Sherman Says Lenvatinib Approval "Likely" as FDA Decision Date Nears

Steven Sherman, MD

With a deadline of April 14, the FDA will soon make its final approval decision on the oral multikinase inhibitor lenvatinib as a treatment for patients with progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC).

The FDA is reviewing lenvatinib based on findings from the phase III SELECT trial, which were published today in The New England Journal of Medicine. SELECT randomized 392 patients with RAI-refractory DTC to lenvatinib or placebo, with lenvatinib reducing the risk of disease progression by 79% (HR = 0.21; P <.001).

Eisai, the manufacturer of lenvatinib, is hoping that the drug will become the second targeted treatment approved in recent years for RAI-refractory advanced DTC. Sorafenib (Nexavar) was approved in this setting in November 2013.

For additional insight on lenvatinib ahead of the FDA’s decision, we reached out to the lead investigator of SELECT, Steven I. Sherman, MD, associate vice-provost for Clinical Research, and professor and chair, Endocrine Neoplasia and Hormonal Disorders, at MD Anderson Cancer Center. Sherman, who says the FDA will “likely” approve lenvatinib, discusses the efficacy and safety data for the drug, sequencing with lenvatinib and sorafenib, and other emerging therapeutic options for advanced thyroid cancer.

OncLive: Can you discuss the design and results of the SELECT trial?

Dr. Sherman: This was a randomized phase III trial of lenvatinib against “placebo.” It is really not placebo, it is really TSH-Suppression hormone therapy, which is the standard of care. The starting dose was 24 mg daily, and patients were randomized in a 2:1 ratio lenvatinib versus placebo. They were evaluated radiographically at baseline by a centralized radiology team that was blinded to treatment assignment. That was both for determining eligibility as well as monitoring response. Patients continued on the drug until progression or severe/intolerable adverse events. The primary endpoint was an improvement in progression-free survival, which was what was observed in the study.

The original anticipation was that we would see an improvement from 8 to 14 months in the progression-free survival. That is how the study was powered. In fact, the final results were markedly greater than that. In the placebo arm, the progression-free survival was 3.6 months and in the lenvatinib arm, it was 18.3 months, with a hazard ration of 0.21.

Can you discuss the safety profile for lenvatinib?

So the adverse events that were seen were fairly typical of what had been seen in the earlier studies with lenvatinib and anticipated for other antiangiogenic drugs. The most common adverse event was hypertension, which although it was seen in about two-thirds of patients, in only about 1% of patients was this something that proved intractable to management. Usually it could be treated with appropriate antihypertension therapy or occasionally, dose modification of lenvatinib.

Other common events grade 3 or above included proteinuria, which had been seen in the earlier studies, and diarrhea, fatigue, decreased appetite, and weight loss, which were consistent with the earlier observations.

Specific to this population of patients, there was a very low frequency of hand-foot syndrome or palmar-plantar erythrodysesthesia. I point that out because the drug already approved in this patient cohort, sorafenib, had a very high frequency of palmar-plantar erythrodysesthesia that was observed in the pivotal phase III DECISION study. But that was only seen grade 3 and above by 3.5% of patients receiving lenvatinib in this trial.

Can you comment on the treatment-related deaths reported in the SELECT trial?

There were six deaths that were considered by the treating investigator to be potentially or definitely related to lenvatinib—probably related or possibly related. One was a pulmonary embolism and one was a hemorrhagic stroke, and these were also seen in patients by other clinicians who did not consider them related, but they have been reported with antiangiogenic therapies otherwise, so that would make sense. With four of the six, no specific cause of death was identified, and there was worsening general health, which is usually associated with progression of disease, although that wasn’t specifically defined by the treating investigators.

So given the benefits and risks you’ve discussed, do you anticipate that the FDA will approve the drug, and if so, what would be the significance for clinical practice?

I think the fact that the FDA waived an ODAC hearing in 2014 and that Dr [Richard] Pazar [director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research] specifically praised both the design of the study and its results, suggests that FDA approval is likely, although we are obviously all waiting on that final determination.

If FDA approval is received and the drug is commercially available in the United States, I think based on the results of this study, that this could become the drug of choice for first-line therapy for patients with progressive, radioactive iodine-refractory, differentiated thyroid cancer.

The other point is that a significant subset of patients in this study had previously received other tyrosine kinase inhibitor treatment, including and mostly sorafenib, and there was significant prolongation and a very similar prolongation of progression-free survival in that subset as well. So I think that this drug also readily becomes the alterative therapy if a patient progresses who is already on another TKI, such as sorafenib.

Based on the results seen in the SELECT and DECISION trials, how does the efficacy and safety of sorafenib compare with lenvatinib?

There are some differences between the two clinical trials in their design. One had to do with eligibility—in the SELECT trial for lenvatinib, patients were assessed using RECIST version 1.1, vs. 1.0 in the sorafenib DECISION trial. The other thing is eligibility was based on a centralized review of imaging to document progression of disease in the lenvatinib trial, and I don’t think that was required in the sorafenib trial. That said, if you look at the placebo arms, the progression-free survival appeared to be a bit more rapid in the lenvatinib study placebo, so they may not be completely comparable. Having said that, the degree of improvement and progression-free survival would appear to be markedly higher with lenvatinib than sorafenib. So I personally think that the effectiveness of lenvatinib is going to be superior to that of sorafenib in this patient cohort.

So in terms of sequencing the two agents in this patient population, you would use lenvatinib first?

Yes.

Are there any other emerging treatments on the horizon for advanced thyroid cancer?

Lenvatinib will presumably be the second drug with approval for first-line therapy. Cabozantinib, which is FDA approved for medullary thyroid cancer, is currently under trial in a small phase II study through the International Thyroid Oncology Group. Cabozantinib is under study specifically for second-line patients who have failed one or two previous courses of antiangiogenic TKI therapy. And so that is going to be an important study, results for which are anticipated later this year.

Moving into other approaches to the disease, I think there are proposals that are under consideration in looking at combination approaches and in particular there is interest in how immunotherapies may apply to thyroid cancer, but no data are available as of yet.

And finally, there is a randomized trial of vandetanib, which works as both an antiangiogenic VEGF-R inhibitor, but also as an EGFR inhibitor. There was a randomized phase II trial published several years ago with results that look similar to what was seen in the phase III trial of sorafenib. There is now a phase III trial for vandetanib that is ongoing as well, and I don’t know when results will be available for that.

Disclosure: Dr Sherman disclosed that he has received consulting fees from Eisai, Bayer, and Exelixis.