Adding Everolimus to Sorafenib Improves PFS by 14 Months in Refractory Differentiated Thyroid Cancer

Marcia S. Brose, MD, PhD

Marcia S. Brose, MD, PhD

The addition of everolimus to sorafenib extended progression-free survival (PFS) in patients with metastatic differentiated thyroid carcinoma (DTC) that had progressed on sorafenib alone, according to findings from a single-arm open-label phase II study presented at the 2015 American Society of Clinical Oncology Annual Meeting.

The study showed a median PFS of about 14 months following introduction of everolimus, without a significant increase in toxicity. As such, everolimus represents the first potential effective therapy in the second-line setting for patients with advanced radioiodine-refractory DTC.

Tissue analysis from patients with DTC treated with sorafenib whose disease had progressed has demonstrated activation of the PI3K/Akt/mTOR signaling pathway, according to lead investigator Marcia S. Brose, MD, PhD, regarding the rationale for choosing everolimus as add-on therapy.

“We took progressing nodules and saw that there was tumor heterogeneity, and some of the cells [in progressing patients] had upregulation of Akt pathway,” said Brose, assistant professor of otorhinolaryngology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. “We also did an analysis of all of the patients pretreatment, and it turned out that patients who had elevated levels of phospo Akt in the nucleus were more likely to not get a response. So in two different settings we saw that high phospho Akt was associated with the worse outcome, whether it was [during] response or at the time of progression.”

Sorafenib is the standard first-line treatment for advanced radioiodine-refractory DTC, approved by the US Food and Drug Administration for this indication in 2013, following the completion of the DECISION trial. All patients eventually become resistant to sorafenib, however, and experienced disease progression. “All of these patients progressed on an average of about 11 months [based on DECISION], so while it was great to give these patients an extra year of PFS, there was no option after that,” said co-investigator Christian Squillante, MD, senior fellow at the University of Pennsylvania.

Thirty-five patients with metastatic or unresectable iodine-refractory thyroid carcinoma and evidence of disease progression by RECIST criteria were enrolled in the single-arm study. Patients were started on sorafenib at a dosage of 200 mg/day lower than their previously tolerated dose, combined with everolimus, 5 mg/day. If tolerated, doses of both were increased incrementally to a maximum daily dosage of 800 mg/day of sorafenib and 10 mg/day of everolimus.

Patients who progressed on sorafenib alone were enrolled while still taking sorafenib. Those who had previously discontinued sorafenib due to progression were treated with sorafenib again for at least 1 month prior to enrollment in order to reacclimate them to sorafenib before starting the combination.

Thirty-three of 35 patients enrolled were dosed; 3 withdrew due to toxicity or other medical issues prior to imaging, leaving 30 patients evaluable for response. Of these, 22 patients (73%) derived clinical benefit, defined as either a partial response or stable disease >6 months. The best response was stable disease >6 months in 21 of the 22 patients with clinical benefit. The median PFS was 13.9 months (95% CI, 7.15-24.75), which met the primary endpoint, as the null hypothesis was rejected.

The sequential administration of sorafenib and everolimus, rather than initiating the combination upfront, enabled more than 50% of patients to achieve daily doses of 10 mg of everolimus and at least 600 mg of sorafenib. According to Brose, these doses are greater than those observed in prior trials of the combination, which she attributes to acclimation of the skin to sorafenib prior to starting everolimus, and the few instances of grade 3/4 toxicity. “Hand-foot skin reactions were temporal to the first few months,” she said. “Because patients went into progression a year out [on sorafenib], by the time they went on everolimus, they weren’t having problems with hand-foot skin reaction that could be made worse.”

Most adverse events were grade 1 or 2, with the most common being malaise/fatigue, diarrhea, anemia, leukopenia, hypocalcemia, hypercholesterolemia, and weight loss. Grade 3/4 adverse events included anemia (24.2%), hypokalemia (21.2%), leukopenia (15.2%), and hypophosphatemia (12.1%).

Brose MS, Troxel AB, Yarchoan M, et al. A phase II study of everolimus and sorafenib in patients with metastatic differentiated thyroid cancer who have progressed on sorafenib alone.J Clin Oncol. 2015;33 (suppl). Abstract 6072.