On May 18, 2017 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, with a primary focus on myelodysplastic syndromes (MDS), reported details relating to a poster presentation addressing Intravenous Rigosertib in Second-line Higher Risk MDS at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place June 2nd-6th in Chicago (Press release, Onconova, MAY 18, 2017, View Source [SID1234519224]).

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Further Rationale for Rigosertib in a Second-line HR-MDS Setting
Abstract Number: 7056

Title: Relationship of Bone Marrow Blast (BMBL) response to Overall Survival (OS) in a Multicenter study of Rigosertib (Rigo) in Patients with Myelodysplastic Syndromes (MDS) with Excess Blasts Progressing on or After Treatment with a Hypomethylating Agent (HMA).
Date: Monday, June 5, 2017
Time and Location: 8:00 AM — 11:30 AM, McCormick Place, Hall A
Presenter: Aref Al-Kali, MD, Mayo Clinic – Rochester, Minnesota

On May 18, 2017 NewLink Genetics Corporation (NASDAQ:NLNK) reported that an abstract describing data from a clinical study of its IDO pathway inhibitor, indoximod, in combination with chemotherapeutic agents for patients with newly diagnosed acute myelogenous leukemia (AML), is now available on the website of the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (Press release, NewLink Genetics, MAY 18, 2017, View Source [SID1234519222]).

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An infographic accompanying this announcement is available at View Source

"These data to be presented at the EHA (Free EHA Whitepaper) Congress further highlight clinical results presented at AACR (Free AACR Whitepaper) in April and to be presented at ASCO (Free ASCO Whitepaper) in June, supporting the hypothesis that the IDO pathway is central to immune suppression in cancer," said Charles J. Link, Jr., M.D., Chief Executive Officer and Chief Scientific Officer. "NewLink Genetics has two separate and distinct types of IDO pathway inhibitors in clinical development. Indoximod, which is wholly owned by NewLink Genetics, has a proposed differentiated mechanism within the IDO pathway and acts as a tryptophan mimetic having a direct effect on immune cells to reverse immune suppression used by cancer to protect itself."

Indoximod in combination with chemotherapeutic agents

Initial results from the Phase 1b portion of a Phase 1b/randomized Phase 2a trial of indoximod in combination with chemotherapeutic agents, idarubicin and cytarabine, for patients with newly diagnosed AML will be presented as an e-poster (Abstract number E-912) by Ashkan Emadi, M.D., Ph.D., Associate Professor of the University of Maryland Greenebaum Comprehensive Cancer Center, at EHA (Free EHA Whitepaper) in Madrid on Friday, June 23, 2017, 9:30 AM to Saturday, June 24, 7:00 PM CET and is titled: Indoximod in Combination with Idarubicin and Cytarabine for Upfront Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML): Phase 1 Report.

This study uses a conventional remission induction and consolidation protocol for patients with newly diagnosed AML. Indoximod is given orally starting on day 8 of induction onward. The Phase 1 portion evaluated three dose levels of indoximod (600 mg, 1000 mg, 1200 mg) in combination with the standard of care 7+3 chemotherapy. Twelve patients were enrolled, as of March 1, 2017. The results indicate indoximod does not appear to add significant toxicity to standard remission induction and consolidation therapy for patients with newly diagnosed AML. Initial data suggest a low rate of minimal residual disease (MRD-neg) after one cycle of induction chemotherapy.

Nicholas N. Vahanian, M.D., President and Chief Medical Officer added, "Importantly, these data support further clinical investigation of our IDO pathway inhibitors in combination with currently available therapies, such as chemotherapy for patients with newly diagnosed Acute Myeloid Leukemia (AML)."

Key findings presented from the study include:

Combination treatment with indoximod and conventional remission induction and consolidation therapy was well tolerated without adding significant toxicity
Five of 6 (83%) evaluable patients treated with indoximod (600 mg or 1000 mg) achieved complete remission, with no evidence of minimal residual disease
About Indoximod
Indoximod is an investigational, orally available small molecule targeting the IDO pathway. The IDO pathway is one of the key immuno-oncology targets involved in regulating the tumor microenvironment and immune escape.

NewLink Genetics is currently evaluating indoximod in multiple combination studies for patients with various types of cancer including melanoma, acute myeloid leukemia, pancreatic cancer and prostate cancer.

On May 18, 2017 Nektar Therapeutics (Nasdaq: NKTR) reported its presence at the upcoming 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, where it will share updated data from clinical studies of NKTR-214. ASCO (Free ASCO Whitepaper) will take place June 2-6, 2017 in Chicago (Press release, Nektar Therapeutics, MAY 18, 2017, View Source [SID1234519221]).

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NKTR-214 is an investigational immuno-stimulatory therapy designed to expand specific cancer-fighting CD8+ effector T cells and natural killer (NK) cells directly in the tumor micro-environment and increase expression of PD-1 on these immune cells.

"We look forward to providing updates on NKTR-214, including the first data from the PIVOT trial evaluating NKTR-214 in combination with nivolumab, as well as updated data from the monotherapy trial of NKTR-214, including I-O naïve RCC patients who received sequential checkpoint therapy following treatment with NKTR-214," said Mary Tagliaferri, M.D., Senior Vice President of Clinical Development at Nektar Therapeutics. "NKTR-214’s unique mechanism which selectively increases tumor-killing TILs, combined with its favorable safety profile and clinical activity, support our combination trials of NKTR-214 with existing checkpoint inhibitors such as nivolumab and atezolizumab, as well as other immuno-oncology mechanisms in development."

NKTR-214 targets CD122 specific receptors found on the surface of cancer-fighting immune cells in order to stimulate their proliferation. In clinical and preclinical studies, treatment with NKTR-214 resulted in expansion of these cells and mobilization into the tumor micro-environment.1,2,3 NKTR-214 has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

The abstracts published in advance of the ASCO (Free ASCO Whitepaper) meeting which were made available yesterday on the ASCO (Free ASCO Whitepaper) website at www.asco.org include preliminary data only as of February 7, 2017. Updated and additional patient data from these trials will be presented at ASCO (Free ASCO Whitepaper).

Abstract 2545/Poster 37: "Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy."
Presenter: Chantale Bernatchez, Ph.D., The University of Texas MD Anderson Cancer Center
Poster Session: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Date and Time: Monday, June 5, 2017 – 8:00 a.m. – 11:30 a.m. CDT
Location: Hall A

Abstract e14040: "A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors." Diab, A., et al.
Publication abstract to be included online in the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting Proceedings, a Journal of Clinical Oncology supplement.

Nektar will host an analyst and investor event with clinical investigators on Saturday, June 3, 2017 at 6:00 pm CDT in Chicago, IL during the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting.

Presenters will include lead investigators from the NKTR-214 trial: Dr. Adi Diab, Assistant Professor, Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center, Dr. Nizar Tannir, Professor, Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center and Dr. Michael Hurwitz, Assistant Professor of Medicine (Medical Oncology) at Yale Cancer Center.

To register for the webcast of the event please visit: View Source

Seating is limited to attend the event in person, please contact [email protected] for more information.

On May 18, 2017 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that it will present results from seven studies at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting to be held June 2 to 6, 2016 in Chicago, Ill (Press release, Myriad Genetics, MAY 18, 2017, View Source [SID1234519220]). Abstracts of the Company’s presentations are currently available at: abstracts.asco.org

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“We look forward to presenting important new research at ASCO (Free ASCO Whitepaper) in collaboration with our academic partners, advancing personalized medicine in the field of oncology,” said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. “Our presentations will highlight advances in companion diagnostics, hereditary cancer risk assessment, and prediction of oncologic outcomes, all of which are designed to meaningfully improve clinical care for patients.”

A list of Myriad presentations at ASCO (Free ASCO Whitepaper) 2017 is below. Follow Myriad on Twitter via @MyriadGenetics and stay informed about symposium news and updates by using the hashtag #ASCO17.

Title

Author Poster/Abstract Number

Day/Time Myriad Product

Podium Presentation

Evaluation of BRCA1/2 and homologous
recombination defects in ovarian cancer and
impact on clinical outcomes Melinda Yates Abstract 5511 Monday,
June 5,
2017: 8:00-
9:30 a.m.
CDT.
Room
E450ab

myChoice
HRD
Poster Discussion
Quantifying Gender Ascertainment Bias in
Hereditary Cancer Testing

Anthony Chen Abstract 6516
Poster Board
338 Monday,
June 5,
2017: 1:15-
4:45 p.m.
and 4:45-
6:00 p.m.
CDT. Myriad
myRisk
Poster Presentations
Expanded Yield of Multiplex Panel Testing in
Fully Accrued Prospective Trial

Performance of Mutation Risk Prediction
Models in a Racially Diverse Multi-Gene Panel
Testing Cohort

Gregory Idos Abstract 1525
Poster Board
183

Abstract 1523
Poster Board
181

Monday,
June 5,
2017: 1:15-
4:45 p.m.
CDT. Myriad
myRisk
Development and Validation of a Residual Risk
Score to Predict Breast Cancer Risk in
Unaffected Women Negative for Mutations on a
Multi-Gene Hereditary Cancer Panel

Elisha Hughes Abstract 1579
Poster Board
237 Monday,
June 5,
2017: 1:15-
4:45 p.m.
CDT. Myriad
myRisk
Safety of Multiplex Gene Testing for Inherited
Cancer Risk in a Fully Accrued Prospective
Trial Allison Kurian Abstract 1576
Poster Board
234 Monday,
June 5,
2017: 1:15-
4:45 p.m.
CDT.

Myriad
myRisk
Multi-Gene Hereditary Cancer Testing among
Men with Breast Cancer Krystal Brown Abstract 1532
Poster Board
190 Monday,
June 5,
2017: 1:15-
4:45 p.m. CDT. Myriad
myR

On May 18, 2017 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved two new indications for KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, for certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer (Press release, Merck & Co, MAY 18, 2017, View Source [SID1234519216]).

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In the first-line setting, KEYTRUDA is now approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible 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. In the second-line setting, KEYTRUDA is now approved 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. KEYTRUDA is approved for use in these indications 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.

Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab). Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see "Selected Important Safety Information" below.

"KEYTRUDA is now available for use as a first-line treatment option for patients with advanced urothelial bladder cancer who are not eligible for the standard of care, cisplatin-based chemotherapy," said Dean F. Bajorin, M.D., study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. "With the second-line indication, KEYTRUDA also provides a new option for patients with advanced urothelial bladder cancer – and is the only anti-PD-1 therapy to show an overall survival benefit versus chemotherapy in a phase 3 study."

"These two indications mark important additions to the growing list of tumors and treatment settings for which KEYTRUDA is now approved. This FDA approval further demonstrates Merck’s commitment to help improve the lives of patients with many types of advanced cancer," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.

The KEYTRUDA clinical development program includes more than 30 tumor types in nearly 500 clinical trials, including more than 250 trials that combine KEYTRUDA with other cancer treatments. Currently, Merck has the largest immuno-oncology clinical development program in bladder cancer, with 29 trials underway involving KEYTRUDA as monotherapy and in combination, including four registration-enabling studies.

Data Supporting First-Line Cisplatin-Ineligible Approval

The first-line approval is based on data from a multicenter, open-label, single-arm trial, KEYNOTE-052, investigating KEYTRUDA in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medication were excluded from the trial. Patients received KEYTRUDA at a dose of 200 mg every three weeks until unacceptable toxicity or disease progression; patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were objective response rate (ORR), according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, as assessed by independent radiology review, and duration of response.

The efficacy analysis showed an ORR of 29 percent (95% CI: 24, 34), with a complete response rate of 7 percent and a partial response rate of 22 percent. The median duration of response had not been reached (range: 1.4+ to 17.8+ months). The median follow-up time was 7.8 months.

In KEYNOTE-052, KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 11 percent of patients. 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 three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22 percent 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 percent of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Data Supporting Second-Line Post-Platinum Failure Approval

The second-line approval is based on data from a multicenter, randomized, active-controlled trial, KEYNOTE-045, investigating KEYTRUDA in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded from the trial. Patients were randomized to receive either KEYTRUDA 200 mg every three weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens, all given intravenously, every three weeks (n=272): paclitaxel 175 mg/m2 (n=84), docetaxel 75 mg/m2 (n=84), or vinflunine 320 mg/m2 (n=87). Treatment continued until unacceptable toxicity or disease progression; patients without disease progression could be treated for up to 24 months. The major efficacy outcomes were overall survival (OS) and progression-free survival (PFS), as assessed by a blinded independent central review (BICR) per RECIST 1.1; additional efficacy outcome measures were ORR, as assessed by BICR per RECIST 1.1, and duration of response.

KEYTRUDA demonstrated superior OS compared to chemotherapy. Findings demonstrated that KEYTRUDA resulted in a 27 percent reduction in the risk of death compared to chemotherapy – with 155 events (57%) observed in the KEYTRUDA arm, compared to 179 events (66%) in the chemotherapy arm (HR, 0.73 [95% CI: 0.59, 0.91], p=0.004); the median OS was 10.3 months (95% CI: 8.0, 11.8) in the KEYTRUDA arm, compared to 7.4 months (95% CI: 6.1, 8.3) in the chemotherapy arm. In October 2016, the study was stopped early at the recommendation of an independent Data Monitoring Committee following an interim analysis that showed KEYTRUDA met the superiority thresholds for OS in the overall study population.

There was no statistically significant difference between KEYTRUDA (pembrolizumab) and chemotherapy with respect to PFS. There were 218 events (81%) observed in the KEYTRUDA arm, compared to 219 events (81%) in the chemotherapy arm (HR, 0.98 [95% CI: 0.81, 1.19], p=0.833). The median PFS was 2.1 months (95% CI: 2.0, 2.2) in the KEYTRUDA arm, compared to 3.3 months (95% CI: 2.3, 3.5) in the chemotherapy arm.

Analysis of the ORR endpoint showed a statistically significant improvement with KEYTRUDA, as compared to chemotherapy. The ORR was 21 percent (95% CI: 16, 27) in the KEYTRUDA arm (with a complete response rate of 7 percent and a partial response rate of 14 percent), compared to 11 percent (95% CI: 8, 16) in the chemotherapy arm (with a complete response rate of 3 percent and a partial response rate of 8 percent) (p=0.002). The median duration of response for patients treated with KEYTRUDA had not yet been reached (range: 1.6+ to 15.6+ months), compared to 4.3 months (range: 1.4+ to 15.4+ months) in the chemotherapy arm. The median follow-up time for this trial was 9.0 months.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in eight percent of patients. 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 percent 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 versus 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 percent of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

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 nearly 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 (pembrolizumab) 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 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 (pembrolizumab) 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 cHL, 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.

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-052, KEYTRUDA was discontinued due to adverse reactions in 11 percent 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 percent 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 percent 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 versus 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 percent 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.

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 nearly 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.