Should lenvatinib be used as first-line therapy for slowly progressing radioiodine-refractory thyroid carcinoma?
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Lenvatinib is my preference as a first-line therapy when patients need treatment beyond levothyroxine and thyroid-stimulating hormone suppression.
We do not have a head-to-head comparison of lenvatinib and sorafenib, and we probably never will. We need to rely on a basic principle of oncology: Always use your best drug first. Lenvatinib is more active in this disease than sorafenib. There is no other setting in oncology where you would use a less effective drug before a more effective drug.
If you look at the study data, despite different patient populations and study designs, there is a clear winner. The ORR with lenvatinib is 65%, and the PFS benefit is 16 months. With sorafenib, the response rate is 12%, and the PFS benefit is 5 months. These are huge differences.
In the SELECT trial, the median duration of response with lenvatinib was 30 months. That is great activity in the oncology world. The study, in my mind, was a home run for patients with iodine-refractory differentiated thyroid cancer. We do not see results like that often enough.
We also can consider OS data. Among patients aged at least 65 years, there is an OS benefit with lenvatinib compared with placebo in the SELECT trial, even though crossover was allowed. That is an important piece of data. When we compare the apple of sorafenib to the orange of lenvatinib, there is a clearly better drug.
There is an argument that lenvatinib works just as well as a second-line agent, whereas data with sorafenib as a second-line agent are unknown. So, when sequencing agents, sorafenib may be a better first choice. However, data presented at ASCO Annual Meeting in 2017 demonstrated that only 53% of patients treated with a TKI in the first line went on to receive a second-line therapy. If you wait to start lenvatinib and give sorafenib first, only half of the patients are going to get it. That means half the patients are not going to get the best drug for their disease.
If I were a patient, I would want the best drug first. If someone said they could give me a drug that has 12% response rate or a drug with 65% response rate, there is only one right answer.
Copher R, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2017.35.15_suppl.e17589.
Lori Wirth, MD, is medical director of Massachusetts General Hospital’s Center for Head and Neck Cancers and associate professor of medicine at Harvard Medical School. Disclosure: Wirth reports consultant fees from Bayer, Cue Biopharma, Eisai, Iovance Biotherapeutics, Loxo Oncology and Merck.
Sorafenib was the first of the TKIs, approved in 2013, so it is clearly the therapy with the most experience and the one with which oncologists and endocrinologists are most familiar.
In trials, researchers observed a smaller rate of dose reduction due to side effects with sorafenib vs. lenvatinib, and data suggest sorafenib may have better tolerability for some patients due to a different toxicity profile. The two therapies are comparable in price.
The decision of which drug to use depends on several patient characteristics, including the patient’s age, burden of disease and other comorbidities, as well as quality-of-life factors. We have data that suggest that lenvatinib works well as a second-line therapy after sorafenib. Data on sorafenib prescribed after lenvatinib, however, are still needed. Additionally, side effects must be considered, such as treatment-emergent hypertension observed with lenvatinib and sorafenib-associated hand-foot syndrome.
Some of the more catastrophic adverse effects, such as stroke and myocardial infarction, may be more pronounced with lenvatinib. For someone with severe vascular problems who has had other treatments that did not work, such as mTOR inhibitors, I might consider sorafenib. We recently published a case of a young woman with vertebral and carotid artery dissections that were clearly related to lenvatinib. Would this have happened with sorafenib? We don’t know, but the anti-VEGF effects are stronger at full dose with lenvatinib vs. sorafenib. A definitive answer would require a head-to-head comparison of the two drugs.
Sorafenib also has always had a good patient-access program. If there was any issue with insurance coverage, it was always possible to fall back on sorafenib. Lenvatinib now has a similar program.
In cases of slowly progressing radioiodine-refractory thyroid carcinoma, the question might be whether full-dose sorafenib is better tolerated than a lower dose of lenvatinib, with the option of escalating. Given the choice, I would take the latter; however, I can see a case being made for sorafenib.
Jochen Lorch, MD, MS, is a medical oncologist who specializes in head and neck cancers at Dana-Farber Cancer Institute and is assistant professor of medicine at Harvard Medical School. Disclosure: Lorch reports research support to his institution from Bayer, Bristol-Myers Squibb, Millennium and Novartis, and consultant honoraria from Bayer and Genentech.