VEMURAFENIB FOR THYROID CANCER

Vemurafenib (Zelboraf, Roche/Genentech), a BRAF inhibitor marketed for use in the treatment of melanoma, has now shown activity in patients with refractory papillary thyroid cancer.

For the approximately 25% to 50% of patients with unresectable papillary thyroid cancer refractory to treatment with radioactive iodine, currently the available options include sorafenib (Nexavar, Bayer HealthCare) and lenvatinib (Lenvima, Eisai), which are both vascular endothelial growth factor receptor (VEGFR) multikinase inhibitors.

About half of these tumors harbor BRAF mutations, and for this patient population, vemurafenib offers a new treatment option with a new mechanism of action, say researchers reporting results from a phase 2 study published online July 22 in the Lancet Oncology.

Best responses, depending on prior treatment, ranged from 27% to 38%.

"To our knowledge, our trial represents the first prospective clinical trial and the largest dataset to assess treatment with vemurafenib for this patient population," write the authors of the international, multicenter study.

"Thyroid cancers progress slowly, but when patients do progress, there are very few treatment options," lead author Marcia S. Brose, MD, from the Abraham Cancer Center, University of Pennsylvania, in Philadelphia, told Medscape Medical News.

She explained that when the study was started, sorafenib was the only drug approved by the US Food and Drug Administration for use in these patients. It was then joined by lenvatinib, which was approved in 2015.

"But these options are not enough, as patients will ultimately progress on these agents and need additional treatments," she added. "This study is important because vemurafenib is the first non-VEGFR inhibitor to show activity in this tumor type, expanding the treatment options for these patients."

Writing in an accompanying commentary, Keith C. Bible, MD, PhD, and Mabel Ryder, MD, of the Mayo Clinic, Rochester, Minnesota, agree that the activity seen with vemurafenib is indeed real.

However, they say that several questions need to be addressed regarding when vemurafenib is best used, its activity in combination with VEGFR inhibitors currently indicated in this setting, and the clinical significance of vemurafenib-associated or vemurafenib-induced cutaneous and noncutaneous malignant disease.

"The current study 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. "Nonetheless, it remains uncertain as to whether a personalised approach in this context improves outcomes conclusively," they add.The open-label, nonrandomized study, conducted at 10 international academic centers and hospitals, included 51 patients with papillary thyroid cancers refractory to radioactive iodine and positive for BRAFV300E mutation. Dr Brose indicated that this mutation is present in up to 50% of patients with thyroid cancer and correlates with aggressive tumor characteristics. So, she said, "evaluating the activity of vemurafenib in this setting was appropriate."

Patients were given vemurafenib 960 mg twice daily every 28 days. Dose interruptions and reductions were allowed for symptomatic management of adverse events. Treatment was continued until disease progression or intolerable toxicities occurred.

Patients entered the study in one of two cohorts on the basis of prior exposure to multikinase inhibitors targeting VEGFR. Cohort 1 included 26 patients who had no prior exposure to these agents; cohort 2 included 25 patients who had been exposed.

Tumor assessment was undertaken locally with CT or MRI every 8 weeks using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Any bone lesions were not judged as target lesions but were followed as nontarget lesions.

Results

At baseline, 12% of patients in cohort 1 and 28% of patients in cohort 2 had been treated with chemotherapy (taxane or an anthracycline). Of patients in cohort 2, 84% had previously been treated with sorafenib, and 40% had been treated with small molecules, such as cediranib (AZD-2171, AstraZeneca), pazopanib (Votrient, Novartis), and sunitinib (Sutent, Pfizer).

The table below shows the clinical responses reported for cohorts 1 and 2.

	Cohort 1 (n = 26)	Cohort 2 (n = 25)
Median duration of treatment	63.6 weeks	27.6 weeks
Partial response (PR)	38.5%	27.3%
Stable disease (SD)	35%	27.3%
Disease control rate (PR + SD)	73%	55%
Median progression-free survival (PFS)	18.2 months	8.9 months
Median duration of response	16.5 weeks	7.4 months
Median survival	Not reached	14.4 months

The primary endpoint was best overall response (complete or partial) in patients in cohort 1, as confirmed on two assessments at least 4 weeks apart.

With a 38.5% partial response, the study met its primary endpoint of a planned best response of 28% in cohort 1.

Grade 3/4 adverse events were reported for 65% and 68% of patients in cohorts 1 and 2, respectively.

Serious adverse events were as follows: cutaneous squamous cell carcinoma (27% in cohort 1 and 20% in cohort 2); keratoacanthoma (8% in cohort 1 and 12% in cohort 2); dyspnea (8% in each cohort); pneumonia (8% in cohort 2); hypotension (8% in cohort 2); cerebrovascular accident (8% in cohort 2); and squamous cell carcinoma (8% in cohort 1). One patient in each cohort was reported to have a cutaneous pigmented lesion.

What's Next?

In their commentary, Dr Bible and Dr Ryder indicate that it is an open question as to when to use vemurafenib. "Under what circumstances is vemurafenib best administered as primary, or salvage, monotherapy in differentiated thyroid cancer refractory to radioactive iodine, particularly by comparison with alternative VEGFR-directed multikinase inhibitors?" they ask.

Dr Brose pointed out that FDA-approved therapies should be the first agents of choice. However, she noted that all her patients eventually progress on these. "If their tumors harbor a BRAFV600E mutation, vemurafenib will be my next agent of choice," she told Medscape Medical New