First new, first-line treatment option for advanced or unresectable HCC approved in Europe in a decade

HATFIELD, UK & KENILWORTH, NJ, USA I August 23, 2018 I Eisai and Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the European Commission (EC) has granted a marketing authorization for the oral receptor tyrosine kinase (RTK) inhibitor LENVIMA® (lenvatinib), as a single agent for the first-line treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy. Treatment options for this type of liver cancer are limited, and the prognosis is poor.LENVIMA is the first new, first-line treatment for advanced or unresectable HCC in a decade to show an overall survival (OS) treatment effect by statistical confirmation of non-inferiority against standard of care.

Liver cancer is the second leading cause of cancer-related deaths and is estimated to be responsible for nearly 750,000 deaths per year globally (69,000 per year in Europe), with over 780,000 cases newly diagnosed each year (71,000 per year in Europe). Hepatocellular carcinoma represents about 90 percent of primary liver cancer cases and due to the underlying nature of the disease, surgery is generally not an option.

“Patients with hepatocellular carcinoma are faced with a cancer that is difficult to treat and has a particularly poor prognosis, with only one systemic first-line treatment option currently available,” said Gary Hendler, Chairman and CEO, Eisai EMEA. “LENVIMA is the first new treatment option to be made available in this first-line systemic treatment setting in over a decade and represents an important new therapeutic option for patients. Eisai and Merck are therefore committed to working together to ensure that patients have rapid access to LENVIMA across Europe.”

“Today’s approval brings an important new first-line treatment option to patients with hepatocellular carcinoma in Europe,” said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. “As a result of our efforts with Eisai on LENVIMA, we continue to make significant progress in gaining regulatory approval in countries around the world, as we strive together to make this medicine available to patients in need as quickly as possible.”

This approval was based on results from REFLECT (Study 304), an open-label, Phase 3 trial where LENVIMA demonstrated a treatment effect on OS by statistical confirmation of non-inferiority when compared with the standard of care, sorafenib, in 954 patients with previously untreated unresectable HCC. LENVIMA also demonstrated statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR).

Currently, LENVIMA is marketed in Japan for the treatment of HCC and in the United States for the treatment of first-line unresectable HCC, and applications seeking approval for this indication have been submitted to additional countries.

About the REFLECT Trial (Study 304)
REFLECT was a large (n=954), Phase 3, randomized, multi-center, open-label trial conducted by Eisai to compare the efficacy and safety of LENVIMA versus sorafenib as a first-line systemic treatment in patients with unresectable HCC. Patients at 154 trial sites in 20 countries were randomized to receive LENVIMA 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60 kg, respectively) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was OS, tested first for non-inferiority to sorafenib, then for superiority. The key secondary efficacy endpoints of this study included PFS, time to progression (TTP) and ORR, tested for superiority to sorafenib.

REFLECT showed that LENVIMA achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with LENVIMA experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted as prespecified in the statistical analysis plan when 351 events had occurred in the LENVIMA arm and 350 events had occurred in the sorafenib arm. Patients randomized to the LENVIMA arm did not have a statistically significant improvement in OS compared to those in the sorafenib arm. LENVIMA showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

  • Median PFS was doubled with LENVIMA compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with LENVIMA versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77; p<0.0001) per RECIST 1.1.
  • LENVIMA showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 9-15%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.0001), and 19% (95% CI: 15-22%) with LENVIMA versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
  • In REFLECT, the most common adverse events (all grades) observed in ≥30% of patients treated with LENVIMA were hypertension, diarrhea, decreased appetite, fatigue and decreased weight. Fatal adverse events determined by the investigator to be related to LENVIMA treatment occurred in 11 (2%) patients and included hepatic failure (three patients), cerebral hemorrhage (three patients), and respiratory failure (two patients).

The results of the REFLECT trial were published online in The Lancet (Vol 391(10126):1163-1173) on February 9, 2018.

About LENVIMA ® (lenvatinib) capsules 10 mg and 4 mg
LENVIMA® (lenvatinib) is a kinase inhibitor that is indicated in the U.S.:

  • For the treatment of patients with locally recurrent or metastatic, progressive radioactive iodine-refractory differentiated thyroid cancer (DTC)
  • In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
  • For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)

LENVIMA, discovered and developed by Eisai, is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases 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. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will develop and commercialize LENVIMA jointly, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA® (pembrolizumab). In addition to ongoing clinical studies of the combination, the companies will jointly initiate new clinical studies evaluating the LENVIMA/KEYTRUDA combination to support 11 potential indications in six types of cancer, as well as a basket trial targeting six additional cancer types. The LENVIMA/KEYTRUDA combination is not approved in any cancer types today.

About Eisai Co., Ltd.
Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as “giving first thought to patients and their families and to increasing the benefits health care provides,” which we call our human health care philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realize our human health care philosophy by delivering innovative products in various therapeutic areas with high unmet medical needs, including Oncology and Neurology.

As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing and emerging countries.

For more information about Eisai Co., Ltd., please visit

The development of lenvatinib underscores Eisai’s human health care mission, the company’s commitment to innovative solutions in disease prevention, cure and care for the health and well-being of people worldwide. Eisai is committed to the therapeutic area of oncology and to address the unmet medical needs of patients and their families.

Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit

About Merck
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.