On September 27, 2017 Pfizer Inc. (NYSE: PFE) reported that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved BAVENCIO (avelumab, genetically recombinant Injection 200mg/mL for intravenous use) as the first and only treatment indicated for curatively unresectable Merkel cell carcinoma (MCC), a rare and aggressive cancer, in Japan (Press release, Pfizer, SEP 27, 2017, View Source [SID1234520658]).

“Today marks the approval of the first-ever treatment indicated for Merkel cell carcinoma in Japan, making this a significant milestone for patients living with this devastating type of skin cancer,” said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck KGaA, Darmstadt, Germany, which operates as EMD Serono in the US and Canada. “This decision by the MHLW also signifies the first approval of an anti-PD-L1 in Japan.”

“This is the fifth approval for BAVENCIO in 2017 and the first in an Asian market,” said Andreas Penk, M.D., Regional President Oncology International Developed Markets, Pfizer Oncology. “Today’s announcement demonstrates our continued determination to provide access to our immunotherapy for people around the world living with hard-to-treat cancers such as Merkel cell carcinoma.”

MCC is a designated rare disease in Japan and is estimated to affect fewer than 100 patients.[2],[3] BAVENCIO previously received Orphan Drug Designation from the MHLW in December 2016.

“Until now, there were no licensed treatments for MCC in Japan,” said Dr Naoya Yamazaki, Chief of the Department of Dermatologic Oncology, National Cancer Center Hospital, Japan. “As a cancer that progresses quickly and has, for so many, a poor prognosis, today’s approval is a huge step forward for people impacted by this destructive disease.”

This approval is based on data from JAVELIN Merkel 200, an international, multicenter, single-arm, open-label, Phase II study in patients with metastatic MCC.[1]

The JAVELIN Merkel 200 study is the largest registrational clinical trial for an immunotherapy in metastatic MCC. The results of this study were previously presented at the June 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual congress and published in the October 2016 edition of Lancet Oncology.

The MHLW’s decision follows BAVENCIO’s recent approval by the European Commission on September 18, 2017, as a monotherapy for the treatment of adult patients with metastatic MCC (mMCC). BAVENCIO was also granted marketing authorization by Swissmedic on September 05, 2017, for the treatment of patients with mMCC, whose disease has progressed after at least one chemotherapy treatment. Earlier this year, the US Food and Drug Administration (FDA) granted accelerated approval* for BAVENCIO for the treatment of mMCC and patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy.

The clinical development program for BAVENCIO, known as JAVELIN, involves at least 30 clinical programs and more than 6,300 patients evaluated across more than 15 different tumor types. In addition to mMCC, these cancers include breast, gastric/gastro-esophageal junction, head and neck, Hodgkin’s lymphoma, melanoma, mesothelioma, non-small cell lung, ovarian, renal cell carcinoma and urothelial carcinoma.

About Merkel Cell Carcinoma

MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings.[4],[5] MCC, which is also known as neuroendocrine carcinoma of the skin or trabecular cancer, often starts in those areas of the skin that are most often exposed to the sun, including the head and neck, and arms.[4],[6] Risk factors for MCC include sun exposure and infection with Merkel cell polyomavirus. Caucasian males older than 50 are at increased risk.[4],[6] MCC is often misdiagnosed as other skin cancers and grows at an exponential rate on chronically sun-damaged skin.[6-8] Current treatment options for MCC include surgery, radiation and chemotherapy.[5] Treatment for metastatic or Stage IV MCC is generally palliative.[5]

About JAVELIN Merkel 200

The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Merkel 200 trial, a Phase II, open-label, single-arm, multicenter study, in metastatic MCC.[1] The trial excluded patients with active or a history of central nervous system (CNS) metastasis, prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies, active or a history of autoimmune disease, a history of other malignancies within the last 5 years, organ transplant, and conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C. Patients received BAVENCIO 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

The JAVELIN Merkel 200 study is the largest registrational clinical trial for an immunotherapy in metastatic MCC. The results of this study were previously presented at the June 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual congress and published in the October 2016 edition of Lancet Oncology.

About BAVENCIO

BAVENCIO (avelumab) is a human antibody specific for a protein called PD-L1, or programmed death ligand-1. BAVENCIO is designed to potentially engage both the adaptive and innate immune systems. By binding to PD-L1, BAVENCIO is thought to prevent tumor cells from using PD-L1 for protection against white blood cells, such as T cells, exposing them to anti-tumor responses. BAVENCIO has been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

*Indications in the US[9]

The US Food and Drug Administration (FDA) granted accelerated approval for BAVENCIO for the treatment of (i) mMCC in adults and pediatric patients 12 years and older and (ii) patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications were approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information from the US FDA Approved Label

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5 and 11 (0.6 %) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon re-initiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life threatening (Grade 4) thyroid disorders. Thyroid disorders including hypothyroidism, hyperthyroidism, and thyroiditis were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus, including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade 3 equal to or greater) hyperglycemia and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4)infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least one month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, greater than or equal to 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reactions (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, greater than or equal to 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%). and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades greater than or equal to 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%) and urinary tract infection (21%).

Selected laboratory abnormalities (grades 3-4, greater than or equal to 3%) inpatients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatatse (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Please see full US Prescribing Information and Medication Guide available at www.BAVENCIO.com.

On September 27, 2017 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported that the U.S. Food and Drug Administration (“FDA”) has granted orphan drug designation to tucatinib for the treatment of HER2-positive (HER2+) metastatic colorectal cancer (Press release, Cascadian Therapeutics, SEP 27, 2017, View Source [SID1234520657]). Tucatinib is an investigational oral, small molecule kinase inhibitor that is highly selective for HER2 and is the Company’s lead product in development.

The FDA’s Orphan Drug Designation program provides orphan status to drugs defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases that affect fewer than 200,000 people in the United States. Orphan designation qualifies the sponsor of the drug for certain development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemption and 7-year marketing exclusivity upon FDA approval.

“We are pleased to receive FDA orphan drug designation for tucatinib in HER2+ metastatic colorectal cancer, our second orphan designation in addition to breast cancer with brain metastases,” said Scott Myers, President and CEO of Cascadian Therapeutics. “We believe tucatinib has the potential to address unmet medical needs of patients in a broad range of HER2-positive cancers. We are currently supporting an investigator-initiated study evaluating tucatinib for the treatment of patients with HER2+ metastatic colorectal cancer.”

“We are conducting a Phase 2 study called MOUNTAINEER evaluating tucatinib in combination with trastuzumab for patients with HER2 amplified metastatic colorectal cancer,” said John Strickler, MD, Assistant Professor of Medicine, Division of Medical Oncology, Duke University Medical Center, and principal investigator of the MOUNTAINEER study. “There remains an unmet clinical need for new treatments for patients with HER2 amplified metastatic colorectal cancer. Tucatinib is a potent and selective inhibitor of HER2 in vitro, and is active in non-clinical HER2+ colorectal tumor models. Based on these data, we believe tucatinib has the potential to be a new therapeutic option for these patients.”

The study, known as MOUNTAINEER, is currently recruiting participants. Additional details about MOUNTAINEER can be found at www.clinicaltrials.gov (NCT03043313).

The American Cancer Society estimates 135,430 new cases of colorectal cancer will be diagnosed in the U.S. in 2017, and expects colorectal cancer to cause over 50,000 deaths in 2017. Colorectal cancer is the third leading cause of cancer death in both men and women in the U.S. While the prevalence of HER2 amplified colorectal cancer varies depending on study methods and population, approximately 3-to-8 percent of these patients would be expected to potentially benefit from HER2-targeted therapy.1

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without inhibition of EGFR. Inhibition of EGFR has been associated with clinical toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.2,3 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 (HER2+) are more aggressive and historically have been associated with poor overall survival, compared with HER2-negative cancers.

On September 27, 2017 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported that the first patient has been dosed in the Phase 1 clinical trial (see www.clinicaltrials.gov, identifier NCT03189030) designed to evaluate the safety and tolerability of a personalized live, attenuated double-deleted Listeria monocytogenes (pLADD) immunotherapy for adults with metastatic colorectal cancer that is microsatellite stable (MSS) (Press release, Aduro Biotech, SEP 27, 2017, View Source [SID1234520656]). The personalized immunotherapy has been engineered with patient-specific neoantigens that were identified and selected using state-of-the-art neoantigen identification technology developed by Hanlee Ji, M.D., associate professor of medicine at the Stanford University School of Medicine.

“Our pLADD program leverages our extensive capabilities relating to the use of Listeria as a delivery mechanism for cancer antigens and Dr. Ji’s innovative neoantigen technology used to identify immunogenic antigens specific for an individual patient,” said Natalie Sacks, M.D., chief medical officer of Aduro Biotech. “Together, we believe these two cutting edge technologies represent a new approach to treating patients who have relapsed following prior chemotherapy. We look forward to evaluating initial proof-of-concept in this Phase 1 clinical trial.”

Clinical Design of Phase 1 PLADD Trial in Adults with Metastatic Corlorectal Cancer
The Phase 1 clincial single-arm trial is designed to evaluate the safety and tolerability of a personalized immunotherapy made using patient-specific antigens and Aduro’s proprietary live, attenuated, double-deleted Listeria monocytogenes platform technology. The trial is seeking to enroll approximately 10 patients with metastatic colorectal cancer that is MSS. Patients will receive their patient-specific immunotherapy once every three weeks.

About pLADD
Personalized LADD, or pLADD, is a second-generation LADD technology that is designed to leverage the immune-activating activity of the Listeria bacterial vector in combination with neoantigens, which are unique, patient-specific tumor markers exclusively expressed in an individual’s tumor cells. Once administered, pLADD therapies are expected to mobilize the immune system in two ways–first, through the immediate recognition of the presence of Listeria as being foreign, and subsequently, through a specific and customized immune attack on cells containing the tumor neoantigens presented by pLADD.

To create a patient-specific pLADD therapy, a physician begins by removing tumor cells from the patient. These cells are analyzed in order to molecularly characterize (sequence) the tumor, including any mutations that are unique to the patient’s own tumor cells. Predictive algorithms for antigen processing are run to identify pertinent tumor antigens. Aduro then creates a LADD strain engineered to enable the presentation of multiple selected neoantigens in dendritic cells, with the aim of inducing a targeted, robust anti-cancer immune response.

Preclinical Data with pLADD
Preclinical data showed that mouse pLADD strains targeting tumor-specific neoepitopes induced a robust immune response, including induction of cytokines, chemokines, and antigen-specific CD8+ T cells. In preclinical models of pLADD, remodeling of the tumor microenvironment with an increase in the CD8:Treg ratio was observed. The combination of pLADD with an anti PD-1 agent led to a sustained immune response and significantly improved efficacy in these mouse tumor models.

On September 27, 2017 Takara Bio Inc. (Takara Bio), reported that the first patient with pancreatic cancer has been enrolled into Oncolytic Virus HF10(TBI-1401) phase I clinical trial in Japan on September　26, 2017 (Press release, Takara Bio, SEP 27, 2017, View Source [SID1234520647]).

This clinical trial will be conducted in patients with unresectable advanced pancreatic cancer to evaluate safety of HF10 in combination with existing chemotherapeutic drug.

In this clinical trial, the HF10 manufactured at Center for Gene and Cell Therapy, Takara Bio’s facility, will be used.
Regarding domestic development and sales of oncolytic virus HF10, Takara Bio has an exclusive licensing agreement with Otsuka Pharmaceutical Co., Ltd., and both companies will consult with each other and aim for the early approval of HF10 in Japan.

On September 27, 2017 Pelican Therapeutics (“Pelican”), a subsidiary of Heat Biologics, Inc. (“Heat”) (Nasdaq: HTBX), entered into a manufacturing agreement with KBI Biopharma, Inc., a global biopharmaceutical contract development and manufacturing organization, for cGMP production of its PTX-35 antibody and PTX-15 fusion protein (Press release, Heat Biologics, SEP 27, 2017, View Source [SID1234520646]). PTX-35 and PTX-15 have the potential to improve clinical response in combination with Heat’s ImPACT therapeutic platform and other immunotherapy drugs by simulating the production of antigen-specific T-cells.

“We selected KBI as our manufacturing partner because, based on our assessment, they have strong development capabilities, and possess the agility and flexibility to help Pelican prepare for early development of both our Phase 1 and 2 clinical trials,” said Rahul Jasuja, CEO of Pelican.

Under the agreement, KBI Biopharma will offer comprehensive development and manufacturing services, which Pelican expects will offer advantages such as speed, productivity, stability and flexibility over traditional approaches to cell line development.

In May 2016, Pelican was awarded a $15.2 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT) to support these manufacturing efforts, as well as to complete a 70-patient, Phase 1 clinical trial incorporating one or more of these compounds.