FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

In continuation of my update on lenvatinib

Woodcliff Lake, NJ and Kenilworth, announced today that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor Lenvima (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT (Study 304), where Lenvima demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

“Unresectable hepatocellular carcinoma is an extremely difficult-to-treat cancer, with no new first-line systemic therapy options for more than a decade,” said Dr. Ghassan Abou-Alfa, medical oncologist, Memorial Sloan Kettering Cancer Center. “REFLECT is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC. The efficacy and safety data from REFLECT are important findings for oncologists and others in the multidisciplinary teams who treat liver cancer, as well as for our patients who are affected by it.”

Adverse reactions, some of which can be serious or fatal, may occur with Lenvima, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the severity of the adverse reaction, Lenvima should be monitored, withheld or discontinued. Based on its mechanism of action and data from animal reproduction studies, Lenvima can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see “Important Safety Information” below.

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 when 351 events had occurred in the Lenvima arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, 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<0.001) 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) per RECIST 1.1.
• Lenvima showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with Lenvima versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
  • Per mRECIST: Treatment with Lenvima resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with Lenvima resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
  • Per RECIST 1.1: Treatment with Lenvima resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with Lenvima resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib

In addition, median time to progression (TTP) was doubled with Lenvima compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with Lenvima versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

In REFLECT, the most common adverse reactions (≥20%) observed in patients treated with Lenvima were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism and nausea. The most common serious adverse reactions (≥2%) reported in patients treated with Lenvima were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%).

The most common adverse reactions (≥20%) observed in patients who received sorafenib were palmar-plantar erythrodysesthesia syndrome, diarrhea, fatigue, hypertension, abdominal pain, decreased appetite, rash, decreased weight and arthralgia/myalgia. The most common serious adverse reactions (≥2%) reported in patients who received sorafenib were ascites (2%) and abdominal pain (2%).

It is also important to note that the dose for Lenvima for patients with unresectable HCC is based on the patient’s weight (12 mg for patients weighing 60 kilograms or more, 8 mg for patients weighing less than 60 kilograms); the recommended dosage and dose adjustments are described in the full prescribing information.

“Eisai strives to be a leading global R&D-based pharmaceutical company, driven by our human health care (hhc) mission to improve the lives of patients and their loved ones,” said Shaji Procida, President and Chief Operating Officer, Eisai Inc., and Commercial Head of the Oncology Business Group, Americas at Eisai. “That purpose is what has propelled us toward this win for patients with unresectable hepatocellular carcinoma. Our goal is to bring monumental solutions to patients and health care providers, changing expectations for the oncology landscape, and we look forward to continuing this work in our ongoing collaboration with Merck.”

“We are pleased by the FDA approval of Lenvima as it marks an important advancement in the treatment of unresectable hepatocellular carcinoma,” said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. “With our shared mission to find solutions for difficult-to-treat cancers, we look forward to working with Eisai to help bring this needed option to patients and physicians.”

Lenvima, a kinase inhibitor, was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In May 2016, Lenvima was approved in the U.S. in combination with everolimus, for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Under the collaboration, Eisai and Merck initiated co-commercialization activities for Lenvima in the U.S. in June 2018. Since the initial launch, more than 10,000 patients were treated with Lenvima, which is approved in more than 50 countries worldwide.

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FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

FDA Approves Lenvima (lenvatinib) for the Treatment of Patients with Advanced Renal Cell Carcinoma

In continuation of my update on Lenvatinib

 Lenvatinib

Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) approved Lenvima (lenvatinib), the company's multiple receptor tyrosine kinase inhibitor, in combination with everolimus for the treatment of patients with advanced renal cell carcinoma(aRCC) who were previously treated with an anti-angiogenic therapy. This approval was based on the impressive results of the registration study (Study 205), in which the once daily combination of 18 mg Lenvima and 5 mg everolimus demonstrated a substantial improvement in progression-free survival (PFS), powerful objective response rate (ORR) and clinically meaningful overall survival (OS) when compared with everolimus alone, a standard of care for patients with aRCC who have received prior anti-angiogenic therapy.

"Lenvatinib plus everolimus is the first and only FDA-approved regimen that successfully combines treatments that employ tyrosine kinase and mTOR inhibition, the primary targets of advanced RCC treatment for the past decade," said Robert Motzer, M.D., Memorial Sloan Kettering Cancer Center, New York, and the principal investigator of the study. "This combination regimen led to enhanced efficacy and helped patients with advanced RCC live longer without disease progression or death than those treated with everolimus alone. These noteworthy findings advance the treatment paradigm for this patient population."

Lenvima was granted Breakthrough Therapy designation by the FDA for this indication, and the application received Priority Review, which is assigned to drugs the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition.

In Study 205, a Phase 2 trial, Lenvima and everolimus (LEN+EVE) resulted in a median PFS nearly three times that of everolimus alone. The median PFS, or the length of time from randomization until disease progression or death, in patients treated with the combination (n=51) was 14.6 months (95% CI: 5.9–20.1) compared with 5.5 months (95% CI: 3.5–7.1) for those treated with everolimus alone (n=50) (HR 0.37; 95% CI: 0.22–0.62). The combination regimen resulted in a 63% reduction in the risk of disease progression or death compared with everolimus alone. The treatment effect of the combination on PFS was supported by a retrospective independent review.

The objective response rate was 37% (95% CI: 24–52) in patients treated with the combination regimen (35% partial response + 2% complete response) compared to 6% (all partial response, 95% CI: 1–17) in patients treated with everolimus alone.

The patients who received LEN+EVE experienced a 10.1-month increase in median OS compared with those who received everolimus monotherapy (25.5 months [95% CI: 16.4–32.1] versus 15.4 months [95% CI: 11.8–20.6]; HR 0.67; 95% CI: 0.42–1.08). This OS analysis was conducted when 63% of deaths had occurred in the combination arm and 74% of deaths had occurred in the everolimus arm.

The safety of this combination regimen was also examined in Study 205. Serious risks from treatment with the combination of Lenvima and everolimus may include hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid-stimulating hormone suppression/thyroid dysfunction, and embryofetal toxicity. The most common adverse reactions observed in study patients treated with Lenvima and everolimus (greater than 30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events and proteinuria. The most common serious adverse reactions (greater than or equal to 5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%) and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients receiving Lenvima and everolimus and 54% in patients receiving everolimus. The most common adverse reactions (greater than or equal to 5%) resulting in dose reductions in patients treated with Lenvima and everolimus were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%) and proteinuria (5%).

Treating physicians are likely to be familiar with many of the adverse reactions observed for this combination regimen based on their prior experience with these types of drugs. Prescribers may be able to manage certain adverse reactions (such as nausea, vomiting, diarrhea and hypertension) with a proactive plan that includes concomitant medications and/or dose reductions, interruptions and/or discontinuations.

"Rates of renal cell carcinoma have been on the rise over the past several decades, and unfortunately, advanced RCC remains an incurable disease. Since the VEGF pathway is known to be involved in the growth of renal cell tumors, it is important to have a diverse offering of therapeutic options, including treatments that continue to target VEGF inhibition," said Sumanta Kumar Pal, M.D., Assistant Professor, Department of Medical Oncology & Therapeutics Research and Co-Director, Kidney Cancer Program at City of Hope in Duarte, Calif. "The combination regimen of lenvatinib and everolimus provides a new treatment for patients with advanced RCC whose disease continues to progress despite prior treatment with an anti-angiogenic therapy."

Lenvima was first approved in the U.S. on February 13, 2015, for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

"By bringing this breakthrough treatment to patients with advanced RCC, Eisai now offers an efficacious option in a second difficult-to-treat tumor type, just 15 months after its initial approval, and we look forward to continued exploration of LENVIMA in additional malignancies," said Alton Kremer, M.D., Ph.D., Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "This also marks the second time in four months that one of Eisai's oncology treatments has been granted a new indication following Priority Review from the FDA. These milestones, as well as the ongoing development of innovative agents in our pipeline, underscore our steadfast commitment to Eisai's human health care (hhc) mission of identifying and addressing the unmet needs of people living with cancer."

About Study 205

Study 205, the Phase 2 study, was a multicenter, randomized trial in patients (n=153) with unresectable advanced or metastatic RCC who were previously treated with an anti-angiogenic therapy and randomized 1:1:1 to receive a combination of 18 mg LENVIMA plus 5 mg everolimus once a day, LENVIMA only (24 mg once a day) or everolimus only (10 mg once a day) administered orally in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary efficacy endpoint of this study was investigator-assessed PFS. Other endpoints of the study included ORR, OS and safety.

The results of this study were published online in The Lancet Oncology in October 2015, following an oral presentation at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.

FDA Approves Lenvima (lenvatinib) for Differentiated Thyroid Cancer

LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4- [3chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carbox- amide methanesulfonate. The molecular formula is C₂₁H₁₉ClN₄O₄•CH₄O₃S, and the molecular weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is:

The U.S. Food and Drug Administration today granted approval to Lenvima(lenvatinib) to treat patients with progressive, differentiated thyroid cancer (DTC) whose disease progressed despite receiving radioactive iodine therapy (radioactive iodine refractory disease).

FDA Approves Lenvima (lenvatinib) for Differentiated Thyroid Cancer

Eisai announces FDA approval of LENVIMA (lenvatinib) for treatment of RAI-refractory DTC

Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) approved the company's receptor tyrosine kinase inhibitor LENVIMA™ (lenvatinib) for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC). LENVIMA was approved following a priority review by the FDA, which is designated for drugs the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition. LENVIMA demonstrated a statistically significant progression-free survival (PFS) prolongation and response rate in patients with progressive, differentiated thyroid cancer who had become refractory to radioactive iodine (RAI) therapy.

"In the pivotal Phase 3 SELECT clinical trial, recently published in the New England Journal of Medicine, treatment with LENVIMA resulted in a highly statistically significant improvement in progression-free survival and a high overall response rate in patients with locally recurrent or metastatic, progressive, RAI-refractory DTC," said Lori J. Wirth, M.D., study investigator and medical director of the Center for Head and Neck Cancers at the Massachusetts General Hospital. "The thyroid cancer community welcomes an agent that offers a significant, effective option for the treatment of differentiated thyroid cancer in patients who have progressed after becoming refractory to RAI therapy."

Eisai announces FDA approval of LENVIMA (lenvatinib) for treatment of RAI-refractory DTC