San Antonio, Texas USA (UroToday.com) The management of metastatic renal cell carcinoma (RCC) has seen a rapid change in the over the last 2 years with the addition of several treatment options to the armamentarium available for the treatment advanced RCC. Most exciting has been the approval of PD1 immunotherapy (nivolumab) by the FDA as a second line treatment for patients with advance RCC. Recently several trials have been initiated which includes some of this novel treatments in the 1st line setting which may change the landscape of treatment of the disease.
In this session, Dr. Choueiri from the Dana Faber Cancer institute presented the current state-of-the-art management of metastatic RCC. The 1st line management of advance RCC has not changed significantly since the COMPARZ trial which showed comparable survival in patients treated with sunitinib or pazopanib, with pazopanib having better side effect profile. Most the progress being done is in the second line treatment with the addition of nivolumab, cabozantinib and lenvatinib all showing a significant difference in progression and overall survival not seen with prior second line treatments such as axitinib or everolimus.
The publication of Checkmate-25 in 2015 showed a significant improved overall survival (OS) patients treated with nivolumab compared to everolimus in the second line setting. Surprisingly there was no difference in progression free survival (PFS) between the 2 groups. The expression of PD-L1 was found to be prognostic but not predictive of response which ratifies this discordance between the OS and PFS. Given the significant difference is OS seen with checkpoint inhibitors, nivolumab is now being assessed as 1st line therapy in combination with ipilimumab vs. sunitinib in Checkmate 214.
The combination of VEGF + mTOR inhibitors in 1st line therapy was associated with severe side effects and no improvement in survival. A recent study by Motzer and colleagues (Lancet Oncol, 2015), showed that the addition of a lenvatinib to everolumis as a second line treatment showed a significant improvement in PFS compared to lenvatinib or everolimus alone (14.6 months vs. 7.4 months vs. 5.5 months). Given this data the CLEAR study was been launched to assess the effect of the combination of lenvatinib and everolimus in the 1st line setting.
Cabozantinib, c-MET inhibitor that targets the MET pathway, has shown good response in patients who have failed VEGF treatment. The MET pathway appears to be upregulated with complete blockade with the VEGF pathway which may explain the increase invasiveness and metastatic potential of some tumors following VEGF blockade. The effect of cabozantinib as a second line agent was then tested against everolims showing a significant difference in both PFS and OS. There is ongoing accrual of patients into a trial looking at cabozantinib as 1st line agent compared to sunitinib.
When asking the question if this clinical trials translate to clinical practice there are several limitations that clinical trials pose such as tight selection criteria which leaves gap in patients with poor performance status, older patients, patient in whom nephrectomy was not possible, patients with brain metastasis, and those with renal and liver dysfunction. Dr. Choueiri has initiated an international multi-institutional database including 35 centers which seeks to finds this answers to this questions. Even with the known limitations associated with database research, the data was been able to be used to provide answers to key questions previously unknown. For example, the data was used to assess the progression free survival (PFS) of patients eligible for trials vs. patients found ineligible treated with 1st line therapy (citation). The study showed that a significant amount of patients (43%) would have been found ineligible for a clinical trial given current criteria. On evaluation of cohort PFS there was clear difference between the groups with ineligible patients having a worse PFS (5.2 months vs. 8.7 months, p>0.001). The database was also used to assess the impact of cytoreductive nephrectomy in the targeted area, given the slow accrual from the CARMENA trial (Citation). The data showed that cytoreductive nephrectomy is associated with a survival advantage. The data base currently being enriched with tumor and serum samples with the hope to able to further the study with genetic profiling and biomarker discovery.
In summary, there is great excitement regarding the use of these novel agents in the primary setting along with potential combinations which may further improve the survival of patients with advance RCC. Furthermore, the addition of biological samples to the multi-institutional database has the potential to allow the study of unrepresented populations to allow a better generalization of the survival data into the clinical setting.
Presented By: Toni Choueiri, MD, Dana Faber Cancer Institute
Written By: Andres F. Correa, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center
17th Annual Meeting of the Society of Urologic Oncology - November 30 -December 2, 2016 – San Antonio, Texas USA