Systemic therapies for metastatic renal cell carcinoma (mRCC) have expanded dramatically over the past 3 years.
Most recently, on Dec. 19, 2017 cabozantinib was approved by the FDA for use in untreated advanced renal cell carcinoma. This approval expands the label for cabozantinib, which was previously restricted to treatment for patients with prior anti-angiogenic treatment. The expansion to first-line therapy was based on an Alliance cooperative group trial termed CABOSUN, in which patients were randomized to either cabozantinib or sunitinib as initial treatment of mRCC.1
With the vascular endothelial growth factor (VEGF) pathway driving tumorigenesis and progression in clear cell RCC, first line treatment of mRCC has relied heavily on small molecule tyrosine kinase inhibitors (TKIs) of VEGF receptors, including pazopanib or sunitinib. The COMPARZ study demonstrated non-inferiority between these two agents in this setting2.
After pazopanib or sunitinib are employed in the first-line setting, resistance to VEGF targeted therapy presents a therapeutic challenge. In particular, tumors that express the receptors, MET and AXL, have been associated with poor prognosis and resistance to VEGF inhibitors3.
Cabozantinib is a small molecule inhibitor with activity against both MET and AXL in addition to VEGF receptors. In RCC murine models, cabozantinib has been shown to rescue sunitinib resistance4. Therefore, cabozantinib could offer clinical benefit to patients previously treated with sunitinib. Support for this hypothesis was initially furnished by the METEOR trial5, in which patients with advanced RCC who had previously received anti-angiogenic therapy clinically benefited from cabozantinib, leading to FDA approval on April 25, 2016.
To test whether MET and AXL are drivers of RCC disease progression on VEGF receptor targeted therapy required a different study. To test this hypothesis, we designed the CABOSUN study, which enrolled 157 patients with intermediate and poor risk (by International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] criteria6), previously untreated mRCC and randomized them to either standard of care sunitinib or cabozantinib. 81% of patients were intermediate risk and 19% of patients had poor risk mRCC. The treatment arms were well-balanced.
A substantial number of patients in the study had bone metastases (37% of patients treated with cabozantinib and 36% of patients treated with sunitinib), and from prior analysis, patients who have bone metastases have worse outcomes than patients without bone metastases7.
CABOSUN met its primary endpoint, demonstrating a superior investigator-assessed median progression-free survival (PFS) for cabozantinib compared to sunitinib (8.2 vs 5.6 months, respectively; HR 0.66, 95% CI 0.46-0.95, p=0.012)1. Compared to sunitinib, cabozantinib had similar grade 3/4 adverse events, including diarrhea (10%), fatigue (6%), hypertension (28%), palmar-plantar erythrodysesthesia (8%) and hematologic events (3%). The initial publication was based on a data cutoff of April 2016.
An independent review of the CABOSUN data applied additional FDA censoring rules: patients were censored if they started non-protocol cancer therapy or if they had more than 2 missing assessments. Similar to the initial results, the independent review confirmed the PFS benefit (median PFS 8.6 months with cabozantinib vs. 5.3 months with sunitinib, HR 0.48, 95% CI 0.31-0.74, p=0.0008)8.
This benefit in PFS was shown across subsets of patients regardless of IMDC criteria or presence of bone metastases. The study did not show a statistically significant difference in overall survival (median 26.6 months vs. 21.2months, HR 0.80, 95% CI 0.53-1.21, p=0.29)8 but was not powered for the overall survival (OS) endpoint.
Thus, cabozantinib is the first multi-targeted TKI to demonstrate superiority in delaying disease progression when compared to sunitinib in the first-line setting.
Over the past year alone, several treatments have improved first-line therapy for mRCC patients. In addition to cabozantinib, the phase III trial CheckMate 214, which randomized patients to the immunotherapy combination of ipilimumab and nivolumab versus sunitinib, also improved PFS as well as OS in treatment-naïve, intermediate and poor risk mRCC patients9.
When choosing between immunotherapy versus cabozantinib for treatment-naïve patients, we recommend considering the comorbidities of the patient as well as sites of metastases. The immune mediated toxicities from combination immunotherapy should be carefully considered in patients who have underlying autoimmune disorders.
In addition, patients with metastases in sensitive sites such as the spinal column may need a faster response from cabozantinib instead of the slower time to response and possibility of tumor inflammation from immunotherapy.
When choosing between immunotherapy versus cabozantinib for treatment-naïve patients, we recommend considering the comorbidities of the patient as well as sites of metastases.
Preliminary data also suggest that biomarkers could help with treatment decisions in the future. For example, MET expression may predict for benefit of cabozantinib8, and there is a population of patients whose tumors express PD-L1 who may have more favorable outcomes to nivolumab plus ipilimumab9.
Is there a population of mRCC patients who could still derive benefit from sunitinib? In CheckMate-214, sunitinib demonstrated superior objective response rate (ORR) and PFS when compared to the ipilimumab-nivolumab combination in favorable risk mRCC patients9.
Therefore, a select population of patients with RCC are still dependent on the VEGF pathway and can benefit from directed VEGF inhibition with sunitinib rather than immunotherapy. The activity of cabozantinib relative to sunitinib in the good-risk population has not been evaluated in prospective studies.
Outside of clinical trials, sunitinib also remains a preferred first-line treatment option for patients with non-clear cell RCC, given that studies of ipilimumab plus nivolumab as well as cabozantinib have been limited to patients with clear cell RCC, the predominant RCC histology.
Future research is needed to define the role of these agents in patients with non-clear cell subtypes of RCC. Trials currently enrolling patients with non-clear cell RCC include SAVOIR (NCT03091192) and PAPMET for papillary RCC (NCT02761057) as well as atezolizumab+bevacizumab (NCT02724878) and ipilimumab-nivolumab for non-clear cell RCC (NCT02982954).
In conclusion, the armamentarium of systemic agents available for first-line mRCC has expanded beyond pazopanib and sunitinib over the past year and now includes immunotherapy as well as cabozantinib. We await results from several ongoing phase III studies, in which VEGF and immunotherapy options are combined for mRCC patients.
References:
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;35:591-7.
Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-31.
Harshman LC, Choueiri TK. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J 2013;19:316-23.
Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2016;35:2687-97.
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373:1814-23.
Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter
study. J Clin Oncol 2009;27:5794-9.Kalra S, Verma J, Atkinson BJ, et al. Outcomes of Patients With Metastatic Renal Cell Carcinoma and Bone Metastases in the Targeted Therapy Era. Clin Genitourin Cancer 2017;15:363-70.
Choueiri TK, Hessel C, Halabi S, et al. Progression free survival by independent review and updated overall survival results from Alliance A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma. Annals of Oncology 2017;28:v605-v49.
Escudier B, Tannir N, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab v sunitinib for treatment-naive advanced or metastatic renal cell carcinoma including IMDC risk and PD-L1 expression subgroups. Annals of Oncology 2017;28:v605-v49.
