­­Frontline Strategies in RCC:
Capturing Pivotal New Data, Optimizing Treatment Options





Editor’s note: This report by the Kidney Cancer Journal integrates recently published peer-reviewed medical literature and results presented at two meetings, the European Society of Medical Oncology (ESMO) sessions and the Society for Immunotherapy of Cancer (SITC) meeting, both held in late 2017. The content, compiled independently by the journal, was assessed for accuracy, clarity, and relevance by the three peer reviewers whose investigative work has focused on trends covered in this report. 


Compelling evidence for the approval of two therapies as frontline strategies in intermediate and poor-risk advanced renal cell carcinoma (RCC) has raised expectations that significant improvements in progression-free survival and overall survival are possible with a manageable safety profile in patients previously treated with the conventional antiangiogenic standard of care. Cabozantinib was approved for all first-line RCC patients on December 19, 2017 so it can be considered a new standard of care option. Clinicians can look forward to a broader spectrum of therapy to optimize outcomes, based on results from two pivotal trials analyzed here. 

The momentum of two clinical trials has generated expectations and excitement that a realignment of strategies in the first-line treatment of renal cell carcinoma has indeed arrived. For 10 years, the focus of frontline therapy generally has been antiangiogenic agents that target the vascular endothelial growth factor (VEGF) and its receptors, and the blockade of the VEGF signaling pathway has been the standard treatment based on improved clinical outcomes in randomized phase III trials.1 However, recent results presented at the European Society of Medical Oncology (ESMO) meeting in 2017 suggest how this realignment of strategies may take shape in the coming year as the FDA considers approval of new options for frontline therapy in RCC.

As we look beyond ESMO and attention turns toward further exploration of immunotherapy, including the combination of ipilimumab-nivolumab, and the rationale for using the TKI cabozantinib, there is wide speculation on how the treatment algorithm will change, what special considerations, including PD-L1 status, could be important in selecting appropriate therapy, and how new combinations can be sequenced to achieve optimal outcomes. As much as ESMO helped clarify these choices, it also presented even more challenges and questions still to be addressed as phase III investigations further explore the importance of:

  • multi-pathway inhibition involving not only VEGF but also MET and AXL.
  • the role of biomarkers such as PD-L1 status and how that could be integrated into assessments to identify patients who may benefit from immune-oncology based treatment.
  • the tolerability of various agents
  • the presence or absence of bone metastases and other pre-existing conditions, such as autoimmune disease.
  • risk status and how that may stratify patients for various treatments, including the use of sunitinib.

Two Therapies and their Mechanisms of Action Cabozantinib
Cabozantinib (Cabometyx) is a small-molecule inhibitor of the VEGF receptor and, in addition, inhibits MET and AXL, receptors shown to be upregulated in VHL-deficient RCC cells and associated with resistance to VEGF-directed therapy in preclinical RCC models.1 Furthermore, cabozantinib has been shown to directly inhibit migration and invasion in RCC cell lines that have been stimulated with hepatocyte growth factor, the ligand for MET.1 Cabozantinib tablets were approved by regulatory authorities on the basis of a randomized phase III trial in patients with mRCC previously treated with at least one VEGF-targeted agent, with demonstration of progression-free survival (PFS) and overall survival (OS) benefits compared with a mammalian target of rapamycin inhibitor, everolimus, which was commonly used in the refractory setting.2 Prior limited prospective data had supported the hypothesis that VEGF targeting would have a greater clinical effect compared with mammalian target of rapamycin inhibition in mRCC.3 Based on the recent CABOSUN results, Cabometyx has now been approved by the FDA for the treatment of patients with advanced RCC, expanding the label to previously untreated patients.4

CABOSUN and the Results at ESMO
If one were looking for significant new data to reframe the debate on frontline treatment of metastatic RCC, CABOSUN produced compelling results at the 2017 ESMO meeting. By significantly extending progression-free survival (PFS) compared with sunitinib as initial targeted therapy for intermediate- and poor-risk patients with metastatic RCC as assessed by an independent radiological review committee, the results extended earlier findings from CABOSUN. (Figures 1,2)

Figure 1. Kaplan-Meier Plot of Progression-Free Survival per IRC.
(To view a larger version of this figure, click here).

Figure 2. Forest Plots of Progression-Free Survival per IRC.
(To view a larger version of this figure, click here).

In assessing cabozantinib as initial targeted therapy for patients with poor- or intermediate-risk clear-cell metastatic RCC, CABOSUN also:

  • Included patients who had a notable number of other independent adverse prognostic risk factors such as a high rate of bone metastases.5
  • Produced radiographic findings that showed cabozantinib significantly prolonged median PFS compared with sunitinib (8.6 months vs 5.3 months).
  • Safety profiles of the drugs appeared to be consistent with prior reports. A comparable percentage of cabozantinib- and sunitinib-treated patients experienced grade 3 or grade 4 adverse events (68% vs 65%).

Combination of Ipilimumab and Nivolumab (ipi-nivo)
Nivolumab (Opdivo) is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, nivolumab has become an important treatment option across multiple cancers.6 Nivolumab is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

Ipilimumab (Yervoy) is a monoclonal antibody that works to activate the immune system by targeting  CTLA-4, a protein receptor that downregulates the immune system. Cytotoxic T lymphocytes  (CTLs) can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to function.7 Ipilimumab was approved by the FDA in 2011 for the treat- ment of melanoma.

Checkmate -214: Comparing IO With Sunitinib
CheckMate -214 is a phase 3, randomized, open-label study evaluating the combination of nivolumab plus ipilimumab versus sunitinib in patients with previously untreated advanced or metastatic RCC. Patients in the combination group received nivolumab  3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients in the comparator group received sunitinib 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment. Patients were treated until progression or unacceptable toxic effects.

The primary endpoints of the trial were overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) in an intermediate- to poor-risk patient population (approximately 75% of patients).8 Safety was a secondary endpoint. The key findings from Checkmate -214 revealed:

  • The median overall survival (OS) was not reached with the combination versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95; P = .0003). In those specifically with intermediate- and poor-risk RCC, who constituted about 75% of the intent-to-treat (ITT) population, median OS was not reached in the nivolumab and ipilimumab arm and was 26.0 months in the sunitinib arm, a 37% reduction in the risk of death (HR, 0.63; 99.8% CI, 0.44-0.89; P <.0001). Overall survival for the combination versus sunitinib in those with favorable risk has not yet been reported. (Figures 3,4)
  • The overall response rate (ORR) favored the combination over sunitinib in intermediate/poor risk patients irrespective of baseline tumor PD-L1 expression while a PFS benefit with the combination was seen only in patients with PD-L1 ≥1%. (Figure) For the favorable risk group, the sunitinib arm was favored over the combination for PFS and ORR.

Figure 3. PFS per IRRC: IMDC intermediate/poor risk. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab + ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma (RCC): results from CheckMate -214, including overall survival by subgroups. Society for Immunotherapy for Cancer 2017 meeting; Abstract 038.
(To view a larger version of this figure, click here).

Figure 4. OS: IMDC intermediate/poor risk. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab + ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma (RCC): results from CheckMate -214, including overall survival by subgroups. Society for Immunotherapy for Cancer 2017 meeting; Abstract 038.
(To view a larger version of this figure, click here).

Grade 3/4 adverse events (AEs) were reported in 46% of patients (252/547) in the combination group, compared with 63% of patients (337/535) in the sunitinib group. The most common grade 3/4 AEs in the combination group were fatigue (4%), diarrhea (4%), nausea (2%), decreased appetite (1%), and, in less than 1% each, pruritus, hypothyroidism and hypertension. In the sunitinib group, the most common grade 3/4 AEs were hypertension (16%), fatigue (9%), Palmar-plantar erythrodysaesthesia syndrome (9%), diarrhea (5%), stomatitis (3%), mucosal inflammation (3%), nausea (1%), decreased appetite (1%), and in less than 1% each, hypothyroidism and dysgeusia. Adverse events (AEs) leading to discontinuation were reported in 22% of patients (120/547) in the combination group, compared with 12% of patients in the sunitinib group (64/535). Seven treatment-related deaths occurred in the combination group and four in the sunitinib group.

Checkmate -214 delineated the role of PD-L1 expression to a greater extent than has previously been elucidated. Programmed death-ligand 1 (PD-L1) expression level impacted response to nivolumab plus ipilimumab, regardless of risk category. In patients with IMDC intermediate/poor risk and PD-L1 ≥1%, ORR was 53% with nivolumab plus ipilimumab, versus 22% with sunitinib (P<.0001). By comparison, if patients with IDMC intermediate/poor risk had PD-L1 <1%, ORR with nivolumab plus ipilimumab was 37%, compared to 22% with sunitinib (P = .0252). Results in the ITT population showed that nivolumab plus ipilimumab was associated with a statistically significant improvement in ORR in patients with PD-L1 ≥1% (53% vs 22%; P<.0001), but not for patients with PD-L1 <1% (36% vs 35%; P = .8799).

Several conclusions were drawn from the Check-Mate -214 trial and presented at the SITC meeting. The authors suggested that the combination regimen should be considered as a new standard-of-care option for patients with intermediate/poor risk advanced RCC. The results were considered compelling in view of the OS benefit across PD-L1 expression levels, supporting the use of the combination as an alternative to sunitinib. Additionally, the safety profile of the combination was manageable with patients reporting a better quality of life than with sunitinib.

Interpreting the Data in CABOSUN:
Why Was Cabozantinib Superior to Sunitinib?
There are numerous factors potentially at play in determining why cabozantinib is under consideration as frontline therapy based on CABOSUN data and the recent approval of cabozantinib for first-line patients.. As background, one should be aware of what patient groups were selected as part of the trial enrollment process. CABOSUN focused on IMDC intermediate- and poor-risk groups because these groups would capture 70% to 80% of all patients with advanced disease who are the most in need of systemic therapy and disease control, whereas the favorable-risk group includes many patients with relatively indolent, lower-volume disease.9,10

The study also included a patient population with a high rate of bone metastases; this is known to be a negative prognostic factor in RCC. With a high percentage of patients with poor risk factors, including bone metastases, enrolled in the CABOSUN trial, this study picked up on an observation from a large French study that showed patients with RCC with bone metastases had a reduced benefit from sunitinib.11 This was true even when the French group adjusted for known prognostic factors in advanced RCC. There is a trend suggesting cabozantinib is of benefit in this subset, based on additional findings. The phase III METEOR trial, for example, showed a marked improvement in PFS and OS in patients with bone metastases who received cabozantinib compared with everolimus.12 In CABOSUN, investigators also found a PFS benefit with cabozantinib in all subgroups of patients, including those with bone metastases.

The Target Profile: Can Biomarkers Predict Clinical Activity?
One explanation for the superiority of cabozantinib over sunitinib may be related to the target profile of cabozantinib, which includes the MET and AXL pathways in addition to VEGFR. Efforts to uncover the strength of such an association are ongoing. The HGF/MET pathway has attracted increasing attention in recent years as a promising molecular target for cancer therapy. An improved understanding of the involvement of this pathway in kidney development and in renal pathological conditions has suggested the targeting of this pathway as a promising strategy for the treatment of kidney cancer.

The observation that the kidney is an abundant source of hepatocyte growth factor (HGF) and its activators, may explain, at least in part, why patients with germline MET mutations exhibit only kidney cancer.13 These studies also demonstrated that mutated MET might be more easily activated than wild-type MET and more likely to remain activated for longer periods after stimulation. Although the role of MET expression in tumors was investigated in the METEOR trial it does not appear to be to be predictive of the clinical activity of cabozantinib over everolimus, there is still widespread interest in this possible connection  and other blood and tissue biomarkers that could yield clues as to the activity of cabozantinib.14

The AXL Pathway and Its Role in RCC
AXL signaling is also implicated in tumor growth and survival. Activation of AXL by its cognate ligand GAS6 promotes cell proliferation, migration, and protection from apoptosis; in many contexts, AXL functions in concert with other receptors to amplify downstream signaling pathways.15 Despite the success of anti-angiogenic agents in treating RCC, a fraction of patients do not respond to systemic therapy, and responding patients eventually progress and succumb to their disease. Resistance to VEGF-targeted therapy is mediated by upregulation of alternative angiogenic and invasive pathways, including MET and AXL.

Zhou et al hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior.16 In their study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, which targets VEGF, MET and AXL.

Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. Zhou et al demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models.

The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes pro-metastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.  These findings need to be confirmed in further studies elucidating the role of biomarkers in resistance to sunitinib. But if confirmed, this could represent an important new direction in our ability to assess the prognostic significance of such biomarkers.

Evidence from two pivotal trials comparing new therapeutic approaches as initial therapy for patients with metastatic RCC of poor or intermediate risk to a long standing standard of care sunitinib are likely to have a meaningful impact on the treatment paradigm if one or both of these options is approved, as expected in early 2018.  This may mean that for the first time in more than 10 years, the standard of care in these patients, which has been sunitinib, will undergo significant change with the approval of Cabometyx achieved in 2017 and the expected approval of ipi-nivo in 2018.

1. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298-2308.
2. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus evero-limus in advanced renal-cell carcinoma. N Eng J Med. 2015;373:1814-1823.N Engl J Med. 2015 Nov 5;373(19):1814-23
3. Park K, Lee J-L, Park I, et al. Comparative efficacy of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitor as second-line therapy in patients with metastatic renal cell carcinoma after the failure of first-line VEGF TKI. Med Oncol. 2012;29:3291-3297.
4. Cabometyx prescribing information revision, December 2017.
5. ChoueiriTK, Hessel C, Halabi S, et al. Progression-free survival by independent review and overall survival update for the Alliance A031203 CABOSUN trial of cabozantinib vs sunitinib in metastatic renal cell carcinoma. 2017 ESMO annual meeting, Sept. 8-12, Madrid, Spain; oral presentation #LBA38.
6. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Eng Med. 2015;373: 1803-1813.
7. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;33: 7711-23.
8. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab + ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma (RCC): results from CheckMate214, including overall survival by subgroups. Society for Immunotherapy for Cancer 2017 meeting; Abstract 038.
9. Ko JJ, Choueiri TK, Rini BI, et al: First-, second-, third-line therapy for mRCC: Benchmarks for trial design from the IMDC. Br J Cancer. 2014;110:1917-1922
10. Stukalin I, Alimohamed N, Heng DY: Contemporary treatment of metastatic renal cell carcinoma. Oncol Rev. 2016 10:295.
11. Beuselinck B, Oudard S, Rixe O, et al: Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib. Ann Oncol. 2011; 22:794-800.
12. 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.
13. Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer: rationale and progress. Nat Rev. Cancer. 2012;12:89-10.
14.Giubellino A, Linehan WM, Bottaro DP. Targeting the MET signaling pathway in renal cancer. Expert Rev Anticancer Ther. 2009;9:785-793.
15. Rankin EB, Giaccia AJ, The Receptor Tyrosine Kinase AXL in Cancer Progression. Cancers.2016;88:pii:E103.
16. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35: 26687-2697. KCJ

Keywords: renal cell carcinoma, intermediate and poor risk-patients, cabozantinib, CABOSUN, Checkmate214, ipilimumab, nivolumab, AXL, MET, sunitinib, standard of care, progression-free survival, overall survival.

Corresponding Author: Toni K. Choueiri, MD, Dana Farber Cancer Institute, 440 Brookline Ave, Boston, MA 02215 Email




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