Thomas Powles, MBBS
Cabozantinib (Cabometyx) demonstrated consistent benefits compared with everolimus (Afinitor) for patients with advanced, pretreated renal cell carcinoma (RCC) in a subgroup analysis of the phase III METEOR trial that explored MET expression, according to a presentation by Thomas Powles, MD, MBBS, MRCP, at the 2016 International Kidney Cancer Symposium.
In April 2016, cabozantinib was approved by the FDA as a treatment for patients with advanced RCC following prior anti–angiogenic therapy. The TKI blocks multiple VEGF receptors, making it a potent angiogenesis inhibitor. Additionally, the agent uniquely inhibits RET and MET, raising the potential for MET expression to act as a predictive biomarker.
The median overall survival (OS) in those with high MET expression was 22.0 months with cabozantinib versus 15.2 months with everolimus (HR, 0.55; 95% CI, 0.31-0.99). In those with low MET expression, the median OS with cabozantinib was 20.8 versus 18.4 months with everolimus (HR, 0.72; 95% CI, 0.52-1.00).
These data showed a pattern toward greater benefit in patients with high MET expressing tumors; however, this trend was neither clinically meaningful nor statistically significant and was largely driven by small sample size and imbalances in the patient populations, said Powles, leader of the genitourinary cancer group at Barts Cancer Institute (BCI), London, United Kingdom
METEOR was a randomized phase III trial directly comparing the efficacy and safety of cabozantinib and everolimus in 658 patients with advanced RCC who progressed following VEGFR TKI treatment. Patients received daily cabozantinib at 60 mg (n = 330) or everolimus at 10 mg (n = 328). Approximately 30% of patients had received ≥2 prior VEGFR TKIs.
Across the full study by independent radiology review, median OS was 21.4 months (95% CI 18.7-not estimable) with cabozantinib compared with 16.5 months (95% CI, 14.7-18.8) with everolimus (HR, 0.66; 95% CI, 0.53-0.83; P
= .00026). Median progression-free survival (PFS) was 7.4 months with cabozantinib compared with 3.9 months with everolimus (HR, 0.51; 95% CI, 0.41-0.62; P
<.0001). Furthermore, cabozantinib achieved a better objective response rate (ORR) of 17% versus 3% with everolimus (P
In a secondary analysis of the study, MET expression was quantitated from archival or recently biopsied tumor tissue samples by immunohistochemistry using the SP44 antibody, and classified as MET high or low using a cut off of ≥50% for tumor tissue cells stained with an intensity of ≥2+ by immunohistochemistry. Overall, 15% of patients were classified as MET high, 59% as MET low, and 26% as MET unknown.
“I think we know more about [staining] with PD-L1 than we do in this particular area, and it’s a really hard area which I think we need to work on a lot more,” said Powles. “My gut feeling is we’re not going to be doing this in 20 years time,” he added.
When presenting the baseline characteristics of patients by MET status, Powles pointed out that the number of patients with high MET status was relatively small (cabozantinib, n = 50; everolimus, n = 51). In the MET low group, 150 patients were treated with cabozantinib and 162 were treated with everolimus.
The median PFS in those with high MET expression was 7.4 months with cabozantinib versus 3.7 months with everolimus (HR, 0.38; 95% CI, 0.23-0.62). In those with low MET expression, the median PFS with cabozantinib was 7.3 versus 4.2 months with everolimus (HR, 0.57; 95% CI, 0.43-0.76). The median PFS in those with unknown MET status was 9.1 months with cabozantinib versus 3.7 months with everolimus (HR, 0.52; 95% CI, 0.37-0.72).
“PFS is probably the more accurate endpoint that we have in VEGF-targeted therapy,” stated Powles. Overall, cabozantinib was superior for OS, PFS, and ORR regardless of MET status.
Archival tumor MET expression status by immunohistochemistry does not appear to be a predictive biomarker for benefit with cabozantinib in patients with advanced RCC. Although, Powles added that immunohistochemistry may not be the way forward in terms of tissue analysis, rather, molecular profiling of samples will be more informative.
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(7):917-927.
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