 886 patients randomized, 560 (63%) had PD-L1-positive tumors. At data cut-off in June 2018, the median followup time was 12 months for the combination therapy arm and 11.5 months for the sunitinib arm. The findings presented at the 2019 symposium are from a subgroup analysis of patients with previously untreated advanced RCC.

Co-lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School in Boston, and colleagues compared the effects of the treatment approach according to Memorial Sloan Kettering Cancer Center (MSKCC) and IMDC risk groups (favorable-, intermediate-,and poor-risk).

Among patients with MSKCC favorable-risk disease, the median PFS, in months, was not estimable (NE) and the ORR was 66% in the avelumab-axitinib group, whereas the median PFS and ORR were 16.7 months and 38%, respectively in the sunitinib arm.

For patients with MSKCC intermediate-risk disease, the median PFS was 13.3 months and the ORR was 50% in the combination arm compared with 7.9 months and 24% in the sunitinib-treated patients. In the MSKCC poor-risk patients, the median PFS and ORR were 5.6 months and 31% for those treated with the dual regimen and 2.8 months and 9%, respectively. The findings for the IMDC risk groups were similar.

Treatment effect by PD-L1 status

For patients with PD-L1-positive tumors, the median PFS and ORR were 13.8 months and 55%, respectively, in the avelumab-axitinib group, compared with 7.2 months and 26% in the sunitinib arm. Among patients PD-L1-negative tumors, the median PFS and ORR were 16.1 months and 47%, respectively, for recipients of the combination therapy, compared with 11.1 months and 28% for the sunitinib group.

“These results do support avelumab plus axitinib as a new first-line-standard of care for patients with advanced RCC,” Dr Choueiri told symposium attendees.


Powles T, Rini BI, Plimack ER, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. Data presented at the 2019 Genitourinary Cancers Symposium held in San Francisco February 14-16. Abstract 543.

Choueiri TK, Motzer RJ, Campbell MT, et al. Subgroup analysis from JAVELIN Renal 101: Outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Data presented at the 2019 Genitourinary Cancers Symposium held in San Francisco February 14-16. Abstract 544

Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. DOI: 10.1056/NEJMoa1816047.