On May 23, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported that the independent Data Safety Monitoring Board (DSMB) of the UNITY-CLL Phase 3 trial has successfully completed a pre-specified interim analysis to assess the contribution of TG-1101 (ublituximab) and TGR-1202 in the combination regimen of TG-1101 plus TGR-1202 (Press release, TG Therapeutics, MAY 23, 2017, View Source [SID1234519270]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

In conducting the analysis, the DSMB reviewed efficacy data from approximately 50 patients per arm in the UNITY-CLL study who were eligible for at least one response evaluation. Based on the overall response rate data available, and in accordance with the statistical analysis plan in the study’s Special Protocol Assessment (SPA), the DSMB determined that contribution has been established and recommended the Company cease enrollment into the single agent arms. Accordingly, the study will now continue enrollment in a 1:1 ratio to only the two combination arms: the investigational arm of TG-1101 (ublituximab) plus TGR-1202 and the control arm of obinutuzumab plus chlorambucil. Additionally, the DSMB reviewed safety data from all patients on study (n > 270) as of the data cut-off date, including patients with both treatment naive and relapsed/refractory Chronic Lymphocytic Leukemia (CLL), and again identified no safety concerns in any treatment group (treatment naïve or previously treated) and recommended the continuation of the study without modification.

"We are extremely pleased that the DSMB has once again found no safety concerns that would require modifying the study. This is particularly comforting when we consider that the safety population now includes over 60 front-line CLL patients treated for more than 6 weeks with TGR-1202 alone or in combination with TG-1101. As most who have followed this area will recall, treatment naïve CLL patients appear to be exquisitely sensitive to the autoimmune mediated side effects of idelalisib, with approximately 50% experiencing Grade 3/4 liver toxicity by week 6 in a published study," stated Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer. Mr. Weiss continued, "We are also very pleased that, in accordance with our SPA, the DSMB has determined that contribution has been adequately demonstrated, enabling us to eliminate the single agent arms from continued enrollment. We are also excited to report that we continue to see strong interest in the study and enrollment remains robust. We continue to view the demand for this study as a strong indication of the need for alternative treatments for patients with CLL, even in the front-line setting. Given the current rate of enrollment, we are now targeting complete enrollment by year end, ahead of our previous guidance, which would put us in a position to report pivotal Overall Response Rate (ORR) data in the third quarter of 2018."

ABOUT UNITY-CLL PHASE 3 TRIAL

UNITY-CLL is a Global Phase 3 randomized controlled clinical trial in patients with Chronic Lymphocytic Leukemia (CLL) that includes two key objectives: first, to demonstrate contribution of each agent in the TG-1101 + TGR-1202 regimen, and second, to demonstrate superiority in Progression Free Survival (PFS) over the standard of care to support the submission for full approval of the combination. In addition, upon completion of enrollment, this trial will evaluate Overall Response Rate (ORR) for accelerated approval. The study initially randomized patients into four treatment arms: TG-1101 plus TGR-1202, TG-1101 single agent, TGR-1202 agent, and an active control arm of obinutuzumab plus chlorambucil. Pursuant to the Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA), an early interim analysis was conducted to assess contribution of each single agent which, upon success, allowed for early termination of both single agent arms.

On May 23, 2017 Sophiris Bio Inc. (NASDAQ: SPHS) (the "Company" or "Sophiris"), a late stage clinical biopharmaceutical company developing topsalysin (PRX302) for the treatment of patients with urological diseases, reported that it has received the regulatory clearance for the diluent – the medium in which topsalysin is diluted (Press release, Sophiris Bio, MAY 23, 2017, View Source [SID1234519269]). Clinical sites can now begin dosing eligible patients in a Phase 2b study in localized prostate cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

On May 23, 2017 Debiopharm International SA (Debiopharm – www.debiopharm.com), part of Debiopharm Group, a Switzerland-based biopharmaceutical company, and ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that Debiopharm has acquired ImmunoGen’s IMGN529/DEBIO 1562, a clinical-stage anti-CD37 ADC for the treatment of patients with B-cell malignancies, such as non-Hodgkin lymphomas (NHL) (Press release, ImmunoGen, MAY 23, 2017, View Source [SID1234519268]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

This Smart News Release features multimedia. View the full release here: View Source

Under the terms of the agreement, ImmunoGen received a $25 million upfront payment for IMGN529/DEBIO 1562 and is entitled to a $5 million milestone payment to be paid after completion of the transfer of ImmunoGen technologies related to the asset, which the parties expect to achieve by the end of 2017. In addition, ImmunoGen is eligible for a second success-based milestone payment of $25 million upon IMGN529/DEBIO 1562 entering a Phase 3 clinical trial.

"The purchase of IMGN529/DEBIO 1562 from a pioneer in the field of ADCs represents a strategic investment leveraging our expertise and track record in Oncology and supports our strong commitment to deliver targeted therapies and precision medicines to help patients suffering from severe diseases," stated Bertrand Ducrey, CEO of Debiopharm.

"IMGN529/DEBIO 1562 has already generated compelling clinical data and we look forward to further exploring it in combination with Rituxan, which could provide an attractive alternative to conventional chemotherapies for patients with NHL such as diffuse large-cell B-cell lymphoma (DLBCL)," said Chris Freitag, vice president of clinical research and development of Debiopharm.

IMGN529/DEBIO 1562 demonstrated evidence of anticancer activity in NHL in a Phase 1 monotherapy trial and successfully completed a safety run-in study in combination with Rituxan. The product is now ready to move forward into a Phase 2 trial in NHL, and particularly in DLBCL for which it has Orphan Drug status.

"With a strong history of developing and bringing oncology drugs to market, Debiopharm offers the right mix of resources and capabilities to advance IMGN529/DEBIO 1562 through its next phase of development," stated Mark Enyedy, president and chief executive officer of ImmunoGen. "Consistent with the strategic review of our portfolio undertaken last fall, this transaction further enables us to prioritize our development efforts on mirvetuximab soravtansine and our IGN programs, while generating near-term value from IMGN529/DEBIO 1562."

On May 23, 2017 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that abstracts highlighting progress in the rucaparib clinical development program will be presented at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place June 2-6 in Chicago (Press release, Clovis Oncology, MAY 23, 2017, View Source [SID1234519267]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Four abstracts highlighting ongoing rucaparib clinical trials will showcase some of the multiple cancer types in which the compound is being studied, including germline and somatic BRCA-mutated, relapsed, high-grade ovarian cancer; metastatic castration-resistant prostate cancer associated with homologous recombination deficiency; and HER2 negative metastatic breast cancer.

"The abstracts being presented at ASCO (Free ASCO Whitepaper) 2017 highlight the depth of our clinical program exploring the potential of rucaparib as a precision medicine therapeutic for multiple cancer types," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "The oncology community has taken great interest in PARP inhibitors and the role of these novel therapeutics within the cancer treatment paradigm. We are pleased to describe these current clinical studies evaluating rucaparib in various solid tumor settings at this prestigious meeting, and importantly, we look forward to announcing the top-line results from ARIEL3 in the ovarian cancer maintenance treatment setting by the end of June."

Rucaparib is Clovis Oncology’s oral, potent, small-molecule inhibitor of PARP1, PARP2 and PARP3. In December 2016, the FDA approved rucaparib (Rubraca) tablets as monotherapy for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a deleterious BRCA mutation (germline and/or somatic) as identified by an FDA-approved companion diagnostic test.

The ARIEL3 pivotal study of rucaparib is a randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance treatment to platinum-sensitive ovarian cancer patients can extend the period of time for which the disease is controlled after a response to platinum-based chemotherapy. Top-line results from ARIEL3 are anticipated by the end of June, and the Company plans to provide a more comprehensive presentation of the ARIEL3 results in a scientific session at a medical meeting later this year. Pending positive data, the Company intends to submit a supplemental New Drug Application (NDA) for a second line or later maintenance treatment indication within approximately four months of the database lock.

The three trials-in-progress abstracts accepted for presentation at the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting comprise:

Abstract TPS5603 (Poster #423b) – ARIEL4: An International, Multicenter Randomized Phase 3 Study of the PARP Inhibitor Rucaparib vs Chemotherapy in Germline or Somatic BRCA1- or BRCA2-Mutated, Relapsed, High-Grade Ovarian Carcinoma

Presenter: Amit M. Oza, MD, Princess Margaret Cancer Centre, University Health Network
Session: Gynecologic Cancer
Date/Time: Saturday, June 3, 1:15-4:45 p.m. CDT
Location: Hall A
Abstract TPS1117 (Poster #103b) – An open-label, phase II study of rucaparib, a PARP inhibitor, in HER2 negative metastatic breast cancer patients with high genomic loss of heterozygosity: RUBY.

Presenter: Anne Patsouris, MD, Institute of West Cancerology Paul Papin
Session: Breast Cancer-Metastatic
Date/Time: Sunday, June 4, 8:00-11:30 a.m. CDT
Location: Hall A
Abstract TPS5087 (Poster #160b) – Trial of RucaparIb in ProsTate IndicatiONs 3 (TRITON3): An International, Multicenter, Randomized, Open-Label Phase 3 Study of Rucaparib vs Physician’s Choice of Therapy for Patients (Pts) with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Associated with Homologous Recombination Deficiency (HRD)

Presenter: Charles J. Ryan, MD, University of California San Francisco Helen Diller Family Comprehensive Cancer Center
Session: Genitourinary (Prostate) Cancer
Date/Time: Monday, June 5, 1:15-4:45 p.m. CDT
Location: Hall A
Additionally, Clovis’ companion diagnostics collaborator Foundation Medicine will present results from a genomic-profiling study:

Abstract 5512 (Oral #5512) – Comprehensive genomic profiling (CGP) with loss of heterozygosity (LOH) to identify therapeutically relevant subsets of ovarian cancer (OC)

Presenter: Julia Andrea Elvin, MD PhD, Foundation Medicine, Inc.
Session: Clinical Science Symposium
Date/Time: Monday, June 5, 8:48-9:00 a.m. CDT
Location: E450ab
Clovis’ rucaparib posters will be available online at View Source as of the time they are presented at the meeting.

About Rucaparib

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in ovarian cancer as well as several additional solid tumor indications. The MAA submission in Europe for an ovarian cancer treatment indication was submitted and accepted during the fourth quarter of 2016. Additionally, rucaparib is being developed as maintenance treatment for ovarian cancer in the ARIEL3 trial for patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, as well as biomarker negative patients. Topline results from ARIEL3 are expected by late June, which, pending positive data, is expected to be followed by the submission of a sNDA for a second line or later maintenance treatment indication. Rucaparib is also being developed in patients with mutant BRCA tumors and other DNA repair deficiencies beyond BRCA – commonly referred to as homologous recombination deficiencies, or HRD. Studies open for enrollment or under consideration include prostate, breast, pancreatic, gastroesophageal, bladder and lung cancers. Clovis holds worldwide rights for rucaparib.

On May 23, 2017 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has accepted for review a supplemental Biologics License Application (sBLA) for KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, seeking approval for treatment of patients with recurrent or advanced gastric or gastroesophageal junction adenocarcinoma who have already received two or more lines of chemotherapy (Press release, Merck & Co, MAY 23, 2017, View Source [SID1234519266]). The FDA granted Priority Review with a PDUFA, or target action, date of Sept. 22, 2017.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"An estimated nearly one-hundred-thousand people are living with gastric cancer in the U.S., yet little progress has been made in bringing forward new treatment options to these patients for whom chemotherapy has long been the standard of care," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We look forward to working with the FDA to bring KEYTRUDA to people with gastric cancer who have progressed after receiving chemotherapy and are in urgent need of another option."

The application submitted to the FDA is seeking approval for KEYTRUDA monotherapy in previously treated patients at a fixed dose of 200 mg administered intravenously every three weeks. The application is based on data from cohort one of the phase 2 KEYNOTE-059 trial investigating KEYTRUDA in heavily pretreated patients with recurrent or advanced gastric or gastroesophageal junction adenocarcinoma that has progressed after two or more lines of chemotherapy. Data from cohort one of KEYNOTE-059 will be presented at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, June 2 – 6, 2017 during an oral session on Sunday, June 4 at 9:00 a.m. – 9:12 a.m. CDT (Location: Hall D2).

Merck is committed to investigating new approaches across the spectrum of cancers with more than 500 clinical trials evaluating KEYTRUDA (pembrolizumab) in more than 30 tumor types, including multiple gastrointestinal cancers like gastric cancer. Specific to gastric cancer, Merck’s broad clinical development program encompasses all stages of advanced disease and is investigating KEYTRUDA as monotherapy and in combination with other cancer treatments across multiple lines of therapy. To date, the program includes four gastric cancer registration-enabling studies and numerous other gastrointestinal cancer studies are underway.

About Gastric Cancer

Gastric cancer, also called stomach cancer, is a type of cancer that begins in the stomach and tends to develop slowly over many years. Most gastric cancers are adenocarcinomas, which develop from the cells of the innermost lining (mucosa) of the stomach. Risk factors for gastric cancer include gender, age, ethnicity, geography and infection with Helicobacter pylori. Worldwide, gastric cancer is the fifth most common type of cancer and the third leading cause of cancer death. Each year there are approximately 952,000 newly diagnosed cases of gastric cancer resulting in approximately 723,000 deaths worldwide. It is estimated that in 2017, more than 10,000 people will die from gastric cancer in the U.S. alone.

About KEYTRUDA (pembrolizumab) Injection

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.

Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial.

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 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 (pembrolizumab) 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 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.

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 (pembrolizumab) 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. 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 and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA (pembrolizumab) 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.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), 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 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.

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.

Based on its mechanism of action, KEYTRUDA (pembrolizumab) 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 (pembrolizumab) 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-002, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

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%).

When KEYTRUDA was administered in combination with pemetrexed and carboplatin, 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%). The study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA plus chemotherapy, as compared to chemotherapy alone, for any specified adverse reaction.

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.

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 of 40 pediatric patients with advanced melanoma, PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma, patients were treated with KEYTRUDA for a median of 43 days (range 1 to 414 days), with 24 patients (60%) receiving treatment for 42 days or more. The safety profile in 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 that includes more than 500 clinical trials 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.