Mirati Therapeutics Announces Presentation Of KRAS G12C Chemistry Advances At The 255th American Chemical Society (ACS) National Meeting And Exposition

On August 16, 2018 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical stage targeted oncology company, reported that a KRAS G12C poster will be presented by scientists from Mirati and Array BioPharma at the 255thAmerican Chemical Society (ACS) National Meeting & Exposition being held in Boston, MA, August 19-23, 2018 (Press release, Mirati, AUG 16, 2018, View Source [SID1234529038]). The poster will focus on the discovery and preclinical characterization of covalent inhibitors of KRAS G12C that have demonstrated potent pathway inhibition in cells and efficacy in tumor xenograft models.

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"We are looking forward to the first public presentation of our orally-active series of covalent inhibitors of KRAS G12C. We will describe the identification of novel lead matter and the structure-based approach that led to increases in potency. Further, we will present in vivo data for an early lead molecule that resulted in regressions in a xenograft tumor model. These results led us to our lead candidate, MRTX849, that has a planned IND (investigational new drug) filing in Q4 2018," said Matt Marx, Ph.D., Vice President of Drug Discovery.

Details for the poster presentation are listed below.

Poster Title: Structure-based drug discovery of a selective, covalent KRAS G12C inhibitor with oral activity in animal models of cancer
Poster Number: MEDI 144
Date and Time: Sunday, August 197:00 PM
Location: Exhibit Hall B1, Boston Convention & Exhibition Center

Immutep to Present at the BioCentury 25th Annual NewsMakers in the Biotech Industry Conference

On August 16, 2018 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a biotechnology company developing novel immunotherapy treatments for cancer and autoimmune diseases, reported that it has been invited to present at the BioCentury 25th Annual NewsMakers in the Biotech Industry Conference on Friday, September 7, 2018, at the Millennium Broadway Hotel & Conference Center in New York City (Press release, Immutep, AUG 16, 2018, View Source [SID1234529023]).

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Marc Voigt, CEO of Immutep, is scheduled to present a corporate overview and business update at 11:30 am ET on Friday, September 7, 2018, with one-on-one meetings held throughout the day.

Hosted by BioCentury, only 48 companies are handpicked to present their stories to institutional investors in the Biotech sector. At the NewsMakers conference held in 2017, more than 500 delegates congregated at NewsMakers, including money managers who controlled more than $600 billion in equity assets, with over $50 billion dedicated to healthcare and $15 billion dedicated to biotech.

Iovance Biotherapeutics Announces Clinical Trial Updates with Collaborators MD Anderson and Moffitt Cancer Center

On August 16, 2018 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a biotechnology company developing novel cancer immunotherapies based on tumor-infiltrating lymphocyte (TIL) technology, reported updates from its clinical collaborations with The University of Texas MD Anderson Cancer Center (MD Anderson) and Moffitt Cancer Center (Moffitt) (Press release, Iovance Biotherapeutics, AUG 16, 2018, View Source;p=RssLanding&cat=news&id=2363888 [SID1234528960]). Under the MD Anderson collaboration, the company announced that the first patient was dosed with LN-145 in the Phase 2, multi-arm clinical trial (NCT03449108). The company also announced that preliminary data from an investigator-sponsored Non-Small Cell Lung Cancer (NSCLC) study with Moffitt will be presented at the upcoming IASLC 19th World Conference on Lung Cancer (WCLC) on September 24, 2018 in Toronto, Canada.

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"The start of patient dosing in the study at MD Anderson allows for exploration of TIL as a platform for treatment of multiple new solid tumors. Furthermore, this targeted patient population is left with very few treatment options and therefore is an unmet medical need. We are extremely pleased to be collaborating with MD Anderson as we investigate the potential of LN-145 to treat these patients with sarcomas and ovarian cancer," said Dr. Maria Fardis, PhD, MBA, president and chief executive officer of Iovance Biotherapeutics. "We are also pleased that the preliminary data from the investigator-sponsored study at Moffitt has been accepted for presentation at the upcoming World Lung Conference in September. We look forward to further exploring the possibility of TIL as a potential treatment option for patients with lung cancer."

The first MD Anderson study will enroll up to 54 patients. The endpoints for the trial are safety and efficacy of Iovance-manufactured LN-145 for the treatment of patients with soft tissue sarcoma, osteosarcoma and platinum-resistant ovarian cancer. The trial utilizes Iovance’s Gen 2 manufacturing process. A second clinical study is also in start-up under the collaboration using TIL manufactured by MD Anderson and using urelumab as a co-stimulatory agent during the manufacturing process. Additional information on this study is available at www.clinicaltrials.gov using the identifier number NCT03610490.

The ongoing investigator-sponsored study in NSCLC is currently underway in collaboration with Moffitt, Stand Up To Cancer, and other collaborators and is designed to allow dosing of the combination of TIL manufactured by Moffitt and nivolumab in NSCLC patients. An abstract titled, Safety and Clinical Activity of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes (TIL) Combined with Nivolumab in NSCLC, has been accepted for presentation at the upcoming WCLC. The full details of the presentation are expected to be released in September. Additional information on this study is available at www.clinicaltrials.gov using the identifier number NCT03215810.

Eisai And Merck Announce FDA Approval Of LENVIMA® (lenvatinib) Capsules For First-line Treatment Of Unresectable Hepatocellular Carcinoma (HCC)

On August 16, 2018 Eisai Inc. and Merck (NYSE: MRK), known as MSD outside of the United States and Canada , reported that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor LENVIMA (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) (Press release, Eisai, AUG 16, 2018, View Source [SID1234528952]). This approval was based on results from REFLECT (Study 304), where LENVIMA demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

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

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

REFLECT showed that LENVIMA achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with LENVIMA experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted when 351 events had occurred in the LENVIMA arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, LENVIMA showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

Median PFS was doubled with LENVIMA compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with LENVIMA versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77) per RECIST 1.1.
LENVIMA showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with LENVIMA versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
Per mRECIST: Treatment with LENVIMA resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with LENVIMA resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
Per RECIST 1.1: Treatment with LENVIMA resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with LENVIMA resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib
In addition, median time to progression (TTP) was doubled with LENVIMA compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with LENVIMA versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

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

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

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

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

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

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

About the REFLECT Trial (Study 304)
REFLECT was a large (N=954) phase 3, randomized, multicenter, open-label trial conducted by Eisai to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with unresectable hepatocellular carcinoma (HCC). Patients at 154 trial sites in 20 countries were randomized to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60 kg, respectively) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was overall survival, tested first for non-inferiority to sorafenib, then for superiority. Patients randomized to the LENVIMA arm did not have a statistically significant improvement in OS compared to those in the sorafenib arm. The key secondary efficacy endpoints of this study included progression-free survival, time to progression and objective response rate, tested for superiority to sorafenib. The results of the REFLECT trial were published online in The Lancet (Vol 391(10126):1163-1173) on February 9, 2018 .

About Unresectable Hepatocellular Carcinoma (HCC)
The prevalence and mortality rate of hepatocellular carcinoma have been rising steadily over the past decade. Hepatocellular carcinoma is the most common type of liver cancer, accounting for about 90% of cases of primary liver cancer. The stage of disease at diagnosis largely determines treatment approach, with potentially curative options, like resection or transplantation, only available for early stage HCC. Unresectable HCC, a type of liver cancer that cannot be removed by surgery, has a worse prognosis, with a median survival of less than one year. Unfortunately, approximately 70% of patients are diagnosed too late to be eligible for resection or transplantation, and there have been limited treatment options available for patients with unresectable disease.

About LENVIMA (lenvatinib) capsules 10 mg and 4 mg
LENVIMA (lenvatinib) is a kinase inhibitor that is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
LENVIMA, discovered and developed by Eisai , is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

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%. Fistulas and gastrointestinal perforations have also been reported in other lenvatinib clinical trials and in post-marketing experience. Pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula, and pneumothorax occurred in association with tumor regression or necrosis. In most cases of fistula formation or gastrointestinal perforation, risk factors such as prior surgery or radiotherapy were present.

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.

Wound Healing Complications. Wound healing complications, including fistula formation and wound dehiscence, can occur with LENVIMA. Withhold for at least 6 days prior to scheduled surgery. Resume after surgery based on clinical judgment of adequate wound healing. Permanently discontinue in patients with wound healing complications.

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%).

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 or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with RCC or DTC 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 or RCC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe hepatic impairment. Reduce the dose for patients with DTC or RCC and severe hepatic impairment.

For more information about LENVIMA please see available full Prescribing Information .

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

Inovio Treats First Patient in Immuno-Oncology Study for Advanced or Metastatic Bladder Cancer in Combination with Roche/Genentech’s Atezolizumab

On August 16, 2018 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported that it has dosed its first patient in a Phase 1/2a study designed to evaluate the safety, immunogenicity and clinical efficacy of INO-5401, Inovio’s novel cancer immunotherapy that encodes multiple cancer antigens, plus INO-9012, a T cell activator, in combination with atezolizumab, (F. Hoffman-La Roche Ltd.) a PD-L1 inhibitor, for the treatment of advanced or metastatic bladder cancer (Press release, Inovio, AUG 16, 2018, View Source;for-Advanced-or-Metastatic-Bladder-Cancer-in-Combination–with-RocheGenentechs-Atezolizumab/default.aspx [SID1234528951]). The trial, which is being managed by Inovio, is expected to enroll approximately 85 patients at sites located in the United States and Spain.

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Dr. J. Joseph Kim, Inovio’s President and Chief Executive Officer, said, "We are very encouraged to dose our first patient with the aspiration that we can demonstrate the immense potential of our INO-5401 immunotherapy to treat advanced bladder patients as well as those with other cancers. This also marks the second time in less than a month that Inovio has dosed a cancer patient, combining INO-5401, our T cell-generating immunotherapy with a checkpoint inhibitor. Bladder cancer is considered an immunogenic tumor and our approach is to combine INO-5401/INO-9012 with atezolizumab as we believe this may provide a synergistic therapeutic effect by generating functional and activated T cells while simultaneously inhibiting PD-L1. We remain on track and look forward to producing interim clinical results in 2019."

This open-label, multi-center Phase 1/2a study plans to enroll 85 patients divided into two cohorts. Cohort A includes patients with confirmed disease progression during or following prior checkpoint inhibitor therapy, while Cohort B patients are treatment naïve and unfit for cisplatin-based therapy. Primary endpoints are incidence of AEs, antigen-specific immunologic activation and objective response rate (ORR) in Cohort A. Secondary endpoints are Cohort B’s ORR, duration of response, progression free survival and overall survival. Exploratory endpoints are correlation of biomarkers to anti-tumor activity. A safety run-in will be performed for the first six patients enrolled in Cohort A to monitor emergence of any dose limiting toxicities. INO-5401 and INO-9012 (10 mg DNA combined in 1ml) will be administered by intramuscular injection followed by electroporation every 3 weeks for first 4 doses, every 6 weeks for 6 doses and every 12 weeks until disease progression. Atezolizumab (1200 mg IV) will be administered every 3 weeks until disease progression. Tumor imaging, disease assessment (per RECIST and iRECIST) and biopsies, blood and urine samples will be collected at set time points including prior to study treatment, on treatment and at disease progression (see www.clinicaltrials.gov, identifier NCT03502785).

About Advanced Bladder Cancer

The prognosis for patients with advanced unresectable or metastatic bladder cancer is poor, with limited treatment options. It is a disease that has seen no major advances for more than 30 years until the approvals of checkpoint inhibitors. Expected survival is generally less than 12 months; in the U.S., five-year survival of patients with distant metastasis is 5%. In the U.S., an estimated 81,190 new cases of bladder cancer are expected in 2018.

About INO-5401

INO-5401 includes Inovio’s SynCon antigens for hTERT, WT1 and PSMA, and has the potential to be a powerful cancer immunotherapy in combination with checkpoint inhibitors. The National Cancer Institute previously highlighted hTERT, WT1 and PSMA among a list of important cancer antigens, designating them as high priorities for cancer immunotherapy development. These three antigens are known to be over-expressed, and often mutated, in a variety of human cancers, and targeting these antigens may prove efficacious in the treatment of patients with cancer.