The dawn of tyrosine kinase inhibitor use in oncology occurred with the recognition that imatinib, a small organic ATP analogue that preferentially interacts with the ATP binding pocket of a kinase domain and inhibits ATP binding, was capable of reversing the hematologic abnormalities associated with chronic myelogenous leukemia. This led to its examination in solid tumors. In 2001, a case report documented a dramatic response of a gastrointestinal stromal tumor (GIST) to imatinib, a small organic molecule that inhibited ATP binding to the kit receptor (Joensuu et al. 2001). What is remarkable about this observation and the subsequent experience was the recognition that inhibition of signaling caused by a “driver mutation” not only prevented growth, but also triggered massive apoptotic death of tumor cells, thereby leading to substantial reductive effects on tumor mass. Indeed the term, “oncogene addiction” was coined in an attempt to explain why a small organic ATP analogue that targeted the kinase domain of a receptor could have such profound effects on a solid tumor in the context of a multitude of other genetic abnormalities (Pagliarini et al. 2015).

It was a report from Carlomagno and colleagues in 2002 that first brought this into focus for MTC (Carlomagno et al. 2002). They demonstrated vandetanib, a tyrosine kinase inhibitor with known activity against the vascular endothelial growth factor receptor 2 (KDR) and the epidermal growth factor receptor (EGFR), also targeted the RET receptor and inhibited RET-mediated MTC transformation and growth. Although these observations prompted excitement in the MEN2 community, convincing the pharmaceutical manufacturer to invest in a clinical trial for a rare thyroid cancer required perseverance. A phase II trial led by Wells et al. in patients with metastatic MTC demonstrated that 20 % of the 30 treated patients experienced a 30 % or greater reduction of tumor size (Wells et al. 2010) and a second phase II trial with a lower dose performed by Robinson and colleagues showed substantial activity (Robinson et al. 2010). The results of these trials convinced the manufacturer to support the first phase III trial ever performed for MTC. This trial of vandetanib (300-mg starting dose) demonstrated a prolongation of progression-free survival of 11 months with a hazard ratio of 0.46 and an objective response rate of 45 % (Wells et al. 2012). The design of the study (patients on placebo were permitted to cross over to active drug if they had disease progression) will make a determination of overall survival difficult, although an analysis is planned. Serum CT and carcinoembryonic antigen (CEA) response rates (decline in serum CT and CEA) were 62 and 59 %, respectively, and were durable (Wells et al. 2012). Vandetanib was approved for treatment for metastatic MTC in April 2011 by the Food and Drug Administration (FDA) in the USA and in February 2012 by the European Medicine Agency (EMA). The speed of evaluation and approval was remarkable. From the time of treatment of the first patient in the phase II trial to approval was less than 7 years.

After the identification of vandetanib activity, additional kinase inhibitors were found to have activity against RET. Among these was cabozantinib, a multi-kinase agent with greater affinity for RET and KDR than vandetanib and activity against the MET oncogene (Table 1). In a phase I/II trial, 10 of 35 patients (29 %) with measureable MTC had a partial response (>30 % reduction in tumor diameter) and an additional 15 of 37 patients (41 %) had stable disease for an overall response rate of 68 % (Kurzrock et al. 2011). These findings led to a phase III study of cabozantinib that differed in several significant ways from the earlier phase III study for vandetanib. The first was the requirement that patients have evidence of progression during a 14-month period prior to entry (the vandetanib phase III study did not require disease progression). The second was a study design in which crossover from placebo to active drug was not permitted, making it possible to compare overall survival of the treatment and placebo groups. Thus, patients were randomized to either cabozantinib 140 mg or placebo. The estimated progression-free survival for cabozantinib was 11.2 months compared with 4 months for the placebo, a highly significant difference. The overall response rate was 28 % for cabozantinib and 0 % for the placebo group (Elisei et al. 2013). A recent analysis (a mean of 52.4 months after study initiation) showed a 5.5-month overall survival advantage of cabozantinib over placebo, although this did not reach statistical significance in the intention to treat analysis (Schlumberger et al. 2015). However, there was evidence of a 24.5-month survival advantage for patients with codon M918T mutations compared to placebo (44.3 vs. 18.9 months), a statistically significant improvement. Cabozantinib was approved for marketing November 2012 by the FDA and March 2014 by the EMA.

It is important to recognize that both US and European regulatory agencies have cautioned physicians that these agents should be used only in patients with progressive metastatic MTC. There is no evidence that these agents are curative and at the approved doses toxicity occurs commonly. Despite these concerns, there is the sense that these agents are altering clinical outcomes in a subset of patients with metastatic MTC as will be discussed later in this chapter.

At this time, there is no basis for choosing one of the approved therapies over another—there have been no direct comparison of these two agents. There may be legitimate reasons to consider one or the other. For example, it may be appropriate to consider cabozantinib over vandetanib in a patient who is on a pharmacological agent(s) that prolongs the QT interval; similarly, in a patient who develops palmar-plantar erythrodysesthesia on cabozantinib, it may be appropriate to consider switching the patient to vandetanib.

One of the remarkable but not highlighted findings in the phase II and III studies of both vandetanib and cabozantinib is the subset of the patients who had very substantial tumor responses within the first several months of treatment, suggesting a phenomenon similar to that observed for GIST tumors treated with imatinib. The rapidity of response (as evidenced by reductions of tumor size and rapid and sustained decreases in tumor markers) suggests a triggering of apoptotic cell death similar to that observed earlier in treatment of GIST tumors with imatinib. Alternatively, this could result from an inhibition of vascular flow. The finding that tyrosine kinase inhibition of RET activity downregulates ATF4 and through it enhances apoptosis (Bagheri-Yarmand et al. 2015), provides a plausible regulatory mechanism for the rapid effect of kinase inhibitors on tumor size, the so-called phenomenon of oncogene addiction. Another potential mechanism is the effects of vandetanib and cabozantinib on VEGFR2. There is clear evidence of increased VEGF and VEGFR2 expression by MTC and tumor vasculature. Some of the effects to cause rapid MTC death may be related to a reduction in blood flow to the tumor. The fact that each of the tyrosine kinase inhibitors with activity in MTC targets not only RET, but also VEGFR2 provides credence to this thought process.

How long should one continue therapy before determining that a particular therapy is or is not effective? There seem to be at least two different patterns of response. The first is characterized by rapid (within the first month or two) decreases in serum CT and CEA and radiographic evidence at first imaging (usually 3 months after initiation of therapy) of response. In this situation, continuation of therapy is axiomatic. Inevitably, the rate of response slows. A question for which there is no answer at present when this happens is whether to continue the therapeutic agent at the initial dose, with potential development of toxicity, or to consider a dose reduction. In most cases, if there is no toxicity, it is appropriate to continue the initial dose. If toxicity develops, a dose reduction will become mandatory. Dose reduction is usually associated with a plateauing or reversal of the response. A second pattern of positive response is defined by a slow but continuous decline in tumor markers and a reduction in the size of the lesion over a 6-, 9-, and 12-month period with continued declines over a 1- to 2-year period. Therapy should not be discontinued if there is no response at time of first radiographic assessment. This type of response is often durable for a number of years.

In a substantial minority of patients, after an initial response, there will be progression of disease, either at the site(s) of initial response or other sites. Unless there is a specific explanation for the progression, such as a drug holiday because of side effects, in most cases it will be appropriate to discontinue the therapeutic agent and consider the options discussed below.

The recognition that multi-kinase inhibitors, particularly those that target RET and VEGFR2, have activity in MTC led to an examination of kinase inhibitors with similar target specificity in phase II MTC trials. None has been examined in a phase III trial, but the results of phase I/II trials for several are promising. These agents are summarized in Table 1 and are also highlighted in several recent reviews. Some of these agents, particularly sunitinib (Carr et al. 2010) and lenvatinib (Schlumberger et al. 2012), have significant activity and could be considered as potential third-line therapy in MTC. Other agents including axitinib, pazopanib (Bible et al. 2014), and sorafenib have lower levels of activity (Table 1). Another of these agents, motesanib (Sherman et al. 2008), despite comparable activity against RET and VEGFR2 in vitro, had little activity in a phase II MTC trial, presumably because of diarrhea-induced malabsorption of the agent leading to inadequate plasma concentrations (Schlumberger et al. 2009).

The signaling molecules targeted with high affinity (RET, VEGFR, EGFR, and MET) by the two approved tyrosine kinase inhibitors have broad importance in human biology and regulate the neurologic, gastrointestinal, vascular, dermatologic and hepatic systems, and among others. It is therefore not surprising that multi-kinase inhibitors that target several of these receptor systems should have toxicity. Indeed, the term “targeted therapy” refers to an agent that targets a specific signaling pathway in a neoplastic process, but conveniently ignores that the fact that these same signaling systems are important for a broad spectrum of normal biologic processes. The challenge for the clinician is to balance the substantial positive effects of these agents (on-target effects) with their off-target toxicity.

Tables 2 and 3 list the most common side effects and laboratory abnormalities observed with the two approved agents from their phase III studies (Elisei et al. 2013; Wells et al. 2012). The range of toxicity for both agents is significant, particularly when prescribed at the approved starting dose of 300 mg for vandetanib and 140 mg for cabozantinib. There have been no trials reported that directly compare the approved starting doses to lower dose therapy, although an FDA-mandated trial comparing vandetanib 300–150 mg for treatment of MTC is currently underway. There have been no trials that directly compare vandetanib to cabozantinib.