Clinical information guide - lenvima.com

1 FOR RAI-REFRACTORY DTC. Clinical information guide Indication LENVIMA (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC). Important Safety information Warnings and Precautions Hypertension was reported in 73% of patients on LENVIMA vs 16%. with placebo (44% vs 4% grade 3). Blood pressure should be controlled prior to treatment and monitored throughout. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at grade 2.

2 Discontinue for life-threatening hypertension Please see Important Safety information throughout and accompanying full Prescribing information . The SELECT Trial A phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with locally recurrent or metastatic RAI-refractory DTC1. RANDOMIZATION. LENVIMA. Patients with locally recurrent or Treatment to disease progressiona (n=261). metastatic RAI-refractory DTC. Stratified by 24 mg once daily (N=392) Major efficacy outcome measure geographic region All patients must have had Progression-free survival prior VEGF/VEGFR- Placebo radiographic evidence of disease targeted therapy progression within 12 months prior (n=131) once daily Other efficacy outcome measures age Objective response rate to randomization, confirmed by Patients could cross over independent radiologic review to LENVIMA at Overall survival disease progressiona 2: 1.

3 VEGF=vascular endothelial growth factor; VEGFR=vascular endothelial growth factor receptor. Determined by blinded, independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) version a RAI-refractory was defined as1. 1 or more measurable lesions with no iodine uptake on RAI scan iodine uptake with progression within 12 months of RAI therapy or having received cumulative RAI activity >600 mCi (22 GBq), with the last dose administered at least 6 months prior to study entry Baseline patient demographics1. Of the 392 patients randomized 51% were male; the median age was 63 years; 40% were older than 65 years; 79% were white; 54% had an Eastern Cooperative Oncology Group performance status (ECOG PS).

4 Of 0; and 24% had received 1 prior VEGF/VEGFR-targeted therapy metastases were present in 99% of patients: lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. the histological diagnoses were papillary thyroid cancer (66%) and follicular thyroid cancer (34%); of those with follicular histology, 44% had H rthle cell and 11% had clear cell subtypes 67% of patients in the LENVIMA arm did not demonstrate iodine uptake on any radioiodine scan, compared to 77% in the placebo arm 59% of patients in the LENVIMA arm and 61% of patients in the placebo arm progressed, according to RECIST , within 12 months of prior 131I therapy of patients in the LENVIMA arm and of patients in the placebo arm had received prior cumulative activity >600 mCi (22 GBq)

5 131I, with the last dose administered at least 6 months prior to study entry The median cumulative RAI activity administered prior to study entry was 350 mCi ( GBq). SELECT=Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid. 2. Study design/efficacy Efficacy outcome measures in SELECT. Major efficacy outcome measure1. Progression-free survival (PFS)1,2. The time from randomization until objective tumor progression or death in the intent-to-treat (ITT) population; measured in SELECT according to RECIST Other efficacy outcome measures1. Objective response rate (ORR)1,2. The percentage of patients with tumor size reduction of a predefined amount and for a minimum time period following treatment; the sum of complete responses and partial responses Complete response (CR)1,3.

6 No detectable evidence of tumors following treatment Partial response (PR)1,3. A 30% reduction in tumor size following treatment Overall survival (OS)1,2. The time from randomization until death from any cause in the ITT population Response criteria RECIST1-3. A standardized set of criteria for measuring response in Clinical trials; RECIST version was used for efficacy evaluation in SELECT. Important Safety information (cont'd). Warnings and Precautions Cardiac dysfunction was reported in 7% of patients on LENVIMA vs 2% with placebo (2% vs 0% grade 3). Monitor for signs/symptoms of cardiac decompensation.

7 Withhold for grade 3 cardiac dysfunction. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction Please see Important Safety information throughout and accompanying full Prescribing information . 3. Efficacy outcomes in SELECT. Major efficacy outcome measure: PFS1. Median (months) (95% CI). LENVIMA: ( ). Placebo: ( ). HR (95% CI): ( ). P< PFS (probability). 0 2 4 6 8 10 12 14 16 18 20 22 24 26. Time (months). Number of subjects at risk LENVIMA 261 225 198 176 159 148 136 92 66 44 24 11 3 0. Placebo 131 71 43 29 19 13 11 5 4 2 2 2 0 0.

8 CI=confidence interval; NE=not estimable; HR=hazard ratio. Median PFS1. months (95% CI: ) in the LENVIMA arm vs months (95% CI: ) in the placebo arm (HR [95% CI]: [ ]; P< ). A statistically significant prolongation in PFS was demonstrated in patients treated with LENVIMA compared to those receiving placebo 107 events (41%) occurred in the LENVIMA arm vs 113 events (86%) in the placebo arm 93 patients (36%) who received LENVIMA progressed vs 109 patients (83%) who received placebo Death occurred in 14 patients (5%) who received LENVIMA vs 4 patients (3%) who received placebo Important Safety information (cont'd).

9 Warnings and Precautions Arterial thromboembolic events were reported in 5% of patients on LENVIMA vs 2%. with placebo (3% vs 1% grade 3). Discontinue following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months 4. Efficacy outcomes in SELECT (cont'd). Other efficacy outcome measure: ORR1. 65% ORR in the LENVIMA arm vs 2% in the placebo arm (P< ). 2% of patients in the LENVIMA arm achieved a CR vs 0 patients in the placebo arm 63% of patients in the LENVIMA arm achieved a PR vs 2% of patients in the placebo arm Other efficacy outcome measure: OS1.

10 Efficacy Median OS not estimable No statistically significant difference in OS between the LENVIMA and placebo arms (HR [95% CI]: [ ]; P= ). Upon confirmation of progression, 109 patients (83%) randomly assigned to placebo crossed over to receive open-label LENVIMA. Important Safety information (cont'd). Warnings and Precautions Across Clinical studies in which 1,160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. ALT and AST. increases (grade 3) occurred in 4% and 5% of patients on LENVIMA, respectively, vs 0% with placebo.