Updated Analysis on DECISION Trial Hints at Survival Benefit

Marcia S. Brose, MD, PhD

An updated analysis of a phase III trial hints at a possible survival advantage for patients with radioactive iodine-refractory differentiated thyroid cancer treated with the tyrosine kinase inhibitor sorafenib.

The DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer) trial met the primary endpoint of extending progression-free survival (PFS). Neither the primary analysis nor a follow-up analysis 9 months afterward showed a difference in median overall survival (OS), which had yet to be reached in the sorafenib or placebo arm, reported Marcia S. Brose, MD, PhD, an assistant professor of Otorhinolaryngology at the University of Pennsylvania in Philadelphia, at the 2014 Annual Meeting of ASCO in Chicago, Illinois.

However, an analysis that employed statistical methods to account for crossover in the placebo group yielded a statistically significant 39% reduction in the survival hazard in favor of sorafenib therapy.

“The results of the survival analysis should be considered exploratory,” said Brose. “We won’t have a reliable assessment of overall survival until we have more data from long-term follow-up.”

DECISION was a multicenter, randomized, placebo-controlled trial that evaluated oral sorafenib 400 mg twice daily in patients with locally advanced or metastatic radioactive iodine-refractory thyroid cancer. Disease had progressed within the previous 14 months, associated with at least one measurable lesion. Treatment continued until disease progression, at which time patients could receive open-label sorafenib.

The trial had a primary endpoint of PFS, and the primary analysis included 417 patients. As reported at the 2013 ASCO meeting, the results showed an almost doubling of median PFS in the sorafenib group (10.8 vs 5.8 months with placebo,P<.0001). Median OS had yet to be reached in either treatment group when the primary analysis occurred on August 31, 2012.

An updated survival analysis in May 2013 still showed no significant difference between treatment groups. Median OS in the placebo arm was 36.5 months but still had not been reached in the sorafenib group. The hazard ratio suggested a trend in favor of the sorafenib arm (HR 0.88; 95% CI: 0.63-1.24;P= .24).

DECISION investigators published the primary results inThe Lancetin April. About three-fourths of patients in the placebo arm crossed over to open-label sorafenib at progression. To account for the confounding effect of crossover on overall survival, Brose and colleagues reanalyzed the data and employed iterative parameter estimation (IPE) and rank-preserving structural failure time (RPSFT) analyses to correct for placebo crossover to open-label sorafenib.

The IPE correction resulted in a greater reduction in the survival hazard in favor of sorafenib, but the difference from placebo still did not achieve statistical significance (HR 0.79; 95% CI: 0.57-1.11). In contrast, RPSFT correction yielded a survival hazard ratio of 0.69, which proved to be statistically significant (95% CI: 0.49-0.99).

&ldquo;The key message from the DECISION trial is that we now have something that works to offer our patients with progressive, radioactive iodine-refractory thyroid cancer,&rdquo; said Brose. &ldquo;Quite literally, we have had no effective treatments for this group of patients. This is a major development for patients and for the clinicians who treat them.&rdquo;

Also at ASCO, a separate report from the DECISION investigators described the safety and tolerability of sorafenib. Although almost all patients in the sorafenib arm had one or more adverse event, most events were grade 1/2 in severity, Francis Worden, MD, an associate professor of Medical Oncology at the University of Michigan in Ann Arbor, reported in a poster presentation on behalf of DECISION investigators.

During the first treatment cycle, 37% of patients treated with sorafenib had a dose interruption. The proportion of patients requiring a dose interruption declined to less than 10% by the fifth cycle. Across cycles 2 through 9, 50% to 60% of patients in the sorafenib arm had a dose reduction.

The rate of sorafenib discontinuation related to adverse events was 4% during cycle one, declining to less than 2% during the remaining cycles.

Brose MS, Jarzab B, Elisei R, et al. Updated overall survival analysis of patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC) treated with sorafenib on the phase 3 DECISION trial.J Clin Oncol