On January 21, 2020 Northern Arizona University reported that melanoma is the most lethal type of skin cancer and unusually common in Arizona, where residents are exposed to higher-than-average amounts of ultraviolet radiation (Press release, Northern Arizona University, JAN 21, 2020, View Source [SID1234553361]). However, Northern Arizona University scientists believe the formula for a combination of melanoma-fighting drugs is within reach.

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Matthew Salanga, an assistant professor in NAU’s Department of Biological Sciences, is leading an 18-month project funded through a Flinn Foundation grant of $100,000. His team, which includes experts in experimental biology, computational systems biology and translational medicine, will study melanoma tumors on zebrafish, a small minnow-sized fish that has 70 percent of the same genes that are found in humans. Physiologically, zebrafish also have pigment cells in their skin, called melanocytes, which give them their stripes and their name. In humans, these cells are responsible for creating a tan when exposed to the sun, and if dysregulated can give rise to melanoma.

The majority of melanoma skin cancers are the result of a specific mutation in the BRAF gene (BRAF V600E). BRAF is a type of enzyme known as a protein kinase that adds a phosphate group to other proteins in cell signaling pathways. For this project, zebrafish that express the human form of mutated BRAF are employed to test strategies for treating melanoma.

"Fish don’t often get cancer," said Salanga, an expert in cell and developmental biology, "but in the lab, we can engineer fish to contain human genes that we know are associated with cancer. Essentially, it’s a way to use non-human vertebrates as though they were human. We call this humanization."

Currently there are around 30 zebrafish carrying the BRAF V600E human oncogene in Salanga’s lab that have visible melanoma tumors, and that number will grow as the study progresses. Activated BRAF acts to promote cell growth and proliferation. Salanga explains that the V600E mutation of BRAF leaves it stuck in the "on" position. This can result in unrestricted cell growth and proliferation. Drugs have been developed that specifically target and suppress tumor cells that have aberrant BRAF kinase activity. These drugs are in a class of drug called protein kinase inhibitors (PKIs), and are currently used clinically. However, not all patients respond and many relapse after a few months of therapy.

Researchers try to predict best drug combinations for inhibiting kinase activity

Salanga believes that there is a combination and dosage of PKIs recognizing distinct conformations of the BRAF kinase that can shut down the misfiring proteins and kill tumor cells dependent on oncogenic BRAF activity.

"The crux of the project is trying to predict which set of currently available drugs will work the best at inhibiting BRAF’s ability to turn things on inappropriately," he said. "Molecular profiling of tumor cells might be used to guide the drug selection for individual patients."

Critical to the NAU-based pilot project team is Richard Posner, a professor in NAU’s Department of Biological Sciences and William Hlavacek, a scientist at Los Alamos National Laboratory. Posner and Hlavacek are computational systems biologists who have developed mathematical models for predicting optimal strategies to target mutations in BRAF. In recent work, they and their collaborators predicted that two-drug combinations will be able to effectively suppress mutant BRAF (V600E) signaling. These predictions were validated in melanoma cell lines. The researchers are leveraging this computation pipeline to predict therapeutic responses to novel combinations of U.S. Food and Drug Administration-approved drugs in humanized zebrafish harboring melanoma skin cancer.

Also involved in the project is Haiyong Han, a scientist in the Molecular Medicine Division at the Translational Genomics Research Institute (TGen). His specialty is pancreatic cancer, which could potentially be treated using similar therapeutic strategies that are being proposed for melanoma.

The researchers, including undergraduate and graduate students, will be adding various combinations of inhibitors to see if they can find combinations that are most effective in targeting mutated RAF proteins.

Salanga says taking the melanoma-fighting research from the lab to medical facilities could happen quickly, as 150 PKIs are already in various stages of safety testing, and many are approved by the FDA.

"TGen and its partners can carry out these PKI clinical trials fairly routinely through its patient network and its scientists, who assist in these human studies. We could see humans receiving treatments like this within the next year or two," he said.

Although early detection of melanoma contributes to an 89 percent, five-year survival rate, metastatic melanoma is often lethal, with less than a 20 percent survival rate.

NAU’s grant for the project was awarded by the Flinn Foundation under its Seed Grants to Promote Translational Research initiative.

On January 21, 2020 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported that it has commenced an underwritten public offering of $325,000,000 in shares of its common stock (Press release, Blueprint Medicines, JAN 21, 2020, View Source [SID1234553360]). In addition, Blueprint Medicines expects to grant the underwriters a 30-day option to purchase up to an additional $48,750,000 in shares of its common stock in connection with the public offering. All shares of common stock will be offered by Blueprint Medicines.

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Blueprint Medicines expects to use the net proceeds of the offering to further build its global commercial infrastructure to support additional planned regulatory filings and commercial launches for AYVAKIT and pralsetinib, if approved, in the U.S. and Europe; to fund clinical trials for avapritinib in systemic mastocytosis (SM), including its ongoing registration-enabling Phase 2 PIONEER clinical trial for indolent and smoldering SM, as well as future indication expansion clinical trials; to fund clinical trials for pralsetinib in RET-driven cancers, including its Phase 3 AcceleRET Lung clinical trial for pralsetinib in first-line RET-altered NSCLC and its planned Phase 3 clinical trial for pralsetinib in first-line RET-mutant MTC, as well as future indication expansion clinical trials; to fund its planned Phase 1 trial for BLU-263 in healthy volunteers and future clinical trials for BLU-263 and other future drug candidates; to fund manufacturing costs for AYVAKIT and for ongoing and anticipated drug development efforts for its most advanced drug candidates; and the balance, if any, to fund additional discovery research efforts, its other ongoing and planned clinical trials, working capital requirements and other general corporate purposes.

Goldman Sachs & Co. LLC and Cowen and Company, LLC are acting as joint book-running managers for the offering. Canaccord Genuity LLC, JMP Securities LLC, and Raymond James & Associates, Inc. are acting as co-lead managers for the offering. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed or as to the actual size or terms of the offering.

A registration statement on Form S-3 (File No. 333-216573) relating to these securities has been previously filed with the Securities and Exchange Commission (SEC) and has become effective. This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

The offering will be made only by means of a prospectus. A copy of the prospectus supplement relating to the offering will be filed with the SEC and may be obtained, when available, from Goldman Sachs & Co. LLC by mail at Prospectus Department, 200 West Street, New York, NY 10282, by telephone at (866) 471-2526, by fax at (212) 902-9316, or by email at [email protected], or from Cowen and Company, LLC, c/o Broadridge Financial Services, 1155 Long Island Avenue, Edgewood, NY 11717, Attention: Prospectus Department, or by telephone at (833) 297-2926.

On January 21, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that the pivotal Phase 3 trial evaluating its anti-PD-1 antibody tislelizumab in combination with two chemotherapy regimens for the first-line treatment of patients with squamous non-small cell lung cancer (NSCLC), met the primary endpoint of improved progression-free survival (PFS) at the planned interim analysis, as assessed by independent review committee (IRC) (Press release, BeiGene, JAN 21, 2020, View Source [SID1234553359]). In this study, patients with previously untreated advanced squamous NSCLC were randomized to receive either tislelizumab in combination with paclitaxel and carboplatin, tislelizumab in combination with nanoparticle albumin-bound (nab) paclitaxel (ABRAXANE) and carboplatin, or paclitaxel and carboplatin alone. Based on the pre-planned interim analysis, both tislelizumab treatment arms crossed the pre-specified efficacy boundary compared to chemotherapy alone. The safety profile of tislelizumab in both combinations in this trial was consistent with the known risks of each study treatment, and no new safety signals were identified.
"Tislelizumab was recently approved in China for patients with relapsed or refractory classical Hodgkin’s lymphoma, and we have a broad development program with more than 5,000 patients enrolled in over 25 tislelizumab studies, including 15 potentially registration-enabling trials," commented Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology at BeiGene. "We are extremely excited about the compelling results that tislelizumab demonstrated in this Phase 3 trial and for its potential use as a first-line treatment for patients in China with advanced squamous NSCLC. We look forward to continuing the development program for tislelizumab in lung cancer, which includes three other Phase 3 trials, and reporting additional data."
The company plans to discuss its plans for filing a supplemental new drug application (sNDA) for tislelizumab as a first-line treatment for squamous NSCLC with the Center for Drug Evaluation (CDE) at the National Medical Products Administration (NMPA) in China and to present these data at an upcoming medical meeting.
This trial (NCT 03594747, known as BGB-A317-307) is a Phase 3, randomized, open-label, multi-center trial investigating tislelizumab combined with either paclitaxel and carboplatin or nab-paclitaxel (ABRAXANE, which is commercialized by BeiGene in China) and carboplatin compared with paclitaxel and carboplatin alone in patients with

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untreated stage IIIB or IV squamous NSCLC from mainland China, regardless of PD-L1 expression. The primary endpoint is PFS per IRC. Key secondary endpoints include overall survival and safety. The study began enrolling patients in July 2018, and 360 patients were randomized 1:1:1 to receive tislelizumab (200mg every three weeks) in combination with each of the chemotherapy regimens or chemotherapy only, until disease progression, unacceptable toxicity, physician decision or consent withdrawal. Patients on the chemotherapy-only control arm who experienced disease progression, verified by central independent review, were eligible to cross over to receive tislelizumab monotherapy.
"Squamous NSCLC remains a significant unmet need, representing approximately 30 percent of patients with NSCLC in China. This Phase 3 study was designed to assess the impact of tislelizumab given in combination with chemotherapy as a potential treatment to improve outcomes in patients with advanced squamous NSCLC, for whom prognoses are typically quite poor. These results give us hope that we could have a new treatment option for these patients," commented Jie Wang, M.D., Professor at the Cancer Hospital Chinese Academy of Medical Sciences, in Beijing, China and lead investigator for the trial.
About Non-Small Cell Lung Cancer
In contrast to most Western countries where lung cancer death rates are decreasing, lung cancer incidence rate is still increasing in China.12 There were approximately 770,000 new cases of lung cancer in China in 2018 and it is the leading cause of cancer-related death in both men and women, with approximately 690,500 deaths in China in 2018.3 Non-small cell lung cancer (NSCLC) comprises the most common form of lung cancer in China.4
About Tislelizumab
Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.
Tislelizumab is approved by the China National Medical Products Administration (NMPA) as a treatment for patients with classical Hodgkin’s lymphoma who received at

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least two prior therapies. A supplemental new drug application (sNDA) for tislelizumab in patients with previously treated locally advanced or metastatic urothelial carcinoma has been granted priority review by the Center for Drug Evaluation at the NMPA and is currently under review.
Tislelizumab is being studied in a broad clinical program as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. Currently, 15 potentially registration-enabling clinical trials are being conducted in China and globally, including 11 Phase 3 trials and four pivotal Phase 2 trials.
Tislelizumab is not approved for use outside of China.

On January 21, 2020 OBI Pharma, Inc., a Taiwan biopharma company (TPEx: 4174), reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for OBI-999 for the treatment of Gastric Cancer (Press release, OBI Pharma, JAN 21, 2020, View Source [SID1234553356]). OBI-999 is a first-in-class antibody drug conjugate targeting Globo H, a glycolipid antigen. On December 26, 2019 OBI-999 was granted Orphan Drug Designation for Pancreatic Cancer.

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A Phase 1/2 clinical trial of OBI-999 has commenced enrollment at the University of Texas M.D. Anderson Cancer Center, with Dr. Apostolia M Tsimberidou as the Principal Investigator, in patients with locally advanced or metastatic solid tumors, including Gastric, Pancreatic, Colorectal and Esophageal Cancers (ClinicalTrials.gov Identifier: NCT04084366). The objective of the trial is to verify the safety and preliminary efficacy profile of OBI-999 in these patient populations.

Tillman Pearce, MD, CMO, OBI Pharma noted, "Advanced gastric cancer is an orphan disease where targeted therapies are lacking for the majority of patients. OBI-999 is an antibody-drug conjugate therapeutic targeting the cancer-associated glycolipid antigen, Globo H. OBI-999 incorporates a validated payload, MMAE, with a proprietary linker technology. It has demonstrated high effectiveness in xenograft models of metastatic gastric cancer that overexpress Globo H. Clinical development of this agent will be guided by evaluation of patients based on a validated Globo H immunohistochemistry assay, which will allow selection of patients whose tumors overexpress this tumor antigen for clinical investigation."

About Gastric Cancer

Gastric cancer (GC), or stomach cancer, is a disease in which malignant cancer cells form in the lining of the stomach. The majority of GC (90-95%) presents as adenocarcinomas arising from the mucosa layer. Some of the potential risk factors associated with GC include Helicobacter pylori infection, high intake of salt, low consumption of fruits and vegetables, obesity, heavy alcohol consumption, chronic atrophic gastritis and cigarette smoking.

GC is a deadly disease and an estimated prevalence in 2019 at 100,189 individuals in the US, with a low 5-year survivability of 31.0%. Current standard treatment options for patients with advanced or recurrent GC are associated with limited efficacy and unfavorable toxicity profile, especially for extended use or maintenance treatment in a patient population which is often already frail and cachectic.

About Orphan Drug Designation (ODD)

The orphan drug designation provides OBI Pharma with potential benefits, including market exclusivity upon regulatory approval is received, exemption of FDA application fees, and tax credits for qualified clinical trials. The FDA’s Office of Orphan Drug Products grants orphan status to support development of medicines for rare diseases or conditions that affect fewer than 200,000 people in the U.S.

About OBI-999

OBI-999 is a novel first-in-class Antibody Drug Conjugate (ADC) with a proprietary linker technology that provides a consistent Drug-to-Antibody ratio (DAR) for cancer treatment that is based on Globo H, an antigen expressed in up to 15 epithelial cancers. OBI-999 uses a Globo H antibody to target cancer cells of high Globo H expression. By releasing a small molecule chemotherapeutic drug through the specificity of the antibody, it directly deploys cytotoxic therapy at the targeted cancer cells. OBI-999 is currently in a Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT04084366) to test its safety and efficacy as an oncology ADC therapy. In pre-clinical xenograft animal models in multiple tumor types (gastric, pancreatic, lung and breast), OBI-999 has demonstrated profound tumor shrinkage at various doses. In pre-clinical single and repeated dose toxicology studies, OBI-999 was well-tolerated, and achieved a favorable safety margin which warrants further clinical development. OBI Pharma owns global rights to OBI-999.

On January 21, 2020 AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that a supplemental New Drug Application (sNDA) for LYNPARZA has been accepted and granted priority review by the U.S. Food and Drug Administration (FDA) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations, who have progressed following prior treatment with a new hormonal agent (Press release, Merck & Co, JAN 21, 2020, View Source [SID1234553355]).

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A Prescription Drug User Fee Act (PDUFA) date is set for the second quarter of 2020.

The sNDA acceptance for review by the FDA is based on positive results from the Phase 3 PROfound trial, which were presented during a Presidential Symposium at the 2019 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) congress.

Results of the PROfound trial showed LYNPARZA met its primary endpoint, significantly reducing the risk of radiographic disease progression or death by 66% in patients with BRCA1/2 or ATM-mutated mCRPC and improved radiographic progression-free survival (rPFS) to a median of 7.4 months vs. 3.6 months for patients receiving abiraterone or enzalutamide (HR 0.34 [95% CI, 0.25-0.47], p<0.0001).

The trial also met the key secondary endpoint of rPFS in the overall population of men with HRR-mutated (HRRm) mCRPC (those with mutations in BRCA1/2, ATM, CDK12 or 11 other HRRm genes), where LYNPARZA reduced the risk of radiographic disease progression or death by 51% and improved rPFS to a median of 5.8 months vs. 3.5 months for those receiving abiraterone or enzalutamide (HR 0.49 [95% CI, 0.38-0.63], p<0.0001).

The safety and tolerability profile of LYNPARZA in the PROfound trial did not differ from that observed in prior clinical trials. The most common adverse events (AEs) ≥20% for LYNPARZA compared to abiraterone or enzalutamide were anemia (47% vs.15%), nausea (41% vs. 19%), fatigue and asthenia (41% vs. 32%), decreased appetite (30% vs. 18%) and diarrhea (21% vs. 7%). Grade 3 or above AEs were anemia (22% vs. 5%), fatigue and asthenia (3% vs. 5%), vomiting (2% vs. 1%), dyspnea (2% vs. 0%), urinary tract infection (2% vs. 4%), nausea (1% vs. 0%), decreased appetite (1% each), diarrhea (1% vs. 0%) and back pain (1% vs. 2%). AEs led to dose interruptions in 22% of patients on LYNPARZA vs. 4% of patients on abiraterone and enzalutamide and discontinuation of treatment in 16% of patients on LYNPARZA vs. 9% on abiraterone and enzalutamide.

PROfound is the first Phase 3 trial evaluating a targeted treatment in biomarker-selected prostate cancer patients. LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, was most recently approved in the U.S. on Dec. 27, 2019, as a first-line maintenance treatment for germline BRCA-mutated (gBRCAm) metastatic pancreatic cancer that has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. It is also approved in the U.S. as a first-line maintenance treatment in BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy and for the treatment of gBRCAm HER2-negative metastatic breast cancer patients previously treated with chemotherapy.

About PROfound

PROfound is a prospective, multi-center, randomized, open-label, Phase 3 trial evaluating the efficacy and safety of LYNPARZA vs. new hormonal agents (e.g. abiraterone or enzalutamide) in patients with mCRPC who have progressed on prior treatment with a new hormonal anticancer treatment and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway, among them BRCA1/2, ATM and CDK12.

The trial was designed to analyze patients with HRRm genes in two cohorts: the primary endpoint was in those with mutations in BRCA1/2 or ATM genes and then, if LYNPARZA showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes; key secondary endpoint).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%), and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONS—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—gBRCAm, HER2-negative Metastatic Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).

DRUG INTERACTIONS

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

INDICATIONS

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Advanced gBRCAm Ovarian Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

gBRCAm, HER2-negative Metastatic Breast Cancer

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

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About Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Prostate cancer is the second-most common cancer in men and is associated with a significant mortality rate. In the U.S. this year, it is estimated that more than 191,000 people will be diagnosed with prostate cancer and more than 33,000 people will die of this disease. More than one in four patients with mCRPC harbor an HRR mutation.

Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. mCRPC occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis. Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. Despite an increase in the number of available therapies, five-year survival for men with mCRPC remains low.

About Homologous Recombination Repair (HRR) Mutations

Homologous recombination repair (HRR) plays a significant role in maintaining the genetic stability of cells and suppressing tumor growth by repairing damaged DNA. Mutations, or defects, in homologous recombination (HR) pathway genes – which include ataxia telangiectasia mutated (ATM) and BRCA1/2 genes – increase the risk for breast, ovarian, pancreatic, prostate and other cancers.

About LYNPARZA (olaparib)

LYNPARZA is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop LYNPARZA and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.