MD Conference Express - ENDO 2015 - (Page 26)

SElECTED UPDATES Lenvatinib targets particular fibroblast growth factor receptors, which might evoke unique responses. The SELECT study was a phase 3 pivotal trial with a median PFS (the primary end point) of 18.3 months for the patients receiving lenvatinib (n = 261) and 3.6 months for those receiving placebo (n = 131; HR, 0.21; 99% CI, 0.14 to 0.31; P < .001) [Schlumberger M et al. N Engl J Med. 2015]. PRs were achieved by 63% of patients receiving lenvatinib, and complete responses were achieved by 2%. AEs led to dose reductions in 68% of patients and discontinuation in 14% of patients. Response to lenvatinib was not predicted by RAS or BRAF mutations. Notably, treatment with MKIs with angiogenic targets can lead to the rare but dangerous and potentially fatal AEs of bowel perforation and fistulas, bleeding in the tumor or other organs, thromboembolism, and cardiac effects that can include arrhythmias, coronary artery disease, and LV dysfunction. These affect 1% to 2% of patients. Ezra E.W. Cohen, MD, University of California San Diego, La Jolla, California, USA, discussed the treatment of MTC, which accounts for about 5% of thyroid cancers. Distant metastases carry a poor prognosis with a median overall survival (OS) of about 2 years. Among MTC, 75% are sporadic and about 65% are RET mutated. Hereditary MTC is almost universally RET mutated. Patients with metastatic or recurrent disease that is not curable do not necessarily require therapy and may be better served by observation. Ideally, therapy should be initiated when the patient has good performance status, no to minimal symptoms, and evidence of disease progression within the last 6 to 12 months. Patients who are symptomatic from their disease need systemic therapy. The MKIs vandetanib and cabozantinib offer meaningful therapeutic options for MTC. Vandetanib was approved as a result of a phase 3 trial that met its primary end point of PFS [Wells SA et al. J Clin Oncol. 2012]. Patients with a RET mutation, particularly the M918T mutation, had a tremendous benefit from vandetanib. Vandetanib has a black box warning about QTc prolongation that occurred in 8% of patients who received it. Cabozantinib is also approved for MTC, based on a phase 3 trial [Elisei R et al. J Clin Oncol. 2013]. Among 219 patients who received cabozantinib, 94% showed target lesion regression, whereas 27% of the 111 patients receiving placebo had target lesion regression. The median PFS was 11.2 months for cabozantinib vs 4.0 months for placebo (HR, 0.28; 95% CI, 0.19 to 0.40; P < .001). Patients with the RET M918T mutation had a prolonged PFS relative to patients with other RET mutations (HR, 0.15; 95% CI, 0.08 to 0.28) [Sherman SI et al. ASCO. 2013]. Patients with RAS mutations also benefited from cabozantinib. 26 May 2015 Maria E. Cabanillas, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, USA, discussed evidence to support salvage therapy after failure of a firstline kinase inhibitor in advanced thyroid cancer. A retrospective review of adult patients with metastatic DTC found that median OS was 24 months for patients treated with sorafenib alone (n = 35) and 63 months for those receiving salvage therapy (n = 25; P = .013) [Dadu R et al. J Clin Endocrinol Metab. 2014]. PFS was 7.4 months (n = 15; 95% CI, 3.1 to 11.3) for all patients treated with sorafenib, and PFS was 11.3 months (n = 17; 95% CI, 5.3 to 24.4) for salvage therapy. A phase 3 study of lenvatinib vs placebo in DTC found that patients who were TKI-naïve had a PFS of 18.7 months with lenvatinib treatment (n = 229; 95% CI, 16.4 to not estimable), while TKI-pretreated patients had a PFS of 15.1 months (n = 93; 95% CI, 8.8 to not estimable) [Schlumberger M et al. N Engl J Med. 2015]. A phase 2 trial of vemurafenib in patients with papillary thyroid cancer found that vascular endothelial growth factor receptor-2 inhibitor (VEGFR2i)-naïve patients (n = 9) had a PR rate of 35%, median PFS of 15.6 months (95% CI, 11.2 to not reported), and OS not reached [Brose MS et al. Eur J Cancer. 2013; (abstr 28)]. The VEGFR2i-pretreated patients (n = 6) had a PR rate of 29%, median PFS of 6.3 months (95% CI, 5.39 to not reported), and median OS of 9.8 months (95% CI, 7.39 to not reached). A phase 1 study of cabozantinib in DTC found that patients previously treated with a VEGF pathway inhibitor still responded to cabozantinib [Cabanillas ME et al. Thyroid. 2014]. In MTC, very little evidence exists for salvage therapy. A phase 3 trial comparing cabozantinib vs placebo in 330 patients with metastatic MTC found that 43% of previously treated patients (19 of 44 patients) achieved a PR with cabozantinib [Elisei R et al. J Clin Oncol. 2013]. A retrospective study found that changing to a different, but similar, TKI in MTC yielded responses that were quite variable with a brief median time to failure [Weitzman SP et al. ENDO. 2015]. Recent trials and drug approvals have led to new options for advanced DTC and advanced MTC. Salvage therapy can benefit patients whose first-line TKI has failed, with greater evidence of benefit in DTC than MTC. www.mdce.sagepub.com http://www.facebook.com/mdconferencexpress http://mdce.sagepub.com

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MD Conference Express - ENDO 2015