Vemurafenib ‘New Option’ For Radioactive Iodine-Resistant BRAFV600E-Positive Papillary Thyroid Cancer

Inoperable, radioactive iodine-refractory papillary thyroid cancer with a BRAFV600E mutation may respond to vemurafenib

medwireNews: Phase II study findings point to a possible role for vemurafenib in patients with unresectable or metastatic papillary thyroid cancer refractory to radioactive iodine that tests positive for a BRAFV600E mutation.

After a median of 18.8 months, the BRAF kinase inhibitor given at a starting dose of 960 mg twice daily achieved a partial response in 38.5% of 26 patients who had never received a multikinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), say Marcia Brose, from the University of Pennsylvania in Philadelphia, USA, and co-workers.

Stable disease of at least 6 months was also reported for 35.0% of the group, giving an overall disease control rate of 73.0%, with median progression-free survival (PFS) of 18.2 months and median duration of response of 16.5 months, they report in The Lancet Oncology.

And a partial response and stable disease of at least 6 months were each reported for 27.3% of a further 22 patients who had previously been treated with a VEGFR multikinase inhibitor and were followed up for a median of 12.0 months while using vemurafenib. Disease control was therefore achieved in 55.0%; median PFS and duration of response were 8.9 and 7.4 months, respectively.

While the response rate was poorer for patients pretreated with a VEGFR multikinase inhibitor than treatment-naive counterparts, the researchers note that the patients had also been exposed to other agents and the rate “might still suggest a clinical benefit”.

They write that “the extent to which patients previously exposed to only one VEGFR inhibitor would benefit from vemurafenib treatment in the second-line setting is not clear, and because of the few patients in this study who had received only one previous line of therapy, this question warrants further investigation.”

Safety analysis showed a profile “generally consistent” with that reported for vemurafenib in melanoma patients, the researchers say.

The majority of multikinase VEGFR inhibitor-naïve and pre-treated patients experienced grade 3–4 side effects (65 and 68%, respectively), while dose reductions (58 and 48%) and interruptions (85 and 64%) were also common.

Three patients experienced a second non-cutaneous malignancy during vemurafenib therapy, of which two cases of squamous cell carcinoma were considered possibly related to treatment.

“Although the clinical usefulness of screening all patients with papillary thyroid cancer for BRAFV600E mutations at the time of diagnosis remains to be elucidated, our data suggest that screening for these mutations in the setting of disease refractory to radioactive iodine could identify potential treatment options offering clinical benefit for these patients”, the team concludes.

The authors of an accompanying comment question the optimal timing of vemurafenib treatment relative to that of VEGFR multikinase inhibitors in this patient population and how best to manage malignancy associated with the BRAF inhibitor.

Nevertheless, Keith Bible and Mabel Ryder, from the Mayo Clinic in Rochester, Minnesota, USA, say the study findings “clearly indicate that vemurafenib has meaningful clinical activity” in this radioactive iodine-refractory population.

“The current report by Brose and colleagues reflects clear progress towards the laudable goal of personalised medicine in the context of differentiated thyroid cancer refractory to radioactive iodine”, they write, adding that they “look forward with optimism to further advances and therapeutic opportunities towards the goal of defining context-dependent optimised treatments.”

References

Brose MS, Cabanillas ME, Cohen EEW, et l. Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; Advance online publication 22 July. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30166-8

Bible KC, Ryder M. Mutated BRAF and personalised medicine in differentiated thyroid cancer. Lancet Oncol 2016; Advance online publication 22 July. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30230-3

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