On November 8, 2020 Aptevo Therapeutics Inc. ("Aptevo") (NASDAQ:APVO), a biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIR bispecific technology platform, reported that its Board of Directors has approved the adoption of a limited duration stockholder rights plan and declared a dividend distribution of one right for each outstanding share of common stock (Press release, Aptevo Therapeutics, NOV 8, 2020, View Source [SID1234570271]). The record date for such dividend distribution is November 23, 2020. The rights plan expires, without any further action being required to be taken by Aptevo’s Board of Directors, on November 8, 2021.

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The adoption of the rights plan is intended to protect Aptevo and its stockholders from the actions of third parties that Aptevo’s Board of Directors determines are not in the best interests of Aptevo and its stockholders, and to enable all stockholders to realize the full potential value of their investment in Aptevo. The rights plan provides the Board of Directors with time to make informed decisions that are in the best long-term interests of Aptevo and its stockholders and does not prevent Aptevo’s Board of Directors from considering any offer to acquire Aptevo that it considers to be in the best interest of Aptevo’s stockholders.

The rights plan is similar to stockholder rights plans adopted by other publicly-traded companies. Under the rights plan, the rights generally would become exercisable only if a person or group acquires beneficial ownership of 10% or more of Aptevo’s common stock in a transaction or series of transactions not approved by Aptevo’s Board of Directors. In that situation, each holder of a right (other than the acquiring person or group, whose rights will become void and will not be exercisable) will have the right to purchase, upon payment of the exercise price and in accordance with the terms of the rights plan, a number of shares of Aptevo’s common stock having a market value of twice such price. In addition, if Aptevo is acquired in a merger or other business combination after an acquiring person acquires 10% or more of Aptevo’s common stock, each holder of the right would thereafter have the right to purchase, upon payment of the exercise price and in accordance with the terms of the rights plan, a number of shares of common stock of the acquiring person having a market value of twice such price. The acquiring person or group would not be entitled to exercise these rights. In the rights plan, the definition of "beneficial ownership" includes derivative securities.

Stockholders who beneficially owned 10% or more of Aptevo’s outstanding common stock prior to the first public announcement by Aptevo of the adoption of the rights plan will not trigger the rights plan so long as they do not acquire beneficial ownership of any additional shares of common stock at a time when they still beneficially own 10% or more of such common stock, subject to certain exceptions as set forth in the rights plan.

Further details of the rights plan will be contained in a Current Report on Form 8-K and in a Registration Statement on Form 8-A that Aptevo will be filing with the Securities and Exchange Commission (SEC). These filings will be available on the SEC’s web site at www.sec.gov. Copies will also be available on the Investors section of Aptevo’s corporate website at www.aptevotherapeutics.com.

On November 7, 2020 Eisai reported results from Study 218, a Phase 2 trial comparing the safety and efficacy of two different starting doses (18 mg versus 14 mg once daily) of LENVIMA, an orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, plus everolimus (5 mg once daily) in patients with clear-cell renal cell carcinoma (RCC) following treatment with an anti-angiogenic therapy, with prior anti-PD-1/PD-L1 therapy permitted, during an oral presentation at the International Kidney Cancer Symposium (IKCS) 2020 (Press release, Eisai, NOV 7, 2020, View Source [SID1234570276]). Results indicate that the lower starting dose (14 mg) of LENVIMA did not meet the threshold for non-inferiority compared to the FDA-approved starting dose (18 mg).

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"With the influx of options for patients in the advanced RCC space, it is important that we continue to evaluate data in order to determine the most effective course of action that may help maximize therapeutic effects while managing tolerability for patients," said Sumanta Pal, MD, Co-director of the Kidney Cancer Program and clinical professor, Department of Medical Oncology & Therapeutics at City of Hope Comprehensive Cancer Center, Duarte, Calif., and lead investigator of the study. "The results from Study 218 show the potential benefit of LENVIMA plus everolimus in patients with advanced RCC, while providing a similar safety profile seen in previous studies."

The objective of this randomized, open-label, Phase 2 trial (NCT03173560) was to assess whether a starting dose of LENVIMA 14 mg once daily plus everolimus 5 mg once daily would provide similar efficacy with an improved safety profile compared to the FDA-approved dosage of LENVIMA 18 mg once daily plus everolimus 5 mg once daily. The primary efficacy endpoint was noninferiority of LENVIMA 14 mg versus 18 mg for objective response rate (ORR) at Week 24 (ORRWK24) (odds ratio: >0.76; P-value: ≤ 0.045) based on investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. The primary safety endpoint was superiority of the proportion of patients with intolerable Grade 2 or any ≥ Grade 3 treatment-emergent adverse events (TEAEs) within 24 weeks after randomization in the 14 mg versus 18 mg treatment arms. Some key secondary endpoints included overall ORR, progression-free survival (PFS) overall survival (OS) and safety. The study enrolled 343 patients.

In the primary efficacy analysis (n=311 patients), ORR at week 24 for patients treated with LENVIMA at the lower starting dose (14 mg) was not non-inferior to ORR at week 24 for patients treated with the approved starting dose (18 mg) (odds ratioORRWK24: 0.88 [90% CI: 0.59-1.32]; P-value: 0.2676). ORR at Week 24 for patients starting with 14 mg and 18 mg was 32.1% (95% CI: 24.7-39.4) and 34.8% (95% CI: 27.3-42.3), respectively. In the primary safety analysis (n=309), the occurrence of intolerable Grade 2 or any ≥ Grade 3 TEAEs was similar between the 14 mg and 18 mg treatment arms: 82.8% vs. 79.6% (P-value: 0.4763), respectively. The 18 mg starting dose of LENVIMA plus everolimus 5 mg demonstrated a similar safety profile as seen in a previous Phase 2 trial (Study 205). In the full safety analysis set (all patients who were randomized and received at least one dose of study drug, n=341), TEAEs led to:

discontinuation in 32.4% vs. 26.8% of patients who received LENVIMA 14 mg and 18 mg, respectively;
dose interruption in 74.6% vs. 83.3% of patients who received LENVIMA 14 mg and 18 mg, respectively; and
dose reductions in 67.6% vs. 69.6% of patients who received LENVIMA 14 mg and 18 mg, respectively.
Overall ORR (based on the primary efficacy analysis set of n=311) for patients starting with 14 mg and 18 mg of LENVIMA was 34.6% (95% CI: 27.1-42.1) and 40.6% (95% CI: 32.9-48.4), respectively (odds ratio: 0.77 [90% CI: 0.52-1.14]). Median PFS and median OS indicated a numerical benefit for patients treated with LENVIMA at 18 mg compared to LENVIMA at 14 mg:

Median PFS was 11.1 months (95% CI: 9.0-12.9) for patients treated with 14 mg vs. 14.7 months (95% CI: 11.1-20.3) for patients treated with 18 mg; and
Median OS was 27.0 months (95% CI: 18.3-NE) for patients treated with 14 mg vs. NE (95% CI: 23.8-NE) for patients treated with 18 mg.
Some of the most common any-grade TEAEs (≥ 20%) across the 14 mg and 18 mg treatment arms included diarrhea (68.2% vs. 72.0%), hypertension (30.1% vs. 35.7%), proteinuria (22.5% vs. 35.7%), decreased appetite (35.3% vs. 34.5%), and nausea (30.6% vs. 31.0%). Serious TEAEs (≥ 2%) occurred in 49.1% of patients who received LENVIMA 14 mg and 48.8% of patients who received LENVIMA 18 mg.

"This research demonstrates our commitment to advancing our understanding of our oncology compounds and generates key insights for the medical community to help inform treatment decisions around dosing," said Dr. Corina Dutcus, Vice President of Clinical Research for the Oncology Business Group at Eisai. "This study, in which 343 patients received LENVIMA plus everolimus, helps to contribute to the growing body of evidence supporting the role of this TKI-mTOR combination in the advanced RCC treatment paradigm."

Study 218 was conducted as a post-marketing commitment to the U.S. Food and Drug Administration and the European Medicines Agency (EMA) following priority review designation (in the U.S.) and approval of LENVIMA plus everolimus for the treatment of patients with advanced RCC who were previously treated with an anti-angiogenic therapy. LENVIMA is marketed as KISPLYX in the European Union and Switzerland for this indication.

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.

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

About Renal Cell Carcinoma (RCC)

Worldwide, it is estimated there were more than 403,000 new cases of kidney cancer diagnosed and more than 175,000 deaths from the disease in 2018. In the U.S. alone, it is estimated there will be nearly 74,000 new cases of kidney cancer diagnosed and almost 15,000 deaths from the disease in 2020. Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancers are RCCs. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 30% of patients with RCC will have metastatic disease at diagnosis, and as many as 40% will develop metastases after primary surgical treatment for localized RCC. Survival is highly dependent on the stage at diagnosis, and with a 5-year survival rate of 12% for metastatic disease, the prognosis for these patients is poor.

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. 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.

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.

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 6, 2020 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical need, reported that it is hosting a Virtual R&D Day today (Press release, BerGenBio, NOV 6, 2020, View Source [SID1234570917]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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The online event will begin at 13.00pm CET (04.00am PST/06.00am CST). Please click here to register.

The event will feature experts from academic institutions across Europe and the US, highlighting the role of AXL kinase as an essential mediator of the biological mechanisms underlying life-threatening diseases, such as cancer, fibrosis and infectious diseases, including COVID-19.

Each presentation will be followed by a Q&A session. Further details on the presentations can be found in the agenda below.

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "BerGenBio has always been committed to pursuing excellence and innovation in R&D.We remain a world leader in understanding the role and function of AXL biology, and with our collaborators we have demonstrated that AXL is a key driver of immune evasive and drug-resistant metastatic cancer, as well as other aggressive diseases. We are grateful to all our speakers, who during today’s event will beproviding insights into the latest AXL research, including the clinical benefit seen from bemcentinib."

On November 6, 2020 Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology), a biopharmaceutical company committed to advancing new medicines for patients battling cancer, reported financial results for the three months ending September 30, 2020, and provided an overview of recent corporate highlights (Press release, Verastem, NOV 6, 2020, View Source [SID1234570541]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"The third quarter of 2020 was marked most notably by the sale of the COPIKTRA (duvelisib) franchise to Secura Bio in a deal valued at up to $311 million, plus royalties. This strategic transaction allows us to focus our resources and efforts on advancing the VS-6766 and defactinib combination program in KRAS mutant solid tumors and provides us with a cash runway until at least 2024," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "Looking ahead to the remainder of the year, we remain on track to commence two new company-sponsored, registration-directed Phase 2 clinical trials by year end, one in low-grade serous ovarian cancer (LGSOC) and one in KRAS mutant non-small cell lung cancer (NSCLC)."

Third Quarter 2020 and Recent Highlights

Presented Updated Data from the Phase 1/2 FRAME Study in Patients with LGSOC. In mid-September, Verastem reported positive updated results from the ongoing investigator-initiated Phase 1/2 FRAME study coinciding with a virtual oral presentation by Dr. Udai Banerji, Institute of Cancer Research and The Royal Marsden, at the 2nd Annual RAS-Targeted Drug Development (RTDD) Summit. The FRAME study is evaluating VS-6766, Verastem’s RAF/MEK inhibitor, in combination with defactinib, its FAK inhibitor, in patients with LGSOC. The results demonstrated that the novel, intermittent, combination dosing schedule used in the FRAME study continues to show encouraging clinical activity, durability and a favorable safety profile in patients with KRAS mutant LGSOC, including patients who had previously progressed following treatment with a MEK inhibitor.

New Data Published in The Lancet Oncology Supports Potential of VS-6766. An investigator-initiated Phase 1 study evaluating the intermittent dosing schedule of VS-6766 was published in the November issue of The Lancet Oncology. Tolerability and antitumor activity were observed across various cancers with RAS/RAF/MEK pathway mutations. The dose escalation study was the first to evaluate a dual RAF/MEK inhibitor using innovative intermittent dosing schedules in patients harboring RAS/RAF pathway mutations.

On Track to Commence Phase 2 Registration-Directed Trials in Lead Indications This Year. Following a meeting with the U.S. Food and Drug Administration (FDA), Verastem reported that the FDA is supportive of its adaptive study design for the planned Phase 2 registration-directed trial evaluating VS-6766 and defactinib in patients with recurrent LGSOC. Verastem expects to commence registration-directed clinical trials in both recurrent LGSOC and KRAS mutant non-small cell lung cancer by the end of 2020. Assuming a positive outcome from these registration-directed trials, Verastem expects to submit New Drug Applications to the FDA requesting accelerated approval for VS-6766 alone or in combination with defactinib in both LGSOC and KRAS mutant NSCLC.

Closed COPIKTRA Sale to Secura Bio in a Deal Totaling $311 Million, Plus Royalties. Verastem recently announced the closing of a strategic transaction selling global commercial and development rights to COPIKTRA in all oncology indications to Secura Bio, Inc. The transaction, which carries a total deal value of up to $311 million, plus royalties, provides Verastem with a cash runway until at least 2024 and will allow the Company to focus its resources and efforts on the clinical development of VS-6766 and defactinib in KRAS mutant solid tumors.

Presented New Preclinical Research Demonstrating Synergy and Tumor Regression with VS-6766 in Combination with G12C Inhibitors. In a virtual poster presentation, also at the RTDD Summit, Verastem highlighted new preclinical researchwhere VS-6766 showed synergy with KRAS-G12C inhibitors in reducing cancer cell viability across a panel of KRAS-G12C mutant NSCLC and colorectal cancer (CRC) cell lines. This enhanced cellular anti-cancer activity of the combination correlated with deeper and more durable inhibition of ERK pathway signaling compared to G12C inhibition alone. The anti-tumor effects of VS-6766 were stronger than the effects of trametinib at a comparable dose.
Third Quarter 2020 Financial Results

Total Revenue for the three months ending September 30, 2020 (2020 Quarter) was $78.6 million, compared to $9.0 million for the three months ending September 30, 2019 (2019 Quarter).

Sale of COPIKTRA license and related assets revenue for the 2020 Quarter was $70.0 million, compared to $0.0 for the 2019 Quarter. The 2020 Quarter was comprised of a $70.0 million upfront payment recognized as part of the COPIKTRA sale to Secura Bio Inc.

License and collaboration revenue for the 2020 Quarter was $2.8 million, compared to $5.0 million for the 2019 Quarter. The 2019 Quarter included a $5.0 million upfront payment received pursuant to a license and collaboration agreement executed between Verastem Oncology and Sanofi in July 2019. The 2020 Quarter was primarily comprised of $2.5 million for Sanofi achieving two development milestones under the license and collaboration agreement.

Net product revenue for the 2020 Quarter was $5.8 million, compared to $4.0 million for the 2019 Quarter.

Cost of sales as a result of the sale of COPIKTRA license and related assets for the 2020 Quarter was $31.2 million, compared to $0.0 million for the 2019 Quarter. The 2020 Quarter comprised of the intangible asset, certain duvelisib inventory, net duvelisib contract prepaid balances and certain manufacturing equipment for the amounts of $19.2 million, $6.0 million, $5.8 million, and $0.2 million, respectively, delivered to Secura Bio Inc. as part of the COPIKTRA sale.

Total research and development (R&D) and selling, general and administrative (SG&A) expenses for the 2020 Quarter were $31.6 million, compared to $34.4 million for the 2019 Quarter.

R&D expense for the 2020 Quarter was $11.0 million, compared to $12.2 million for the 2019 Quarter. The decrease of $1.2 million, or 10%, was primarily related to a decrease in contract research organization costs and lower employee related expense.

SG&A expense for the 2020 Quarter was $20.6 million, compared to $22.2 million for the 2019 Quarter. The decrease of $1.6 million, or 7%, primarily resulted from the company’s shift in strategic direction which led to lower commercial program and employee related expense. The 2020 Quarter includes $3.5 million of nonrecurring transaction expenses directly attributable to the COPIKTRA sale to Secura Bio Inc.

Net income (loss) for the 2020 Quarter was $13.1 million, or $0.08 per share (basic and diluted), compared to $(30.1) million, or $(0.41) per share (basic and diluted), for the 2019 Quarter.

For the 2020 Quarter, non-GAAP adjusted net income was $18.8 million, or $0.11 per share (diluted), compared to non-GAAP adjusted net loss of $26.2 million, or $0.35 per share (diluted), for the 2019 Quarter. Please refer to the GAAP to Non-GAAP Reconciliation attached to this press release.

Verastem Oncology ended the third quarter of 2020 with cash, cash equivalents and short-term investments of $205.7 million.

Financial Guidance and Outlook

With the proceeds from the sale of COPIKTRA, Verastem has a cash runway until at least 2024 to deliver on the current programs for VS-6766 and defactinib, including clinical and regulatory milestones and development in LGSOC and KRAS mutant NSCLC. Verastem expects its 2020 operating expenses to be approximately 40% lower than its 2019 operating expenses. As a result of its new strategic direction and operating plans, along with the sale of the COPIKTRA franchise during the third quarter 2020 and associated transition activities, the Company expects total operating expenses for the full year 2020 to be in the range of $80 million to $90 million. Beginning in 2021 Verastem expects its annual operating expenses to be approximately $50 million.

Use of Non-GAAP Financial Measures

To supplement Verastem Oncology’s condensed consolidated financial statements, which are prepared and presented in accordance with generally accepted accounting principles in the United States (GAAP), the Company uses the following non-GAAP financial measures in this press release: non-GAAP adjusted net loss and non-GAAP net loss per share. These non-GAAP financial measures exclude certain amounts or expenses from the corresponding financial measures determined in accordance with GAAP. Management believes this non-GAAP information is useful for investors, taken in conjunction with the Company’s GAAP financial statements, because it provides greater transparency and period-over-period comparability with respect to the Company’s operating performance and can enhance investors’ ability to identify operating trends in the Company’s business. Management uses these measures, among other factors, to assess and analyze operational results and trends and to make financial and operational decisions. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of the Company’s operating results as reported under GAAP, not in isolation or as a substitute for, or superior to, financial information prepared and presented in accordance with GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. The determination of the amounts that are excluded from non-GAAP financial measures is a matter of management judgment and depends upon, among other factors, the nature of the underlying expense or income amounts. Reconciliations between these non-GAAP financial measures and the most comparable GAAP financial measures for the three months ended March 31, 2020 and 2019 are included in the tables accompanying this press release after the unaudited condensed consolidated financial statements.

About VS-6766

VS-6766 (formerly known as CH5126766, CKI27 and RO5126766) is a unique inhibitor of the RAF/MEK signaling pathway. In contrast to other MEK inhibitors in development, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors.

About Defactinib

Defactinib (VS-6063) is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors. The Company has received Orphan Drug designation for defactinib in ovarian cancer and mesothelioma in the US, EU and Australia. Preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.i,ii

About the VS-6766/Defactinib Combination

RAS mutant tumors are present in ~30% of all human cancers, have historically presented a difficult treatment challenge and are often associated with significantly worse prognosis. Challenges associated with identifying new treatment options for these types of cancers include resistance to single agents, identifying tolerable combination regimens with MEK inhibitors and new RAS inhibitors in development addressing only a minority of all RAS mutated cancers.

The combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mt tumors. In an ongoing investigator-initiated Phase 1/2 FRAME study, the combination of VS-6766 and defactinib is being evaluated in patients with LGSOC, KRASmt NSCLC and colorectal cancer (CRC). Updated interim data from this study presented at the 2nd Annual RAS-Targeted Drug Development Summit in September 2020 demonstrated a 56% overall response rate and long duration of therapy among patients with KRAS-G12 mt LGSOC. Based on an observation of higher response rates seen in NSCLC patients with KRAS-G12V mutations in the study, Verastem will also be further exploring the role of VS-6766 and defactinib in KRAS-G12V NSCLC. The FRAME study was expanded in August 2020 to include new cohorts in pancreatic cancer, KRASmt endometrial cancer and KRAS-G12V NSCLC.

On November 6, 2020, GT Biopharma, Inc. (the "Company") reported that it entered into a Securities Purchase Agreement with two purchasers (individually, a "Purchaser," and collectively, the "Purchasers") pursuant to which the Company has issued to the Purchasers Convertible Debentures in an aggregate principal amount of $250,000 (the "Debentures"), which Debentures are convertible into the Company’s common stock (the "Common Stock") at a price of $0.20 per share (Filing, 8-K, GT Biopharma, NOV 6, 2020, View Source [SID1234570455]).

The issuance of the Debentures was made in reliance on the exemption provided by Section 4(a)(2) of the Securities Act of 1933, as amended (the "Securities Act"), for the offer and sale of securities not involving a public offering and Regulation D promulgated under the Securities Act.

The foregoing summaries of the Securities Purchase Agreement, and the Debentures are qualified in their entirety by reference to the full text of the agreements, which are attached hereto as Exhibits 10.1 and 4.1, respectively, and are incorporated herein by reference.

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