On November 19, 2020 Ampersand Capital Partners, a leading private equity firm dedicated to growth-oriented investments in the healthcare sector, reported the oversubscribed, $670 million closing of the Ampersand Continuation Fund together with related investment vehicles ("AMP-CF") (Press release, Ampersand Medical Group, NOV 19, 2020, View Source [SID1234571445]). AMP-CF was formed to acquire the equity interests of three portfolio companies previously held by multiple mature Ampersand funds. StepStone Group and affiliated investors ("StepStone"), a leading player in the private equity secondary market, is the lead investor in the transaction.

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AMP-CF provided all Ampersand limited partners the option of reinvesting their proceeds or receiving full or partial liquidity, and also admitted new limited partners who wished to invest in the growth prospects of the three portfolio companies. In addition to StepStone, AMP-CF received commitments from a broad group of secondary and primary investors, including many prior Ampersand limited partners that elected to reinvest.

Notably, the closing of the fund was completed less than 45 days after StepStone’s commitment and exceeded the $600 million target necessary to acquire the AMP-CF assets, providing additional capital to support Confluent’s continued growth.

Ampersand Partner Trevor Wahlbrink commented, "We are very pleased that AMP-CF was so well received in the marketplace. The strong response from current and new limited partners confirms our belief that creating AMP-CF was a win-win opportunity for all of Ampersand’s key constituents. All of the AMP-CF portfolio companies are high-quality assets that we know exceptionally well, and the Ampersand team remains excited about their long-term growth prospects."

Ampersand Founder and Confluent Chairman Rick Charpie noted, "With an initial five-year term, and access to capital for additional acquisitions and secondary purchases, AMP-CF positions Confluent’s management and investors to continue taking a long-term view of the Company’s future growth opportunities. As the majority investor in Confluent, we look forward to working with the Company’s exceptional management team to build on Confluent’s position as a leading designer and manufacturer of complex, finished medical devices to the world’s largest OEM’s."

Goodwin Procter LLP served as legal counsel to Ampersand. Debevoise & Plimpton LLP served as legal counsel to StepStone.

On November 19, 2020 Day One Biopharmaceuticals reported that In PNOC014, an ongoing Phase 1 Pacific Pediatric Neuro-Oncology Consortium (PNOC) network study sponsored by the Dana-Farber Cancer Institute, nine patients under 18 years of age with relapsed low-grade glioma have been treated with DAY101 (Press release, Day One, NOV 19, 2020, View Source [SID1234571444]).

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Of the eight patients with RAF fusions, two patients achieved a complete response by Response Assessment for Neuro-Oncology (RANO), three had a partial response, and three achieved prolonged stable disease. The median time to response for these patients was only 10.5 weeks, and the most common side effects were skin rash and hair color changes.
The US Food and Drug Administration (FDA) has granted DAY101 BTD for the treatment of pediatric patients with advanced low-grade glioma harboring RAF alteration. The FDA has also granted DAY101 Orphan Drug Designation for the treatment of malignant glioma.
Day One is starting a global, single-arm, monotherapy, registration-enabling Phase 2 study of DAY101 for children and young adults with recurrent or progressive BRAF-altered low-grade gliomas.
South San Francisco, November 19, 2020: Day One Biopharmaceuticals, a company driven to develop promising new oncology therapies for both children and adults living with cancer, announced interim results from PNOC014, an ongoing Phase 1 investigator-sponsored study conducted by Dana-Farber and the Pacific Pediatric Neuro-Oncology Consortium (PNOC) of DAY101 in children with radiographically recurrent/progressive low-grade gliomas and other MAP kinase pathway activated tumors.

DAY101 is an investigational agent designed as an oral, once-weekly, brain-penetrant pan-RAF kinase inhibitor and is being developed by Day One for children and adults living with cancer. Over 250 patients have received DAY101 in clinical trials thus far. Early studies have demonstrated evidence of anti-tumor activity in adult and pediatric populations with specific genetic alterations in the RAS/MAP kinase pathway.

Preliminary results from PNOC014 were presented at the 25th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, held virtually November 19-22, 2020 (CTNI-19) and can be viewed in this link by any registered attendee. The objective of the PNOC014 study is to assess the pharmacokinetics, safety and preliminary efficacy of DAY101 in children with recurrent or progressive pediatric low-grade gliomas and other RAS/RAF/MEK/ERK pathway activated tumors. Preliminary data from the nine patients in the first three dose escalation cohorts receiving once-weekly oral DAY101 were reviewed. Linear PK and predominantly grade 1-2 dermatological side effects were observed, including one grade 3 elevation in a muscle enzyme called creatinine phosphokinase or CPK. No grade 4 adverse events have been reported based on these preliminary data. A maximum tolerated dose has not been reached. Tumor response was assessed by an independent radiologic reviewer.

"We found in an independent analysis of the nine patients treated in the ongoing Phase 1 study that the majority had responses or stable disease based upon Response Assessment for Neuro-Oncology (RANO) criteria," says Dr. Karen D. Wright, Senior Physician at Dana-Farber and Assistant Professor of Pediatrics at Harvard Medical School and principal investigator and author of the Phase 1 study.

DAY101 has been granted BTD by the FDA for the treatment of pediatric patients with an advanced low-grade glioma harboring an activating RAF alteration who require systemic therapy and who have either progressed following prior treatment or who have no satisfactory alternative treatment options. The BTD is designed to speed the development and regulatory review of new medicines that are intended to treat a serious condition and that have shown encouraging early clinical results, which demonstrate substantial, meaningful improvement over available medicines and where there is significant unmet medical need. The FDA granted this designation based on all of the available clinical data from the DAY101 development program, including data from the PNOC014 study. As noted above, DAY101 has also received Orphan Drug Designation from the FDA for the treatment of malignant glioma.

"These preliminary Phase 1 data suggest that DAY101, a CNS penetrant inhibitor of BRAF and CRAF fusions and mutations, appears to be well-tolerated and may have meaningful anti-tumor activity in pediatric patients with low-grade glioma," says Dr. Samuel Blackman, founder and Chief Medical Officer of Day One Biopharmaceuticals. "Of the eight patients with a confirmed RAF-fusion, we observed that two patients achieved a complete response, three had a partial response, and three achieved stable disease with a median time to response of 10.5 weeks. The observed complete responses, rapid onset of responses, and durability of responses observed thus far make us excited about the potential that DAY101 may have for providing meaningful clinical improvements for pediatric patients with RAF-altered low-grade gliomas in the coming years."

Pediatric low-grade glioma is the most common form of childhood brain cancer, with over a thousand new diagnoses each year in the U.S. RAF alterations, including BRAF mutations and RAF fusions, are the most common cancer-causing genetic mutations in pediatric low-grade gliomas. These genetic alterations are also found in multiple adult solid tumors. Low-grade glioma can impact a child’s health in many ways depending on tumor size and location, including vision loss and motor dysfunction. While most children with low-grade gliomas survive their cancer, children who do not achieve a cure following surgery face years of increasingly aggressive chemotherapy that can have lasting effects on learning, cognition, and quality of life. There are no FDA approved therapies for pediatric low-grade glioma, and current treatments are associated with significant acute and life-long adverse effects. As a result, the unmet medical need for these patients remains high.

The PNOC014 trial is supported by the PLGA Fund at the Pediatric Brain Tumor Foundation, the Team Jack Foundation, Team Nathan, Day One, the Takeda Pharmaceutical Company, Dana-Farber Cancer Institute (DFCI), and the National Cancer Institute of the National Institutes of Health under award number P50 CA 165962 as part of the prestigious SPORE grant for Targeted Therapies in Gliomas awarded to Dana-Farber and Brigham and Women’s Hospital under Dr.’s Tracey Batchelor and Mario Suva and for which Dr. Wright is co-Principal Investigator on project 1 with co-collaborators Dr. Michael Eck and Dr. Daphne Haas-Kogan.

"Day One is launching a global Phase 2 monotherapy trial concurrent with the ongoing Phase 1 trial, evaluating the efficacy and safety of DAY101 administered orally, once-a-week in pediatric patients with relapsed or progressive low-grade glioma harboring a BRAF-alteration. The study will be conducted in collaboration with PNOC, is called FIREFLY-1 and PNOC026, and is intended to support DAY101 registration," noted Dr. Jeremy Bender, CEO of Day One. "Day One’s rapid clinical, manufacturing, and regulatory execution of the DAY101 program demonstrates the commitment of this capable team. Children with cancer and their families are waiting for more options."

On November 19, 2020 Eisai reported the presentation of three abstracts including investigational data in thyroid cancer and osteosarcoma at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Virtual Congress 2020 from November 20-22, 2020 (Press release, Eisai, NOV 19, 2020, View Source [SID1234571443]).

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New safety and efficacy data on LENVIMA (lenvatinib), an orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, will be presented from two trials in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC). Presentations include results from Study 211, a Phase 2 study evaluating and comparing the starting dose of LENVIMA (18 mg vs 24 mg) (Abstract #426P), as well as results from Study 308, a pivotal Phase 3 trial showing that LENVIMA significantly prolonged progression free survival (PFS) compared to placebo in patients in China (Abstract #421P).

Eisai will also be presenting a Trials in Progress e-poster of Study 230 (NCT04154189), a Phase 2 trial, evaluating ifosfamide and etoposide with and without LENVIMA in children, adolescents and young adults with relapsed or refractory osteosarcoma. (Abstract #443TiP).

"At this year’s ESMO (Free ESMO Whitepaper) Asia, Eisai continues to build on its research for patients by delivering new investigational data on LENVIMA in RAI-refractory DTC and osteosarcoma, the most common type of bone cancer," said Dr. Takashi Owa, Vice President, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. "We believe the deepening of the global body of evidence on these therapies will enhance our understanding of their clinical value, thus furthering our full dedication to serving patients and their families – our core corporate mission illustrated by our human health care philosophy."

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.

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.

The full list of Eisai e-posters is included below. All e-posters are available for viewing via the ESMO (Free ESMO Whitepaper) Asia website.

Cancer Type(s)

Study/Trial

Abstract Name

Virtual Presentation Details

Lenvatinib

Thyroid Cancer

Study 211

A Multicenter, Randomized, Double-Blind Phase 2 Trial of Lenvatinib in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer to Evaluate the Safety and Efficacy of a Daily Oral Starting Dose of 18 mg

E-Poster

Abstract #: 426P

Marcia S. Brose, MD

Study 308

A Multicenter, Randomized, Double-blind, Placebo (PBO)-controlled, Phase 3 Trial of Lenvatinib (LEN) in Patients (Pts) With Radioiodine-Refractory Differentiated Thyroid Cancer (RR-DTC) in China

E-Poster

Abstract #: 421P

Ming Gao, MD

Osteosarcoma

Study 230

A multicenter, open-label, randomized phase 2 study to compare the efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide and etoposide in children, adolescents and young adults with relapsed or refractory osteosarcoma

E-Poster

Trial in Progress

Abstract #: 443TiP

Nathalie Gaspar, MD

About LENVIMA (lenvatinib) Capsules

LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory 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)
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy, and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial
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. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.

Important Safety Information

Warnings and Precautions

Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, 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, 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. 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 1,327 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. Across clinical studies of 1,823 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.

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 at least 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 (≥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 + pembrolizumab – treated patients were fatigue (65%), hypertension (65%), musculoskeletal pain (65%), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain (33%), headache (33%), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia (26%), dyspnea (24%), cough (21%) and rash (21%).

Adverse reactions led to dose reduction or interruption in 88% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (32%), hypertension (26%), diarrhea (18%), nausea (13%), palmar-plantar erythrodysesthesia (13%), vomiting (13%), decreased appetite (12%), musculoskeletal pain (11%), stomatitis (9%), abdominal pain (7%), hemorrhages (7%), renal impairment (6%), decreased weight (6%), rash (5%), headache (5%), increased lipase (5%) and proteinuria (5%).

Fatal adverse reactions occurred in 3% of patients receiving LENVIMA + pembrolizumab, including gastrointestinal perforation, RPLS with intraventricular hemorrhage, and intracranial hemorrhage.

Serious adverse reactions occurred in 52% of patients receiving LENVIMA + pembrolizumab. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).

Permanent discontinuation due to adverse reaction (Grade 1-4) occurred in 21% of patients who received LENVIMA + pembrolizumab. The most common adverse reactions (>2%) resulting in discontinuation of LENVIMA were gastrointestinal perforation or fistula (2%), muscular weakness (2%), and pancreatitis (2%).

Use in Specific Populations

Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after 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 (pembrolizumab).

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 13 different tumor types (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer, and triple-negative breast cancer) across 19 clinical trials.

On November 19, 2020 Epic Sciences, Inc. reported it has entered into an exclusive license and collaboration agreement with Dr. Peter Kuhn and the USC Michelson Center for Convergent Bioscience (Press release, Epic Sciences, NOV 19, 2020, View Source [SID1234571442]). Dr. Kuhn is a founding member of the USC Michelson Center and leads USC’s Convergent Science Institute in Cancer (CSI-Cancer). The collaboration will improve Epic’s platform and enable more precise characterization of rare circulating tumor cells (CTCs), which Epic is developing into liquid-biopsy diagnostics used for characterizing a patient’s cancer to guide treatment decisions.

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Epic is a global leader in the identification and characterization of CTCs. Epic’s platform, originally licensed from Dr. Kuhn’s laboratory at The Scripps Research Institute, uses state-of-the-art Carl Zeiss optics coupled with AI-trained machine-vision algorithms to analyze blood treated with fluorescent antibodies. Epic’s platform provides unsurpassed sensitivity with the ability to detect one rare cell in ten million nucleated cells. Today Epic’s platform is used to make treatment decisions for patients with advanced prostate cancer marketed by Exact Sciences and is used in over 100 ongoing clinical trials of cancer therapeutics conducted by Epic’s corporate and academic research partners.

The Epic and USC Michelson partnership will give Epic exclusive access to the next generation, comprehensive liquid biopsy from Dr. Kuhn’s laboratory and expand Epic’s platform to provide in-depth characterization of both the cell-free fractions and CTCs in the liquid biopsy using genomic, proteomic and AI-based morphological tools, all from a single blood draw.

Rick Wenstrup, Chief Medical Officer of Epic Sciences, focused on the application of Epic’s enhanced platform in the monitoring of minimal residual disease (MRD) in cancer, "The ability to identify circulating neoplastic cells and cells from the tumor microenvironment, provides additional information critical to understanding the current state of a patient’s disease and offers the ability to monitor cancer status, and response to a specific therapy."

Epic plans to offer this next-generation CTC technology as part of its suite of Comprehensive Cancer Profiling technologies, that includes Epic’s ctDNA capabilities as a comprehensive solution designed to meet the growing needs of clinicians for precision medicine diagnostic tests and for pharmaceutical partners as they seek to develop life-changing therapies.

"We are excited about this collaboration with Epic Sciences intended to accelerate our goals towards improved cancer patient outcomes," said Dr. Kuhn, adding that "It also advances Epic Sciences further towards a data science company."

About Comprehensive Cancer Profiling

Epic Sciences’ Comprehensive Cancer Profiling provides a multi-technology approach to liquid biopsy from a single blood draw to complete several types of analyses. The Company leverages its exclusive license to technologies from The Scripps Research Institute and the University of Southern California to drive its high-throughput proprietary CTC capabilities. The enrichment-free approach reveals both genotypic and phenotypic insights and minimizes the risk of CTCs being missed. By combining CTC technology with ctDNA and immune cell analysis we enable a comprehensive analysis that is both minimally invasive and highly accurate.

On November 19, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that the China National Medical Products Administration (NMPA) has approved XGEVA (denosumab) for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors and in patients with multiple myeloma (MM) (Press release, BeiGene, NOV 19, 2020, View Source [SID1234571441]). Developed by Amgen and licensed to BeiGene in China under a strategic collaboration commenced earlier this year, XGEVA is also approved and marketed in China for the treatment of adults and skeletally mature adolescents with giant cell tumor of the bone (GCTB) that is unresectable or where surgical resection is likely to result in severe morbidity.

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"We began commercializing XGEVA in China in July of this year and are excited to offer it for prevention of skeletal-related events, which can be caused by bone metastases from solid tumors and MM and can include pathologic fractures, spinal cord compression, as well as the need for surgery or radiation to the bone," said Xiaobin Wu, Ph.D., General Manager of China and President of BeiGene. "This approval provides us with an opportunity to offer these patients in China a new medicine to help prevent SREs and is an important addition to our expanding oncology product portfolio."

The approval of XGEVA for the prevention of SREs in patients with bone metastasis from solid tumors and MM was based on clinical results from four randomized international trials that enrolled over 7,000 patients (NCT00321464, NCT00330759, NCT00321620, and NCT01345019). In each trial, the main outcome measure was demonstration of noninferiority of time to first SRE as compared to the standard of care zoledronic acid. Supportive secondary outcome measures included superiority of time to first SRE and time to first and subsequent SRE, respectively. XGEVA significantly delayed the time to first SRE compared to zoledronic acid in patients with bone metastases from breast cancer, castration-resistant prostate cancer (CRPC), as well as from other solid tumors including non-small cell lung cancer (pre-specified integrated analysis; p < 0.0001). In patients with lytic lesions due to MM, XGEVA was noninferior to zoledronic acid in delaying the time to first SRE.

The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. For multiple myeloma patients receiving XGEVA, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVA was osteonecrosis of the jaw. All adverse reactions seen in the clinical trials were similar for both XGEVA and zoledronic acid.

"Amgen is accelerating our oncology pipeline for patients in China with difficult-to-treat cancers through our collaboration with BeiGene," said My Linh Kha, Vice President & General Manager, Amgen Japan Asia-Pacific (JAPAC). "We congratulate our teams and celebrate the approval of this new indication of XGEVA for the prevention of skeletal-related events. With the approval of XGEVA in this new indication, we are excited about the positive health impact it may have for patients in China."

About Skeletal-Related Events in Patients with Bone Metastases from Solid Tumors and in Patients with Multiple Myeloma

Bone metastasis occurs when cancer cells break away from the original tumor and spread to the bones, where they begin to multiply.i Bone is the third most frequent site of metastasis, following lung and liver.ii While nearly all types of cancer can spread or metastasize to the bones, prostate and breast cancer are responsible for the majority of metastases, up to 70 percent.iii Osteolytic lesion is a type of bone metastases characterized by destruction of normal bone, which is present in more than 90 percent of patients with multiple myeloma during the course of the disease.iv

About XGEVA (denosumab)

XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. XGEVA is also indicated for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity and for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

U.S. Approved Indications

XGEVA is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.

XGEVA is indicated for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

XGEVA is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Important U.S. Safety Information

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary.

Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity

XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient

Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture

Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone (GCTB) and in Patients with Growing Skeletons

Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in XGEVA-treated patients with GCTB and in patients with growing skeletons within one year of treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia after treatment discontinuation and treat appropriately.

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation

Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures. When XGEVA treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures.

Embryo-Fetal Toxicity

XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions

The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

For multiple myeloma patients receiving XGEVA, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVA was osteonecrosis of the jaw.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, pain in extremity, nasopharyngitis, musculoskeletal pain, toothache, vomiting, hypophosphatemia, constipation, diarrhea, and cough. The most frequent serious adverse reactions were osteonecrosis of the jaw, bone giant cell tumor, anemia, pneumonia, and back pain. The most frequent adverse reaction resulting in discontinuation of XGEVA was osteonecrosis of the jaw.