Revised Risk Categories in NCCN Guideline for Metastatic Renal-Cell Carcinoma Affects Preferred Front-Line Options

Wayne Kuznar

June 2019, Vol 10, No 3 - 2019 NCCN Conference


Orlando, FL—The updated guideline on the management of metastatic ­renal-cell carcinoma (RCC) from the National Comprehensive Cancer Network (NCCN), version 3.2019, underwent a major shift in its risk categories to define preferred and alternative first-line treatments.

The updated guideline was summarized by Eric Jonasch, MD, Professor, Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, at the NCCN 2019 Conference.

Based on findings from the CheckMate-214 clinical trial, “good” or low risk is now a category of its own instead of being combined with the intermediate-­risk category, according to Dr Jonasch. In CheckMate-214, outcomes in patients at low risk were better with upfront sunitinib (Sutent) treatment than with the immunotherapy combination of ipilimumab (Yervoy) and nivolumab (Opdivo). Intermediate and poor risk have now been combined into 1 risk category for the purpose of defining preferred first-line treatment options.

The list of preferred first-line therapies in the 2 risk categories may soon expand to include the combination of pembrolizumab (Keytruda) and axitinib (Inlyta), as well as the combination of avelumab (Bavencio) plus axitinib, based on the Javelin Renal 101 and KEYNOTE-­426 studies, said Dr Jonasch. Each of these combinations was superior to sunitinib in patients with advanced RCC, but these combinations are yet to be approved by the FDA for this indication. The expected approvals should make the updated guideline treatment algorithm “quite dynamic and quite interesting,” he said.

Upfront cytoreductive nephrectomy may still be appropriate in selected patients with advanced RCC. Dr Jonasch said that in an individual with excellent performance status, a low metastatic disease burden, and a readily resectable primary tumor, “it still makes sense and is practical to remove that primary tumor prior to initiating systemic therapy, but really for everyone else, I think it makes sense to initiate systemic therapy via immune-oncology therapy or tyrosine kinase inhibitor therapy” before nephrectomy.

He reviewed the 3 recent upfront systemic therapy clinical trials mentioned above that have prompted a change or will soon prompt changes in the NCCN’s treatment recommendations for metastatic RCC.

In CheckMate-214, more than 1000 patients with advanced or metastatic RCC and no previous therapy were randomized to the combination of nivolumab plus ipilimumab or to standard sunitinib therapy. In intermediate- and poor-risk patients, the objective response rate (ORR) and overall survival (OS) were significantly improved (P <.0001) in the nivolumab plus ipilimumab arm. The complete response rate of 16% with the immunotherapy combination in the intermediate- to poor-risk group with PD-L1 expression ≥1% “hasn’t been seen before in patients with metastatic RCC,” said Dr Jonasch.

In the favorable-risk patients in CheckMate-214, however, the confirmed ORR and progression-free survival (PFS) were significantly improved with sunitinib versus nivolumab/­ipilimumab. These results provided the impetus to change the risk categorization in the updated NCCN guideline and suggest “that there’s a different biology for these good-risk patients,” Dr Jonasch said.

JAVELIN Renal 101 randomized patients with advanced RCC to avelumab plus axitinib or to sunitinib as first-line treatment; the results showed that PFS favored avelumab plus axitinib over sunitinib in the PD-L1–positive patients (P <.0001) and in the overall study population (P = .0001). Unlike in CheckMate-214, subgroup analysis showed an advantage to avelumab plus axitinib in all risk categories. OS data are still immature.

In KEYNOTE-426, patients with advanced RCC assigned to the combination of pembrolizumab plus axitinib had significant improvements in OS and PFS compared with sunitinib. The benefit of the combination was observed regardless of PD-L1 status and was independent of risk category.

Cabozantinib (Cabometyx) was approved by the FDA in 2017 for the treatment of advanced RCC on the basis of the CABOSUN clinical trial, in which front-line cabozantinib improved PFS compared with sunitinib in patients with intermediate or poor risk, but without the high complete response rate that was observed with nivolumab plus ipilimumab.

The preferred agents in the second-­line setting in the NCCN guideline are nivolumab, cabozantinib, lenvatinib (Lenvima) plus everolimus (Afinitor), and axitinib when the first-line therapy was a vascular endothelial growth factor receptor inhibitor. If a previous immunotherapy agent was used, the recommended second-line option is enrollment in a clinical trial or other approved agents.

In the advanced non–clear-cell RCC setting, preferred strategies are enrollment in a clinical trial or sunitinib; other recommended regimens include cabozantinib and everolimus.

First-line pembrolizumab monotherapy may soon be an option for the treatment of non–clear-cell advanced RCC after an analysis of cohort B in the KEYNOTE-427 clinical trial, which demonstrated an ORR of 24.8%, said Dr Jonasch.