NCCN Continuing Education
Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-24-003-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until February 10, 2025. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/94825; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: February 10, 2024; Expiration date: February 10, 2025
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Kidney Cancer
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Kidney Cancer
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
John L. Gore, MD, MS, Panel Member
Ryan Schonfeld, BA, Guidelines Coordinator, NCCN
Mary Elizabeth Stein, PhD, Associate Scientist/Medical Writer, NCCN
Lisa A. Gurski, PhD, Manager, Licensed Clinical Content, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Robert J. Motzer, MD, Panel Chair, has disclosed receiving grant/research support from AVEO Pharmaceuticals, Inc., Bristol Myers Squibb, Eisai Inc., Exelixis Inc., Merck & Co., Inc., and Pfizer Inc.; and serving as a consultant for Merck & Co., Inc., and Takeda Pharmaceuticals North America, Inc.
Eric Jonasch, MD, Panel Vice Chair, has disclosed serving as a consultant for AVEO Pharmaceuticals, Inc., Eisai Inc., Exelixis, Inc., Ipsen, Merck & Co., Inc., NiKang Therapeutics, Inc., and Novartis Pharmaceuticals Corporation; and receiving grant/research support from Arrowhead Pharmaceuticals, AVEO Pharmaceuticals, Inc., Corvus Pharma, Merck & Co., Inc., NiKang Therapeutics, Inc., and ProfoundBio.
Naomi Haas, MD, Panel Member, has disclosed serving as a paid consultant for Bristol Myers Squibb, and Eisai Inc.; and serving as a nonpaid consultant for Pfizer Inc.
Payal Kapur, MD, Panel Member, has disclosed serving as a consultant for ClearNano Inc.
M. Dror Michaelson, MD, PhD, Panel Member, has disclosed serving as a scientific advisor for Eisai Inc., Janssen Pharmaceutica Products, LP, and Merck & Co., Inc.
Amir Mortazavi, MD, Panel Member, has disclosed receiving grant/research support from Astellas Pharma US, Inc., Bristol Myers Squibb, Genentech, Inc., GSK, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and Seagen.
Brian Shuch, MD, Panel Member, has disclosed serving as a consultant for Genentech, Inc., Johnson & Johnson,Merck & Co., Inc., Telix Pharmaceuticals and Veracyte.
Jeffrey Sosman, MD, Panel Member, has disclosed serving as a consultant for Jazz Pharmaceuticals, Inc., and Pfizer Inc.; and serving as a scientific advisor for Pfizer Inc.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Bristol Myers Squibb; Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Seagen. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc., Rahway, NJ, USA.
Overview
Renal cell carcinoma (RCC) comprises slightly more than 4% of all new cancers in the United States, with a median age at diagnosis of 64 years.1 Approximately 85% of kidney tumors are RCC, and approximately 70% of these are clear cell RCC (ccRCC).2–4 Other less common subtypes include papillary, chromophobe, TFE3-rearranged, TFEB-altered (translocation) RCC, and collecting duct carcinoma.5 SMARCB1-deficient renal medullary carcinoma is a rare and aggressive RCC variant that almost exclusively arises in patients who have sickle-cell trait or hemoglobin SC disease, or, rarely, sickle cell disease.6 The most recent pathologic classification system now has close to 20 types of RCC, with several additional emerging entities.7 The histologic diagnosis of RCC is established after surgical removal of renal tumors or after biopsy.
Smoking, obesity, chronic kidney disease, and hypertension are established risk factors for RCC development. Several hereditary types of RCC also exist, with von Hippel-Lindau (VHL) disease being the most common. VHL disease is caused by an autosomal-dominant constitutional mutation in the VHL gene that predisposes to benign and malignant cysts/tumors.8–11 Other hereditary types include FH-deficient and SDH-deficient RCC, associated with germline genetic alterations (also see “Hereditary RCC Syndromes” in the discussion within the full version of these guidelines, available at NCCN.org)
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with ccRCC and non–clear cell RCC (nccRCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with relapsed or stage IV advanced RCC.
Systemic Therapy Options for Patients With Relapsed or Stage IV Disease
Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology. Recommendations for first-line treatment of ccRCC are also stratified by risk groups based on the Memorial Sloan Kettering Cancer Center (MSKCC) Prognostic Model and the International Metastatic RCC Database Consortium (IMDC) (see KID-D in the full version of these guidelines, available at NCCN.org).
First-Line Systemic Therapy Options for Patients With ccRCC
Axitinib With Pembrolizumab
Axitinib is a selective, second-generation tyrosine kinase inhibitor (TKI) of VEGFRs, whereas pembrolizumab is a monoclonal antibody that selectively binds to PD-1 (expressed on activated T cells) and blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, both expressed on tumor cells and antigen-presenting cells. Data from the randomized phase III KEYNOTE-426 trial, which included patients with favorable-, intermediate-, or poor-risk RCC, resulted in the approval of axitinib in combination with pembrolizumab for first-line treatment of patients with advanced RCC belonging to any of the risk groups. In the trial, 861 enrolled patients received either axitinib/pembrolizumab or sunitinib; those receiving the combination regimen had a significantly higher objective response rate (ORR) compared with sunitinib (59% vs 36%, respectively), and longer median progression-free survival (PFS) than those receiving sunitinib (15.1 vs 11.1 months, respectively) (hazard ratio [HR], 0.69; 95% CI, 0.57–0.84; P<.001). The HR favored axitinib/pembrolizumab.12 A subsequent exploratory analysis with a 31-month median follow-up period corroborated these data.13 A 5-year follow-up analysis continued to show statistical benefit in ORR and PFS for the pembrolizumab/axitinib combination versus sunitinib. Overall survival (OS) rates were 41.9% versus 37.1% for pembrolizumab/axitinib and sunitinib, respectively.14 The NCCN Guidelines continue to include axitinib/pembrolizumab as a category 1, preferred, first-line therapy option for patients with ccRCC across all risk groups.
Cabozantinib With Nivolumab
Cabozantinib, a multitargeted TKI of VEGFRs, MET, and AXL, in combination with nivolumab, an anti–PD-1 antibody, is approved for first-line treatment of patients with advanced RCC.15 In the randomized phase III CheckMate 9ER trial, 651 patients received either cabozantinib/nivolumab or sunitinib. Median PFS was 16.6 and 8.3 months for the cabozantinib/nivolumab combination and sunitinib, respectively. The ORR was 55.7% versus 27.1% (P<.001) for those receiving cabozantinib/nivolumab versus sunitinib, respectively.16 Patients receiving combination treatment also reported delayed time to deterioration of patient-reported outcome scores compared with sunitinib.17 In a 3-year updated analysis, median OS was 49.5 months with cabozantinib/nivolumab compared with 35.5 months with sunitinib (HR, 0.70; 95% CI, 0.56–0.87; P=.0014) and median duration of response (DoR) was 22.1 versus 16.1 months for cabozantinib/nivolumab versus sunitinib, respectively.18 Cabozantinib/nivolumab is a category 1, preferred first-line therapy option for patients with ccRCC across all risk groups in the NCCN Guidelines.
Lenvatinib With Pembrolizumab
Lenvatinib is a multitargeted TKI of VEGFR-1, -2, and -3; FGFR-1, -2, -3, and -4; PDGFR-α; c-KIT; and RET.19 The randomized, phase III CLEAR trial evaluated the efficacy of either lenvatinib/pembrolizumab, lenvatinib/everolimus, or sunitinib. Those receiving lenvatinib/pembrolizumab had significantly longer median PFS of 23.9 months versus 9.2 months for those receiving sunitinib (HR, 0.39; 95% CI, 0.32–0.49; P<.001) and a higher ORR (71%) than those receiving sunitinib (36.1%).20 In a follow-up analysis, those receiving lenvatinib/pembrolizumab had a median OS of 33.7 months versus 33.4 months for those receiving sunitinib (HR, 0.72; 95% CI, 0.55–0.93).21 The NCCN panel recommends first-line lenvatinib/pembrolizumab as a category 1, preferred treatment option for patients with ccRCC across all risk groups.
Ipilimumab With Nivolumab
Ipilimumab is a monoclonal antibody that selectively blocks the interaction between the negative regulator CTLA-4 (expressed early on activated T cells) and its ligands CD80/CD86 (expressed on antigen-presenting cells). The phase III CheckMate 214 trial compared combination ipilimumab/nivolumab followed by nivolumab monotherapy versus sunitinib monotherapy in patients with advanced RCC.22 In the intermediate risk/poor risk population, which were the cohorts in the intended analysis, median OS was 47 months for ipilimumab/nivolumab versus 26.6 months (HR, 0.68; 95% CI, 0.58–0.81) for sunitinib, the ORR was 42% vs 27%, and the HR for PFS was 0.73 (95% CI, 0.61–0.87). After a median follow-up of 67.7 months, median OS for the favorable-, intermediate-, and poor-risk patients combined was 55.7 vs 38.4 months (HR, 0.72), median PFS was 12.3 versus 12.3 months (HR, 0.86), and ORR was 39.3% versus 32.4% in the ipilimumab/nivolumab arm versus the sunitinib arm, respectively, in the intent-to-treat population. For patients with favorable risk, median OS was 74.1 months with ipilimumab/nivolumab versus 68.4 months with sunitinib, and ORR and median PFS were lower in those receiving ipilimumab/nivolumab (29% and 15.3 months, respectively) versus sunitinib (52% and 25.1 months, respectively). However, a higher proportion of patients achieved a complete response (CR) with ipilimumab/nivolumab compared with those who received sunitinib regardless of risk group.22–24
During the Version 1.2024 update to these NCCN Guidelines, the panel reevaluated the data available on survival benefits of ipilimumab/nivolumab in favorable-risk patients and concluded that ipilimumab/nivolumab should remain as a category 2A, other recommended regimen for first-line treatment of patients with ccRCC of favorable risk. The panel continues to recommend the combination of ipilimumab/nivolumab as a first-line, category 1, preferred regimen for the treatment of ccRCC of poor/intermediate risk (see Figure 1).
Principles of systemic therapy for relapse or stage IV disease: first-line therapy for clear cell histology. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer, Version 2.2024 [KID-C 1 of 3].
Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2024.0008
Cabozantinib
In the open-label, randomized phase II CABOSUN trial, patients with intermediate- or poor-risk advanced RCC received either cabozantinib or sunitinib. Those treated with cabozantinib showed a significantly increased median PFS and higher ORR compared with those treated with sunitinib.25 Based on these results, the panel recommends first-line cabozantinib as a category 2A, preferred treatment option for poor- and intermediate-risk patients with ccRCC. The panel also recommends first-line cabozantinib as a category 2B, other recommended regimen for favorable-risk patients with ccRCC.
Axitinib With Avelumab
Axitinib/avelumab combination is approved for first-line treatment of patients with advanced RCC. Data from the randomized phase III JAVELIN Renal 101 trial, which included patients with favorable-, intermediate-, or poor-risk RCC, supported the combination therapy’s approval for this indication.26,27 For both the overall population and patients with PD-L1–positive tumors, those receiving axitinib/avelumab had significantly longer PFS than those receiving sunitinib. This benefit was observed across all risk groups. For median OS, data were immature for all groups in both the primary26 and 13-month interim27 analyses. Extended follow-up of the trial showed that median OS was not reached for the axitinib/avelumab arm (95% CI, 42.2 months–not estimable [NE]) versus 37.8 months with sunitinib (HR, 0.79; 95% CI, 0.643–0.969). Median PFS was 13.9 months for patients in the combination arm versus 8.5 months for those in the sunitinib arm (HR, 0.67; 95% CI, 0.568–0.785; one-sided P<.0001).28 Axitinib/avelumab combination is a first-line, category 2A, other recommended regimen for patients with ccRCC across all risk groups in the NCCN Guidelines.
Pazopanib
Pazopanib is an oral multitargeted TKI/angiogenesis inhibitor of VEGFRs, PDGFR-α and -β, FGFR-1 and -3, cytokine receptor (Kit), interleukin-2 receptor–inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). The drug’s safety and efficacy were evaluated in an open-label phase III study. Patients with advanced ccRCC who received 0 to 1 prior treatment received either pazopanib or placebo. PFS was significantly longer and ORR was significantly higher with pazopanib versus placebo in the treatment-naïve subpopulation,29 but there was no difference in OS between the groups.30 Notable grade 3 toxicity was hepatotoxicity, indicated by elevated levels of alanine (30%) and aspartate (21%) transaminase.29 Therefore, it is critical to monitor liver function before and during treatment with the drug.
Additionally, the COMPARZ noninferiority study of sunitinib versus pazopanib showed that these 2 drugs have similar safety and efficacy.31,32 Pazopanib is listed as a first-line, category 2A, other recommended regimen for patients with ccRCC across all risk groups in the NCCN Guidelines.
Sunitinib
Sunitinib is a multikinase inhibitor targeting several receptor tyrosine kinases, including PDGFR-α and -β; VEGFR-1, -2, and -3; c-KIT; FMS-like tyrosine kinase 3 (FLT3); colony-stimulating factor-1 receptor (CSF-1R); and neurotrophic factor receptor (RET).33–36 The efficacy of first-line sunitinib was studied in a randomized phase III trial, in which patients with metastatic RCC received either sunitinib or IFN-α.33 Median PFS was longer in those receiving sunitinib across all risk groups. Updated results demonstrated a strong trend toward OS advantage of sunitinib over IFN-α in the first-line setting.37 Sunitinib is recommended as a first-line, category 2A, other recommended regimen for patients with ccRCC across all risk groups in the NCCN Guidelines.
Active Surveillance for Select, Asymptomatic Patients With ccRCC
A subset of patients with advanced ccRCC show slow or delayed progression of disease and could benefit from initial active surveillance because of the toxicity of systemic therapies. A phase II trial of patients with treatment-naïve, asymptomatic, metastatic RCC followed patients on active surveillance through radiographic assessment at defined intervals until a decision was made to initiate systemic therapy.38 Of the 48 patients included in the analysis, the median time of surveillance from registration to initiation of systemic therapy was 14.9 months. This study demonstrated that a subset of patients with advanced ccRCC can safely undergo active surveillance before starting systemic therapy. In a prospective, observational study of 504 patients with metastatic RCC, the median OS was not reached (95% CI, 122 months–NE) in patients who received active surveillance versus 30 months for those treated with systemic therapy.39,40 The NCCN panel has included active surveillance as a category 2A, useful in certain circumstances option for select, asymptomatic patients with favorable-risk ccRCC.
Axitinib
As a second-line therapy for patients with ccRCC, axitinib treatment led to higher ORR and longer median PFS compared with sorafenib.41 In a randomized phase III trial in which treatment-naïve patients received either axitinib or sorafenib, median PFS was not significantly longer in those receiving axitinib versus sorafenib but axitinib had an acceptable toxicity profile.42 The NCCN panel has included first-line axitinib as a category 2B, useful in certain circumstances option for patients with ccRCC across all risk groups.
High-Dose IL-2
IL-2–based immunotherapy achieved long-lasting complete or partial remissions in a small subset of patients, but high-dose IL-2 is associated with substantial toxicity, and attempts to characterize tumor or patient factors for best response to this therapy have been unsuccessful.43–45 For highly selected patients with ccRCC, first-line high-dose IL-2 has been designated as useful in certain circumstances (category 2B designation for favorable-risk patients and category 3 for poor-/intermediate-risk patients).
Temsirolimus
Temsirolimus is an inhibitor of the mTOR protein. The randomized, open-label phase III ARCC study enrolled previously untreated patients with advanced RCC who had ≥3 unfavorable prognostic factors.46 Patients received IFN-α alone, temsirolimus alone, or the combination of temsirolimus and IFN-α. Those who received temsirolimus alone showed improvement in OS and median PFS over those receiving IFN-α alone or combination therapy. The NCCN panel has included first-line temsirolimus as a category 3, useful in certain circumstances option for poor- and intermediate-risk patients with ccRCC.
Subsequent Systemic Therapy Options for Patients With ccRCC
The recommended subsequent therapies for ccRCC are further categorized based on whether the patients have received any prior immuno-oncology (IO) therapy (see Figure 2). In addition, because the randomized registrational trials for several of these recommendations began prior to the approval of IO combination therapy and very few patients enrolled on these trials received up-front IO combination therapy, none of the therapies in the subsequent therapy table are designated as category 1 level evidence in this setting.
Principles of systemic therapy for relapse or stage IV disease: subsequent therapy for clear cell histology. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer, Version 2.2024 [KID-C 2 of 3].
Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2024.0008
Cabozantinib
In the randomized phase III METEOR trial, patients with disease progression after previous TKI therapy received cabozantinib or everolimus. Median PFS was significantly longer and ORR significantly higher in patients receiving cabozantinib versus everolimus.47 The final analysis of the METEOR trial showed a statistically significant increase in OS in the cabozantinib arm versus the everolimus arm.48,49
Additionally, a network meta-analysis comparing the relative effectiveness of subsequent treatment options for RCC found the probability of longer PFS during the analyzed 3 years to be higher with cabozantinib compared with everolimus, nivolumab, axitinib, sorafenib, and best supportive care.50 Based on these data, the panel has included cabozantinib as a subsequent, other recommended therapy option for patients with ccRCC regardless of their prior IO therapy status.
Lenvatinib With Everolimus
FDA approved lenvatinib, a multitargeted kinase inhibitor, in combination with everolimus, an mTOR inhibitor, for treating advanced ccRCC following one prior antiangiogenic therapy.51
In a randomized phase II trial, patients with metastatic or unresectable, locally advanced ccRCC who had received prior antiangiogenic therapy received either combination lenvatinib/everolimus, single-agent lenvatinib, or single-agent everolimus. PFS and median OS were significantly longer in patients receiving lenvatinib/everolimus versus everolimus monotherapy.52,53 A prospective study with 55 patients of metastatic ccRCC, heavily pretreated with prior immune checkpoint inhibitors (ICIs) and VEGFR-TKIs, showed a median PFS of 6.2 months and a median OS of 12.2 months with lenvatinib/everolimus.54 The NCCN panel recommends lenvatinib/everolimus as a subsequent, other recommended therapy option for patients with ccRCC regardless of their prior IO therapy status.
Nivolumab
In the randomized phase III CheckMate 025 trial, patients with advanced ccRCC who were previously treated with ≥1 lines of antiangiogenic therapy received either nivolumab or everolimus. Patients receiving nivolumab had significantly longer OS and significantly higher ORR than those receiving everolimus.55 An independent analysis was performed to determine the efficacy of nivolumab-based baseline factors, such as number and location of metastases, risk group, number of prior therapies, and specific prior therapies (ie, sunitinib, pazopanib, IL-2); a consistent OS benefit and ORR were observed across all baseline factors.56 In the final analysis of Checkmate 025, long-term follow-up (60 months) showed continued OS (26% vs 18%) and PFS (5% vs 1%) benefit with nivolumab versus everolimus.57 Median OS and median PFS showed an HR of 0.73 (95% CI, 0.62–0.85) and 0.84 (95% CI, 0.72–0.99), respectively, for nivolumab versus everolimus. Based on these data, the panel has included nivolumab as a category 2A, subsequent therapy option for patients with ccRCC who have not received any prior IO therapy.
Axitinib
The randomized phase III AXIS study compared second-line axitinib versus sorafenib. Median PFS was significantly longer and ORR significantly higher in patients receiving axitinib versus sorafenib.41 Updated AXIS results showed that while OS did not significantly differ between the groups, patients receiving axitinib had a continued improvement in PFS.58 The NCCN Guidelines include axitinib as a category 2A, other recommended subsequent therapy option for patients with prior IO therapy, and useful in certain circumstances for patients naïve to any prior IO therapy.
Axitinib With Pembrolizumab
Axitinib/pembrolizumab combination is approved for first-line treatment of metastatic ccRCC and has shown benefits in PFS, ORR, and OS compared with sunitinib. Although the NCCN panel agrees that there are limited data to support the use of axitinib/pembrolizumab in a second-line setting, they also agree it could be considered as a treatment option in patients with advanced ccRCC whose disease progressed after prior therapies. In a recent study, 38 patients with ccRCC who had disease progression and had received prior ICI or VEGFR-TKI therapy were treated with axitinib/pembrolizumab. Median PFS was 9.7 months (95% CI, 4.1–15.3) at a median follow-up of 17.1 months. The ORR was 25% (all partial responses).59 Among 17 patients who had previously received ipilimumab/nivolumab and then second-line axitinib/pembrolizumab, the median PFS was 11.1 months and ORR was 31.4%. Based on these data, the panel added axitinib/pembrolizumab as a category 2A, other recommended option for patients who are IO therapy–naïve, and useful in certain circumstances for patients who received prior IO therapy.
Cabozantinib With Nivolumab
The NCCN panel recommends cabozantinib/nivolumab as a category 2A, other recommended option for patients who are IO therapy–naïve, and useful in certain circumstances for patients who received prior IO therapy. Although there are no prospective or retrospective published data showing the benefit of cabozantinib/nivolumab in later lines of therapy in the treatment of advanced RCC, the panel’s decision was based on available data for combined ICI/TKI combinations of similar class, such as lenvatinib/pembrolizumab and axitinib/pembrolizumab.
Ipilimumab With Nivolumab
The phase I CheckMate 016 trial included treatment-naïve patients and those who had received 1 to ≥4 prior treatment regimens. Only the ORR results were stratified by treatment status: ORRs in the N3I1 and N1I3 arms were approximately 46% and 39%, respectively. OS and PFS data were not stratified by treatment line, but were similar.60 In a single-arm, phase II trial (TITAN-RCC), 32% of the 98 patients who experienced disease progression after second-line nivolumab had an objective response with ipilimumab/nivolumab.61 The panel considers ipilimumab/nivolumab as a category 2A, other recommended option for patients who are IO therapy–naïve, and useful in certain circumstances option for patients who received prior IO therapy.
Lenvatinib With Pembrolizumab
The phase II KEYNOTE-146 trial included 3 groups of patients: treatment-naïve; those who had previously received at least one line of treatment that did not include anti–PD-1 or anti–PD-L1 ICIs; and those who had previously received at least one anti–PD-1 or anti–PD-L1 ICI. Treatment-naïve patients had the highest ORR and the longest PFS; ORR and PFS were comparable in the ICI-naïve and ICI treatment–experienced groups. Median OS was only met in the ICI-naïve group.62 In a longer follow-up (results are unpublished),63 the ORR for treatment-naïve, previously treated but ICI-naive, and ICI-pretreated population was 77.5%, 52.9%, and 58.7%, respectively, consistent with previous observations. The median DoR was 24.2 months, 9 months, and 14.1 months, respectively. The longer follow-up data showed OS and PFS benefit for lenvatinib/pembrolizumab in all 3 treatment groups, with the treatment-naïve population showing the highest benefit, followed by the ICI-pretreated groups, and then the pretreated ICI-naïve group. The NCCN panel considers lenvatinib/pembrolizumab a category 2A, other recommended option for patients who are IO therapy–naïve, and useful in certain circumstances option for patients who received prior IO therapy.
Pazopanib
A phase III trial comparing pazopanib with placebo also included patients who had received prior cytokine therapy. PFS was significantly longer with pazopanib versus placebo in the treatment-experienced subpopulation,29 but OS was similar between the groups.30 Additionally, a prospective phase II trial evaluated second-line pazopanib in patients with advanced metastatic RCC previously treated with a targeted agent (ie, bevacizumab, sunitinib). A total of 27% of patients had an objective response to pazopanib; 49% had stable disease (SD). Median PFS was 7.5 months, regardless of prior treatment regimen. Estimated OS rate at 24 months was 43%.64 The panel has included pazopanib a category 2A, useful in certain circumstances subsequent therapy option for patients with ccRCC regardless of their prior IO therapy status.
Sunitinib
Sunitinib also has demonstrated substantial antitumor activity as a second-line therapy in patients with metastatic RCC whose disease had progressed on cytokine therapy.34,65 Studies investigating the sequential use of sunitinib and sorafenib are mostly retrospective. There are limited prospective data that suggest a lack of total cross-resistance between TKIs, either sorafenib followed by sunitinib failures or vice versa—an observation that is consistent with their differences in target specificities and slightly different toxicity spectra that sometimes permit tolerance of one agent over another.66–70 Sunitinib is considered a category 2A, useful in certain circumstances subsequent therapy option for patients with ccRCC regardless of their prior IO therapy status.
Tivozanib
Tivozanib, a multitargeted TKI of VEGFR-1, -2, and -3; c-kit; and PDGFR β, is approved for patients with relapsed or refractory advanced RCC who previously received ≥2 systemic therapies.71 Data from the randomized phase III TIVO-3 trial, which enrolled treatment-experienced patients with relapsed or refractory advanced ccRCC, supported the drug’s approval. Patients receiving tivozanib had significantly longer PFS than those receiving sorafenib; OS was similar between the groups.72,73 In a recently updated analysis, tivozanib also increased quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) compared with sorafenib (15.04 vs 12.78 months, respectively).74 Based on these data, the panel considers tivozanib as a category 2A, other recommended subsequent therapy option for patients who have received ≥2 prior IO therapies, and a useful in certain circumstances option for those who are IO therapy–naïve, but have received ≥2 prior systemic therapies (see Figure 2).
Axitinib With Avelumab
Extrapolating on the first-line JAVELIN Renal 101 data for poor-/intermediate-risk patients, the panel added axitinib/avelumab as a category 3, useful in certain circumstances subsequent therapy option for patients with ccRCC regardless of their prior IO therapy status.
Everolimus
Everolimus (RAD001) is an orally administered mTOR inhibitor. In the randomized phase III RECORD-1 trial, everolimus was compared with placebo for the treatment of metastatic RCC in patients whose disease had progressed on treatment with sunitinib or sorafenib. The median PFS was significantly longer for everolimus versus placebo, but OS was similar between the groups.75,76 Everolimus is listed as a category 2A, useful in certain circumstances subsequent therapy option for patients with ccRCC regardless of their prior IO therapy status.
Bevacizumab
Phase II trials have shown benefit of bevacizumab monotherapy after prior treatment with a cytokine.77 Bevacizumab is a category 2B, useful in certain circumstances subsequent therapy option for patients with ccRCC regardless of their prior IO therapy status.
High-Dose IL-2 (for Selected Patients)
High-dose IL-2 is listed as a category 2B, useful in certain circumstances subsequent therapy option for selected patients with excellent performance status and normal organ function regardless of their prior IO therapy status.
Temsirolimus
The randomized phase III INTORSECT trial compared the efficacy of temsirolimus versus sorafenib following first-line sunitinib as a treatment for patients with ccRCC or nccRCC. Although a significant OS advantage was observed for sorafenib, PFS was similar between the groups.78 The panel considers temsirolimus a category 2B, useful in certain circumstances subsequent therapy option for patients with ccRCC regardless of their prior IO therapy status.
Belzutifan
Belzutifan inhibits the transcription factor hypoxia-inducible factors 2α (HIF-2α) and blocks the heterodimerization of HIF-2α with HIF-2β, thereby inducing tumor regression. Follow-up from an expansion cohort of patients with ccRCC who had received ≥1 prior therapies in a phase I/II trial of belzutifan showed a disease control rate of 80% among 55 patients. Median PFS was 14.5 months, with 51% reporting a PFS of 12 months. The most common adverse events reported were anemia, fatigue, hypoxia, and dyspnea, among others.79,80 Based on these results, belzutifan was considered well tolerated with a favorable safety profile as a single agent. Belzutifan was recently approved by the FDA for patients with advanced RCC who were previously treated with PD-1 or PD-L1 inhibitor and VEGF-TKI.81,82 The open-label, randomized, phase III Litespark-005 trial that led to the approval compared belzutifan to everolimus in 746 patients with advanced ccRCC that had progressed after first-line therapies. Results from this trial were presented at the 2023 ESMO Congress and were not yet published at the time of writing.83 At median follow-up of 18.4 months, median PFS was 5.6 months for the belzutifan arm compared with 5.6 months for everolimus (HR, 0.75; 95% CI, 0.63–0.90; P<.001). Median OS and ORR for the belzutifan versus everolimus arm were 21 months and 21.9% versus 17.2 months and 3.5%, respectively. At median follow-up of 25.7 months, PFS remained at 5.6 months for belzutifan and everolimus (HR, 0.74; 95% CI, 0.63–0.88), and OS and ORR were 21.4 months and 22.7% versus 18.1 months and 3.5%, respectively.83 Based on these data, belzutifan is a recommended option for patients with ccRCC who received prior IO therapy. The panel added belzutifan as a category 2B, subsequent therapy option useful in certain circumstances for patients with ccRCC who are IO therapy–naïve (see Figure 2).
Systemic Therapy for Patients With nccRCC
Clinical trials of targeted agents have predominantly focused on patients with ccRCC due to its high prevalence.84 Data from systematic reviews, meta-analyses, and phase II studies with targeted agents also show some activity in patients with nccRCC. Compared with responses in ccRCC, however, the response rates with these agents are significantly lower for nccRCC. Therefore, according to the NCCN panel, enrollment in clinical trials remains the preferred strategy for nccRCC.
Cabozantinib
The randomized phase II SWOG 1500 trial compared the MET-targeted TKIs cabozantinib, crizotinib, and savolitinib with standard-of-care sunitinib in patients with advanced papillary RCC who had previously received up to 1 previous systemic therapy, excluding VEGF- and MET-targeted TKIs. Assignment to the crizotinib and savolitinib arms was halted due to results of a prespecified futility analysis.85 Patients receiving cabozantinib had significantly longer PFS and a higher ORR than those receiving sunitinib. Cabozantinib remains as a category 2A, preferred option for patients with nccRCC in the NCCN Guidelines.
Sunitinib
Two recent randomized phase II studies compared first-line sunitinib with first-line everolimus in patients with nccRCC. Although data from the ASPEN trial86 suggested that patients receiving sunitinib had significantly longer PFS than those receiving everolimus, data from the ESPN trial87 suggested that both OS and PFS were similar between the groups. Additionally, a meta-analysis of randomized clinical trials for patients with nccRCC found that TKI treatment reduced the risk of progression compared with mTOR inhibitors.88 The study found that sunitinib significantly reduced the risk of progression compared with everolimus in the first-line setting. However, no significant differences between TKIs and mTOR inhibitor treatment were found for OS and ORR. Sunitinib, which was previously listed under preferred option for patients with nccRCC, was moved to other recommended regimens in Version 1.2024 of the NCCN Guidelines based on the results from the phase II SWOG 1500 trial85 (see Figure 3).
Principles of systemic therapy for relapse or stage IV disease: systemic therapy for non-clear cell histology. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer, Version 2.2024 [KID-C 3 of 3].
Citation: Journal of the National Comprehensive Cancer Network 22, 1; 10.6004/jnccn.2024.0008
Lenvatinib With Everolimus
Extrapolating on data from the phase III lenvatinib/everolimus trial in patients with ccRCC,52 the panel added the combination therapy as a category 2A, other recommended regimen for patients with nccRCC. In a single-arm phase II trial (ClinicalTrials.gov identifier: NCT02915783), 41 patients with unresectable advanced or metastatic nccRCC who had not previously received prior systemic therapy received combination lenvatinib/everolimus.89 The authors reported an ORR of 26% (95% CI, 12%–45%). Eight patients experienced a partial response (PR; papillary, n=3; chromophobe, n=4; unclassified, n=1) and no patients had a CR. The median duration of response was NE. Eighteen patients (58.1%) had SD, and the clinical benefit rate (CR + PR + durable SD [duration ≥23 weeks]) was 61% (95% CI, 42%–78%). The median PFS was 9.2 months (95% CI, 5.5–NE) and median OS was 15.6 months (95% CI, 9.2–NE). Although the panel conceded that the number of enrolled patients was small, they generally felt that lenvatinib/everolimus treatment led to improved patient outcomes across all nccRCC subtypes.
Nivolumab
A retrospective analysis evaluating response to at least one dose of nivolumab in 35 patients with metastatic nccRCC found that 20% had a PR and 29% had SD, with a median follow-up of 8.5 months and median PFS of 3.5 months.90 A separate retrospective analysis found modest responses with PD-1/PD-L1 inhibitors in 43 patients also with metastatic nccRCC.91 An objective response was achieved in 8 (19%) patients, including 4 (13%) who received PD-1/PD-L1 monotherapy. Based on these data, the panel considers nivolumab a category 2A, other recommended regimen for patients with nccRCC.
Nivolumab With Cabozantinib
Two separate patient cohorts defined by nccRCC histology in a phase II open-label trial received nivolumab/cabozantinib combination.92 ORR for patients with papillary, unclassified, or translocation RCC was 48% with a median follow-up of 13.1 months. Median PFS was 12.5 months (95% CI, 6.3–16.4) and median OS was 28 months (95% CI, 16.3–NE). A study of patients with chromophobe RCC closed early due to the lack of efficacy. Based on these results, the panel added nivolumab/cabozantinib under other recommended options as first- or subsequent-line treatment of relapsed or stage IV nccRCC (see Figure 3).
Pembrolizumab
Cohort B of the phase II KEYNOTE-427 study assessed the efficacy and safety of pembrolizumab monotherapy in 165 patients with systemic therapy–naïve, newly diagnosed or recurrent stage IV nccRCC.93 Most (∼72%) patients had confirmed papillary RCC, approximately 13% had chromophobe RCC, and approximately 16% had unclassified RCC histology. ORR across all subtypes was approximately 27% (ORR by histology was 29% for papillary, 10% for chromophobe, and 31% for unclassified). Overall PFS and OS were 4.2 and 28.9 months, respectively. Based on these data, the panel added pembrolizumab as a category 2A, other recommended regimen for patients with nccRCC.
The NCCN Guidelines for Kidney Cancer continue to recommend the following therapies under the useful in certain circumstances category: axitinib,94 bevacizumab,95 bevacizumab/erlotinib,96,97 bevacizumab/everolimus,98,99 erlotinib,100 everolimus,101–103 nivolumab/ipilimumab,104 pazopanib,98,105 and temsirolimus.46,106,107
Conclusions
The treatment landscape of advanced RCC, including the clear cell and non–clear cell histologies, is evolving constantly. These NCCN Guidelines Insights discuss the latest clinical data regarding the systemic therapy recommendations for patients with relapsed or stage IV RCC included in Version 2.2024 of the NCCN Guidelines for Kidney Cancer. For a complete list of the recent updates, see the full version of these guidelines at NCCN.org.
References
- 1.↑
National Cancer Institute. Cancer stat facts: kidney and renal pelvis cancer. Accessed November 6, 2023. Available at: http://seer.cancer.gov/statfacts/html/kidrp.html
- 2.↑
Moch H, Gasser T, Amin MB, et al. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer 2000;89:604–614.
- 3.↑
Leibovich BC, Lohse CM, Crispen PL, et al. Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. J Urol 2010;183:1309–1315.
- 4.↑
Lipworth L, Morgans AK, Edwards TL, et al. Renal cell cancer histological subtype distribution differs by race and sex. BJU Int 2016;117:260–265.
- 5.↑
Moch H, Amin MB, Berney DM, et al. The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs—part A: renal, penile, and testicular tumours. Eur Urol 2022;82:458–468.
- 6.↑
Msaouel P, Hong AL, Mullen EA, et al. Updated recommendations on the diagnosis, management, and clinical trial eligibility criteria for patients with renal medullary carcinoma. Clin Genitourin Cancer 2019;17:1–6.
- 7.↑
Trpkov K, Hes O, Williamson SR, et al. New developments in existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol 2021;34:1392–1424.
- 9.↑
DeVita VT Jr, Lawrence TS, Rosenberg SA, et al, eds. Cancer: Principles and Practice of Oncology, 8th ed. Lippincott Williams & Wilkins; 2008.
- 11.↑
DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 10th ed. Wolters Kluwer Health; 2015.
- 12.↑
Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–1127.
- 13.↑
Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21:1563–1573.
- 14.↑
Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426. J Clin Oncol 2023; 41(Suppl):Abstract LBA4501.
- 15.↑
U.S. Food & Drug Administration. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. Accessed November 6, 2023. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma
- 16.↑
Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829–841.
- 17.↑
Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open- label, randomised, phase 3 trial. Lancet Oncol 2022;23:292–303.
- 18.↑
Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol 2023;41(Suppl):Abstract 603.
- 19.↑
U.S. Food & Drug Administration. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. Accessed November 6, 2023. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-plus-pembrolizumab-advanced-renal-cell-carcinoma
- 20.↑
Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384:1289–1300.
- 21.↑
Choueiri TK, Eto M, Motzer R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol 2023;24:228–238.
- 22.↑
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–1290.
- 23.↑
Quhal F, Mori K, Fajkovic H, et al. Immunotherapy-based combinations in the first-line treatment of metastatic renal cell carcinoma with sarcomatoid features: a systematic review and network meta-analysis. Curr Opin Urol 2022;32:61–68.
- 24.↑
Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer 2022;128:2085–2097.
- 25.↑
Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol 2017;35:591–597.
- 26.↑
Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–1115.
- 27.↑
Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol 2020;31:1030–1039.
- 28.↑
Haanen JBAG, Larkin J, Choueiri TK, et al. Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. ESMO Open 2023;8:101210.
- 29.↑
Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–1068.
- 30.↑
Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer 2013;49:1287–1296.
- 31.↑
Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722–731.
- 32.↑
Motzer RJ, Hutson TE, McCann L, et al. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 2014;370:1769–1770.
- 33.↑
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–124.
- 34.↑
Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16–24.
- 35.↑
Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007;25:884–896.
- 36.↑
Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25–35.
- 37.↑
Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584–3590.
- 38.↑
Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol 2016;17:1317–1324.
- 39.↑
Harrison MR, Costello BA, Bhavsar NA, et al. Active surveillance of metastatic renal cell carcinoma: results from a prospective observational study (MaRCC). Cancer 2021;127:2204–2212.
- 40.↑
Bex A. Increasing the evidence for surveillance of metastatic renal cancer. Cancer 2021;127:2184–2186.
- 41.↑
Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–1939.
- 42.↑
Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 2013;14:1287–1294.
- 43.↑
McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23:133–141.
- 44.↑
Rosenberg SA, Mulé JJ, Spiess PJ, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985;161:1169–1188.
- 45.↑
Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127–3132.
- 46.↑
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–2281.
- 47.↑
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814–1823.
- 48.↑
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917–927.
- 49.↑
Motzer RJ, Escudier B, Powles T, et al. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer 2018;118:1176–1178.
- 50.↑
Amzal B, Fu S, Meng J, et al. Cabozantinib versus everolimus, nivolumab, axitinib, sorafenib and best supportive care: a network meta-analysis of progression-free survival and overall survival in second line treatment of advanced renal cell carcinoma. PLoS One 2017;12:e0184423.
- 51.↑
U.S. Food & Drug Administration. Lenvatinib in combination with everolimus. Accessed November 6, 2023. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/lenvatinib-combination-everolimus
- 52.↑
Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16:1473–1482.
- 53.↑
Motzer RJ, Hutson TE, Ren M, et al. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol 2016;17:e4–5.
- 54.↑
Wiele AJ, Bathala TK, Hahn AW, et al. Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and vascular endothelial growth factor receptor- tyrosine kinase inhibitor therapies. Oncologist 2021;26:476–482.
- 55.↑
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–1813.
- 56.↑
Escudier B, Sharma P, McDermott DF, et al. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol 2017;72:962–971.
- 57.↑
Motzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer 2020;126:4156–4167.
- 58.↑
Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013;14:552–562.
- 59.↑
Dizman N, Austin M, Considine B, et al. Outcomes with combination pembrolizumab and axitinib in second and further line treatment of metastatic renal cell carcinoma. Clin Genitourin Cancer 2023;21:221–229.
- 60.↑
Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol 2017;35:3851–3858.
- 61.↑
Grimm MO, Esteban E, Barthélémy P, et al. Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2023;24:1252–1265.
- 62.↑
Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol 2021;22:946–958.
- 63.↑
Lee CH, Yogesh Shah A, Rao A, et al. Final database lock results of the phase 2 cohort of lenvatinib + pembrolizumab for progressive disease after a PD-1/PD-L1-containing therapy in metastatic clear cell renal cell carcinoma. Oncologist 2023;28(Suppl 1):S3–4.
- 64.↑
Hainsworth JD, Rubin MS, Arrowsmith ER, et al. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium phase II trial. Clin Genitourin Cancer 2013;11:270–275.
- 65.↑
Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295:2516–2524.
- 66.↑
Dudek AZ, Zolnierek J, Dham A, et al. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer 2009;115:61–67.
- 67.↑
Eichelberg C, Heuer R, Chun FK, et al. Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis. Eur Urol 2008;54:1373–1378.
- 68.↑
Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol 2009;182:29–34.
- 69.↑
Zimmermann K, Schmittel A, Steiner U, et al. Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology 2009;76:350–354.
- 70.↑
Garcia JA, Hutson TE, Elson P, et al. Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab. Cancer 2010;116:5383–5390.
- 71.↑
Tivozanib capsules for oral use. Prescribing information. AVEO Pharmaceuticals, 2021. Accessed December 12, 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212904s000lbl.pdf
- 72.↑
Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 2020;21:95–104.
- 73.↑
Sakellakis M, Zakopoulou R. Current status of tivozanib in the treatment of patients with advanced renal cell carcinoma. Cureus 2023;15:e35675.
- 74.↑
Szarek M, Needle MN, Rini BI, et al. Q-TWiST analysis of tivozanib versus sorafenib in patients with advanced renal cell carcinoma in the TIVO-3 study. Clin Genitourin Cancer 2021;19:468.e1–468.e5.
- 75.↑
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–456.
- 76.↑
Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116:4256–4265.
- 77.↑
Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–434.
- 78.↑
Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32:760–767.
- 79.↑
Jonasch E, Bauer TM, Papadopoulos KP, et al. Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: extended 41-month follow-up in the clear cell renal cell carcinoma cohort. Eur J Cancer 2024;196:113434.
- 80.↑
Bauer TM, Choueiri TK, Papadopoulos KP, et al. The oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC): updated follow-up of a phase I/II study. J Clin Oncol 2021;39(Suppl):Abstract 273.
- 81.↑
U.S. Food & Drug Administration. FDA approves belzutifan for advanced renal cell carcinoma. Accessed December 19, 2023. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma
- 82.↑
Belzutifan tablets for oral use. Prescribing information. Merck Sharpe & Dohme LLC, 2023. Accessed December 19, 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215383s006lbl.pdf
- 83.↑
Albiges L, Rini BI, Peltola K, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): randomized open-label phase III LITESPARK-005 study. Ann Oncol 2023;34(Suppl 2):Abstract LBA88.
- 84.↑
de Velasco G, McKay RR, Lin X, et al. Comprehensive analysis of survival outcomes in non-clear cell renal cell carcinoma patients treated in clinical trials. Clin Genitourin Cancer 2017;15:652–660.e1.
- 85.↑
Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet 2021;397:695–703.
- 86.↑
Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016;17:378–388.
- 87.↑
Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol 2016;69:866–874.
- 88.↑
Ciccarese C, Iacovelli R, Brunelli M, et al. Addressing the best treatment for non-clear cell renal cell carcinoma: a meta-analysis of randomised clinical trials comparing VEGFR-TKis versus mTORi-targeted therapies. Eur J Cancer 2017;83:237–246.
- 89.↑
Hutson TE, Michaelson MD, Kuzel TM, et al. A single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol 2021;80:162–170.
- 90.↑
Koshkin VS, Barata PC, Zhang T, et al. Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma. J Immunother Cancer 2018;6:9.
- 91.↑
McKay RR, Bossé D, Xie W, et al. The clinical activity of PD-1/PD-L1 inhibitors in metastatic non-clear cell renal cell carcinoma. Cancer Immunol Res 2018;6:758–765.
- 92.↑
Lee CH, Voss MH, Carlo MI, et al. Phase II trial of cabozantinib plus nivolumab in patients with non-clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol 2022;40:2333–2341.
- 93.↑
McDermott DF, Lee JL, Ziobro M, et al. Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol 2021;39:1029–1039.
- 94.↑
Park I, Lee SH, Lee JL. A multicenter phase II trial of axitinib in patients with recurrent or metastatic non-clear-cell renal cell carcinoma who had failed prior treatment with temsirolimus. Clin Genitourin Cancer 2018;16:e997–1002.
- 95.↑
Irshad T, Olencki T, Zynger DL, et al. Bevacizumab in metastatic papillary renal cell carcinoma (PRCC). J Clin Oncol 2011;29(Suppl):Abstract e15158.
- 96.↑
Menko FH, Maher ER, Schmidt LS, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer 2014;13:637–644.
- 97.↑
Srinivasan R, Gurram S, Al Harthy M, et al. Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer. J Clin Oncol 2020;38(Suppl):Abstract 5004.
- 98.↑
Buti S, Bersanelli M, Maines F, et al. First-line PAzopanib in NOn-clear-cell Renal cArcinoMA: the Italian retrospective multicenter PANORAMA study. Clin Genitourin Cancer 2017;15:e609–614.
- 99.↑
Voss MH, Molina AM, Chen YB, et al. Phase II trial and correlative genomic analysis of everolimus plus bevacizumab in advanced non-clear cell renal cell carcinoma. J Clin Oncol 2016;34:3846–3853.
- 100.↑
Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol 2009;27:5788–5793.
- 101.↑
Blank CU, Bono P, Larkin J, et al. Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF- targeted therapy: subgroup analysis of REACT. J Clin Oncol 2012;30(Suppl):Abstract 402.
- 102.↑
Koh Y, Lim HY, Ahn JH, et al. Phase II trial of everolimus for the treatment of nonclear-cell renal cell carcinoma. Ann Oncol 2013;24:1026–1031.
- 103.↑
Escudier B, Molinie V, Bracarda S, et al. Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. Eur J Cancer 2016;69:226–235.
- 104.↑
Tykodi SS, Gordan LN, Alter RS, et al. Safety and efficacy of nivolumab plus ipilimumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase 3b/4 CheckMate 920 trial. J Immunother Cancer 2022;10:e003844.
- 105.↑
Jung KS, Lee SJ, Park SH, et al. Pazopanib for the treatment of non-clear cell renal cell carcinoma: a single-arm, open-label, multicenter, phase II study. Cancer Res Treat 2018;50:488–494.
- 106.↑
Dutcher JP, de Souza P, McDermott D, et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol 2009;26:202–209.
- 107.↑
Venugopal B, Ansari J, Aitchison M, et al. Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma. BMC Urol 2013;13:26.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.
© 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
