Targeted Therapy in Refractory Thyroid Cancer

Current Achievements and Limitations

Lucia Brilli; Furio Pacini

Disclosures

Future Oncol. 2011;7(5):657-668. 

In This Article

TKIs as Target Therapy

A turning point in the field of TKIs began with the development of imatinib. This drug was the first kinase inhibitor approved by the US FDA for the treatment of chronic myeloid leukemia. Imatinib therapy resulted in a significant improvement of tumor response, overall survival and patients' outcome in chronic myeloid leukemia compared with previous therapeutic regimens.[17]

In recent years, other new molecules have been developed, acting directly on neoangiogenesis and/or cancer cell proliferation. Some of these molecules have been used in progressive advanced thyroid cancer with promising results. In thyroid cancer, the ideal new drugs are those that are able to inhibit the oncogenic signaling pathways, namely those activated by RET/PTC, RAS and BRAF mutations.

Wild-type TK receptors are activated by ligands binding to the extracellular domain of the receptor, which determines a homo/dimerization of the receptors. In thyroid cancer, an activation of these receptors in the absence of ligand binding can be accomplished by different mechanisms, including overexpression or activating mutations.[18]

Many TKIs do not have a single target but inhibit several proteins potentially involved in tumor growth (Table 1); therefore, this multiple targeting could enhance their therapeutic efficacy. For instance, in addition to oncogene inhibition, TKIs are often also inhibitors of neoangiogenesis, mainly acting on the VEGF receptor (VEGFR). To date, no TKI has obtained a clinical approval in thyroid cancer management but several of them have entered experimental clinical Phase II/III trials in DTC, MTC and ATC.

The demonstration of disease progression is a common inclusion criteria for most clinical trials in thyroid cancer. Disease progression is radiologically assessed using the Response Evaluation Criteria in Solid Tumors (RECIST), which are based on a previous scan performed 6–14 months before the screening assessment. Different timing intervals for the definition of disease progression may account for differences in the interpretation of the progression-free survival (PFS) or the definition of stable disease, which may differ in different studies.

Other inclusion criteria, common to most clinical trials, are represented, for example, by the presence of at least one measurable lesion according to RECIST guidelines, no chemotherapy, radiation or TKI therapy within 4 weeks before the initiation of the study therapy, no other diagnosis of recent malignancy and, in case of DTC, evidence of radioiodine insensitivity.

The following paragraphs will describe the most relevant results of these trials (listed in Table 2).

Motesanib Diphosphate

Motesanib diphosphate (AMG706; Amgen, Thousand Oaks, CA, USA) is a small molecule that targets several TKs: mainly the VEGFRs 1, 2 and 3. Based on promising results of a Phase I study involving patients with advanced solid malignancies,[19] an open-label, multicentric, Phase II trial was conducted, beginning at a dose of 125 mg daily, in patients with DTC and MTC with documented progressive disease, according to the RECIST criteria.[20,21] Among 93 patients with DTC, partial responses (PRs) were confirmed in 14% and stable disease in 67% (maintained for 24 weeks or longer in 35% of those with stable disease), with an estimated median PFS (mPFS) of 40 weeks. In 91 patients with MTC, 2% had confirmed PRs and 81% had stable disease (48% of them lasting at least 24 weeks) with an estimated mPFS of 12 months. From an analysis of biomarkers, lower baseline VEGF levels were correlated with longer PFS.[22]

Sunitinib

Sunitinib (SU011248, Sutent®; Pfizer, NY, USA) has inhibitory activity against RET, VEGFR, PDGF receptor (PDGFR) and other TK receptors. In a Phase II trial, the drug was tested in patients with refractory thyroid cancer, with a treatment schedule of 50 mg once daily, 4 weeks on and 2 weeks off. Among 31 DTC patients, PR was reported in 14% and stable disease in 68%, while in six MTC patients, stable disease was observed in 83%.[23]

De Souza et al. have tested sunitinib at the same dosage in 25 patients with MTC.[24] Among 23 evaluable patients, PR was achieved in eight (35%) with a median duration of response of 37 weeks, while 13 (57%) had stable disease with a median duration of response of 32 weeks. Thus, the clinical benefit rate was 91%.

In another Phase II trial, sunitinib was administered in iodine refractory DTC and MTC under a continuous dose regimen, 37.5 mg orally once a day; the median duration of treatment was 8.5 months and, among 33 evaluable patients, there was one complete response (3%), ten PRs (28%) and 16 patients with stable disease (46%). Interestingly, the authors observed a significant association between decreased (18FDG–PET) uptake and favorable RECIST response.[25]

Ravaud et al. conducted a Phase II trial with sunitinib in patients with thyroid cancer. Among 15 MTC patients, two had a confirmed PR and three had an unconfirmed PR (33.3%). A stable disease for ≥12 weeks was achieved in four patients (26.7%).[26]

Vandetanib

Vandetanib (ZD6474, Zactima®; Astrazeneca Pharmaceuticals, CA, USA) is an oral, small moleculed compound with inhibitory effects on VEGFR2, RET and EGF receptor (EGFR). In vitro vandetanib is able to inhibit the growth of thyroid cancer cells harboring the RET/PTC1 and RET/PTC3 rearrangements, and the M918T RET mutation, but not the V804 mutation.[27] When tested in two, open-label, Phase II trials in metastastic hereditary MTC, one with a dose of 300 mg daily[28] and another with 100 mg daily,[29] vandetanib induced confirmed PRs in 20 and 16% of the patients, respectively, and obtained prolonged stable disease in 53% of the cases in both studies. A 50% reduction in serum calcitonin was observed in 63% of the patients.[28]

A large, Phase III, double-blind, placebo-controlled trial randomized 331 patients with advanced MTC to oral vandetanib 300 mg once-daily or placebo. The results of the study demonstrated that treatment with vandetanib significantly extended PFS, the primary end point of the study. The objective response rate, a secondary end point, was 45 versus 13% across the two groups (p < 0.0001).[30] The FDA and the EMA have recently accepted regulatory submissions for review of the investigational drug for the treatment of advanced MTC.

Vandetanib was also tested in a Phase II trial in advanced DTC patients, comparing PFS in 145 patients with radioiodine refractory thyroid cancers. mPFS in patients taking vandetanib was 11 months, versus 5.8 months in the placebo group. Objective response rate and disease control rate were higher in the vandetanib arm compared with placebo but did not reach statistical significance.[31]

Axitinib

Axitinib (AG-013736; Pfizer, CA, USA) is a selective inhibitor of VEGFR and a less powerful inhibitor of PDGF-β and c-KIT. Following a Phase I trial in patients with advanced solid tumors where one out of five patients with thyroid cancer experienced tumor shrinkage,[32] a multicenter, single-arm, Phase II trial was conducted in 60 subjects with advanced or metastatic thyroid cancer, beginning at a dose of 5 mg twice daily.[33] Stable disease was achieved in 23 patients (38%); PR was observed in two out of 11 (18%) patients with MTC and 14 out of 45 (31%) patients with DTC. With a median follow-up of 16.6 months, the mPFS was 18 months.

XL-184

XL-184 (BMS 907351, cabozantinib; Exelixis, South San Francisco, CA, USA) is an oral inhibitor of several TK receptors. The primary targets are VEGFR2, RET, c-KIT and MET, which is highly expressed in DTC and MTC. In a Phase I trial, 85 MTC patients were enrolled, 37 of them with a minimum follow-up of 17 months.[34] Ten out of 34 (29%) achieved a confirmed PR and 15 out of 37 patients (41%) had a best response of prolonged (≥6 months) stable disease. No correlation was found between RET mutational status, decrease in calcitonin and CEA levels, and tumor response.

A Phase III trial, comparing XL184 and placebo in patients with progressive, metastatic MTC, is ongoing and still under recruitment.[101]

Sorafenib

Sorafenib (BAY 43–9006, Nexavar®; Bayer Health Care, Leverkusen, Germany) is a multikinase inhibitor with activity against VEGFR2 and 3, PDGFR, RAF and RET kinases. It was tested in two Phase II trials,[35,36] at the dose of 400 mg bi-daily, in patients with DTC in a total of 71 patients. PR lasting at least 18 months were obtained in 13 patients (18%), prolonged stable disease (>14 weeks) was observed in 39 patients (55%) and mPFS was between 15 and 21 months. In both studies, thyroglobulin levels demonstrated a marked decrease but this was not clearly associated with the degree or the duration of response.

On the basis of these promising results, a multicenter, double-blind, Phase III trial in locally advanced/metastatic radiodine refractory DTC patients is ongoing and still recruiting.[102]

Unfortunately, sorafenib has demonstrated very low activity in bone metastases and has no effect on the reinduction of 131I uptake[37] – a common observation also found with other TKIs.

In addition, sorafenib has been tested in MTC patients in a Phase II trial,[38] including 16 evaluable patients with sporadic tumor, one patient achieved PR (6%) while 14 had stable disease (93%) with an estimated mPFS of 17.9 months.

Recently, Capdevila et al. tested sorafenib in patients with advanced thyroid carcinoma,[39] among 27 evaluable patients they observed PRs in nine (30%) and stable disease in 13 (36%) patients. With a median follow-up of 11 months, the mPFS was 11.6 months. Interestingly, six out of 12 (50%) patients with MTC obtained a PR, indicating that the drug might be effective in MTC, although the small number of patients requires further prospective studies.

E7080

E7080 (Eisai, Ridgefield Park, NJ, USA) is a potent inhibitor of multiple TK receptors including VEGF, FGF and SCF receptors. It is currently used in a Phase II trial involving DTC and MTC patients.[103] The accruements have just terminated and preliminary results will be available in the near future.

Pazopanib

Pazopanib (GW786034, Votrient®; GlaxoSmithKline, Brentford, UK) targeting VEGFR, PDGFR, c-KIT and other kinases has been used at a daily dose of 800 mg in patients with metastatic, radioiodine-refractory differentiated thyroid cancer with a radiographically confirmed disease progression within 6 months before enrolment. Among 37 evaluable patients, none had a complete response, but 18 (49%) had a confirmed PR. Median overall survival at 1 year was 81%, PFS at 1 year was 47% and median duration of PFS was 11.7 months. Interestingly, pazopanib concentrations were significantly higher in the 18 patients who obtained confirmed RECIST PRs than in those who did not.[40]

PLX4032

PLX4032 (RG7204; Plexxikon, USA/Roche, Switzerland) is a selective inhibitor of the oncogenic V600E mutant, BRAF kinase. In a Phase I study, the drug was tested in solid tumors with this mutation, including three thyroid cancers. Tumor regression (range: 9–16%) was documented in all of them.[41]

AZD6244

ARRY-142886 (Astrazeneca Pharmaceuticals, CA, USA) is an inhibitor of the MEK, which is an enzyme involved in the RAS–RAF–MEK–ERK pathway. Recently, the drug has been used in patients with 131I refractory papillary thyroid carcinoma who had objective evidence of disease progression in the previous 12 months. Best response in 32 evaluable patients, after at least two cycles, was one PR (3%) and 21 patients with stable disease (66%). The mean and mPFSs were 53.6 and 32 weeks, respectively.[42]

Considering all the clinical trials reported here, it is possible to attempt some rough speculation of the specific properties of each drug. Sorafenib seems to be more efficient in the case of classical PTC than poorly DTC, although patient populations were limited in this case;[35] moreover, sorafenib seems to have a more pronounced effect in parenchimal metastases than in bone lesions, and it has been demonstrated that patients with bone metastases have a worse response to sorafenib compared with patients without bone involvement.[37]

Regarding tumor markers, a reduction in their levels does not correlate with tumor response to drugs and this lack of correlation is demonstrated in almost all trials using TKIs.

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