Treatment with cabozantinib reduced the rate of disease progression or death by 42% compared to everolimus in METEOR, a phase III trial comparing cabozantinib to everolimus in patients with advanced clear-cell renal cell carcinoma. The results were reported during the first Presidential Session on Saturday 26 September at the European Cancer Congress (ECC 2015), convening in Vienna, Austria, 25 - 29 September, 2015.
Lead investigator Toni Choueiri, from the Dana Farber Cancer Institute, Lank Centre for Genitourinary Oncology in Boston, USA, presented results, including prespecified subgroup analyses for progression-free survival (PFS), from the open-label phase III METEOR trial (NCT01865747).
Cabozantinib is an inhibitor of multiple tyrosine kinases, including MET, VEGFRs, AXL and RET that demonstrated encouraging clinical activity in earlier trials and is currently authorised for treatment of adult patients with progressive, unresectable locally-advanced, or metastatic medullary thyroid cancer. Expression of MET or AXL may be associated with enhanced tumour cell viability and more aggressive tumour phenotype that negatively impacts overall survival.
Cabozantinib was granted Breakthrough Therapy Designation by the US Food and Drug Administration (FDA) on 24 August 2015 for patients with renal cell carcinoma (RCC) who experienced disease progression following treatment with a tyrosine kinase inhibitor (TKI). This decision was based upon the results of the METEOR study.
Drugs receiving FDA Breakthrough Therapy Designation receive assistance during the investigational process that may include the involvement of FDA senior managers in the review, potential rolling submission and/or Priority Review of the sponsor’s New Drug Application (NDA).
PFS with cabozantinib nearly double that seen with everolimus
In METEOR, patients with measurable disease by RECIST 1.1 and Karnofsky performance status ≥70% were stratified by Memorial Sloan Kettering Cancer Center (MSKCC) prognostic criteria and by the number of prior treatments with VEGFR TKIs, then randomised 1:1 to receive daily administration of cabozantinib at 60 mg or everolimus at 10 mg. Patients were required to have progressed within 6 months of their prior VEGFR tyrosine kinase inhibitors.
Of the 658 patients randomised between August 2013 and November 2014, 71% had undergone treatment with one and 29% of patients had received 2 or more prior VEGFR TKIs. According to MSKCC criteria 46% of patients were favourable, 41% intermediate, and 13% of patients were classified as poor risk.
The study met the primary endpoint of PFS per independent radiology committee; the estimated median PFS among the first 375 randomised patients was 7.4 months with cabozantinib compared to 3.8 months with everolimus, hazard ratio (HR) 0.58; 95% CI 0.45 to 0.75 (p < 0.001).
Secondary endpoints, including the overall response rate (ORR) and overall survival (OS), also favoured cabozantinib. The ORR was significantly improved with cabozantinib over everolimus; ORR was 21% with cabozantinib compared to 5% with everolimus (p < 0.001). At the interim OS analysis (49% information fraction), the HR was 0.67; 95% CI 0.51, 0.89 (p = 0.0050) favouring cabozantinib. The criteria for early rejection of the hypothesis was not met (p ≤ 0.0019), but median OS could not yet be estimated.
Cabozantib was well-tolerated by patients in this setting. The most commonly reported serious adverse events (SAEs) with cabozantinib were abdominal pain, pleural effusion, and diarrhoea, which occurred in 3%, 2.7%, and 2.1% of patients, respectively. SAEs with everolimus included anaemia, dyspnoea, and pneumonia, which were each reported in 3.7% of patients. Treatment discontinuation due to adverse events was reported for 9.1% of patients receiving cabozantinib and 10% of patients receiving everolimus.
Dr. Cora Stenberg, who discussed the study results, said that there was enormous progress in the management of renal cell cancer with seven new drugs approved on the basis of PFS. In the last decade we saw a tremendous amount of research with drugs targeting VEGF and mTOR, and now we are witnessing research efforts in studying VEGF resistence and immunotherapy.
She said that the METEOR Study reached primary endpoint however the overall survival data are not mature. It would be good to understand if there is a biomarker implicated, at least at MET or AXL level. The study results are relevant for patients treated with prior angiogenic therapy. They are also relevant for clear cell renal cell carcinoma but she questioned the sacomatoid group. She sees cabozantinib as TKI potentially relevant in second line or later treatment option.
Improved PFS and ORR were demonstrated with cabozantinib over everolimus in patients with advanced clear-cell renal cell carcinoma who had been pretreated with VEGFR TKIs, according to the investigators. Also, the interim OS analysis showed a trend towards prolonged survival for patients receiving cabozantinib.
The authors suggest that these data will impact treatment decisions for patients with advanced clear-cell renal cell carcinoma and may change the treatment landscape altogether.
4LBA Cabozantinib versus everolimus in patients with advanced renal cell carcinoma: Results of the randomized phase 3 METEOR trial
The study was simultaneously published in the New England Journal of Medicine: Toni Choueiri, et. al, Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma, New England Journal of Medicine, DOI: 10.1056/NEJMoa1510016
The study was sponsored by Exelixis.