NCCN Guidelines Updates: Management of Metastatic Kidney Cancer

The NCCN Guidelines for Kidney Cancer have undergone a major shift in the risk categorization used for designating “preferred” and “other recommended” or “useful under certain circumstances” first-line treatments. In the most recent version of the guidelines, “favorable risk” is now its own risk category and “intermediate risk” and “poor risk” are combined into one category. The treatment recommendations for clear cell renal cell carcinoma are continually revised and more new options are anticipated based on encouraging results from pivotal trials. In his presentation at the NCCN 2019 Annual Conference, Dr. Jonasch described these promising findings.

Abstract

The NCCN Guidelines for Kidney Cancer have undergone a major shift in the risk categorization used for designating “preferred” and “other recommended” or “useful under certain circumstances” first-line treatments. In the most recent version of the guidelines, “favorable risk” is now its own risk category and “intermediate risk” and “poor risk” are combined into one category. The treatment recommendations for clear cell renal cell carcinoma are continually revised and more new options are anticipated based on encouraging results from pivotal trials. In his presentation at the NCCN 2019 Annual Conference, Dr. Jonasch described these promising findings.

Panel Revises Risk Categories, Anticipates New Drug Approvals

An important update to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer was the revision of risk classifications, a result of some clinical trials demonstrating that outcomes with new regimens can differ according to patient risk. These revisions position patients to take advantage of treatments optimal to their specific disease. New treatment regimens are also poised to be used in combination with or to replace current options in the upfront metastatic setting for clear cell renal cell carcinoma (ccRCC), based on recently reported pivotal trials. Some of these new regimens are not yet incorporated into the NCCN Guidelines, but are expected to be soon, according to Eric Jonasch, MD, Professor, Department of Genitourinary Oncology, The University of Texas MD Anderson Cancer Center, and Vice Chair of the NCCN Kidney Cancer Panel.

Major Shift in Risk Categorization

The updated NCCN Guidelines for the management of advanced ccRCC reflect a major shift in the risk categorization used for designating “preferred” and “alternative” first-line treatments. “Classification of RCC is becoming increasingly important; it is no longer just an academic curiosity,” Dr. Jonasch commented.

Previous versions of the guidelines grouped “good” and “intermediate” risk into a single category, with “poor risk” as a separate category. In the 2019 versions of the guidelines, favorable risk is its own risk category, and intermediate and poor risk are combined into one category. This change was a result of findings from the CheckMate 214 study, in which outcomes of patients with favorable-risk disease were better in those treated with sunitinib compared with combination nivolumab/ipilimumab.1

“CheckMate 214 necessitated a recalibration. We now have a category shift where we look at ‘good’ versus ‘intermediate/poor’ in the frontline setting,” Dr. Jonasch said. “Additionally, we have many potential approvals coming in the next 6 months, which makes this algorithm dynamic and interesting.”

Early-Stage Disease

Dr. Jonasch briefly discussed management of early-stage disease, although no major changes were made to the guidelines in the 2019 versions. For stage I–III RCC, primary treatment is partial or radical nephrectomy or, in select patients, active surveillance. Further treatment is typically not recommended.

“Following nephrectomy, adjuvant therapy for RCC has been an exercise in frustration,” he pointed out. Recent studies, mostly using antiangiogenic therapies or everolimus, have been negative with the exception of the S-TRAC trial, which randomized patients with high-risk RCC to 1 year of sunitinib or placebo.2 Sunitinib was associated with an improved relapse-free survival, but was also associated with significant toxicity.

Nephrectomy, Active Surveillance

In metastatic RCC, the selection of upfront cytoreductive nephrectomy versus upfront systemic therapy depends on several factors. Dr. Jonasch recommended upfront nephrectomy for patients with good performance status, a readily resectable primary tumor, and minimal metastatic burden. Alternately, he believes that upfront systemic therapy is appropriate for patients with an unresectable primary tumor, significant metastatic burden, and lower performance status. These recommendations are based on results of a 2018 study of 450 patients randomized to cytoreductive surgery plus sunitinib or sunitinib alone.3 Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic RCC classified as having intermediate- or poor-risk disease.

A period of active surveillance before initiating systemic therapy may also be “a reasonable strategy” for patients with favorable-risk disease, he added.

Emerging Treatments in the Upfront Metastatic Setting

[Editor's note: This section references the NCCN Guidelines for Kidney Cancer, version 3.2019 presented at the NCCN 2019 Annual Conference. For the most recent version, visit NCCN.org.] For advanced/metastatic RCC, nivolumab/ipilimumab was the first immunotherapy combination recommended as a frontline treatment option, which was based on CheckMate 2141; this regimen is FDA-approved. However, in future updates to the guidelines, Dr. Jonasch anticipates that recommended frontline treatments will include pembrolizumab/axitinib, based on KEYNOTE-4264 [Editor's note: This regimen was added to version 4.2019 of the NCCN Guidelines for Kidney Cancer and was FDA-approved on April 19, 2019] and avelumab/axitinib, based on JAVELIN Renal 101,5 currently under consideration by the FDA. “These 3 trials are changing the game to a substantial degree,” he said, “with some tantalizing complete response rates” (Figure 1).

Figure 1.
Figure 1.

Lines of treatment in advanced renal cell carcinoma, 2019.

Abbreviations: HD, high dose; IO, immuno-oncology; VEGFR, vascular endothelial growth factor receptor.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 5.5; 10.6004/jnccn.2019.5008

CheckMate 214 randomized 1,096 previously untreated patients with metastatic RCC to sunitinib or combination nivolumab/ipilimumab. In patients with intermediate- or poor-risk disease, overall survival (OS) and response rates were significantly better with the combination, regardless of PD-L1 expression. Median OS was not reached with combination nivolumab/ipilimumab, but was 26 months with sunitinib. The complete response rate of 16% with nivolumab/ipilimumab in patients with PD-L1–positive tumors and intermediate or poor risk features had not been previously observed in metastatic RCC, Dr. Jonasch noted.

A similar benefit for immunotherapy was not seen in patients with favorable-risk disease in CheckMate 214. Results of this study were the impetus for changing the risk categorization in the most recent NCCN Guidelines, and suggest “that there is a different biology for these good-risk patients,” according to Dr. Jonasch. He added that 60% of patients treated with nivolumab/ipilimumab required corticosteroids for the management of adverse events, with 35% requiring the equivalent of ≥40 mg of prednisone.

KEYNOTE-426 compared pembrolizumab/axitinib versus sunitinib as first-line therapy in 861 patients with advanced RCC. Patients assigned to the combination arm demonstrated significant improvements in OS (P<.0001) and progression-free survival (PFS; P=.0001), which were co-primary end points. The benefit of the combination was observed regardless of PD-L1 status and was independent of risk category.

The JAVELIN Renal 101 study randomized 886 patients with advanced RCC to avelumab plus axitinib or sunitinib as first-line treatment. Results, recently published in The New England Journal of Medicine,5 showed a PFS benefit for avelumab/axitinib, both in patients with PD-L1–positive disease (P<.0001) and in the overall study population (P=.0001); OS data are not yet mature. Unlike CheckMate 214, the benefit for avelumab/axitinib was observed in all risk categories.

Summing up the findings from these studies and describing their current guideline classification, Dr. Jonasch noted that (1) nivolumab/ipilimumab is appropriate for patients with intermediate- or poor-risk disease; (2) pembrolizumab/axitinib and avelumab/axitinib may become available as options for all risk groups, although fewer patients achieve complete responses with these regimens compared with nivolumab/ipilimumab; and (3) patients with good-risk disease can consider sunitinib and pazopanib until combinations of immunotherapy agents and tyrosine kinase inhibitors are approved.

Second-Line Treatment and Sequencing

“Second-line treatment has not changed much, except for the ‘what if’ questions,” Dr. Jonasch continued. The debate will be how the approval of new regimens in the first line will define sequencing. “I don’t think we can currently answer this with certainty.”

Several agents have demonstrated an OS advantage over everolimus in the second-line setting, including nivolumab, cabozantinib, and combination lenvatinib/everolimus. Selection of second-line therapy will depend on the patient’s disease status, comorbidities, and prior lines of treatment.

Management of Advanced Non-ccRCC

In the advanced non-ccRCC setting, preferred strategies are sunitinib or enrollment in a clinical trial. Other recommended agents for this setting include cabozantinib and everolimus. The NCCN Guidelines note that combination bevacizumab/everolimus is useful in select patients with advanced papillary RCC, including those with germline mutations for hereditary leiomyomatosis and RCC (HLRCC). “I’ve tried this combination and have observed dramatic responses in patients with HLRCC,” he said.

Lastly, Dr. Jonasch predicted that first-line monotherapy with pembrolizumab may become an option in advanced non-ccRCC based on an analysis from KEYNOTE-427, with durable responses observed in all histologic subgroups and a response rate of 24.8%.6 “This was very, very good news for patients with non-ccRCC,” he noted.

Disclosures: Dr. Jonasch has disclosed that he is a consultant for Novartis Pharmaceuticals Corporation, Pfizer Inc., and Exelixis Inc.; and that he is a scientific advisor for Genentech, Inc., Eisai Inc., Ipsen, and Peloton Therapeutics, Inc.

References

  • 1.

    Motzer RJTannir NMMcDermott DF Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Eng J Med 2018;378:12771290.

  • 2.

    Ravaud AMotzer RJPandha HS Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016;375:22462254.

  • 3.

    Mejean ARavaud AThezenas D Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med 2018;379:417427.

  • 4.

    Rini BIPlimack ERStus V Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med 2019;380:11161127.

  • 5.

    Motzer RJPenkov KHaanen J Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med 2019;380:11031115.

  • 6.

    McDermott DFLee JLZiobro M First-line pembrolizumab monotherapy for advanced non-clear cell renal cell carcinoma: results from KEYNOTE-427 cohort B [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 546.

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Correspondence: Eric Jonasch, MD, Department of Genitourinary Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374, Houston, TX 77030. Email: ejonasch@mdanderson.org

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    Lines of treatment in advanced renal cell carcinoma, 2019.

    Abbreviations: HD, high dose; IO, immuno-oncology; VEGFR, vascular endothelial growth factor receptor.

References

  • 1.

    Motzer RJTannir NMMcDermott DF Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Eng J Med 2018;378:12771290.

  • 2.

    Ravaud AMotzer RJPandha HS Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016;375:22462254.

  • 3.

    Mejean ARavaud AThezenas D Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med 2018;379:417427.

  • 4.

    Rini BIPlimack ERStus V Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med 2019;380:11161127.

  • 5.

    Motzer RJPenkov KHaanen J Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med 2019;380:11031115.

  • 6.

    McDermott DFLee JLZiobro M First-line pembrolizumab monotherapy for advanced non-clear cell renal cell carcinoma: results from KEYNOTE-427 cohort B [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 546.

    • Crossref
    • Search Google Scholar
    • Export Citation

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