SELECT Trial Establishes Lenvatinib’s Role in RAI-Refractory DTC

Lori J. Wirth, MD

Following its approval, lenvatinib (Lenvima) has become a primary treatment option for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). While other therapies are available for specific genetic alterations, lenvatinib is generally the top pick considered in the first line in the absence of these alterations.

The phase 3 SELECT trial (NCT01321554) which compared lenvatinib with placebo for the treatment of patients with RAI-refractory DTC served as the basis of the agent’s FDA approval in 2015. SELECT, a randomized, placebo-controlled phase 3 trial, sought to investigate the primary end point of progression-free survival (PFS) and secondary end points of overall response rate (ORR), overall survival, and safety.

In the study, lenvatinib elicited a PFS advantage and showed good responses among those with RAI-refractory DTC. Among those treated with lenvatinib, the median PFS was 18.3 months vs 3.6 months for those treated with placebo (HR, 0.21; 99% CI, 0.14-0.31; P <.001). Additionally, lenvatinib exhibited a high ORR of 65%, with most nonresponsive patients showing stable disease.

For safety, the adverse events (AEs) seen with lenvatinib were similar to those previously observed with other VEGFR multikinase inhibitors, including hypertension, diarrhea, decreased appetite, and weight loss. While less common, potentially serious AEs included palmar plantar erythrodysesthesia and transaminitis.

In an interview with Targeted Oncology^TM, Lori J. Wirth, MD, associate professor of medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, delved into how the data from SELECT established lenvatinib as a frontline therapy for patients with RAI-refractory DTC.

Thyroid cancer of a woman, medically 3D illustration, front view: © Axel Kock - stock.adobe.com

Targeted Oncology: Can you discuss the methods and design of the SELECT trial?

Wirth: The SELECT trial was a randomized, phase 3 trial investigating lenvatinib compared to placebo in patients with progressive radioiodine-refractory differentiated thyroid cancer. Thyroid cancer can be relatively indolent, so patients were required to have disease progression within the first 14 months prior to entering the trial in order to be eligible. There was a 2:1 randomization to lenvatinib vs placebo, and then crossover was incorporated into this study design, so it was blinded, of course, and then when patients were found to have disease progression that was centrally confirmed, they were unblinded, and those that were on the placebo arm then were offered crossover to the lenvatinib active drug.

The primary end point of the trial was progression-free survival, and the typical secondary end points investigated as well [were] response rate, overall survival, [adverse] effect profile, and so forth.

What were the efficacy findings from the trial that led the FDA to approve lenvatinib for this patient population?

SELECT did lead to the approval of lenvatinib by healthcare authorities around the world for the treatment of patients with iodine-refractory, progressive, differentiated thyroid cancer, and that was based on a very significant progression-free survival benefit with lenvatinib compared [with] placebo. There was an improvement of 14 months in PFS from the placebo arm to the lenvatinib arm. In the patients randomized to placebo, their median PFS was 3.6 months, whereas in the patients randomized to the lenvatinib arm, their median PFS was over 18 months. That was a big progression-free survival benefit.

We also saw good objective response rates in patients treated with lenvatinib. The objective response rate that was centrally confirmed was 65%, so we see high responses. In the patients who did not meet the criteria for response, most of those patients did have stable disease as their best response. There were very few patients who had disease progression as their best response when they were on lenvatinib in SELECT.

Can you discuss the safety data from the phase 3 SELECT trial?

Lenvatinib is a multikinase inhibitor, and it does inhibit VEGFR1, 2, and 3, as well as several other kinases, and it does have [adverse] effects that are very similar to other VEGFR multikinase inhibitors. So, the most common [adverse] effects that we encountered in SELECT were hypertension, diarrhea, fatigue, maybe a little bit of nausea, [and] anorexia.

We did see some palmar plantar erythrodysesthesia; [that is] the hand-foot syndrome, and then other less common toxicities included transaminitis. There was a relatively low rate of prolonged QT interval, but important to know about because it needs to be monitored, of course. And then there are also very uncommon but potentially serious [adverse] effects that include increasing bleeding or blood clotting disorders.

Following its approval, what is the current role of lenvatinib for the treatment of patients with RAI-refractory differentiated thyroid cancer?

Lenvatinib is 1 of our go-to drugs for patients with progressing iodine-refractory differentiated thyroid cancer. In the US, there are other therapies that are available for a subset of patients with iodine-refractory differentiated thyroid cancer, namely selpercatinib [Retevmo] for patients with RET fusion-positive disease, and then larotrectinib [Vitrakvi] and entrectinib [Rozlytrek] for NTRK fusion-positive disease.

In the absence of those uncommon kinase fusions, lenvatinib is generally considered the first-line therapy for patients when they have progressive iodine-refractory differentiated thyroid cancer. It is interesting because the most common driver alteration that is seen in thyroid cancer is a BRAF V600E mutation, and there is a tissue agnostic approval for dabrafenib [Tafinlar] and trametinib [Mekinist] for BRAF V600E-mutated disease, and that could be considered appropriate to consider in BRAF-mutated iodine-refractory differentiated thyroid cancer as well.

However, we do not have a big trial that has investigated dabrafenib or trametinib in this patient population, particularly in the first-line setting. There was a smaller [National Comprehensive Cancer Network (NCCN)]-sponsored study that was done that did not show activity that seemed to be as good as we saw with lenvatinib in similar patients in the SELECT trial. So, most people, I think, consider lenvatinib as an appropriate first-line therapy, even when a patient's disease harbors a BRAF V600E mutation.

Are there any other trials evaluating lenvatinib in other combinations or disease states?

One of the things that's been a challenge in the field is that in the SELECT trial, we saw that lenvatinib really works so well. It has been difficult to design trials with new approaches that could perform better than lenvatinib. So, I guess it is a good problem to have, but nonetheless, we always want to be moving the field forward.

There has been interest in the combination of lenvatinib plus pembrolizumab [Keytruda] in patients with thyroid cancer. There was a small multicenter, 2-arm, international Florida Oncology Group trial that was performed investigating lenvatinib plus pembrolizumab in 2 different patient cohorts. One in previously untreated patients with iodine-refractory, progressing, differentiated thyroid cancer, and then the second cohort was in patients that were already on lenvatinib who progressed, and at the time of progression, then pembrolizumab was added, and the lenvatinib was continued.

That study has not yet been published, but it has been presented in abstract form at a couple of meetings, and it does look like there is some promise with activity. But again, [it is] very difficult to know whether we could see even better outcomes with lenvatinib/pembrolizumab compared with lenvatinib alone in the previously untreated patient population.

One thing that I will say about that combination that is also of interest is that lenvatinib plus pembrolizumab is being studied in more aggressive thyroid cancers, namely anaplastic thyroid cancer and poorly differentiated thyroid cancer, in a study being conducted in Germany, and then also here in the United States. The preliminary data that had been presented from the German study have looked very intriguing.

What unmet needs still exist in the thyroid cancer space?

There are a number of unmet needs for patients with iodine-refractory differentiated thyroid cancer. One of them, I think, is knowing when to best initiate therapy. We did take a look at this question from the data from the SELECT trial to try to tease out this really important question because of this toxicity profile of lenvatinib and the fact that differentiated thyroid cancer can grow relatively slowly, and patients can be asymptomatic from their disease for some time. There has been an interest in maybe holding off for as long as possible before starting lenvatinib to spare patients having to deal with the [adverse] effect profile of the drug.

We did look at the data that are available from lenvatinib [in] the SELECT trial and did see that it does look like the progression-free survival [and] the objective response rates are better when the drug is started earlier in patients rather than when patients have a higher disease burden or when they are more sick from their thyroid cancer. But still, it is challenging to know when the patient needs to initiate therapy with lenvatinib vs continued disease monitoring and [thyroid stimulating hormone (TSH)] suppression for some time.

I think it is really important to kind of individualize that decision with the patient and talk with the patient about what the patient's goals are and what their considerations are. For patients who want to have the best treatment benefit and perhaps survive as long as possible, there are some data that suggests that earlier initiation of lenvatinib does offer better efficacy, whereas those patients that really want to prioritize quality of life really do not want to have symptoms related to therapy, [so] delaying the initiation of therapy might make sense.

What advice do you have for oncologists using lenvatinib when treating patients with differentiated thyroid cancer?

One piece of advice that I would have for oncologists seeing patients with differentiated thyroid cancer is that this is an uncommon disease. In general, we do not see a lot of patients with differentiated thyroid cancer in our oncology clinics. When patients do not have a large burden of disease and when they are asymptomatic, there is time to learn a little bit more about the disease, and also the particular patient's version of the disease because some differentiated thyroid cancers progressed very slowly over time, others progress more rapidly over time, and getting a handle for exactly what the rate of progression is before initiating therapy can be very helpful to understand.

Another thing that I would say is that it is important to confirm that patients have iodine-refractory disease. There are patients who have metastatic thyroid cancer who might actually benefit from and respond to radioactive iodine, and we want to make sure that radioactive iodine is offered to patients who might have some benefit from that therapy. Our endocrinology colleagues who tend to follow these patients and refer them to us in medical oncology are always happy to discuss their patients and help the medical oncologist who may not know the patient quite as well understand a little bit better what that particular patient's version of thyroid cancer might be.

The other thing that I would say in terms of a tip is that it is important to make sure that patients are in good shape prior to initiating lenvatinib. Patients do need to have good blood pressure control before initiating lenvatinib. Hypertension can be seen early in the course of starting therapy. Patients need to be monitoring their blood pressure, need to know when to call for hypertension, blood pressure management needs to be initiated right away. You don't want to wait a couple of weeks after seeing hypertension before starting drug therapy for hypertension in patients.

We actually analyzed the pharmacodynamics of treatment-emergent hypertension in patients on the SELECT trial and did see that there was a progression-free survival benefit, but also an overall survival benefit in the patients who developed treatment-emergent hypertension on lenvatinib in SELECT. One thing that you do not want to do is stop lenvatinib as soon as patients develop hypertension. You want to optimally manage the hypertension and keep them on lenvatinib because that predicts a strong benefit from the therapy in those patients. The other thing is that I think can be helpful is to make sure that you are taking advantage of your dietitian colleagues to help patients manage the diarrhea and anorexia and mild nausea that can be seen because it can be difficult for patients to maintain a healthy nutritional balance and maintain their weight while on lenvatinib and dealing with that tricky combination of diarrhea,

anorexia, and a little bit of nausea.

REFERENCE:

1. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi:10.1056/NEJMoa1406470