ESMO 2013-VEMURAFENIB FOR BRAF MUTATED THYROID CANCER

Encouraging phase II study results of vemurafenib in molecularly targeted subset of patients.

• Date : 28 Sep 2013
• Topic : Endocrine cancers

Vemurafenib may offer sorely needed novel treatment for a subset of patients with metastatic or unresectable papillary thyroid cancer that is resistant to radioactive iodine therapy. Vemurafenib demonstrated antitumour activity in the phase II study of patients with BRAFV600E-mutated papillary thyroid cancer who were either tyrosine kinase inhibitor (TKI) treatment naive or had received prior TKI treatments; however treatment naive patients showed greater benefit. 

Findings were reported 28 September, 2013 by Dr. Marcia Brose of the  Department of Hematology/Oncology, Abramson Cancer Center of the University of Pennsylvania, USA as a late-breaking abstract in the Head and Neck Proffered Papers Session (Abstract E17-7119) at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress. The European Cancer Congresses are organised in joint partnership with ESSO, EACR, EONS and SIOPE as a forum for the latest in oncology research and to offer multidisciplinary and multi-professional educational opportunities in oncology. The 2013 Congress convened in Amsterdam, The Netherlands from 27 September until 1 October.

Activating BRAF V600E mutations occur in 50% of patients with papillary thyroid cancer

Dr. Brose headed a US research team of vemurafenib, a kinase inhibitor that targets tumours with BRAF V600E mutation, in the treatment of patients with papillary thyroid cancer. Activating BRAFV600E mutations have been reported to occur in approximately 50% of patients with this tumour type and have been established as an indicator of poorer prognosis.

Vemurafenib is approved by EMA and FDA for the treatment of melanoma where BRAF V600E mutation has been identified and was the first drug approved for BRAF mutated cancer, leading the team to hypothesise that vemurafenib inhibition of mutated BRAF kinase may be of clinical benefit to patients with papillary thyroid cancer.

Following the demonstration of response or stable disease in 3 patients with BRAF V600E-mutated papillary thyroid cancer in a phase I trial of vemurafenib, this open-label phase II trial (NCT01286753, NO25530) was designed to evaluate the possible benefit of vemurafenib  in patients with BRAF V600E mutated papillary thyroid cancer. The study’s primary endpoint was the best overall response rate (BORR) as determined by RECIST criteria in the treatment-naive arm. The secondary endpoints were BORR in the pretreated arm, progression-free survival (PFS) and overall survival (OS) in both treatment arms.

Encouraging results from the phase II study

The trial enrolled 51 patients at ten world-wide centres between June 2011 and January 2013. Patients had progressive papillary thyroid cancer that was refractory to radioactive iodine (RAI) and had been confirmed positive for BRAF V600E mutation by cobas^®4800 V600 Mutation Assay. Overall, patients had ECOG Performance Status 0 or 1 and slightly more than half (53%) were aged 65 years.

Patients were assigned to either cohort 1 (C1, n= 26) if they were TKI treatment naive or cohort 2 (C2, n= 25) or if they had been previously treated with TKIs. All patients had undergone prior surgery and RAI treatment. Three (12%) patients in the cohort C1 and 7 (28%) C2 patients had previously received chemotherapy and 21 (84%) C2 patients had received prior sorafenib.

Both cohorts received vemurafenib at 960 mg tablets by mouth twice daily and were assessed for tumour response after every 8 weeks of treatment.

The primary endpoint analysis was preplanned for six months after enrollment of the last patient. The analysis demonstrated BORR for patients in C1 of 35% and 26% in C2; no complete response (CR) was reported and all BORR were partial response (PR). The clinical benefit rate (defined as CR+PR+ stable disease (SD) = 6 months) was 58% and 36%, in C1 and C2, respectively. Median PFS at the time of data cut-off for the analysis was 15.6 months (95% confidence interval [CI] 11.2, NR) in C1 and 6.8 months (95% CI 5.38, NR) in C2. Seven patients in C1 and 11 patients in C2 cohort discontinued treatment due to progressive disease.

The overall toxicity profile was consistent with that seen with vemurafenib treatment in melanoma patients with exceptions of higher rates of weight loss, dysgeusia, anaemia, increased creatinine, and liver laboratory abnormalities that were seen in patients with papillary thyroid cancer. Common adverse events included rash, fatigue, weight loss, and increased bilirubin.

In this study vemurafenib was associated with antitumour activity in treatment-naive and TKI-pretreated patients with RAI refractory, progressive, BRAFV600E-mutated papillary thyroid cancer. The results, especially the tolerability of treatment and median PFS of 15.6 months in TKI treatment-naive patients showed vemurafenib to be an encouraging novel treatment for papillary thyroid cancer that warrants further evaluation.