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28 Aug LENVATINIB SIGNIFICANTLY IMPROVED OVERALL SURVIVAL IN OLDER PATIENTS WITH LOCALLY RECURRENT OR METASTATIC, PROGRESSIVE, RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER ACCORDING TO RESULTS OF SUBANALYSIS OF PHASE 3 SELECT TRIAL

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First kinase inhibitor to show improvement in overall survival in any patient group with RAI-R DTC

Data published in the Journal of Clinical Oncology

WOODCLIFF LAKE, N.J., Aug. 28, 2017 /PRNewswire/ — Eisai Inc. announced data from a prespecified subgroup analysis, which was published in the Journal of Clinical Oncology, showing treatment with lenvatinib (marketed as Lenvima®) resulted in a statistically significant improvement in overall survival (OS) for patients older than 65 years of age with radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC) when compared with placebo (HR: 0.53; 95% CI: 0.31 – 0.91; nominal p=0.020), despite crossover of placebo patients to lenvatinib after progressive disease. Lenvatinib is a multiple receptor tyrosine kinase inhibitor (TKI) (including fibroblast growth factor receptors [FGFR] 1 – 4) approved by the U.S. FDA for locally recurrent or metastatic, progressive, RAI-R DTC.

 

The article, “Effect of Age on the Efficacy and Safety of Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial,” reports the results of a prespecified subanalysis of younger patients (65 years of age or younger) and older patients (older than 65 years of age) in the pivotal Phase 3 SELECT study evaluating lenvatinib versus placebo in patients with progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC) that had recurred locally or had metastasized. The median age was 56 for the younger group (n=155 treated with lenvatinib; n=81 treated with placebo) and 71 for the older group (n=106 treated with lenvatinib; n=50 treated with placebo). Other baseline characteristics were generally similar among all groups, including ECOG performance status, prior VEGF-targeted therapy, histology, and presence of BRAF mutations. 

 

“These data are important to consider because older patients are more likely to have RAI-refractory disease which is associated with a poorer prognosis,” said Marcia Brose, MD, PhD, an associate professor of otorhinolaryngology in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and lead author of the study. “The results are a major milestone as they show, for the first time, that a tyrosine kinase inhibitor can significantly improve overall survival in patients older than 65 with advanced, progressive, RAI-refractory differentiated thyroid cancer.”

 

The OS results of this subanalysis demonstrate the efficacy of lenvatinib for older patients and indicate the association between age and poorer survival outcomes is diminished by treatment with lenvatinib. Progression-free survival (PFS) and objective response rate (ORR) benefits were also maintained in patients treated with lenvatinib regardless of age group as compared with placebo. All p-values other than for the overall population are nominal. Results of safety analyses by subgroup demonstrated that toxicity with lenvatinib was manageable for most patients, including older patients, and dose modification and discontinuation of lenvatinib was more common for older patients.

 

Specifically, median OS was reached only in the older placebo-treated patients (18.4 months; 95% CI; 13.3 – 20.3) – survival data was not mature in the younger patient group – and younger patients who received placebo had statistically significantly longer OS than older patients who received placebo (HR: 0.48; 95% CI: 0.27 – 0.85; p=0.010), demonstrating the known effect of age on prognosis. Despite this, overall survival was not significantly different between age groups for patients who were treated with lenvatinib (HR: 0.78; 95% CI: 0.49 – 1.26; p=0.30). Additionally, older patients who received lenvatinib experienced a statistically significant improvement in OS as compared with older patients who received placebo (HR: 0.53; 95% CI: 0.31 – 0.91; p=0.020). These data further support that treatment with lenvatinib lessened the effect of age as a predictor of poorer survival. Exploratory analyses examining patient baseline characteristics and post-study interventions (including crossover and post-progression therapy) did not identify any confounding factors that could potentially explain the improvement in OS in older patients who received lenvatinib. 

 

In addition to showing a benefit in overall survival for older patients treated with lenvatinib, this analysis showed the PFS benefit of lenvatinib versus placebo was maintained in both age groups (younger patients: median PFS 20.2 vs. 3.2 months, HR: 0.19, 95% CI: 0.13–0.27, p<0.001; older patients: 16.7 vs. 3.7 months, HR: 0.27, 95% CI: 0.17–0.43, p<0.001) and treatment with lenvatinib resulted in better ORR compared with placebo regardless of age (younger patients: odds ratio [OR]: 45.7, 95% CI: 14.8-141.0, p<0.001; older patients: OR: 16.8, 95% CI: 4.7-60.0, p<0.001). 

 

Results for treatment exposure and safety indicated that older patients had a shorter time to first dose reduction and more patients in the older group required a dose reduction to 10 mg/day compared with younger patients. While treatment-related adverse events (AEs) were recorded for nearly all patients, the incidence of severe (grade 3 or higher) treatment-related AEs was significantly higher in older patients than in younger patients (89% and 67%, respectively) and older patients were more likely to experience AEs that required dose modifications. Percentages of patients who experienced serious treatment-emergent AEs were similar in younger (48%) and older (55%) patients in the lenvatinib arm. Fatal treatment-emergent AEs were also similar in younger and older patients (7%, with 1% reported as treatment-related; versus 9%, with 4% reported as treatment-related). The most common treatment-related AEs were the same for both older and younger patients and were hypertension (69% and 67%), diarrhea (57% and 61%), decreased appetite (58% and 45%), decreased weight (50% and 43%) and nausea (46% and 37%).

 

“These results provide further evidence of the efficacy of Lenvima for older patients, a critical insight as we progress toward fully understanding the role of Lenvima as a treatment option for adult patients of all ages with this aggressive form of thyroid cancer,” said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. “Eisai is committed to the ongoing study of the SELECT trial results and other clinical trials with Lenvima, and we are pleased that this important analysis has been published in the Journal of Clinical Oncology.”

For more information, visit http://ascopubs.org/doi/abs/10.1200/JCO.2016.71.6472. 

 

About the SELECT Study
The pivotal SELECT (Study of E7080 LEnvatinib in Differentiated Cancer of the Thyroid) study was a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to compare the PFS of patients with locally recurrent or metastatic RAI-R DTC and radiographic evidence of disease progression within 12 months prior to randomization, treated with lenvatinib (24 mg) once daily or placebo. Other outcome measures of the study included overall response rate (ORR), overall survival (OS) and safety. The study enrolled 392 patients stratified by geographic region, prior VEGF/VEGFR targeted therapy and age and randomized at a ratio of 2:1 to receive treatment with either lenvatinib 24 mg/day (administered orally, once a day) or placebo. The SELECT study was conducted by Eisai in collaboration with the SFJ Pharmaceuticals Group. 

The full results of this study were previously published in the New England Journal of Medicine.

 

About Thyroid Cancer
Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat near the trachea. It is more common in women than in men and most are in their 40s or 50s at the time of diagnosis. Thyroid cancer is the most common endocrine malignancy and global figures show that its incidence has increased significantly over the last 50 years.

 

The most common types of thyroid cancer, papillary and follicular (including Hürthle cell), are classified as differentiated thyroid cancer (DTC) and account for approximately 90% of all cases. While most DTC patients are curable with surgery and radioactive iodine treatment, the prognosis for those patients whose cancers persist or recur is poor. There are limited treatment options for this radioactive iodine-refractory form of thyroid cancer.

 

About Lenvima® (lenvatinib)
Lenvima® (lenvatinib) is a kinase inhibitor that is indicated for: 

  • Differentiated Thyroid Cancer (DTC): single agent for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
  • Renal Cell Cancer (RCC): in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy.

Lenvatinib, discovered and developed by Eisai, is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1-3. Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. 

Selected Safety Information

Warnings and Precautions

  • In DTC, hypertension was reported in 73% of patients on LENVIMA vs 16% with placebo (44% vs 4% grade ≥3). In RCC, hypertension was reported in 42% of patients on LENVIMA + everolimus vs 10% with everolimus alone (13% vs 2% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% of patients had a diastolic blood pressure ≥100 mmHg in the LENVIMA + everolimus–treated group. 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. Discontinue for life-threatening hypertension
  • In DTC, cardiac dysfunction was reported in 7% of patients on LENVIMA vs 2% with placebo (2% vs 0% grade ≥3). In RCC, decreased ejection fraction and cardiac failure were reported in 10% of patients on LENVIMA + everolimus vs 6% with everolimus alone (3% vs 2% grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold LENVIMA for development of grade 3 cardiac dysfunction until improvement to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction
  • In DTC, arterial thromboembolic events were reported in 5% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, arterial thromboembolic events were reported in 2% of patients on LENVIMA + everolimus vs 6% with everolimus alone (2% vs 4% 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
  • 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. In DTC, ALT and AST increases (grade ≥3) occurred in 4% and 5% of patients on LENVIMA, respectively, vs 0% with placebo. In RCC, ALT and AST increases (grade ≥3) occurred in 3% of patients on LENVIMA + everolimus vs 2% and 0% with everolimus alone, respectively. Monitor liver function before initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment grade ≥3 until resolved to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure
  • In DTC, proteinuria was reported in 34% of patients on LENVIMA vs 3% with placebo (11% vs 0% grade 3). In RCC, proteinuria was reported in 31% of patients on LENVIMA + everolimus vs 14% with everolimus alone (8% vs 2% grade 3). Monitor for proteinuria before and during treatment. Withhold dose for proteinuria ≥2 g/24 h. Resume at reduced dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
  • In RCC, diarrhea was reported in 81% of patients on LENVIMA + everolimus vs 34% with everolimus alone (19% vs 2% grade ≥3). Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Withhold dose for diarrhea grade ≥3. Resume at a reduced dose when diarrhea resolves to grade 1 or baseline. Permanently discontinue LENVIMA for grade 4 diarrhea despite medical management
  • In DTC, events of renal impairment were reported in 14% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, events of renal impairment were reported in 18% of patients on LENVIMA + everolimus vs 12% with everolimus alone (10% vs 2% grade ≥3). Withhold LENVIMA for grade 3 or 4 renal failure/impairment. Resume at reduced dose or discontinue, depending on severity/persistence of renal impairment. Active management of diarrhea and any other gastrointestinal (GI) symptoms should be initiated for grade 1 events
  • In DTC, events of GI perforation or fistula were reported in 2% of patients on LENVIMA vs 0.8% with placebo. In RCC, events of GI perforation, abscess, or fistula (grade ≥3) were reported in 2% of patients on LENVIMA + everolimus vs 0% with everolimus alone. Discontinue in patients who develop GI perforation or life-threatening fistula
  • In DTC, QT/QTc interval prolongation was reported in 9% of patients on LENVIMA vs 2% with placebo (2% vs 0% >500 ms). In RCC, QTc interval increases >60 ms were reported in 11% of patients on LENVIMA + everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold dose for QTc interval prolongation >500 ms. Resume at reduced dose when QTc prolongation resolves to baseline
  • In DTC, hypocalcemia (grade ≥3) was reported in 9% of patients on LENVIMA vs 2% with placebo. In RCC, hypocalcemia (grade ≥3) was reported in 6% of patients on LENVIMA + everolimus vs 2% with everolimus alone. Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust LENVIMA as necessary
  • Across clinical studies in which 1,160 patients received LENVIMA monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 4 patients. Withhold LENVIMA for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms
  • Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hemorrhage (grade ≥3) was reported in 2% of patients. In DTC, hemorrhagic events occurred in 35% of patients on LENVIMA vs 18% with placebo (2% vs 3% grade ≥3). There was 1 fatal intracranial hemorrhage case among 16 patients who received LENVIMA and had central nervous system metastases at baseline. The most frequently reported hemorrhagic event was epistaxis (11% grade 1, 1% grade 2). Discontinuation due to hemorrhagic events occurred in 1% of patients on LENVIMA. In RCC, hemorrhagic events occurred in 34% of patients on LENVIMA + everolimus vs 26% with everolimus alone (8% vs 2% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (23% for LENVIMA + everolimus vs 24% with everolimus alone). There was 1 fatal cerebral hemorrhage case. Discontinuation due to hemorrhagic events occurred in 3% of patients on LENVIMA + everolimus. Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (eg, carotid artery). Withhold LENVIMA for the development of grade 3 hemorrhage until resolved to grade 0 or 1. Resume at reduced dose or discontinue based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage
  • In DTC patients with normal baseline thyroid-stimulating hormone (TSH), elevation of TSH level above 0.5 mU/L was observed postbaseline in 57% of patients on LENVIMA vs 14% with placebo. In RCC, grade 1 or 2 hypothyroidism occurred in 24% of patients on LENVIMA + everolimus vs 2% with everolimus alone. In RCC patients with normal or low TSH at baseline, elevation of TSH was observed postbaseline in 60% of patients on LENVIMA + everolimus vs 3% with everolimus alone. Monitor thyroid function before initiation of and at least monthly throughout treatment. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state
  • LENVIMA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy

 

Adverse Reactions

  • In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients vs placebo-treated patients were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decrease (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%)
  • In DTC, adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and in 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (≥10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%)
  • In RCC, the most common adverse reactions (>30%) observed in patients treated with LENVIMA + everolimus vs everolimus alone were diarrhea (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%), decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs 16%), stomatitis/oral inflammation (44% vs 50%), hypertension/increased blood pressure (42% vs 10%), peripheral edema (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%), dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and proteinuria/urine protein present (31% vs 14%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%)
  • In RCC, adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA + everolimus and in 54% of patients receiving everolimus alone. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA + everolimus–treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA + everolimus–treated group and in 12% of patients in the everolimus-treated group

 

Use in Specific Populations

  • Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment
  • LENVIMA may result in reduced fertility in females of reproductive potential and may result in damage to male reproductive tissues, leading to reduced fertility of unknown duration

For more information about LENVIMA, click here for the full Prescribing Information.  

 

About Eisai Inc.
At Eisai Inc., human health care (hhc) is our goal. We give our first thought to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to discover and develop innovative therapies to help address unmet medical needs. 

Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Each group functions as an end-to-end global business with discovery, development, and marketing capabilities. Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Marylandand North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US.

 

About the SFJ Pharmaceuticals Group
The SFJ Pharmaceuticals Group, which includes SFJ Pharma Ltd., is a global drug development company, which provides a unique co-development partnering model for some of the world’s top pharmaceutical and biotechnology companies. SFJ uses its financial strength and core team of pharmaceutical development experts to provide highly customized partnering models in which SFJ provides the funding and clinical development supervision, necessary to obtain regulatory approval for some of the most promising drug development programs of pharmaceutical and biotechnology companies. 

 

Contacts:

Media

Laurie Landau

Eisai Inc.

201-746-2510

 

Investors

Alex Scott

Eisai Inc.

201-746-2177

 

SOURCE Eisai Inc.