What is the SELECT study?
The SELECT study is a phase III trial; it’s a randomised trial using lenvatinib with a control of placebo. This was performed in patients with refractory thyroid carcinoma with advanced disease including metastatic patients with progressive disease. Patients had refractory thyroid carcinoma, refractory means that they had advanced disease which could not be treated with radioiodine. As you know, radioiodine is the usual form of treatment for patients with distant metastases but when there is no uptake of radioiodine in distant metastases or when metastases progress despite uptake of radioiodine, these patients are called refractory to radioiodine.
When the patient has refractory thyroid carcinoma with metastases the overall survival is limited so the median overall survival is between 3-5 years after the discovery of distant metastases. So there is indeed an unmet medical need because these patients need some treatment and we had no effective treatment modalities.
How many people were involved in the study?
This study included 392 patients with refractory thyroid carcinoma; most of them had distant metastases and all patients had progressive disease demonstrated by independent radiological review which eliminated patients who were considered by investigators as progressive disease but in fact had no progression. This is probably why the PFS in the placebo arm was so short, three months.
What are the key findings from your study?
This study compared placebo and lenvatinib treatment. Randomisation was one to two, two in the lenvatinib arm, one in the placebo arm, and the main objective was progression free survival improvement. So the main objective was reached and the PFS, progression free survival, means that the progression from randomisation until progression documented by independent radiological review was 3.6 months in the placebo arm and it was prolonged by 14.7 months to 18.3 months in the lenvatinib arm. So this is a fantastic improvement of progression free survival.
Why is progression free survival an important endpoint?
PFS is probably the best indicator that overall survival is improved. We cannot study direct improvement of overall survival because patients in the placebo arm were allowed to cross over which means that when they progressed in the placebo arm they were allowed to receive lenvatinib. So we had two groups of patients, one treated immediately with lenvatinib and the other group treated after placebo, after progression on placebo, with lenvatinib. So the difference of overall survival between these two groups of patients cannot be demonstrated. The best surrogate marker of improvement of overall survival is improvement of PFS and because the PFS is improved by more than 14 months I believe that overall survival of these patients on the lenvatinib treatment would be improved.
What other endpoints were there?
There is another endpoint which was also dramatically improved which is the objective response rate. We had 65% of objective responses including 2% of complete response. This is probably the first time a complete response has been observed in patients with metastatic refractory thyroid carcinoma, probably the first time ever. This objective response rate is much higher than those reported with previous anti-tyrosine kinase inhibitors. So I think that both PFS prolongation and very high objective response rate make lenvatinib very attractive as treatment.
What side effects did you see and how were they managed?
We have observed side effects, toxicities – hypertension, asthenia, diarrhoea, fatigue, proteinuria, so there were a lot of side effects but all could be managed by dose reduction or withdrawal whenever necessary. So we also used symptomatic treatment and with the decrease in the doses with the symptomatic treatment many patients behaved almost normally. I have some patients in
Villejuif who were treated with lenvatinib and who just continued to work, they had a totally normal life, totally normal. But dose had to be reduced in more than two-thirds of patients and the treatment was discontinued in 14% of patients due to side effects. So it means that it is toxic.
How many people have progressive radioiodine-refractory differentiated thyroid cancer worldwide?
We have a close estimate in France of incidence of refractory thyroid carcinoma with metastatic disease and the incidence is about 5 per million population. So in France with 60 million we have 300 new cases per year and I think the incidence is very similar in all countries but most thyroid cancer patients can be treated and cured with standard treatment and there is a very small proportion of patients who are not curable with standard treatment and these patients are called refractory thyroid carcinoma. So, to give a number, in France we have 8,000 new cases per year and among these 8,000 cases we have 300 cases who are refractory thyroid carcinomas so it’s a very small proportion.
What is the impact of radioiodine-refractory differentiated thyroid cancer on patients?
More than 90% of patients with thyroid carcinoma can be treated and cured so they have a normal life expectancy. Now, among these patients some will develop distant metastases and a third of these patients with distant metastases will be cured with radioiodine. But those who are not cured with radioiodine and who have distant metastases are called refractory thyroid carcinoma. From the discovery of distant metastases the median survival is only 3-5 years, so these patients may die from their disease, from their refractory thyroid carcinoma. The goal of treatment now, the goal of research in the field of thyroid carcinoma is to improve this overall survival of this small group of patients. Lenvatinib is a good example of a treatment which will probably prolong this overall survival significantly.
What treatment options are currently available for radioiodine-refractory differentiated thyroid cancer?
One option is chemotherapy, which is almost ineffective, cytotoxic chemotherapy. The other option is Nexavar, sorafenib, which has been labelled very recently in the US by LGA and in Europe by the EMA. In the SELECT study about 20% of patients had previously received the first line of anti-angiogenic drug and the results, the benefits of lenvatinib treatment, were similar in patients who were naïve for any other treatment, systemic treatment, and in patients in whom lenvatinib was given as second line treatment. So even if these patients have been treated with Nexavar and progressed during Nexavar treatment, they can benefit from lenvatinib treatment and this is very important. So now we have two lines of treatment which have proven to be effective in this disease.
How does sorafenib compare to lenvatinib?
Sorafenib is probably less toxic in terms of novel toxicity but it is also less effective. Objective response rate 12% versus 65% with lenvatinib and also benefits of progression free survival which is only 5-6 months compared to 14.7 months with lenvatinib. So those objective response rates and progression free survival are much better with lenvatinib than with sorafenib. Again, lenvatinib can be given as a second line treatment with a similar efficacy.
What is lenvatinib?
Lenvatinib is a kinase inhibitor which inhibits the three main pathways of angiogenesis, VEGF receptor, MGF receptor and PDGF receptor. By doing this it’s an extremely potent anti-angiogenic drug. Furthermore, lenvatinib acts on the MAP kinase pathway by inhibiting some of these receptors with kinase activity. So it acts like other drugs both on the tumour cells itself and on angiogenesis. Probably the main action of lenvatinib is through this anti-angiogenic effect, more than by the direct effect on tumour cells.
In what other tumour types is lenvatinib being studied?
It’s being investigated in hepatocellular carcinoma and in tumours for which there is no effective treatment. So there are several on-going studies with lenvatinib and probably these studies will give us the same similar positive responses.
Why are you personally interested in studying this new treatment?
I started my medical career more than 30 years ago and I was in charge in Villejuif, which is the largest cancer centre probably in Europe, focusing on thyroid carcinoma. So during these 30 years we have learned how to treat most of these thyroid cancer patients effectively and most patients now are cured. But we have still a small group of patients with refractory thyroid carcinomas for whom there is no effective treatment and this is the first time or the second time, Nexavar is already on the market, but the second drug which is effective in these patients. So this is really fascinating. It was an unmet medical need and now we have an effective treatment. It’s good for our patients but it’s also good for the doctor, even, to have something to do with their patient.
How straightforward will lenvatinib be to use in clinical practice based on your experience from the trial?
We’ll have patients with the metastatic disease, refractory thyroid carcinoma, with proven progression and then these patients obviously need some treatment. So these patients will be maintained on thyroxin treatment at suppressive doses and they may receive some focal treatment modalities like thermal ablation and if there is a progression of the disease in multiple sites they will need some treatment, some systemic treatment. So the choice will be between Nexavar and lenvatinib; I’m sure that lenvatinib will get the label very soon, maybe in a year from now. So which one will be the first? This will be a discussion with the patients and the feeling of the doctor, but I think that in most patients both will be used because with Nexavar or with lenvatinib at the end there is very frequently some progressive disease so there is a need for not only one line of treatment but for several lines of treatment.
Do you have a take home message for doctors?
This is patients with refractory thyroid carcinoma should be treated with drugs and not left outside any treatment. When there is metastasis, when progression has been demonstrated by imaging these patients should be treated with kinase inhibitors, so now the choice is between Nexavar and lenvatinib. Probably most of the patients, again, will receive the two drugs sequentially, starting with Nexavar and then lenvatinib or starting with lenvatinib and then Nexavar. Probably these patients will survive to progression in first line, response, progression, second line, response, progression, and they would probably need a third or fourth line of treatment. So we are still including some patients after two lines of treatment in trials to discover which treatment should be the best after two lines of previous treatment.
