Vandetanib for the Treatment of Medullary Thyroid Cancer

Home , Cabozantinib, Sorafenib, Vandetanib

Published OnlineFirst December 11, 2012; DOI: 10.1158/1078-0432.CCR-12-2353

Clinical Cancer CCR Drug Updates Research

Nicole G. Chau and Robert I. Haddad

Abstract Vandetanib (ZD6474, Caprelsa, AstraZeneca), an oral small-molecule tyrosine kinase inhibitor (TKI) that targets the rearranged during transfection receptor (RET), VEGF receptor (VEGFR2-3), and EGF receptor (EGFR), is the first systemic therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic or progressive advanced medullary thyroid cancer (MTC). In a randomized phase III trial of patients with unresectable, locally advanced, or metastatic MTC, vandetanib improved progression-free survival compared with placebo [HR, 0.46; 95% confidence interval (CI), 0.31–0.69; P < 0.001]. However, the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities, including diarrhea, hypertension, and QTc prolongation. Here, we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in MTC. Clin Cancer Res; 19(3); 1–6. 2012 AACR.

Introduction phopsholipase C, c-jun-NH2-kinase (JNK), and STAT3. In Medullary thyroid carcinoma (MTC), a neuroendocrine addition to RET, other kinase pathways are also important tumor arising from the parafollicular cells of the thyroid, is as evidenced by overexpression of VEGF receptor (VEGFR) characterized by hypersecretion of calcitonin. The majority and EGF receptor (EGFR) in MTC. of cases of MTC are sporadic (75%), whereas the remaining Consequently, targeting these signaling pathways using 25% are hereditary and comprise 1 of 3 autosomal dom- small-molecule tyrosine kinase inhibitors (TKI) has eagerly inant hereditary syndromes: multiple endocrine neoplasia been explored (Fig. 1). Recent phase II studies in patients (MEN) 2A, MEN2B, or familial medullary thyroid carcino- with advanced MTC have shown varying response rates as ma (FMTC). Patients who present with distant metastases at shown in Table 1 (2–8). Vandetanib is the first TKI to diagnosis have a 10-year survival rate of 40%. Traditional complete phase III testing and is the first systemic therapy treatment modalities such as external beam radiation ther- to be approved by the U.S. Food and Drug Administration apy and chemotherapy are largely ineffective in unresect- (FDA) for MTC. able or metastatic MTC. The limited treatment options highlight the unmet medical need for new therapeutic Early Clinical Development approaches in MTC. Vandetanib was initially developed as an oral small- Mutations in the RET proto-oncogene are key pathogenic molecule inhibitor of the VEGFR2 tyrosine kinase (IC50 events in the majority of patients with MTC. Virtually all ¼ 40 nmol/L) and was also found to inhibit VEGFR3 (IC50 patients with the hereditary MTC carry a germline RET ¼ 110 nmol/L) and EGFR (IC50 ¼ 500 nmol/L; ref. 9). mutation. Approximately 65% to 80% of sporadic MTC Subsequent preclinical studies showed that vandetanib tumors harbor a somatic RET mutation. Almost all (98%) inhibited RET mutant forms (MEN2A and MEN2B) and MEN2A cases involve point mutations affecting the extra- RET translocations found in papillary thyroid cancer (10). cellular cysteine-rich domain. About 95% of MEN2B cases Three phase I trials of single-agent vandetanib in patients possess the kinase domain mutation M918T. Up to 80% of with treatment-refractory solid tumors confirmed the sporadic MTC cases harbor a somatic M918T mutation, recommended phase II dose of 300 mg/d with dose-limiting which is associated with poorer prognosis (1). RET receptor toxicities (DLT) of diarrhea, hypertension, and rash (11– tyrosine kinase (RTK) activation leads to signaling through 13). Two of the studies reported asymptomatic QTc pro- multiple pathways including Ras/extracellular signal–regu- longation (11, 12). In one trial of 36 patients, only one lated kinase (ERK), phosphoinositide 3-kinase (PI3K), SRC, partial response was observed (this patient had MTC; ref. 13). Taken together, the phase I and preclinical studies provided rationale for the clinical development of vande- Authors' Affiliation: Medical Oncology, Head and Neck Oncology Pro- gram, Dana-Farber Cancer Institute, Harvard Medical School, Boston, tanib in MTC. Massachusetts Two phase II single-arm, open-label studies of vandeta- Corresponding Author: Robert I. Haddad, Dana-Farber Cancer Institute, nib confirmed efficacy in hereditary MTC. The first phase II 450 Brookline Ave, SW430, Boston MA 02215. Phone: 617-632-3090; Fax: study enrolled 30 patients with hereditary, unresectable, or 617-632-4448; E-mail: [email protected] metastatic MTC to receive vandetanib at 300 mg/d (8). Six doi: 10.1158/1078-0432.CCR-12-2353 partial responses (20%) were observed and 53% of patients 2012 American Association for Cancer Research. had stable disease; median progression-free survival (PFS)

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Table 1. Response rates of TKIs in recent phase II studies in advanced MTC

TKI Sorafenib (2) Sunitinib (3) Motesanib (4) Axitinib (5) Lenvatinib (6) Cabozantinib (7) Vandetanib (8) Nevaxar, Sutent, AMG-706, Amgen/ Caprelsa, Bayer Pﬁzer Takeda Inlyta, Pﬁzer E7080, Eisai XL-184, Exelixis Astra Zeneca Main targets RET RET RET RET RET RET VEGFR2-3 VEGFR2 VEGFR1-3 VEGFR1-3 VEGFR VEGFR2 VEGFR2-3 RAF, KIT, KIT, PDGFR-b, PDGFR, KIT PDGFR-b, KIT FGFR1-4, KIT, MET, KIT, EGFR PDGFR-b FLT-3 PDGFR-b FLT1-3, Tie-2 Response rate 6% 33% 2% 18% 36% 29% 20%

was 27.9 months. The majority of patients experienced at by post-progression cross over from placebo to open-label least one adverse event (diarrhea, rash, fatigue, and nausea). vandetanib. The biochemical response rate (complete A second phase II study with similar eligibility criteria response defined as normalization of serum levels; partial enrolled 19 patients to receive vandetanib at 100 mg/d response defined as 50% decrease from baseline in serum with allowance for postprogression escalation to 300 mg/d calcitonin and CEA for 4 weeks) was better for vandetanib (14). Partial response rate was 16% and stable disease rate than for placebo (69% vs. 3% for calcitonin; P < 0.0001; was 53%, thus confirming the antitumor activity of low- 52% vs. 2% for CEA; P < 0.0001). Vandetanib was associ- dose vandetanib. ated with a delay in time to worsening of pain (HR, 0.61; 95% CI, 0.43–0.87; P ¼ 0.006); however, other health- Late-Stage Development related quality-of-life measures were not evaluated. The pivotal ZETA trial (15) led to the approval of vandetanib for advanced progressive MTC by the U.S. FDA in April Efficacy by mutation status 2011. This international, randomized, double-blind phase A tremendous effort was made to correlate RET genotype III trial evaluated 331 patients with unresectable, locally with response to vandetanib in the ZETA trial. Tissue was advanced, or metastatic MTC (hereditary or sporadic). obtained for RET genotyping in 297 of 298 patients with Patients were randomized 2:1 to receive vandetanib 300 sporadic MTC. Somatic RET mutations were identified in mg daily (n ¼ 231) or placebo (n ¼ 100) until disease 155 patients (52%), and somatic RET mutations were progression. The primary endpoint was PFS, and secondary absent in 8 patients (2.7%; ref. 15). Unfortunately, a large endpoints were objective response rate (ORR), disease proportion of patients was classified as RET mutation status control rate (DCR) at 24 weeks, duration of response, "unknown" (n ¼ 135; 45.3%) due to insufficient tumor overall survival, biochemical response, time to worsening DNA to fulfill stringent testing criteria, making subgroup of pain, safety, and tolerability. Eligibility criteria did not analysis by RET mutation status for PFS and ORR in ZETA include disease progression but required measurable tumor inconclusive. Interestingly, patients with sporadic MTC at baseline and a calcitonin level of at least 500 pg/mL. Most tumors harboring a somatic M198T mutation had a higher patients who enrolled had nonhereditary MTC (90%) and response rate to vandetanib (54.5%; 55 of 101) than metastases (95%). Forty percent had received prior systemic patients with sporadic MTC tumors without a somatic therapy. Calcitonin or carcinoembryonic antigen (CEA) M918T mutation (32%; 33 of 103).Vandetanib appeared doubling time of 24 months, a marker associated with active in all prespecified subgroups (16). more aggressive disease, was present in 51% of patients with respect to calcitonin and 31% of patients for CEA (16). Safety and tolerability The most common and serious adverse events in ZETA are Efficacy listed in Table 2. Vandetanib was associated with higher Vandetanib showed efficacy in all evaluable endpoints in treatment discontinuation rate (12% vs. 3%) and dose the ZETA trial except survival. At a median follow-up of 24 reductions due to adverse events or QTc prolongation months, median PFS was not reached with vandetanib (36% vs. 3%) compared with placebo (15). However, (estimated 30 months) and was 19.3 months with pla- median duration of treatment was much longer for vande- cebo [HR, 0.46; 95% confidence interval (CI), 0.31–0.69; tanib (90.1 vs. 39.9 weeks). Vandetanib at 300 mg/d was P < 0.001; ref. 15]. The 6-month PFS rate was 83% in the associated with QTc prolongation (mean, 35 ms) but there vandetanib group and 63% in the placebo group. Vande- were no reports of torsades de pointes in ZETA. tanib showed a higher ORR than placebo (45% vs. 13%; P < 0.001) and higher DCR (87% vs. 71%; P ¼ 0.001). Of Integration of Vandetanib into the Medullary the 13 patients in the placebo arm who responded, 12 did Thyroid Cancer Treatment Paradigm so after treatment with open-label vandetanib. Overall Few treatment options exist for patients with unresectable survival data were immature at the time of analysis and or metastatic MTC. In metastatic disease, a watch-and-wait revealed no significant difference (HR, 0.89; 95% CI, 0.48– approach is feasible in asymptomatic patients with low 1.65). Final survival assessment is likely to be confounded tumor burden, and no evidence of tumor progression on

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Table 2. Summary of common adverse events occurring with an incidence of 25% and grade IIIþ adverse events occurring with an incidence of 5% on either arm in phase III trials in advanced MTC

ZETA Trial (15) EXAM Trial (18)

Vandetanib Placebo Cabozantinib Placebo (n ¼ 231) (n ¼ 99) (n ¼ 214) (n ¼ 109) Adverse events, all grades in decreasing order of frequency

Adverse event Adverse event (all grades) n (%) n (%) (all grades) n (%) n (%) Diarrhea 130 (56) 26 (26) Diarrhea 135 (63) 36 (33) Rash 104 (45) 11 (11) Hand foot skin reaction 107 (50) 2 (2) Nausea 77 (33) 16 (16) Decreased weight 102 (48) 11 (10) Hypertension 73 (32) 5 (5) Decreased appetite 98 (46) 17 (16) Headache 59 (26) 9 (9) Nausea 92 (43) 23 (21) Fatigue 55 (24) 23 (23) Fatigue 87 (41) 31 (28) Dysgeusia 73 (34) 6 (6) Hair color changes 72 (34) 1 (1) Hypertension 70 (33) 5 (5) Stomatitis 62 (29) 3 (3) Constipation 57 (27) 6 (6) Adverse events (grade III) in decreasing order of frequency

Adverse event (grade III) n (%) n (%) Adverse event (grade III) n (%) n (%)

Diarrhea 25 (11) 2 (2) Diarrhea 34 (16) 2 (2) Hypertension 20 (9) 0 (0) Hand foot skin reaction 27 (13) 0 (0) ECG QT prolonged 18 (8) 1 (1) Fatigue 20 (9) 3 (3) Fatigue 13 (6) 1 (1) Hypertension 18 (8) 1 (1) Decreased weight 10 (5) 0 (0) Decreased appetite 10 (5) 1 (1)

periodic restaging as patients with indolent metastatic dis- times 24 months compared with those with longer dou- ease may survive for years without systemic therapy. For bling times (54% vs. 37%; ref. 16). Judicious evaluation of patients with progressive or symptomatic metastatic disease the treatment risk-to-benefit ratio and close monitoring for and high tumor burden, the National Comprehensive Can- toxicities is critical. Because of the potential of QT prolonga- cer Network (NCCN) encourages clinical trial enrollment. tion, torsades de pointes, and sudden death, vandetanib is In the absence of trial enrolment, systemic therapy with TKIs currently only available through the FDA Vandetanib Risk is preferred over cytotoxic chemotherapy, which is associ- Evaluation Mitigation Strategy (REMS) Program. The goal ated with high toxicity and low efficacy. Vandetanib is of the program is to educate prescribers about the risk, currently the first-line systemic therapy of choice. If a patient appropriate monitoring, and management of QT prolonga- is not a candidate for vandetanib or progresses on vande- tion and to minimize the occurrence of torsades de pointes tanib, NCCN guidelines recommend the use of commer- and sudden death associated with vandetanib. To prescribe cially available TKIs such as sorafenib or sunitinib, although vandetanib, providers must complete provider training and these agents are not FDA approved for the treatment of enroll in the vandetanib REMS program. ECG and serum thyroid cancer and their phase II trials specifically excluded potassium, calcium, magnesium, and thyroid-stimulating patients with prior vandetanib therapy (2, 3). hormone levels should be closely monitored and corrected. In practice, deciding when to initiate vandetanib therapy Concomitant use of drugs that prolong the QT interval or is less clear. The use of vandetanib should be restricted to are associated with torsades de pointes should be avoided, symptomatic or rapidly progressive MTC, which is deter- recognizing that the risk for torsades de pointes may be mined by clinical judgment as neither were part of the ZETA protracted given the drug’s long half-life (t1/2 ¼ 19 days). inclusion criteria. No validated predictors of response to Other common side effects (Table 2) including diarrhea, vandetanib exist to guide patient selection. Subgroup analy- rash, and hypertension can usually be managed with early ses suggest that there may be a greater chance of benefit in recognition, supportive measures, and dose reductions or patients with sporadic MTC tumors harboring the aggres- interruptions for grade III severity (17). Most patients sive M918T mutation and in patients with CEA doubling treated with vandetanib will have an increase in thyroid-

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RET EGFR VEGFR-2 (activating mutations) (overexpression) (overexpression)

Vandetanib PI3K RAS

RAF Figure 1. Activated tyrosine AKT kinase receptors targeted by vandetanib in MTC. MEK

mTOR MAPK

Gene transcription Cell-cycle activation

Survival Growth Proliferation Metastases Angiogenesis

stimulating hormone (78%) and about 50% will require orrhage; ref. 18). In the future, cabozantinib may be an increases in thyroid replacement dose. Given the toxicity alternative first-line treatment option to vandetanib, parti- profile, vandetanib is clearly unjustified for asymptomatic, cularly for patients with rapidly progressive disease or high indolent disease. risk for torsades de pointes, or cabozantinib may be a The MTC treatment schema is quickly evolving as clinical second-line option postprogression after vandetanib; how- trials inform on new therapies. Cabozantinib, an oral kinase ever, the toxicities related to VEGF inhibition must be inhibitor of VEGFR2, RET, and hepatocyte growth factor weighed (Table 2). Future trials of head-to-head upfront receptor (MET), is the only other TKI with randomized comparison of TKIs and sequential approaches are needed phase III data (EXAM trial) in progressive, advanced MTC to inform. Uncertainty exists about the optimal treatment showing a PFS benefit (primary endpoint) compared with strategy when resistance to TKI therapy develops. It is placebo (median PFS ¼ 11.2 vs. 4.0 months; HR, 0.28; 95% unclear how many patients in the ZETA trial received prior CI, 0.19–0.40; P < 0.0001) and an ORR of 28% versus 0% TKIs. In the EXAM trial, about 20% of patients had received (18). Unlike ZETA, the EXAM trial eligibility criteria includ- prior TKI therapy and response was seen regardless of prior ed disease progression by Response Evaluation Criteria in TKI treatment. Evidence to support the use of sorafenib or Solid Tumors (RECIST) within 14 months of screening. sunitinib after vandetanib progression is largely anecdotal. Similar to ZETA, very few patients were considered RET mutation negative, thus subgroup analysis by RET mutation status for PFS was inconclusive. Toxicities associated with Future Challenges VEGF inhibition led to deaths in 1.9% of patients in the Vandetanib represents a paradigm shift in the treatment cabozantinib arm (3 cases of fistula formation and 1 hem- of MTC by validating the efficacy of TKIs in advanced MTC.

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Vandetanib for Medullary Thyroid Cancer

However, challenges remain in optimizing patient selec- ing; however, VEGFR inhibition alone (axitinib) has tion, mitigating treatment toxicities, and identifying strat- shown a response rate less than 20% (5). The clinical efficacy egies to overcome resistance as these therapies are currently of targeting VEGFR without RET inhibition is being evalu- not curative. Mechanisms of primary and acquired resis- ated in MTC in a single-arm phase II trial of pazopanib tance to vandetanib require investigation. Presently, RET (GW786034, Votrient, GlaxoSmithKline; VEGFR1-3, mutations cannot be used clinically to predict response PDGFRa/b, KIT inhibitor) in advanced thyroid cancer to TKIs, although correlations may be strengthened in the (NCT00625846). Interestingly, in a phase II trial of lenvan- future as TKI use and genetic testing in sporadic MTC tinib, there was no difference in treatment response accord- increases. Comparison of sequential tumor biopsies pre/ ing to RET mutation status; however, high baseline levels of posttreatment and upon resistance may provide insight into VEGF and sVEGFR3 correlated with greater tumor shrink- clinical mechanisms of resistance. age, and low levels of ANG2, sTie-2, HGF, and interleukin Characterization of antitumor activity of vandetanib and (IL)-8 were associated with tumor shrinkage and prolonged other TKIs against specific RET mutant and RET wild-type PFS (6). This distinction is important as the main serious tumors may help to better select patients for therapy. ZETA adverse events associated with the current RET TKIs are confirms the clinical efficacy of vandetanib in patients with related to anti-VEGFR or anti-EGFR effects. Greater under- sporadic MTC tumors harboring the M918T mutation. Prior standing of the mechanism of activity of vandetanib will studies hinted that somatic M918T mutations may confer permit rational exploration of sequential or combination sensitivity to RET TKIs; in patients with somatic M198T approaches with other therapies in the future including mutations, 12 of 15 had durable responses or stable disease clinical development in the neoadjuvant or adjuvant setting. in the phase I trial of cabozantinib (7) and 5 of 8 patients had responses to sunitinib (3). However, the clinical efficacy of Conclusions RET vandetanib in patients harboring other mutations such Vandetanib showed clinical efficacy and PFS benefit in In vitro as those associated with MEN2A is less apparent. advanced MTC, thus validating small-molecule TKIs as a studies comparing the activity of 4 TKIs (vandetanib, axitinib, valid therapeutic strategy in this disease. However, the sunitinib, and cabozantinib) in MEN2B, MEN2A, and RET/ toxicities, some serious including QTc prolongation, need PTC1 (papillary thyroid cancer) cell lines reported that to be carefully weighed and managed. Vandetanib is unjus- vandetanib was the most potent inhibitor in MEN2B and tified in the setting of indolent and asymptomatic MTC. The cabozantinib was the most effective in MEN2A and PTC (19), risk–benefit assessment must take into account the toxicity suggesting that mutation-specific therapies may be bene- risks, prolonged treatment administration, and potential ficial. In addition, to avoid maleficence, identification of a indolent course of advanced MTC. The MTC treatment subset of patients for whom vandetanib therapy is futile is paradigm is rapidly changing, as future TKI studies continue in vitro important. For example, studies pinpointed that the to inform. Work is needed to further characterize appro- RET V804M V804L and gatekeeper mutations confer resis- priate patient selection, optimize management upon resistance to vandetanib (20). Although rare, these mutations tance, and examine novel sequential or combination treat- occur in sporadic and hereditary MTC, either alone or in ment approaches. combinationwith otherRETmutations, andthuscouldresult clinically in primary or acquired resistance to vandetanib. Disclosure of Potential Conflicts of Interest TKIs such as sorafenib have shown activity against the V804 R.I. Haddad has a commercial research grant from Astra Zeneca and is mutant in in vitro studies (21). Finally, in patients with RET a consultant/advisory board member for Exelixis. No potential conflicts of wild-type tumors, it remains to be seen whether Ras muta- interest were disclosed by N.G. Chau. tions, identified in 60% to 80% of RET-negative sporadic MTC (22), confer clinical resistance to vandetanib. In vitro Authors' Contributions Conception and design: N.G. Chau, R.I. Haddad studies using cell lines with acquired resistance to vandeta- Development of methodology: R.I. Haddad nib have shown persistent activation of the Ras/Raf/MEK Acquisition of data (provided animals, acquired and managed patients, pathway, which can be partly abrogated by sorafenib (23). provided facilities, etc.): N.G. Chau Analysis and interpretation of data (e.g., statistical analysis, biosta- Ultimately it remains unclear whether the activity of tistics, computational analysis): N.G. Chau vandetanib is predominantly due to inhibition of RET, Writing, review, and/or revision of the manuscript: N.G. Chau, R.I. EGFR, VEGFR, or other kinases. For example, dual inhibi- Haddad tion of RET and EGFR may contribute to the efficacy of vandetanib (24); however, EGFR inhibition alone with Grant Support gefitinib has not produced clinical responses in MTC R.I. Haddad has received research funding from Astra Zeneca. (25). All clinically tested RET inhibitors are nonselective, Received October 18, 2012; revised November 26, 2012; accepted multikinase inhibitors that also inhibit VEGFR signal- November 27, 2012; published OnlineFirst December 11, 2012.

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Vandetanib for the Treatment of Medullary Thyroid Cancer

Nicole G. Chau and Robert I. Haddad

Clin Cancer Res Published OnlineFirst December 11, 2012.

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