Bayer expands global clinical program for darolutamide in prostate cancer

On March 23, 2023 Bayer reported that it has further expanded the global clinical development program for the oral androgen receptor inhibitor (ARi) darolutamide in prostate cancer (Press release, Bayer, MAR 23, 2023, View Source [SID1234629265]). The new Phase III clinical study, ARASTEP, will investigate the efficacy of darolutamide plus androgen deprivation therapy (ADT) versus ADT alone in hormone-sensitive prostate cancer, in patients with high-risk biochemical recurrence (BCR) who have no evidence of metastatic disease by conventional imaging and a positive PSMA PET/CT at baseline. BCR is defined as rising prostate-specific antigen (PSA) levels with a doubling time of <12 months after primary treatment (surgery or radiotherapy).1,2 Darolutamide is already approved under the brand name NubeqaTM for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease as well as metastatic hormone-sensitive prostate cancer (mHSPC). Bayer estimates that the peak sales potential for Nubeqa will exceed €3 billion.

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"Many patients with rising PSA levels following surgery or radiation are at an increased risk of developing metastasis. With ARASTEP, we are optimistic about the potential to help patients at this earlier stage of the disease," said Tara Frenkl, M.D., Senior Vice President and Head of Oncology Development at Bayer. "Darolutamide has already demonstrated efficacy and safety in nmCRPC with the Phase III ARAMIS trial, and in mHSPC with the Phase III ARASENS trial. Our goal is to ensure that as many patients as possible benefit from this therapy, therefore we continue to assess the potential of darolutamide in earlier disease stages."

The study is part of a robust global clinical development program for darolutamide. The compound is also being investigated in further studies across various stages of prostate cancer, including in the ARANOTE Phase III trial evaluating darolutamide plus androgen deprivation therapy (ADT) versus ADT alone for metastatic hormone-sensitive prostate cancer (mHSPC), as well as the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating darolutamide as an adjuvant treatment for localized prostate cancer with very high risk of recurrence.

Darolutamide is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

About the ARASTEP Trial
The ARASTEP trial is a randomized, double-blind, placebo-controlled Phase III study of darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT in hormone-sensitive prostate cancer, in patients with high-risk biochemical recurrence (BCR) who have no evidence of metastatic disease by conventional imaging and a positive PSMA PET/CT at baseline. The primary endpoint of this study is radiological progression-free survival (rPFS), measured by PSMA PET/CT assessed by independent central review. The trial is expected to enroll approximately 750 participants. Patients will be randomized to receive the standard regimen of 600 mg of darolutamide twice a day or matching placebo plus ADT.

About hormone-sensitive prostate cancer and biochemical recurrence (BCR)
Prostate cancer is the second most commonly diagnosed malignancy in men worldwide. In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, and about 375,000 died from the disease worldwide.3

Hormone-sensitive prostate cancer is a type of prostate cancer that needs androgens (male hormones) to grow and therefore stops growing when androgens are not present. Almost all early-stage prostate cancers are androgen-dependent.4

Up to 50% of patients with prostate cancer develop elevated prostate-specific antigen (PSA) levels in their blood after primary therapy (surgery and/or radiation therapy).5 This disease state is called biochemical recurrence (BCR). Current treatment options for patients with biochemical recurrent prostate cancer include prostatectomy, intending to be curative. If these treatments are unsuccessful, androgen deprivation therapy (ADT) is an option to control disease.2

About darolutamide (NubeqaTM)
Darolutamide is an oral androgen receptor inhibitor (ARi) with a distinct chemical structure that binds to the receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. The low potential for blood-brain barrier penetration for darolutamide is supported by preclinical models and neuroimaging data in healthy humans. This is supported by the overall low incidence of central nervous system (CNS)-related adverse events (AEs) compared to placebo as seen in the ARAMIS Phase III trial6 and the improved verbal learning and memory observed in the darolutamide arm of the Phase II ODENZA trial.7

The product is approved under the brand name Nubeqa in more than 80 countries around the world for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). It is also approved for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC) in a number of markets including the U.S., Japan, China and the EU. Filings in other regions are underway or planned.

About Prostate Cancer at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The company has the passion and determination to develop new medicines that help improve and extend the lives of people living with cancer. Prostate cancer is the second most commonly diagnosed cancer in men3 and a key area of focus for Bayer. The company’s franchise includes two products on the market (Nubeqa and Xofigo) and several compounds in development, including a unique approach of advancing targeted alpha therapies. Bayer is focused on addressing the unique needs of prostate cancer patients, providing treatments that extend their lives throughout the different stages of the disease and allowing them to continue their everyday activities, so that they can live longer, better lives.

Onconova Therapeutics And Pangea Biomed Enter Into Research Collaboration To Identify Biomarkers Of Response To Rigosertib

On March 23, 2023 Onconova Therapeutics, Inc. (NASDAQ: ONTX), ("Onconova"), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, and Pangea Biomed, a company combining machine learning and deep RNA analysis to expand access to precision oncology, reported a research collaboration between the companies (Press release, Onconova Therapeutics, MAR 23, 2023, View Source [SID1234629264]). The collaboration will leverage Pangea Biomed’s proprietary algorithmic platform, ENLIGHT, with the goal of identifying biomarkers of response to Onconova’s proprietary investigational product candidate rigosertib.

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Rigosertib has a multi-faceted mechanism of action targeting proteins containing the RAS binding domain, allowing it to modulate the PI3K and PLK1 pathways, as well as the tumor immune microenvironment. Clinical data have suggested the anti-cancer activity of rigosertib plus checkpoint inhibition in KRAS-mutated non-small cell lung cancer, and of rigosertib monotherapy in advanced squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa, an ultra-rare condition driven by PLK1 overexpression.

"Rigosertib’s ability to potently inhibit PLK1 and modulate the tumor immune microenvironment confers broad potential to treat a range of solid cancers," said Steven M. Fruchtman, M.D., President and Chief Executive Officer of Onconova. "By leveraging Pangea’s AI platform to identify predictive biomarkers of response to rigosertib, we aim to inform a precision medicine approach to selecting additional PLK1-dependent tumors and other indications for its potential evaluation. We believe this approach will increase the probability of success for rigosertib’s future development programs."

"Precision medicine is the future of oncology, but gaps in the industry’s current biomarker approaches overly narrow patient populations for promising drugs," said Pangea Biomed Chief Executive Officer Tuvik Beker, Ph.D. "ENLIGHT goes beyond standard biomarkers to expand patient populations for targeted therapies, in addition to surfacing new biomarkers for existing drugs. We’re hopeful our platform can help Onconova accelerate rigosertib’s successful development in a variety of difficult-to-treat cancers."

Pangea Biomed’s ENLIGHT platform is a pan-cancer response predictor that evaluates in vitro, preclinical, and clinical datasets to build genetic interaction maps that infer functional relationships between gene pairs to reveal tumor vulnerabilities to specified therapies. Onconova and Pangea Biomed will chart genetic interactions related to PLK1 to identify a biomarker of response to rigosertib based on its inhibitory activity against this protein. The ENLIGHT platform will then be applied to generate additional genetic interaction maps around other pathways targeted by rigosertib. Per a collaboration agreement between the companies, Onconova retains all rights to rigosertib and will own intellectual property that may result from the research collaboration.

Moderna and Generation Bio Announce Strategic Collaboration to Develop Non-Viral Genetic Medicines

On March 23, 2023 Moderna, Inc. (Nasdaq:MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, and Generation Bio Co. (Nasdaq:GBIO), a biotechnology company innovating genetic medicines for people living with rare and prevalent diseases, reported that the two companies have entered into a strategic collaboration to combine Moderna’s biological and technical expertise with core technologies of Generation Bio’s non-viral genetic medicine platform (Press release, Moderna Therapeutics, MAR 23, 2023, View Source [SID1234629263]). The collaboration aims to expand the application of each company’s platform by developing novel nucleic acid therapeutics, including those capable of reaching immune cells, to accelerate their respective pipelines of non-viral genetic medicines.

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"Moderna continues to invest in innovative technology to enable us to develop a breadth of transformative medicines for patients," said Rose Loughlin, Ph.D., Moderna’s Senior Vice President for Research and Early Development. "Through this collaboration, which builds on Generation Bio’s non-viral genetic medicines platform, we have the potential to target immune cells with diverse nucleic acid cargos and the liver for gene replacement. We are excited to have Generation Bio as our partner as we continue to broaden our therapeutic pipeline and extend the potential benefit of nucleic acid therapeutics to more patients."

"Non-viral DNA therapeutics may offer durable, redosable, titratable genetic medicines to patients suffering from rare and prevalent diseases on a global scale," said Phillip Samayoa, Ph.D., Chief Strategy Officer of Generation Bio. "This collaboration represents a foundational investment in our platform science, both deepening our pipeline of rare and prevalent liver disease programs beyond hemophilia A and accelerating our work to reach outside of the liver with nucleic acid therapies. We are thrilled to collaborate with Moderna to extend genetic medicines to new tissues and cell types through the joint development of novel targeting for our stealth ctLNPs to reach immune cells."

About the Collaboration

Under the terms of the agreement, Moderna may advance two immune cell programs, each of which may use a jointly developed ctLNP to deliver ceDNA. In addition, Moderna may advance two liver programs, each of which may use a liver-targeted ctLNP developed by Generation Bio to deliver ceDNA. Moderna retains an option to license a third program for either immune cells or the liver.

Generation Bio will receive a $40 million upfront cash payment and a $36 million equity investment issued at a premium over recent share prices. Moderna will fund all collaboration work, including a research pre-payment. Generation Bio is also eligible for future development, regulatory and commercial milestone payments, as well as royalties on global net sales of liver-targeted and immune cell-targeted products commercialized under the agreement. The agreement additionally provides Moderna with the right, subject to certain terms and conditions, to purchase additional shares of common stock in connection with a future equity financing by Generation Bio.

Further, Moderna and Generation Bio will both leverage collaboration research to continue to advance in vivo immune cell targeting as a new class of genetic medicines, with downstream economics on products utilizing such technology. Generation Bio is eligible to receive certain exclusivity fees as well as potential development and regulatory milestones and royalties on products that Moderna advances using ctLNP technology developed under the collaboration.

Sirona Biochem Announces Debenture Financing

On March 23, 2023 Sirona Biochem Corp. (TSX-V: SBM) (FSE: ZSB) (OTC: SRBCF) ("Sirona" or the "Company") reported a non-brokered private placement offering of unsecured, convertible debentures (the "Convertible Debentures") (Press release, Sirona Biochem, MAR 23, 2023, View Source [SID1234629262]). The Company is offering Convertible Debentures units (the "Debenture Units") at a price of $1,000 per Debenture Unit for aggregate gross proceeds of up to $1,500,000 (the "Offering").

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Each Debenture Unit will have a face value of (the "Face Value") of $1,120, consisting of $1,000 in principal (the "Principal") and $120 in prepaid interest (the "Prepaid Interest"). The Principal of the Debenture Units will accrue interest at a rate of 12% per annum, which accrued interest ("Accrued Interest") will be paid semi-annually, in arrears. The Company will pay the Prepaid Interest and Accrued Interest in cash or, subject to TSX Venture Exchange ("TSXV") acceptance, may elect to satisfy payment in kind by issuing Shares ("Interest Shares"). In the event of payment in kind, the number of Interest Shares due will be calculated using a conversion price (the "Interest Conversion Price") equal to, subject to acceptance by the TSXV, the maximum Discounted Market Price (as defined in TSXV policies) on the applicable payment due date.

The holder may, at its option, convert in full or in part, the Principal at any time prior to the maturity date (the "Maturity Date"), being the third anniversary of the issue date, into units (the "Units") of the Company at $0.10 per Unit (the "Conversion Price"). Upon conversion of the Principal, the Company will pay Prepaid Interest and unpaid Accrued Interest in cash or, subject to acceptance by the TSXV, in Interest Shares issued at the Interest Conversion Price.

Each Unit will consist of one Share and one non-transferable share purchase warrant (a "Warrant"). Each Warrant will be exercisable by the holder thereof to purchase one Share (a "Warrant Share") at an exercise price of $0.15 at any time prior to the Maturity Date.

The Company shall have the right to redeem the Convertible Debentures prior to the Maturity Date at any time after 6 months from the issue date, by paying holders in cash the Face Value of the Convertible Debentures, together with all Prepaid and Accrued Interest and a redemption penalty payment of 8% of the Face Value. The Company shall give the holders 30 business days’ notice (the "Redemption Notice") to do so. On receipt of a Redemption Notice, a holder may elect to convert all or part of the Principal of the Convertible Debenture into Units at the Conversion Price. All Prepaid and Accrued Interest in respect of the Principal amount so converted shall be, at the election of the holder, either paid in cash or, subject to acceptance by the TSXV, converted into Shares at the Interest Conversion Price, by giving the Company notice (the "Conversion Notice") within 10 business days of receipt of the Redemption Notice.

The closing of the Offering is subject to the receipt of necessary regulatory approvals, including the approval of the TSXV. The Convertible Debentures, Shares, Warrants and any Warrant Shares will be subject to a four-month hold period under applicable securities laws and TSXV policies. The Company may pay eligible finders a fee in connection with the Offering.

The Company plans to use approximately 1/3 of the net proceeds from the Offering for general corporate purposes, and the remainder of the proceeds will used for research and development expenses (including but not limited to, laboratory staff salaries, laboratory materials and intellectual property costs).

Dr. Howard Verrico, the Chief Executive Officer, has agreed to subscribe for $500,000 of Debenture Units. Dr. Verrico’s participation is a "related party transaction" within the meaning of Multilateral Instrument 61-101 Protection of Minority Security Holders in Special Transactions. The Company intends to rely on the exemptions from the formal valuation and minority shareholder-approval requirements of MI 61-101 in respect of related party participation in the Offering. The MI 61-101 exemptions are available as the fair market value of the Debenture Units, and the fair market value of the consideration for the Debenture Units, insofar as it involves Dr. Verrico and other interested parties, will not exceed 25% of the Company’s market capitalization.

This news release does not constitute an offer to sell or the solicitation of any offer to buy, nor shall there be any sale of these securities in any jurisdiction in which such offer, solicitation or sale would be unlawful. The Convertible Debentures and the Shares which may be issued on exercise thereof have not been and will not be registered under the United States Securities Act of 1933, as amended (the "U.S. Securities Act") and may not be offered or sold in the United States absent registration or an applicable exemption from the registration requirements of the U.S. Securities Act and applicable state securities laws.

Eisai to Present Research from Oncology Portfolio at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer

On March 23, 2023 Eisai reporte that it will present two abstracts at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer (#SGOMtg), which is taking place in-person in Tampa, Florida and virtually from March 25-28 (Press release, Eisai, MAR 23, 2023, View Source [SID1234629260]). Notable research to be featured in the Scientific Plenary IX: The Best of the Rest session includes a presentation of real-world outcomes and healthcare resource utilization in patients with recurrent or advanced endometrial carcinoma who were rechallenged with platinum chemotherapy in Europe (Abstract: #17).

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Also to be presented are data from the LEAP (LEnvatinib And Pembrolizumab) clinical program analyzing tumor-response from the lenvatinib (LENVIMA) plus pembrolizumab (KEYTRUDA) arm of the pivotal Phase 3 Study 309/KEYNOTE-775 trial in patients with advanced endometrial carcinoma following at-least one prior platinum-based regimen in any setting (NCT03517449; Abstract: #518).

"We look forward to sharing our data at this year’s SGO Annual Meeting, particularly a new study that will be presented in an oral scientific plenary session featuring real-world outcomes in patients with recurrent or advanced endometrial cancer who were rechallenged with platinum chemotherapy," said Dr. Takashi Owa, Chief Scientific Officer, Senior Vice President, Eisai Co., Ltd. "We believe this research is important to the healthcare providers and patients we aim to serve because it is essential to understand treatment dynamics and related outcomes in clinical practice. As a human health care company, we remain steadfast in our commitment to advance the science of cancer medicine through the generation of real-world evidence."

In March 2018, Eisai and Merck (known as MSD outside the United States and Canada), through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of lenvatinib, both as monotherapy and in combination with Merck’s anti-PD-1 therapy pembrolizumab. To date, more than 10 trials have been initiated under the LEAP clinical program, which is evaluating the combination across multiple tumor types.

This release discusses investigational compounds and investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational compounds or investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

The full list of Eisai presentations is included below. Full abstracts will be posted the day of scheduled presentations.

Study/Compound

Abstract Title

Abstract Type & Details

Real World Evidence

Endometrial Cancer Non-Interventional Study

Real-world outcomes and healthcare resource utilization
in recurrent or advanced endometrial cancer patients
rechallenged with platinum chemotherapy in Europe

Oral Scientific Plenary

Abstract #17

March 28, 2023

10:30-11:45 AM EDT

LEAP clinical program

Study 309/KEYNOTE-775

Characterization of tumor response With lenvatinib plus
pembrolizumab in study 309/KEYNOTE-775

Poster Discussion

Abstract #518

March 27, 2023

10:40-11:20 AM EDT

About Endometrial Carcinoma
Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. Worldwide, it was estimated there were more than 417,000 new cases of uterine body cancer diagnosed and more than 97,000 deaths from the disease in 2020 (these estimates include both endometrial carcinomas and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial carcinoma cases and deaths are slightly lower than these estimates). In the U.S., it is estimated there will be approximately 66,200 new cases of uterine body cancer diagnosed and approximately 13,000 deaths from the disease in 2023. The five-year relative survival rate for metastatic endometrial carcinoma (stage IV) is estimated to be approximately 20%.

About LENVIMA (lenvatinib) Capsules

LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC)
In combination with everolimus for the treatment of adult 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)
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
LENVIMA, discovered and developed by Eisai, is a multiple receptor tyrosine 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. The combination of LENVIMA 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. In syngeneic mouse tumor models, the combination of lenvatinib with an anti-PD-1 monoclonal antibody decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity compared to either treatment alone.

Important Safety Information

Warnings and Precautions

Hypertension. In DTC (differentiated thyroid cancer), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue following an arterial thrombotic event. The safety of resuming 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.

Hepatotoxicity. Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis, and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.

Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

Embryo-Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose.

Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions 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 (≥20%) observed in LENVIMA + pembrolizumab-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). The most common serious adverse reactions (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥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. The most common adverse reactions (≥5%) resulting in dose reductions 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 HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

In EC, the most common adverse reactions (≥20%) observed in LENVIMA and pembrolizumab–treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar–plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).

Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment and for 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end-stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC and severe hepatic impairment.

LENVIMA (lenvatinib) is available as 10 mg and 4 mg capsules.

Please see Prescribing Information for LENVIMA (lenvatinib) at View Source

About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in multiple different tumor types across more than 10 clinical trials.