- © 2011 by American Society of Clinical Oncology
Progress in Molecular Targeted Therapy for Thyroid Cancer: Vandetanib in Medullary Thyroid Cancer
- Corresponding author: Danny Rischin, Department of Medical Oncology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia; e-mail: danny.rischin{at}petermac.org.
Thyroid cancer, the most common endocrine neoplasm, is increasing in incidence and will account for an estimated 48,020 new cases and 1,740 deaths in the United States in 2011.1 Most thyroid cancers arise from thyroid follicular cells. These include differentiated thyroid cancers (DTCs)—papillary thyroid cancer (which accounts for 80% of all thyroid tumors) and follicular thyroid cancer (approximately 15% of thyroid tumors)—as well as the less common anaplastic thyroid cancer.2,3 Medullary thyroid cancer (MTC) is a tumor of the calcitonin-producing parafollicular or C cells of the thyroid and comprises 2% to 3% of all thyroid cancers.2,3 MTC occurs in familial forms as part of the multiple endocrine neoplasia syndromes (MEN2A or MEN2B) and familial MTC in 20% to 30% of cases but more commonly is apparently sporadic. Although the majority of thyroid cancers, other than anaplastic thyroid cancer, are effectively treated with surgery (combined with radioiodine and thyroid-stimulating hormone suppression in high-risk DTC), treatment options with cytotoxic chemotherapy or radiotherapy for patients who develop unresectable recurrent or metastatic MTC or noniodine-avid DTC have been minimally effective.
Several recurrent mutations or gene rearrangements have been identified in both DTC and MTC and seem to be important in the pathogenesis of thyroid cancers. The first of these, recognized more than two decades ago, was a gene rearrangement involving the proto-oncogene RET (rearranged during transformation) in papillary thyroid cancer (so-called RET/PTC gene rearrangements).4 The novel gene fusion results in aberrant expression and activation of the RET kinase in thyroid follicular tissue, which leads to the development of papillary thyroid cancer. Since then, several RET/PTC variants have been identified in 10% to 20% of sporadic papillary tumors in adults, but in up to 50% to 80% of papillary tumors that arise in childhood or after exposure to ionizing radiation (for example, by fallout from the Chernobyl nuclear accident).5 Activating mutations in RET are present in the germline of virtually all patients with hereditary MTC. These mutations may present as part of the MEN2A, familial MTC, or MEN2B syndromes in which there is a genotypic/phenotypic correlation between the type of RET mutation and clinical features such as age of onset and clinical aggressiveness of thyroid tumors, the incidence of pheochromocytoma or hyperparathyroidism, and the presence of developmental abnormalities, mucosal neuromas, and intestinal ganglioneuromas.6 RET mutations are also found in at least 50% of sporadic MTCs.6,7 Activating mutations in BRAF (in particular the V600E mutation) have been identified in approximately 50% of papillary thyroid cancers and correlate with poor outcome.8,9 RAS mutations, particularly those that involve NRAS and HRAS, are found in 10% to 20% of papillary thyroid cancers (usually in the follicular variant) and 40% to 50% of follicular thyroid cancers.10 Translocations that result in a fusion between PAX8 and the peroxisome proliferator-activated receptor γ gene are found in 30% to 40% of follicular thyroid cancers.10,11 Although characterization of these genetic events in thyroid cancer may have diagnostic and prognostic implications, it also provides an opportunity to develop therapies that are targeted at these potential molecular drivers.
In the article that accompanies this editorial, Wells et al12 report the results of a phase III randomized trial using vandetanib (Caprelsa, ZD6474; AstraZeneca, Wilmington, DE), an orally available small-molecule inhibitor of RET as well as the vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor, in patients with locally advanced or metastatic MTC. After the observation of responses to vandetanib in patients with hereditary MTC,13,14 a double-blind, placebo-controlled, phase III study was initiated in which patients with locally advanced or metastatic MTC were randomly assigned in a 2:1 ratio to receive 300 mg of vandetanib daily or a placebo. Remarkably, Wells et al12 were able to accrue 331 patients with this uncommon neoplasm from 23 countries during a period of less than 1 year. Most patients (90%) had sporadic MTC and 95% had metastatic disease. Although 51 patients (23 who received vandetanib and 28 in the placebo group) received open-label vandetanib before progression was documented on a central reading of scans, the study achieved its primary end point with prolongation of progression-free survival (PFS) on the basis of independently reviewed imaging in patients who were treated with vandetanib compared with those who received the placebo (hazard ratio, 0.46; 95% CI, 0.31 to 0.69; P < .001). The median PFS with the placebo was 19.3 months and was not reached in the vandetanib group (but was estimated at 30.5 months). Objective responses were seen in 45% of patients who were treated with vandetanib, with disease control rates of 87% with vandetanib compared with 71% in patients treated with the placebo. Biochemical responses with falling calcitonin and carcinoembryonic antigen levels were seen in 69% and 52% of patients who were treated with vandetanib, respectively. With a median follow-up of 24 months, no differences were seen in overall survival, and although the survival analysis is to be repeated once 50% of patients have died, this end point may be confounded by cross-over.
The activity of vandetanib in MTC is in keeping with that seen with other multitargeted tyrosine kinases that are directed at RET, including sorafenib,15 sunitinib,16 motesanib,17 and cabozantinib,18 in patients with MTC who have been treated in phase I and II studies. Notably, all of these agents are also potent inhibitors of VEGFR2, which raises the possibility that inhibition of VEGF receptor signaling may contribute to the responses that have been observed in MTC. Intriguingly, there have been reports of patients with MTC responding to axitinib,19 a VEGFR inhibitor that purportedly does not inhibit RET at clinically achievable doses.20 Another phase III study in which patients with MTC were randomly assigned to receive cabozantinib (an oral inhibitor of RET as well as VEGFR2 and MET) or a placebo has recently completed accrual. Responses to cabozantinib were seen in 49% (17 of 35) of patients with MTC who were treated on the expansion cohort of a preceding phase I study, including some responses in patients who were previously treated with vandetanib or sunitinib.18
The investigators made a commendable effort to determine the relationship between RET genotype and response to vandetanib.12 Tissue was obtained for RET genotyping from 297 of the 298 patients with sporadic MTC. Mutations in RET were identified in 155 patients (52%), no RET mutations were identified in 8 patients (2.7%), and mutation status was determined to be unknown in 135 patients (45.3%). The last category is large because of the stringent criteria that were associated with the definition of no RET mutation: a patient had to have sufficient DNA available and be negative by allele-specific polymerase chain reaction for M918T and by sequencing each of exons 10, 11, and 13 to 16 of RET to be considered negative. A response rate of 46.4% (13 of 28) was seen in patients with hereditary MTC—similar to the 51.8% (57 of 110) in RET mutation–positive sporadic MTC. The M918T mutation, a tyrosine kinase domain mutation with potent transforming activity in vitro, was the most frequent mutation found in 92% (142 of 155) of the patients with RET mutation–positive sporadic MTC. It is the most common mutation found in MEN2B and in sporadic MTC and has been associated with poor prognosis in both settings.6,7,21–23 The response rate in patients with sporadic MTC and M918T mutations who were treated with vandetanib was 54.5% (55 of 101) compared with the 32% (33 of 103) response rate seen in the patients who were negative for mutations or for whom mutation status was unknown. The remarkable response rate seen in patients with MTC and RET mutations is directly comparable with response rates seen in recent studies of targeted agents studied in genotypically selected populations, such as vemurafenib in melanoma with BRAF V600E mutations (51%)24 or crizotinib in ALK-rearranged non–small-cell lung cancer (57%).25
However, despite the impressive response rate and prolongation in PFS, can we be sure that patients who are treated with vandetanib are truly living better, longer? Improvements in PFS may not be meaningful if they are not accompanied by improvements in symptoms and health-related quality of life. Although the authors report a delay in time to worsening of pain in patients who received vandetanib (Appendix),12 no other patient-reported outcomes, including effects on other tumor-related symptoms or quality of life, are reported. Hence, it is difficult to determine the extent to which the beneficial effects of vandetanib on tumor-related symptoms and delays in tumor progression were counterbalanced by drug-related adverse effects. Frequently observed adverse effects related to vandetanib included diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). Thirty-five percent of patients required dose reductions and 12% of patients discontinued vandetanib because of toxicity. Particularly concerning is the grade 3 QTc prolongation that was seen in 8% of patients who were treated with vandetanib. In most previous studies with vandetanib, these changes were asymptomatic. In contrast, in the present study, in which there was typically a long duration of treatment with vandetanib at a dose of 300 mg daily, there was one sudden death and one death from cardiopulmonary arrest in patients who were receiving vandetanib.26 As a consequence, the US Food and Drug Administration placed a boxed warning regarding QT prolongation, torsades de pointes, and sudden death in the prescribing information for vandetanib and has required a restricted distribution program (risk evaluation and mitigation strategy) with prescriber education focused on patient selection, ECG and electrolyte monitoring, and awareness of drug interactions with other drugs that may prolong the QT interval.26
The potential toxicity associated with long-term administration of vandetanib highlights the importance of appropriate selection of patients for treatment with this agent. The relatively indolent tempo of disease in some patients with MTC who were enrolled onto this trial, which did not require demonstration of progression before entry, is evident from the time to progression of 19.3 months in patients who received the placebo. The risk:benefit ratio of treatment is likely to be unfavorable in asymptomatic patients or patients with a low disease burden who experience slow progression. These patients may be appropriately monitored while not receiving therapy by assessment of the tempo of disease radiologically and through measurement of calcitonin doubling time.27 In contrast, patients who are symptomatic, have a high disease burden, or have rapidly progressing disease stand to benefit the most from treatment with vandetanib.
The study by Wells et al12 establishes the efficacy of vandetanib in patients with locally advanced or metastatic MTC and has led to the registration of the first treatment for this indication. It places MTC alongside tumor types such as melanoma, clear-cell carcinoma of the kidney, and GI stromal tumors, for which the dismal efficacy of conventional cytotoxic chemotherapy contrasts with the remarkable efficacy of tyrosine kinase inhibitors. However, it also highlights a number of key issues to be considered in the design and choice of end points in future phase III trials in unresectable or metastatic thyroid cancer. With regard to vandetanib in MTC, unanswered questions remain about whether the benefit in PFS will translate into improved overall survival, whether this treatment improves quality of life and/or decreases symptom burden, what the optimal timing of this treatment is, what the activity of vandetanib in RET mutation–negative MTC is, how much the VEGFR and epidermal growth factor receptor targeting effects of vandetanib contribute to its activity in MTC, whether the use of lower doses of vandetanib will mitigate toxicities but maintain efficacy, and what mechanisms are responsible for acquired resistance to vandetanib. Finally, the shift away from clinical trials in all-comers with thyroid cancer toward studies such as this one that involve clinically and genotypically defined subsets of patients with thyroid cancer will allow more efficient interrogation of other potential molecular targets in thyroid malignancies.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Benjamin Solomon, AstraZeneca (C), Pfizer (C); Danny Rischin, Amgen (C) Stock Ownership: None Honoraria: Danny Rischin, GlaxoSmithKline Research Funding: Benjamin Solomon, Pfizer Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Manuscript writing: All authors
Final approval of manuscript: All authors
Acknowledgment
J.J.G. is supported by Grant Nos. R01 CA119202 and R01CA139014 from the National Institutes of Health/National Cancer Institute. She also serves as one of the American Society of Clinical Oncology representatives to and serves on the Executive Committee of the American College of Surgeons Commission on Cancer.
