Combination of Lenvatinib and Pembrolizumab Results in Notable Response Rates for Patients with Advanced Renal Cell Carcinoma Based on Interim Analysis of Ongoing Phase 1b/2 Trial

WOODCLIFF LAKE, N.J., Sept. 10, 2017 /PRNewswire/ -- Eisai Inc. today announced interim results from the advanced renal cell carcinoma (RCC) cohort of Study 111, a Phase 1b/2 study investigating lenvatinib (marketed as Lenvima^® in the U.S. and Japan and as Kisplyx^® for RCC in the EU), a multiple receptor tyrosine kinase inhibitor (including fibroblast growth factor receptors [FGFR] 1 – 4), in combination with the Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the United States and Canada) anti-PD-1 therapy, pembrolizumab (marketed as KEYTRUDA^®), in patients with selected solid tumors. In this cohort of both treatment-naïve and previously treated patients with metastatic clear cell RCC (n=30), the confirmed objective response rate (ORR) at week 24, the primary endpoint of the study, was 63% (95% CI: 44 – 80) based on investigator-assessed immune-related RECIST, all of which were partial responses (PR) (n=19), and disease control rate (DCR, complete response [CR] + PR + stable disease [SD]), a secondary endpoint, was 96% (including 33% SD [n=10]). No new safety signals were identified and toxicities were managed with supportive medications, dose interruptions/reductions or drug withdrawal. Lenvatinib and pembrolizumab are not approved for use in combination. These results were presented in an oral proffered paper session today at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid, Spain (Abstract No. 847O).  

"The observed efficacy in the metastatic RCC cohort of Study 111, particularly the 83% response rate among treatment-naïve patients, provides clinical evidence of the anti-tumor activity of lenvatinib in combination with pembrolizumab in patients with RCC," said Chung-Han Lee, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, and lead investigator. "These data are encouraging as we look to continue enrollment in the CLEAR trial, a Phase 3 trial evaluating the combination of this TKI and anti-PD-1 therapy in previously untreated patients with advanced RCC, and better understand how these results may translate to a larger group of patients with this type of cancer."

Secondary endpoints include ORR (measured beyond week 24), progression-free survival (PFS), DCR, duration of response (DOR) and safety and tolerability. ORR measured beyond week 24 remained the same as ORR measured at week 24. Median PFS was not reached at follow up of 9.7 months (95% CI: 9.9 – NE) and median DOR was not reached (95% CI: 8.4 – NE). The most common treatment-emergent adverse events (TEAE), any-grade, for the combination regimen were diarrhea, fatigue, hypothyroidism, stomatitis, nausea and hypertension. Sixteen patients experienced grade 3 TEAEs (the most common were increased lipase and hypertension) and two patients had grade 4 events. Two patients had grade 5 events, both of which were related to disease progression and not considered related to study drugs.

When evaluated based on treatment line, ORR was 83% (95% CI: 52 – 98) for previously-untreated patients (n=12) and DCR was 100% (83% PR [n=10]; 17% SD [n=2]). Median DOR was not reached (95% CI: 10.3 – NE). In previously treated patients (n=18), ORR was 50% (95% CI: 26 – 74) and DCR was 94% (50% PR [n=9]; 44% SD [n=8]). Median DOR was 8.5 months (95% CI: 3.5 – NE).

When evaluated by PD-L1 status, ORR was 71% (95% CI: 42 – 92) for patients with negative PD-L1 status (n=14) and DCR was 100% (71% PR [n=10]; 29% SD [n=4]). Median DOR was not reached (95% CI: 8.4 – NE). In patients with positive PD-L1 status (n=12), ORR was 58% (95% CI: 28 – 85) and DCR was 91% (58% PR [n=7]; 33% SD [n=4]). Median DOR was 10.3 months (95% CI: 3.5 – 10.3).

"This is the second cohort from Study 111 in which the combination of lenvatinib and pembrolizumab resulted in high response rates among patients with a difficult-to-treat, advanced stage cancer," said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "The data to be presented today at ESMO, coupled with the data from the metastatic endometrial cancer cohort presented at ASCO, contribute to our body of knowledge as we continue to study this combination across multiple tumor types."

Lenvima (lenvatinib) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Lenvima (marketed as Kisplyx^® for RCC in the EU) is also indicated in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. This release discusses an investigational use for FDA-approved products. Lenvatinib is not approved for use in combination with pembrolizumab. This release is not intended to convey any conclusions about efficacy or safety of lenvatinib, pembrolizumab or any combination of these two agents. There is no guarantee that any investigational uses of such FDA-approved products will successfully complete clinical development or gain FDA approval.

The Phase 3 CLEAR trial (NCT02811861) evaluating lenvatinib plus pembrolizumab and lenvatinib plus everolimus versus sunitinib as first-line therapy in patients with advanced RCC is currently enrolling; please visit clinicaltrials.gov for more information.

About Study 111

Study 111 is a multicenter, open-label, single-arm Phase 1b/2 basket trial of the combination of lenvatinib (20 mg/day) with pembrolizumab (200 mg intravenously every 3 weeks) in patients with selected solid tumors. The primary endpoint of the Phase 1b study was to determine the maximum tolerated dose of pembrolizumab and lenvatinib in combination. The primary endpoint of the Phase 2 study is investigator-assessed ORR based on immune-related RECIST at week 24. The secondary endpoints include progression-free survival, duration of response, disease control rate, and clinical benefit rate. Thirty patients with metastatic clear cell RCC were evaluated in the RCC cohort. The study is being conducted under an existing clinical trial collaboration agreement between the two companies.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC), also known as renal cell cancer or renal cell adenocarcinoma, is the most common type of kidney cancer, representing about 90% of cases in the United States. Renal cell carcinoma occurs when malignant cells are found in the lining of the tubules in the kidney. While RCC usually grows as a single tumor within a kidney, there may also be two or more tumors in one or both kidneys. In 2017, it is estimated that there will be approximately 64,000 new cases of kidney cancer, and about 14,400 people will die from the disease. Approximately 16% of patients with RCC will have metastases at diagnosis, and as many as 40% will demonstrate metastasis after primary surgical treatment for localized RCC. With a 5-year survival rate ranging from 5% to 12%, the prognosis for these patients is poor.

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. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

Important 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 Maryland and North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US.

KEYTRUDA^® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

SOURCE Eisai Inc.