ORLANDO, FL, USA (UroToday.com) - In this session, Dr. Toni Choueiri highlighted key advances in kidney cancer in 2014 in 5 different areas.
Clinical trials comparing approved targeted agents
Clinical trials comparing approved targeted agents in 2014 provided more information regarding appropriate sequencing of therapies. An update from the COMPARZ trial, which compared pazopanib and sunitinib as primary therapy for metastatic renal cell carcinoma (mRCC), demonstrated non-inferiority of pazopanib with regards to overall survival (OS; HR 0.92, 95% CI 0.79-1.05, p=0.24). Dr. Choueiri commented that this finding will provide a benchmark for future studies using either sunitinib or pazopanib in the primary setting in the future. The INTORSECT trial, comparing temsirolimus vs sorafenib following initial sunitinib treatment, demonstrated no difference in its primary endpoint of progression-free survival (PFS), however, improved OS was seen with sorafenib (median OS 16.64 vs 12.27 months, p=0.01). Dr. Choueiri stated that it was not clear at this point why this OS difference was seen as it could not be attributable to study group differences or differences in tertiary therapies received. Finally, he discussed the phase II RECORD-3 study. This study failed to demonstrate non-inferiority of primary everolimus therapy in mRCC compared to sunitinib. In addition, utilization of everolimus followed by sunitinib resulted in worse overall survival compared to the opposite sequence. As a result, use of a VEGF inhibitor as initial therapy in mRCC remains the standard of care.- Health outcomes research
Next, he moved on to health outcomes research in the last year. He focused first on the International Metastatic RCC Database Consortium (IMDC) prognostic model which uses 6 factors for risk stratification: anemia, thrombocytosis, neutrophilia, Karnofsky performance score < 80, < 1 year from diagnosis to first-line targeted therapy and hypercalcemia. This model was validated to apply both in the first-line and second-line therapy settings. The same model was also demonstrated to be effective for risk stratifying non-clear cell RCC patients as well. Using the IMDC prognostic model allows for appropriate identification of patients most likely to benefit from cytoreductive nephrectomy. Patients with ≤ 3 prognostic factors appear to continue to experience a survival benefit in the targeted therapy era. He then highlighted research examining the effect of ACE inhibitors in mRCC as an example of a successful collaboration between academia and industry. Angiotensin II appears to play a role in tumor growth and angiogenesis. One study presented in 2014 found that patients on VEGF-targeted therapy who are also on an ACE inhibitor experienced improved OS and PFS compared to those not taking an ACE inhibitor. This finding was validated in vitro in his lab, where cell viability decreased when sunitinib was used in combination with ACE inhibitors, but not with other classes of anti-hypertensives. - Biomarkers (early stage, metastatic)
Dr. Choueiri next focused on biomarker work done in 2014. He discussed the validation of two early stage biomarkers in large cohorts. MET variant rs11762213, which was initially reported in 2012 to be predictive of worse cancer outcomes, was validated in a study out of MSKCC in 2014. In addition, a genomic assay for predicting disease recurrence initially reported by Rini et al. in 2010 was externally validated in 2014, which has implications for improving patient selection for adjuvant therapy.
The ultimate goal in biomarker development was the ability to determine the optimal therapy for each individual patient—namely personalized therapy. While many candidate biomarkers exist in metastatic disease, none are quite ready for clinical use. He highlighted 3 studies. McDermott et al. found that good pathologic features like clear cell histology or CAIX were not predictive of response to high dose IL-2. Choueiri et al. demonstrated that patients with PD-L1-positive tumors had worse PFS and OS with pazopanib and sunitinib therapy compared to patients with PD-L1-negative tumors in the COMPARZ trial. Voss et al. demonstrated that patients whose tumors had genomic alterations in mTOR or TSC1 had excellent responses to rapalogs like temsirolimus and everolimus. The PD-L1 and mTOR/TSC1 findings, while preliminary, have implications for improving therapy selection for patients in the future. - Emerging targets and selected clinical trials
Dr. Choueiri then turned his focus to clinical data from trials involving PD-1 inhibitor, nivolumab. Radiographic response was seen in approximately 20% in the phase II trial of single agent nivolumab. A high response rate was seen in PD-L1-positive patients, however there were responses also seen in patients that were PD-L1 negative. He stated that the unreliability of PD-L1 as a marker for response was problematic but ultimately not as problematic as the fact that significant variability exists between different immunohistochemistry assays for PD-L1. He emphasized the urgent need for standardization of the PD-L1 assay.
The combination of nivolumab with either VEGF TKIs (AMIN trial) or ipilimumab (HAMMERS trial) appears to result in increased rates of response (~40-50%) but is accompanied by higher rates of toxicity. Interestingly, response rates were similar in PD-L1-positive and negative tumors, and there actually appears to be improved response with combination therapy in patients who are PD-L1 negative. - Non-clear cell RCC
Finally Dr. Choueiri provided an overview of published work pertaining to non-clear cell RCC. The TCGA found that mitochondrial DNA and TERT upregulation are important to disease biology in chromophobe RCC, and that a low rate of mutations in “cancer relevant genes” (e.g., TP53, mTOR pathway) was seen. He presented the ESPN trial that compared everolimus and sunitinib in non-clear cell RCC, and found no difference in PFS or OS, though a trend for improved OS was seen in non-sarcomatoid RCC patients with sunitinib. He finished by showing that PD-L1 expression is also associated with worse OS and relapse-free survival in non-clear cell RCC as it is in clear cell RCC.
In conclusion Dr. Choueiri stated that while there were no major changes in the therapeutic landscape in mRCC in 2014, advances were made in biomarker and prognostic model validation. Initial PD-1 inhibitor trials demonstrate promising results, but again he stressed that PD-L1 assays need to be standardized. He finished by emphasizing the need for further work in non-clear cell RCC.
Presented by Toni K. Choueiri, MD at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA
Dana-Farber Cancer Institute, Boston, MA USA
Reported by Timothy Ito, MD, medical writer for UroToday.com