Expert Says Lenvatinib Is Standard Frontline Option for RAI-Refractory DTC

The FDA approved lenvatinib as a treatment for patients with RAI—refractory DTC in February 2015, making it the second TKI approved for patients with thyroid cancer. In November 2013, the FDA also approved sorafenib (Nexavar), another tyrosine kinase inhibitor, as a first- or second-line treatment option for patients with RAI-refractory DTC.

The approval for lenvatinib was based on findings from the 392-patient phase III SELECT trial, in which treatment with agent reduced the risk of disease progression by 79% (HR, 0.21; 99% CI, 0.14-0.31;P<.0001).¹Median treatment duration was 13.8 months with lenvatinib and 3.9 months with placebo. Median progression-free survival was 18.3 months versus 3.6 months, respectively.

The objective response rate with lenvatinib was 64.8% versus 1.5% with placebo. Four patients in the lenvatinib arm had complete responses versus none in the placebo group, with partial responses in 165 and 2 patients, respectively.

Treatment-related adverse events reported with lenvatinib include hypertension, proteinuria, decreased weight, fatigue, and diarrhea, along with palmar-plantar erythrodysesthesia syndrome. The most common adverse events with sorafenib are hand-foot skin reaction, diarrhea, alopecia, weight loss, hypertension, rash, decreased appetite, stomatitis, nausea, pruritus, and abdominal pain.

In an interview withTargeted Oncology, Martins, medical director of Outpatient General Oncology/Hematology at Seattle Cancer Care Alliance, medical director of Thoracic/Head and Neck Oncology, and professor at University of Washington School of Medicine, discussed the impact of lenvatinib in patients with DTC, how and when it should be used in clinical practice, and the future potential for the agent.

TARGETED ONCOLOGY:With lenvatinib being on the market for over 1 year, how has the treatment landscape of DTC changed?

MARTINS:

The lenvatinib papers show something very important—that there is a lack of cross-resistance between these tyrosine kinase inhibitors for thyroid cancer. In one of the lenvatinib papers, the response rate in patients who had received a prior TKI was actually pretty high.

We now have 2 options that are FDA approved. The number of options for patients who have RAI-refractory disease has expanded quite a bit and, very frequently, these patients have the opportunity to go from one oral TKI to another oral TKI and remain with disease control.

I would say that lenvatinib is probably the one that has the highest response rates.

TARGETED ONCOLOGY:Is lenvatinib being used, more or less, as the standard of care in the first-line setting?

MARTINS:

I think so. I don&rsquo;t have the data to support that statement, but I would imagine that that is the case.

TARGETED ONCOLOGY:What factors are considered when choosing between sorafenib and lenvatinib as a first-line therapy for patients with DTC?

MARTINS:

The first question in treating patients with thyroid cancer who are RAI-refractory is, &ldquo;Do they need therapy, period?&rdquo; Some patients have a very indolent course of their disease, and they may present with multiple small pulmonary nodules from which they have absolutely no symptoms. We should try to avoid making the treatment into a disease.

There are a number of patients who go years without receiving therapy with very slow-growing tumors. The question is, &ldquo;When is the appropriate time to pull the trigger in therapy?&rdquo;

I think patients are very attracted to the concept of an oral therapy that is not really conventional chemotherapy, and I can certainly understand that. However, these drugs have side effects. Sometimes, once they start taking them, they realize that its appeal is not as benign as one perhaps would fantasize, despite all of the indications we provide upfront. There&rsquo;s nothing like having the experience itself.

TARGETED ONCOLOGY:What are some of the side effects with these agents?

MARTINS:

Although they are both tyrosine kinase inhibitors, side effects do differ from drug to drug. Sorafenib may have, in comparison with other drugs, more of the hand-foot syndrome problem, while lenvatinib may have more of the mucositis or gastrointestinal complaints. They need to be proactively managed. Not infrequently we, as the trials with lenvatinib have shown, have to resort to dose reductions.

TARGETED ONCOLOGY:What are you seeing done differently in clinical practice? Are patients receiving treatment earlier?

MARTINS:

In our practice, we see many more patients with advanced thyroid cancer than we used to. When all we had to offer was conventional chemotherapy, there was nihilism toward benefits of treatment. Now, because we have so many more options and they&rsquo;re not conventional chemotherapy, patients are referred to us much more often than they used to be, even at advanced stage.

TARGETED ONCOLOGY:What other work with lenvatinib is ongoing?

MARTINS:

My intuition is that, as far as with the approvals of both sorafenib and lenvatinib, we may go through a period of a &ldquo;drought&rdquo; of research with tyrosine kinase inhibitors in this area. Obviously, in solid tumor oncology, there is a lot of interest about immunotherapy. Would that also be an option for this disease? I think time will tell.

In lung cancer, which is another disease that I treat, the combination of immunotherapy with TKIs has not that been that exciting.

TARGETED ONCOLOGY:What are some of the biggest questions still remaining with lenvatinib?

MARTINS:

One question that remains is deciding what the ideal starting dose should be. It&rsquo;s very, very frequent that patients require dose reductions, and I think there is a trial looking at that. That is an important question.

Traditionally, in oncology, we focus on finding out what the highest tolerated dose we can deliver to someone is. It would be much harder to find out what is the least equally effective drug we can give to somebody because, most of the time, that would be associated with less side effects. But, evidently, designing such research is complicated.

TARGETED ONCOLOGY:What are the biggest challenges in thyroid cancer to overcome in the next few years?

MARTINS:

There is no question that, despite the reports of driver mutations with anaplastic thyroid cancer, it remains an incredibly hard disease to treat—and, it&rsquo;s a rare one. In thyroid cancer, that is the biggest challenge.

References

1. Schlumberger M, Tahara, Wirth LJ, et al. Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer. N Engl J Med. 2015;372:621-630