Yujie Zhao, MD, PhD

Therapy that targets angiogenesis has been extensively investigated in differentiated thyroid cancer (DTC) and has demonstrated significant antitumor activity. Lenvatinib is a vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitor (TKI) approved by the US Food and Drug Administration (FDA) for radioactive iodine-refractory metastatic DTC. It has shown marked progression-free survival (PFS) benefit in a phase III study (18.3 vs 3.6 months, HR, 0.21; 99% CI, 0.14-0.31; P <.001). The benefit was also evident in patients who were previously treated with VEGFR-targeting kinase inhibitors. Common toxicities of lenvatinib include hypertension (any grade, 69.3%; grade &ge;3, 42.9%), diarrhea (any grade, 59.4%; grade &ge;3, 41.8%), fatigue or asthenia (any grade, 59%; grade &ge;3, 27.5%), decreased weight (any grade, 46.4 %; grade &ge;3, 9.2%), nausea (any grade, 41%; grade &ge;3, 13.7%), and proteinuria (any grade, 32.2%; grade &ge;3, 10.0%). Data for quality of life (QoL) were not collected in this study, although frequent treatment interruption (82.4%) and dose reduction (67.8%) because of toxicities were observed, suggesting that the decision to initiate treatment should be made carefully to preserve QoL.

Differentiated thyroid cancer (DTC) has an excellent prognosis in general, but patients with radioactive iodine-refractory metastatic DTC have a significantly lower 10-year survival.

Because conventional cytotoxic chemotherapy has poor tolerability and low activity, it is rarely used. With advances in the understanding of molecular pathogenesis of DTC, angiogenesis has been identified as an attractive target for therapeutic development in DTC. Sorafenib, a small molecule kinase inhibitor targeting

, was approved by the FDA for patients with metastatic DTC in November 2013.

Thyroid cancer is the most common endocrine malignancy, with an estimated 62,450 new cases and 1950 deaths in 2015.

Thyroid cancers may originate from either follicular cells, which give rise to differentiated or anaplastic thyroid cancers, or from calcitonin-producing C or parafollicular cells, which give rise to medullary thyroid carcinoma (MTC). Differentiated thyroid cancers are divided into two main histology types, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), accounting for about 90% of all thyroid cancers. For DTC, cure can be achieved after surgical resection with or without radioactive iodine ablation (

I-RAI) and thyroidstimulating hormone (TSH) suppression. The 5-year overall survival rate of patients with thyroid cancer is 97.9%.

I-RAI-refractory DTC have a significantly worse prognosis, with a 5-year survival of less than 50%.

For this subset of patients, doxorubicin is the only FDA approved cytotoxic chemotherapy, although it is rarely used because of poor tolerability and low efficacy, with response rates around 25% or less.

In recent years, understanding the molecular pathogenesis of DTC has led to advances in therapy and to regulatory approval of new therapeutic agents for radioactive iodine-refractory metastatic DTC. The key oncogenic genetic alterations in DTC include BRAF (35%-70% in PTC, rarely in FTC), RAS (15%-20% in PTC and 40%-50% in conventional-type FTC), RET/ PTC rearrangement (10%-20% in adult sporadic PTC, 50%-80% in patients with PTC with a history of radiation exposure, and 4%-70% in PTC of children and young adults), and

rearrangement (30%- 40% in conventional-type FTC).

In addition to molecular alterations, tumor angiogenesis supporting tumor cell growth and metastasis represents another critical target in DTC therapeutic development.

The VEGF family comprises seven glycoproteins (VEGF A-E and placental growth factor [PlGF-1 and -2]) and three tyrosine kinase receptors (VEGFR- 1-3).

The interactions of VEGFs with their receptors activate downstream signaling, which results in the release of angiogenic factors, exerting pro-angiogenic effects. Among all VEGFRs, VEGFR2 is considered the main mediator of the angiogenic effects of VEGF.

In addition to VEGF, other pathwayssuch as platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways&mdash;have been found to contribute to tumor angiogenesis and may potentially provide escape mechanisms from anti-VEGF/ VEGFR therapy.

Increased vascularity has been reported in thyroid cancer, and the activity of VEGF/ VEGFR has been found to be associated with disease recurrence and metastasis.

VEGF-targeted therapeutics, including sorafenib, sunitinib, axitinib, pazopanib, vadentinib, lenvatinib, and motesanib, have been extensively tested in preclinical and clinical settings, with various levels of activity.

gene rearrangements are one of the most frequent genetic alterations in PTC. It is particularly common in PTC associated with ionizing radiation exposure

Various RET translocation partners have been identified. Through the translocations, the promoters and Nterminal domain coding region of unrelated gene(s) are linked with the RET tyrosine kinase coding region, leading to constitutively active RET tyrosine kinase, the signaling subunit of a receptor complex for ligands of the glial-cell-line-derived neurotrophic factor (GDNF).

Overexpression of RET/PTC can lead to transformation of thyroid cells in transgenic mice.

Figure 1. Structure of lenvatinib and VEGFR2 complex. A: overall structure of the complex. B: binding pocket of VEGFR2 complex.

Reprinted and adapted with permission from &ldquo;Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealed by Biochemical Characterization&rdquo; by Okamoto K, et al. ACS Med Chem Lett. Jan 1, 201541 with permission from the American Chemical Society.

Lenvatinib (previously E7080) is an oral multikinase inhibitor that selectively inhibits VEGFR 1-3 and other angiogenic pathway receptor tyrosine kinases, including FGFR 1-4 and PDGFR, as well as oncogenic tyrosine kinases KIT and RET.

Cocrystal structure analyses demonstrated that lenvatinib interacts with both the ATP binding site and the neighboring allosteric region of VEGFR2 in DFG-in conformation (

Lenvatinib potently inhibits VEGFR3 and VEGFR2 kinase activities with a half maximal inhibitory concentration (IC

) of 5.2 nmol/L and 4.0 nmol/L, respectively, and inhibits VEGFR1, FGFR1, and PDGF-R&beta; kinases with a four times to ten times lower activity.

Lenvatinib inhibits RET kinase with Ki values of 1.5 nmol/L in cell-free kinase assays.

Lenvatinib demonstrated antitumor activity in preclinical human thyroid cancer models, mainly through angiogenesis inhibition, although inhibition in RET and FGFR may also contribute to its antitumor activity.

Lenvatinib was evaluated in an 82-patient phase I study of advanced refractory solid tumors. Doselimiting toxicities (DLTs) were found to be grade 3 proteinuria at the dose of 32 mg; 25 mg once daily was determined as the maximally tolerated dose (MTD) in this study.

Of note, although two patients developed DLT of grade 3 proteinuria at the dose of 12.5 mg, the decision was made to continue dose escalation. The most frequently observed cumulative toxicities of all grades were hypertension (40%), diarrhea (45%), nausea (37%), stomatitis (32%), and vomiting (23%). Seven patients (9%) had a partial response (PR), and 38 patients (46%) had stable disease as best response. Confirmed PRs were observed in patients diagnosed with renal cell carcinoma, melanoma, and soft tissue sarcoma. In this study, maximum concentration (C

) was achieved within 3 hours, and the median half-life (t

) was between 5.3 and 8.3 hours. No effect of food on exposure or maximum achieved plasma concentrations were observed, but a significant shift of t

from 2 hours in the fasted group to 5 hours in the fed group was observed.

Researchers also found that lenvatinib had no clinically relevant effect on the QTc interval in healthy volunteers.

In another phase I study, E7080 was administered twice daily with a 2-week-on/1-week-off schedule in 27 patients with advanced solid tumors.

DLTs of grade 3 elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (in one patient at the 16-mg dose level) and grade 3 platelet count decrease (in two patients at the 20-mg dose level) were reported. The MTD was eventually determined to be 13 mg twice a day after patients experienced poor tolerability at the 16-mg dose level. The most frequent AEs (&ge;50% of patients) included hematuria (74.1%), fatigue (70.4%), hypertension (66.7%), elevated AST (63.0%), headache (63.0%), proteinuria (63.0%), elevated ALT (55.5%), diarrhea (55.5%), and elevated lactate dehydrogenase (LDH) (51.9%). A durable PR was achieved in one patient with colon cancer. Stable disease was observed in 21 (84%) patients.

In a phase II study of 58 patients with radiative iodine-refractory DTC who had disease progression during the 12 months preceding enrollment, lenvatinib 24 mg once daily was given in 28-day cycles.

As the primary endpoint of the study, objective response rate (ORR) was found to be 50% (95% CI, 37%-63%). The median PFS was 12.6 months (95% CI, 9.9-16.1 months). Among these patients, 29 had prior VEGFR-targeted therapy, including sorafenib, sunitinib, axitinib, and motesanib; 14% of patients received prior anthracycline therapy. No significant ORR difference was detected between VEGFR-targeted therapy treatment-naive and treated patients (46% vs 59%). ORR among patients who received prior sorafenib treatment (14 patients) was 71%.

All patients experienced treatment-related AEs, with the most frequent being hypertension (76%), weight decrease (69%), diarrhea (67%), proteinuria (64%), fatigue (60%), decreased appetite (52%), and nausea (50%). Grade 3 or 4 treatment-related toxicities occurred in 42 patients (72%). Six grade 4 treatment-related AEs were reported, including hypocalcemia, hyperkalemia, abasia, and acute myocardial infarction. Most common grade 3 treatment-related AEs were weight loss (12%), hypertension, proteinuria (10%), diarrhea (10%), fatigue (9%), dehydration (9%), and arthralgia (5%).  Seventy-four percent of patients underwent dose interruptions, 66% of patients required dose reduction, and 26% of patients discontinued treatment because of treatment-related AEs.

Based on the encouraging results of the phase II study, a randomized, double-blind, placebo-controlled, multicenter international phase III study (SELECT) was carried out from August 2011 through October 2012 in 392 patients.

In this study, crossing over from placebo to the lenvatinib arm was allowed upon disease progression. To be enrolled, the patient had to have: at least one measurable lesion without iodine uptake on any RAI scan; or at least one measurable lesion that had progressed within 12 months after RAI therapy; or cumulative activity of iodine-131 that was >600 mCi. Radiologic evidence of progression within the previous 13 months was required for enrollment. Twenty-five percent of patients on lenvatinib and 20.6% patients received one prior TKI. Lenvatinib was given at a daily dose of 24 mg to patients on the treatment arm. The study met its primary endpoint, with a significant median PFS benefit seen in the lenvatinib arm (18.3 vs 3.6 months; HR, 0.21; 99% CI, 0.14-0.31;

<.001) across all prespecified subgroups, including TKI-treated patients and TKI-na&iuml;ve patients (18.7 months and 15.1 months, respectively). Additionally, patient&rsquo;s

mutation status failed to predict PFS benefit associated with lenvatinib. Similar to the results of phase II study, a response rate of 64.8% was observed in the lenvatinib group, with complete responses occurring in 4 (1.5%) patients.

In this study, almost all patients on the lenvatinib arm (97.3%) reported treatment-related AEs, whereas treatment-related AEs were experienced by 59.5% patients in the placebo group. However, treatment duration of lenvatinib was significantly longer than placebo (298.8 vs 67.1 person-years), which may have contributed to the more frequent AEs observed with lenvatinib.

Most patients (75.9%) on the lenvatinib arm reported grade 3 or higher treatmentrelated AEs, versus 9.9% in the placebo group. Frequent treatment-related AEs included hypertension (any grade, 69.3%; grade &ge;3, 42.9%), diarrhea (any grade, 59.4%; grade &ge;3, 41.8%), fatigue or asthenia (any grade, 59%; grade &ge;3, 27.5%), decreased weight (any grade, 46.4%; grade &ge;3, 9.2%), nausea (any grade, 41%; grade &ge;3, 13.7%), proteinuria (any grade, 32.2%; grade &ge;3, 10%), arterial thromboembolic effects (any grade, 5.4%; grade &ge;3, 2.7%), and venous thromboembolic effects (any grade, 5.4%; grade &ge;3, 3.8%). Six deaths (2.3%) that occurred on the lenvatinib arm were deemed to be treatment related. The direct causes of these deaths included pulmonary embolism, hemorrhagic stroke, and general deterioration of physical health, one in each case, but no specific causes of death in the other three patients were reported. Treatment discontinuation, dose reduction, and treatment interruption occurred in 14.2%, 82.4%, and 67.8% patients in the lenvatinib group, respectively. The mean lenvatinib dose was 17.2 mg per day.

Lenvatinib demonstrated significant antitumor activity in radioactive iodine-refractory DTC with a marked PFS benefit when compared with placebo. The activity is observed in both angiogenesis-targeting kinase inhibitor treatment-na&iuml;ve patients and treated patients.

Frequent toxicities include hypertension, diarrhea, fatigue or asthenia, decreased weight, nausea, and proteinuria; therefore, close monitoring of, and adequate management of, side effects are important for patients receiving this agent.

Since DTC often has a relatively indolent disease course, treatment should only be offered to patients with clinically significant disease to preserve QoL.

Efficacy and Tolerability of Lenvatinib and Sorafenib for Radioactive Iodine-Refractory DTC

Sorafenib, an oral small molecule kinase inhibitor that inhibits C-RAF, BRAF, RET, c-KIT, PDGF-R, and VEGFR 1-3, was approved by FDA in November 2013 for the treatment of patients with metastatic DTC based on the data from the phase III DECISION study.

Based on the SELECT study, the FDA approved lenvatinib for patients with radioactive iodine-refractory progressive DTC, which makes this agent the second FDA approved TKI for this disease.

Both the SELECT and DECISION studies have demonstrated improved PFS compared with placebo groups, as well as significant toxicities as evidenced by the frequent dose modifications and interruptions (

). Although no definitive conclusion can be drawn from interstudy comparison, the efficacy data from these two studies suggested a significantly higher PFS and response rate (RR) of lenvatinib. Quality of life was evaluated in the DECISION study, and a slight decrease of QoL was reported at the 2013 annual meeting of the American Thyroid Association.

Unfortunately, no QoL data are available in the SELECT study. Nevertheless, the data of lenvatinib-related toxicity suggest that treatment should only be offered to patients with clinically significant disease.

Table 1. Efficacy of Lenvatinib and Sorafenib in DTC

PFS indicates progression-free survival; OS, overall survival; RR, relative risk; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

The TKI lenvatinib targets multiple kinases, including VEGFR with low IC.

It has demonstrated marked antitumor activity in radioactive iodine-refractory DTC, with impressive improvement across all efficacy parameters in comparison with placebo. Lenvatinib has also demonstrated activities in patients who had previously received VEGFR targeting agents. It appears to be significantly more active than sorafenib; however, both are associated with frequent treatment-related toxicities leading to dose interruption and reduction. Quality of life data of lenvatinib are lacking, although a slight reduction of QoL associated with sorafenib has been reported in patients with thyroid cancer. Thus, the decision of when to initiate treatment for this group of patients must be made carefully, and treatment should be reserved for patients with clinically significant disease, such as those with substantial disease burden, rapidly growing disease or symptomatic disease, to preserve QoL. Although inhibition of angiogenesis has achieved significant success in the treatment of this disease, treatment options for patients whose disease no longer responds to VEGF targeting agents remain to be investigated.

Table 2. Tolerability of Lenvatinib and Sorafenib in DTC

AE indicates adverse effect; HTN, hypertension.

Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy.

Klein M, Vignaud JM, Hennequin V, et al. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma.

Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodinerefractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.

SEER (Surveillance Research Program). SEER Stat Fact Sheets: Thyroid Cancer. May 24, 2015. http://seer.cancer.gov/statfacts/html/thyro. html. Accessed August 10, 2015.

. Devita VT, Rosenberg SA, Depinho RA, Weinberg RA.

Devita, Hellman, and Rosenberg&rsquo;s Cancer: Principles and Practice of Oncology

. Ninth ed. Treatment of Well and Intermediately Differentiated Thyroid Carcinoma. March 16, 2011.

Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments].

Shaha AR, Shah JP, Loree TR. Differentiated thyroid cancer presenting initially with distant metastasis.

Argiris A, Agarwala SS, Karamouzis MV, et al. A phase II trial of doxorubicin and interferon alpha 2b in advanced, non-medullary thyroid cancer.

Sherman SI. Cytotoxic chemotherapy for differentiated thyroid carcinoma.

Woyach JA, Shah MH. New therapeutic advances in the management of progressive thyroid cancer.

Nikiforov YE. Molecular analysis of thyroid tumors.

Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors.

Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor.

Zhou ZH, Cui XN, Xing HG, et al. Changes and prognostic value of serum vascular endothelial growth factor in patients with differentiated thyroid cancer.

Karaca Z, Tanriverdi F, Unluhizarci K, et al. VEGFR1 expression is related to lymph node metastasis and serum VEGF may be a marker of progression in the follow-up of patients with differentiated thyroid carcinoma.

Klubo-Gwiezdzinska J, Junik R, Kopczynska E, et al. The comparison of serum vascular endothelial growth factor levels between patients with metastatic and non-metastatic thyroid cancer, and patients with nontoxic multinodular goiter.

Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer.

Articles

Therapy that targets angiogenesis has been extensively investigated in differentiated thyroid cancer (DTC) and has demonstrated significant antitumor activity.

Yujie Zhao, MD, PhD | Authors

Articles

Levantinib in the Management of Differentiated Thyroid Cancer