NCCN Guidelines for Advanced RCC Could See Changes as More Frontline Data Emerge


Under the 2019 update to the National Comprehensive Cancer Network guidelines, the recommendation on the management of advanced clear cell renal cell carcinoma has undergone a major shift in defining the risk category used to define preferred and alternative first-line treatments.

Eric Jonasch, MD

Eric Jonasch, MD

Under the 2019 update to the National Comprehensive Cancer Network (NCCN) guidelines, the recommendation on the management of advanced clear cell renal cell carcinoma (RCC) has undergone a major shift in defining the risk category used to define preferred and alternative first-line treatments.

Whereas the 2018 version of the guideline considered “good or intermediate risk” as a single category, with “poor risk” as a separate category for the purpose of designating preferred treatments, version 3.2019 now considers “good risk” as a risk category of its own, combining “intermediate risk and poor risk” into a category.1

The preferred frontline treatments in the NCCN guideline could see a change to include pembrolizumab (Keytruda) plus axitinib (Inlyta), as well as avelumab (Bavencio) plus axitinib, (Inlyta) in the coming months as the results of recently completed clinical trials are considered by the FDA and incorporated into the guideline, said Eric Jonasch, MD, in a presentation during the 2019 NCCN Annual Conference.

Until these combinations are approved, however, good-risk patients can be considered for sunitinib (Sutent) or pazopanib (Votrient), said Jonasch, professor in the Department of Genitourinary Oncology at The University of Texas MD Anderson Cancer Center.

The change in risk category comes following the findings from the CheckMate-214 study, in which outcomes in good-risk patients were better with sunitinib than with the combination of ipilimumab (Yervoy) and nivolumab (Opdivo).

“[CheckMate-214] necessitated a recalibration,” he said. “We have now a category shift where we look at ‘good’ versus ‘intermediate/poor’ in the frontline setting. The other thing is that we have a number of potential approvals over the next 6 months … making this algorithm quite dynamic and quite interesting.”

Moreover, for patients with good-risk features, active surveillance before systemic therapy is an option, based on a small prospective study in which patients with favorable-risk disease had a median surveillance time of 22.2 months compared with 8.4 months in those with unfavorable-risk features (P= .0056).2

Upfront cytoreductive nephrectomy may be appropriate in patients with good performance status, a readily resectable primary tumor, and minimal metastatic burden, but not in unselected patients, said Jonasch.

The results of 3 pivotal studies assessing immunotherapy combinations or immunotherapy in combination with a TKI have been released over the past 12 months, and could influence guidelines in the near future.

CheckMate-214 enrolled 1096 patients with advanced or metastatic RCC with no prior therapy who were randomized to the combination of nivolumab and ipilimumab or standard sunitinib.3The 3 primary endpoints were overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) in intermediate- and poor-risk patients, of which ORR (P<.0001) and OS (P<.0001) were significantly improved in the nivolumab/ipilimumab arm. OS was superior with the combination regardless of PD-L1 expression status.

The median OS in intermediate- and poor-risk patients in the nivolumab/ipilimumab arm was not yet reached (95% CI, 28.2 months—not estimable) versus 26.0 months for sunitinib recipients. The 16% complete response (CR) rate with nivolumab plus ipilimumab in the intermediate-/poor-risk group with PD-L1 expression &ge;1% has not yet been observed in patients with metastatic RCC, said Jonasch.

Favorable-risk patients enrolled on the CheckMate-214 trial, however, had a significantly higher confirmed ORR with sunitinib versus nivolumab/ipilimumab (P= .0002) and a significantly longer PFS (P<.0001). These results were the driving force behind changing the risk categorization in the most recent NCCN guideline and suggest &ldquo;that there is a different biology for these good-risk patients,&rdquo; he said.

Regarding safety, 60% of patients who were randomized to nivolumab/ipilimumab in CheckMate-214 required systemic corticosteroids to manage an adverse event, Jonasch noted.

Another pivotal phase III clinical trial was JAVELIN Renal 101, which randomized 886 patients with advanced RCC to avelumab plus axitinib/sunitinib as first-line treatment.4The co-primary endpoints were PFS and OS in PD-L1—positive patients, who constituted 63% of the study population. Results, which were presented at the 2018 ESMO Congress, showed that PFS favored avelumab/axitinib over sunitinib both in the PD-L1&ndash;positive patients (P<.0001) and in the overall study population (P= .0001). Unlike in CheckMate-214, a subgroup analysis showed an advantage to avelumab plus axitinib in all risk categories. OS data were immature at the time of presentation.

Third, the KEYNOTE-426 trial compared pembrolizumab plus axitinib versus sunitinib as first-line therapy in 861 patients with advanced RCC.5Patients assigned to the combination therapy had significant improvements in OS (P<.0001) and PFS (P= .0001), which were the co-primary endpoints. The benefit of the combination was observed regardless of PD-L1 status and independent of risk category.

Additionally, the multikinase inhibitor cabozantinib (Cabometyx) was superior to sunitinib with PFS in intermediate-/poor-risk patients in the CABOSUN study in patients with RCC, but without the CR rates observed with nivolumab/ipilimumab.6

Multiple agents have demonstrated an OS advantage in the second-line setting. How the performance of new frontline combinations will define sequencing of therapies is not yet clear, said Jonasch. Second-line setting regimens include nivolumab, cabozantinib, and the combination of lenvatinib (Lenvima) and everolimus (Afinitor). The selection of second-line therapy will depend on patient disease status, comorbidities, and prior lines of treatment, he said.

In the advanced non-clear cell RCC setting, preferred strategies are enrollment into a clinical trial or sunitinib; other recommended regimens include cabozantinib and everolimus. According to the guideline, the combination of bevacizumab (Avastin) plus everolimus is useful for selected patients with advanced papillary RCC, including those with mutated genes in hereditary leiomyomatosis (HLRCC). &ldquo;I&rsquo;ve tried this in a number of patients and have gotten dramatic responses with that combination in theHLRCC-mutated group of patients,&rdquo; he said.

First-line pembrolizumab monotherapy may become an option in non-clear cell advanced RCC on the basis of an analysis of cohort B from KEYNOTE 427, which showed an ORR of 24.8%.7Durable responses were observed in all histologic subgroups.


  1. Jonasch E. NCCN guidelines update: Management of metastatic kidney cancer. Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.
  2. Rini B, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.Lancet Oncol. 2016;17(9):1317-1324. doi: 10.1016/S1470-2045(16)30196-6.
  3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Eng J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
  4. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Eng J Med.2019;380(12):1103-1115. doi: doi: 10.1056/NEJMoa1816047.
  5. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Eng J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.
  6. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.
  7. McDermott DF, Lee J-L, Ziobro M, et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): results from KEYNOTE-427 cohort B.J Clin Oncol. 2019;37 (suppl; abstr 546).
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