First patient enrolled into phase I/II clinical trial of NY-ESO-1?siTCR?gene therapy against synovial sarcoma in Japan

On January 19, 2018 Takara Bio Inc. (Takara Bio), reported that the first patient with synovial sarcoma has been enrolled into NY-ESO-1・siTCR gene therapy (TBI-1301) phase I/II clinical trial in Japan on January 15-16, 2018.

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In the clinical trial, the gene of TCR which recognizes NY-ESO-1 antigen, a tumor antigen, is transferred ex-vivo to lymphocytes of patients, and the gene-modified lymphocytes are infused back to the patients. The patients will be monitored for safety and efficacy. The Takara Bio’s method for gene transduction, T-cell expansion methods using RetroNectin, and Takara Bio’s original retroviral vectors for siTCR transduction will be used during the cell processing for the clinical trial. NY-ESO-1・siTCR gene transduced lymphocytes manufactured at Center for Gene and Cell Therapy (Kusatsu, Shiga), Takara Bio’s facility, will be used.

Takara Bio attempts to achieve the early-approval utilizing the conditional and term-limited approval system for regenerative medicine under The Law on Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and Medical devices. Takara Bio aims to commercialize the NY-ESO-1・siTCR gene therapy in the fiscal year 2020.

Reference
"Announcement on submission of the Clinical Trial Plan Notification for phase I/II clinical trial of NY-ESO-1・siTCR gene therapy in Japan"
– Our news release January 24, 2017 View Source

Lynparza receives approval in Japan for the treatment of advanced ovarian cancer

On January 19, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US (known as MSD outside the US and Canada) reported that the Japanese Ministry of Health, Labour and Welfare has approved Lynparza (olaparib) tablets (300mg twice daily) for use as a maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, regardless of their BRCA mutation status, who responded to their last platinum-based chemotherapy (Press release, AstraZeneca, JAN 19, 2018, View Source [SID1234523304]). Lynparza is the first poly ADP-ribose polymerase (PARP) inhibitor to be approved in Japan.

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Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: "We are proud to bring this important first-in-class treatment to women with platinum-sensitive relapsed ovarian cancer in Japan who currently have very few treatment options. The trials show that with Lynparza maintenance therapy, women with ovarian cancer can live longer without their disease worsening and Lynparza is well tolerated."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Today’s decision is significant for Lynparza and, more importantly, for Japanese patients living with advanced ovarian cancer. Our global collaboration with AstraZeneca reinforces how our joint efforts can advance science for patients, and we look forward to working together to explore the potential of Lynparza across multiple tumour types."

The approval was granted on the basis of two randomised trials of Lynparza maintenance therapy for platinum-sensitive relapsed ovarian cancer, SOLO-2 and Study 19.

Table 1. Summary of key efficacy results from randomised trials:

Analysis

Reduction in the risk of disease progression or death (PFS)

Reduction in the risk of death (OS)

SOLO-2

[gBRCAm]

n=295

Lynparza

70% (HR 0.30 [95% CI, 0.22-0.41], P<0.0001; median 19.1 vs 5.5 months by investigator-assessed analysis)

Data not yet mature

Placebo

Study 19

[PSR OC*]

n=265

Lynparza

65% (HR 0.35 [95% CI, 0.25-0.49], P<0.0001;

median 8.4 vs 4.8 months)

27% (HR 0.73 [95% CI, 0.55-0.95];

median 29.8 vs 27.8 months)

Placebo

*PSR = Platinum-sensitive recurrent ovarian cancer

In SOLO-2, the most common adverse drug reactions (≥20%) of any grade reported in patients in the Lynparza arm were nausea (66.7%), anaemia (39.0%), fatigue (29.7%), vomiting (25.6%), asthenia (24.1%) and dysgeusia (23.1%).

In Study 19, the most common adverse drug reactions (≥20%) of any grade reported in patients in the Lynparza arm were nausea (64.0%), fatigue (43.4%) and vomiting (21.3%).

Lynparza is also currently under review for use in unresectable or recurrent BRCA-mutated, HER2-negative breast cancer in Japan, with a decision expected in the second half of 2018 based upon a priority review.

NOTES TO EDITORS
About Ovarian Cancer in Japan

Worldwide, ovarian cancer is the seventh most-commonly diagnosed cancer and the eighth most-common cause of cancer deaths in women. In Japan, more than 9,000 women are diagnosed with ovarian cancer every year and the five-year survival rate is 58%, the lowest among all gynaecological cancers. In 2012, 4,758 women with ovarian cancer died, which represents one out of every two patients. As there is no cure for relapsed ovarian cancer, the primary aim of treatment is to slow progression of the disease for as long as possible and improving or maintaining a patient’s quality of life.

About SOLO-2

SOLO-2 was a Phase III, randomised, double-blinded, multicentre trial designed to determine the efficacy of Lynparza tablets as a maintenance monotherapy compared with placebo, in patients with platinum-sensitive, relapsed or recurrent gBRCA-mutated ovarian, fallopian tube and primary peritoneal cancer. The trial, conducted in collaboration with the European Network for Gynaecological Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs National pour l’Etude des Cancers de l’Ovaire et du sein (GINECO), randomised 295 patients with documented germline BRCA1 or BRCA2 mutations who had received at least two prior lines of platinum-based chemotherapy and were in complete or partial response. Eligible patients were randomised to receive 300mg Lynparza tablets twice daily or placebo tablets twice daily.

About Study 19

Study 19 was a Phase II, randomised, double-blinded, placebo-controlled, multicentre trial, which evaluated the efficacy and safety of Lynparza compared with placebo in relapsed, high-grade serous ovarian cancer patients. The trial randomised 265 patients regardless of BRCA mutation status and who had completed at least two courses of platinum-based chemotherapy and their most recent treatment regimen. Eligible patients were randomised to receive Lynparza maintenance monotherapy at a dose of 400mg per day or matching placebo.

About Lynparza (olaparib)

Lynparza is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit tumour DNA damage response (DDR)-pathway deficiencies to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Lynparza is being investigated in a range of DDR-deficient tumour types and is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD 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-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. The collaboration is based on increasing evidence that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors for a range of tumour types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as a monotherapy. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody-Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

Bavarian Nordic Announces Initiation of Clinical Trial with Novel Cancer Immunotherapy Targeting Brachyury in Cancer Metastasis

On January 19, 2018 Bavarian Nordic A/S (OMX: BAVA, OTC: BVNRY) reported the initiation of a clinical trial of BN-Brachyury, a novel cancer immunotherapy candidate designed to target brachyury, a key driver of cancer metastasis in several tumor types (Press release, Bavarian Nordic, JAN 19, 2018, View Source [SID1234523299]). The open-label Phase 1 trial will evaluate the safety and tolerability of the MVA‑BN Brachyury vaccine, followed by a Brachyury encoded fowlpox (FPV) booster in patients.

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The trial will enroll up to 10 patients with metastatic or unresectable, locally advanced malignant solid tumors. Patients will receive two prime doses of MVA-BN Brachyury, followed by multiple booster doses with FPV-Brachyury. The primary endpoint of the study is safety and tolerability, and secondary endpoints include immunologic responses as measured by an increase in brachyury-specific T-cells and other tumor-associated antigens, as well as evidence of clinical benefit such as progression-free survival (PFS) and objective response (OR). The priming vaccine alone, MVA-BN Brachyury, was previously investigated in a Phase 1 study in 38 patients with chordoma or metastatic solid cancers, and was shown to be well-tolerated and to induce brachyury-specific T-cell immune responses in the vast majority of patients.

"The brachyury target represents an exciting new approach to attacking multiple cancers and deadly metastasis," commented Paul Chaplin, President and Chief Executive Officer of Bavarian Nordic. "Based on clinical results to date, we believe that BN-Brachyury may be a viable treatment option for patients with various forms of cancer. We look forward to further expanding the program with a Phase 2 study later this year in patients with chordoma – a rare tumor of the spine known to overexpress brachyury, for which there are currently no systemic treatments of proven efficacy available."

About BN-Brachyury
BN-Brachyury is a novel prime-boost cancer immunotherapy candidate, developed in collaboration with the National Cancer Institute (NCI). The product candidate consists of a prime (MVA-BN) and a booster dose (fowlpox or FPV), which have been modified to express brachyury and to encode three costimulatory molecules, known as TRICOM. Brachyury is a tumor-associated antigen that is overexpressed in major solid tumor indications, as well as several rare, ultra-orphan cancer indications, and is reported to play a key role in the metastasis and progression of tumors. Tumors that overexpress brachyury are believed to be highly resistant to standard therapies, including radiation and chemotherapy, and are associated with decreased survival rates.

First-Time Data for Merck’s KEYTRUDA® (pembrolizumab) in Patients with Previously Treated Advanced Hepatocellular Carcinoma (HCC) to be Presented at 2018 ASCO GI Symposium

On January 19, 2018 -Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported findings from the registrational phase 2 KEYNOTE-224 trial investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with advanced hepatocellular carcinoma (HCC), the most common type of liver cancer, who were previously treated with systemic therapy (sorafenib) (Press release, Merck & Co, JAN 19, 2018, View Source [SID1234523307]). Results showed an overall response rate (ORR) of 16.3 percent (95% CI, 9.8-24.9) (n=17/104) with KEYTRUDA as monotherapy. Data also include six-month overall survival (OS) and progression-free survival (PFS) rates. The findings will be presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal (ASCO GI) Cancers Symposium in San Francisco in an oral presentation on Friday, Jan. 19, from 1:10-1:15 p.m. PT (Location: Level 3 – Room 3014) (Abstract #209).

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"There continues to be a significant need for new options in the treatment of advanced hepatocellular carcinoma," said Andrew Zhu, M.D., Ph.D., lead investigator and director of liver cancer research at Massachusetts General Hospital Cancer Center. "The durable responses observed with KEYTRUDA monotherapy in this difficult-to-treat cancer are encouraging."

"Merck is committed to understanding the clinical benefit of KEYTRUDA monotherapy across a range of gastrointestinal cancers, including advanced liver cancer," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "The findings from this study demonstrate the potential of KEYTRUDA in patients with advanced HCC following prior systemic therapy and support the advancement of our clinical development program in this cancer type."

Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 650 trials studying KEYTRUDA (pembrolizumab) across a wide variety of cancers and treatment settings, including multiple gastrointestinal disorders such as HCC and gastroesophageal cancer.

The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Data in Previously Treated Advanced HCC, KEYNOTE-224 (Abstract #209)

KEYNOTE-224 is a registrational, open-label phase 2 trial investigating KEYTRUDA monotherapy in patients with advanced HCC who had previously received systemic therapy with sorafenib. The primary endpoint is ORR; secondary endpoints include duration of response, disease control rate, time to progression, PFS and OS.

Findings presented at ASCO (Free ASCO Whitepaper) GI were based on data from 104 evaluable patients, previously treated with sorafenib, who received one or more doses of KEYTRUDA (200 mg intravenous infusion on day 1 of each 3-week cycle for up to 35 administrations). Data showed an ORR of 16.3 percent (95% CI, 9.8-24.9) (n=17/104) with a complete response rate of one percent (95% CI, 0.0-5.2) and a partial response rate of 15.4 percent (95% CI, 9.1-23.8). ORR was similar across subgroups with different etiology, including Hepatitis B and Hepatitis C positive patients. At the time of analysis, the median duration of response was 8.2 months (range: 2.3+ to 8.3+) with 94 percent of responses ongoing for six months or longer (calculated per Kaplan-Meier method). The disease control rate was 61.5 percent (95% CI, 51.5-70.9) (n=64/104). The median PFS was 4.8 months (95% CI, 3.4-6.6) with a six-month PFS rate of 43.1 percent. The median OS had not been reached at the time of analysis (95% CI, 9.4-not reached) with a six-month OS rate of 77.9 percent.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. The treatment-related adverse events (any grade occurring in 10% or more of patients) were fatigue (12.5%), increased aspartate aminotransferase (9.6%), diarrhea (9.6%) and pruritus (21.2%). Grade 3-5 treatment-related adverse events occurred in 26 (25%) patients and there was one treatment-related death. Immune-mediated adverse events occurred in 2.9 percent of patients. Seven patients discontinued treatment due to treatment-related adverse events.

About Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults. Worldwide, more than 782,000 new cases of liver cancer were diagnosed in 2012. In the U.S., the incidence of liver cancer has more than tripled since 1980 and it is estimated that 42,220 new cases will be diagnosed in this year. In Europe, around 63,500 new cases were diagnosed in 2012. Risk factors for liver cancer include gender, ethnicity, chronic viral hepatitis (Hep-B or Hep-C) infection, cirrhosis, heavy alcohol abuse and obesity. HCC – which is frequently diagnosed at an advanced stage – has one of the highest mortality rates of solid cancers, with a 5-year survival rate of less than 15 percent.

About KEYTRUDA (pembrolizumab) Injection 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA (pembrolizumab) in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA (pembrolizumab) and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab).

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation.

These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA (pembrolizumab) was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction.

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-052, KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and 3 patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (≥20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

There is limited experience in pediatric patients. In a study, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

Medigene announces participation at six upcoming investor and scientific conferences

On January 19, 2018 Medigene AG (FSE: MDG1, Prime Standard, TecDAX) reported its participation at six upcoming investor and scientific conferences (Press release, MediGene, JAN 19, 2018, View Source [SID1234523298]):

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Precision Medicine World Conference (PMWC) 2018
Date: 22 – 24 January 2018
Location: Mountain View, CA, USA
Dr. Kai Pinkernell, Chief Medical Officer of Medigene, will give a presentation during the PMWC 2018 Immunotherapy Showcase on 23 January at 2 pm on the topic "Using cutting-edge technologies to develop TCR-based immunotherapies".

ASCO-SITC Clinical Immuno-Oncology Symposium
Date: 25 – 27 January 2018
Location: San Francisco, CA, USA

BioCapital Europe
Date: 6 February 2018
Location: Amsterdam, Netherlands
Julia Hofmann, Head of Public & Investor Relations at Medigene, will hold a company presentation on 6 February at 4.40 pm.

Immuno-Oncology 360°
Date: 7 – 9 February 2018
Location: New York, USA
Dr. Thomas Taapken, CFO of Medigene, takes part in the discussion panel entitled "Raising Money in the Current Climate" on 9 February at 2 pm.

CAR-TCR Summit Europe 2018
Date: 20 – 22 February 2018
Location: London, UK
Prof. Dolores Schendel, CEO and CSO of Medigene, will hold a company presentation on 22 February.

ODDO – 11th German Conference
Date: 21 – 22 February 2018
Location: Frankfurt; Germany