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Pfizer Announces U.S. FDA Acceptance and Priority Review of Supplemental New Drug Application for XALKORI® (crizotinib) for the Treatment of Patients with ROS1-Positive Metastatic Non-Small Cell Lung Cancer

On December 8, 2015 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has accepted and granted Priority Review for a supplemental New Drug Application (sNDA) for XALKORI (crizotinib) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive (Press release, Pfizer, DEC 8, 2015, View Source [SID:1234508503]).

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In April 2015, XALKORI received Breakthrough Therapy designation by the FDA for this potential indication. If approved, XALKORI would be the first FDA-approved biomarker-driven therapy for the treatment of ROS1-positive metastatic NSCLC. XALKORI is currently indicated for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The projected FDA action date is April 2016.

Priority Review status accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing and is given to drugs that may offer major advances in treatment or may provide a treatment for which no adequate therapy exists.1

"ROS1 represents the second molecular subgroup of NSCLC in which XALKORI has demonstrated a level of anti-tumor activity that can potentially make a meaningful difference for patients," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "The development of XALKORI in this subgroup of patients is an example of the capability of precision medicine to identify treatments for patients whose tumors contain rare genetic mutations, such as ROS1-positive metastatic NSCLC."

ROS1 rearrangement occurs when the ROS1 gene attaches to another gene and changes the way each gene normally functions, which can contribute to cancer-cell growth. Epidemiology data suggest that ROS1 rearrangements occur in approximately one percent of NSCLC cases. Of the estimated 1.5 million new cases of NSCLC worldwide each year, roughly 15,000 may be driven by oncogenic ROS1 fusions. 2,3

The submission to the FDA is based on data from a multicenter, single-arm Phase 1 study (Study 1001) that evaluated XALKORI in 53 patients with ROS1-positive metastatic NSCLC.3 Data from 50 of these patients were published in the November 20, 2014 issue of The New England Journal of Medicine and showed that XALKORI exhibited marked anti-tumor activity in patients with ROS1-positive metastatic NSCLC. Additionally, the safety profile of XALKORI in ROS1-positive metastatic NSCLC was consistent with that observed in patients with ALK-positive metastatic NSCLC. 4

About XALKORI (crizotinib)

XALKORI is a kinase inhibitor indicated in the U.S. for the treatment of patients with metastatic non-small cell lung cancer whose tumors are anaplastic lymphoma kinase-positive as detected by an FDA-approved test. XALKORI has received approval in more than 85 countries including Australia, Canada, China, Japan, South Korea and the European Union.

XALKORI Important Safety Information

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1669). Transaminase elevations generally occurred within the first 2 months. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.

Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1669), 2.9% of XALKORI-treated patients had any grade ILD, 1.1% had Grade 3/4, and 0.5% had fatal ILD. These cases generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.

QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1560), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5.0% had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECG. Avoid use in patients with congenital long QT syndrome. Consider periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at a reduced dose.

Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 12.3% of patients treated with XALKORI (N=1669). Avoid use in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (N=1669). Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient.

Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 62% of 1669 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities.

Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 90 days (males) respectively, following the final dose of XALKORI.

Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%) decreased appetite (30%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

Lactation: Because of the potential for adverse reactions in breastfed infants, advise females not to breast feed during treatment with XALKORI and for 45 days after the final dose.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.

Celldex Therapeutics Initiates Phase 1/2 Study of Varlilumab in Combination with Atezolizumab in Renal Cell Carcinoma

On December 8, 2015 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported the initiation of an open-label, Phase 1/2 safety and tolerability study examining the investigational combination of varlilumab and Roche’s atezolizumab (MPDL3280A) in patients with unresectable stage III or IV renal cell carcinoma (RCC) (Press release, Celldex Therapeutics, DEC 8, 2015, View Source [SID:1234508499]).

Celldex previously announced the collaboration with Roche to evaluate the novel immunotherapy combination in March 2015. Under the terms of the agreement, Roche will provide atezolizumab, and Celldex will be responsible for conducting and funding the study. Varlilumab is currently being studied in five Phase 1/2 combination studies.

Varlilumab is Celldex’s fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. Atezolizumab is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing PD-L1 from binding to PD-1 and B7.1 on anti-tumor T cells. By inhibiting PD-L1, atezolizumab may enable the activation of anti-tumor T cells. These two antibodies are part of a new class of investigational medicines known as cancer immunotherapies. They are designed to harness the body’s own immune system to fight cancer through separate yet complementary mechanisms of action that may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells.

Data from multiple preclinical tumor models suggest the combination of these two mechanisms are synergistic and enhance anti-tumor immune response compared to either agent alone. Also, in a Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity in patients with refractory RCC were observed, including a durable partial response (duration of response = 13.6+ months) that continued to decrease in tumor volume over time and prolonged stable disease (four patients with a range of 5.3 to 36.2+ months).

"Together, preclinical and clinical data suggest that combining varlilumab and atezolizumab may enhance anti-tumor immune responses compared to monotherapy," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "Varlilumab is an attractive candidate for combination immunotherapy across a variety of cancers due to its target’s restricted expression and strong activity in a variety of tumor models, as well as positive data and a favorable safety profile from our Phase 1 study."

Study Design

Phase 1 study portion

The Phase 1, dose-escalation portion of the study will assess the safety and tolerability of varlilumab at 0.3, 1.0 and 3.0 mg/kg combined with atezolizumab at 1200 mg in order to identify a recommended dose for the Phase 2 portion of the study. The Phase 1 portion will enroll patients with unresectable stage III or IV melanoma, RCC, triple negative breast cancer, bladder cancer, head and neck cancer or non-small cell lung cancer (NSCLC).

Phase 2 study portion

The Phase 2 portion of the study will enroll patients with RCC. The primary objective of this portion of the study is to assess the preliminary anti-tumor efficacy of the varlilumab/atezolizumab combination measured by objective response rate (ORR). Secondary objectives include safety and tolerability, pharmacokinetics, immunogenicity and further assessment of anti-tumor activity across a broad range of endpoints.

In total, the Phase 1/2 study is anticipated to include up to 10 sites in the United States and enroll approximately 60 patients. In each 12-week cycle for both phases of the trial, varlilumab and atezolizumab will be administered once every three weeks (four doses). Patients will be treated with varlilumab until intolerance, disease progression or completion of up to 4 cycles. There is no limit on the duration of treatment with atezolizumab.

About Varlilumab

Varlilumab is a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs.

Sunesis Pharmaceuticals Announces Submission of a Marketing Authorization Application for Vosaroxin for the Treatment of Acute Myeloid Leukemia in Europe

On December 8, 2015 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported that the company has submitted a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for Vosaroxin for the treatment of acute myeloid leukemia in patients aged 60 years and older (Press release, Sunesis, DEC 8, 2015, View Source [SID:1234508495]).

The application is subject to validation by the EMA, a process which typically takes one month, before the formal regulatory review of the application begins.

"Submission of an MAA for vosaroxin in relapsed refractory AML was our top priority in 2015. This milestone brings us closer to delivering a new option to a patient population which has seen little improvement in treatment standards in the last 40 years," said Daniel Swisher, Chief Executive Officer of Sunesis. "We believe the European market opportunity is significant, and look forward to providing updates on our progress with the application throughout 2016."

About QINPREZO (vosaroxin)
QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.

The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.

Nektar Announces First Patient Dosed in Phase 1/2 Clinical Study of NKTR-214, a CD122-Biased Immuno-Stimulatory Cytokine

On December 8, 2015 Nektar Therapeutics (NASDAQ:NKTR) reported that dosing has commenced in the Phase 1/2 clinical study evaluating the efficacy and safety of NKTR-214 in the treatment of solid tumors (Press release, Nektar Therapeutics, DEC 8, 2015, View Source [SID:1234508491]).

NKTR-214 is a novel CD122-biased cytokine designed to preferentially activate the beta and gamma sub-units of the IL-2 receptor in order to proliferate tumor-killing T cells within the body (CD8-positive effector T cells and natural killer T cells) without stimulating regulatory T cells (CD4-positive T cells).

"NKTR-214 is a unique immuno-oncology candidate that is specifically designed to activate and multiply the patient’s own tumor-killing T cells in order to fight cancer more effectively," said Ivan Gergel, M.D., Senior Vice President and Chief Medical Officer of Nektar. "With NKTR-214 in preclinical models, we observed a preferential increase of CD8-positive effector T cells of more than 400-fold compared to regulatory T cells within the tumor itself. We are excited about the start of the clinical study and the potential of NKTR-214 to provide a positive benefit for patients with cancer."

The Phase 1/2 study of NKTR-214 is designed to evaluate patients with advanced solid tumors, including melanoma, renal cell carcinoma and non-small cell lung cancer. The study is being conducted initially at two primary investigator sites: MD Anderson Cancer Center under Drs. Patrick Hwu and Adi Diab; and Yale Cancer Center, under Drs. Mario Sznol and Michael Hurwitz.

NKTR-214 is designed to be administered similarly to the dosing schedules for approved PD-1 and CTLA-4 agents, and will be evaluated on a once every three week dosing schedule in the Phase 1/2 clinical trial. In preclinical studies, NKTR-214 demonstrated a mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T-cells, which promote tumor killing, compared with CD4-positive regulatory T cells, which are a type of cell that can suppress tumor killing.2

About the NKTR-214 Phase 1/2 Study

The dose-escalation stage of the Phase 1/2 study is designed to evaluate safety, efficacy, and define the recommended Phase 2 dose of NKTR-214 in approximately 20 patients with solid tumors. In addition to a determination of the recommended Phase 2 dose, the study will assess preliminary anti-tumor activity, including objective response rate (ORR). The immunologic effect of NKTR-214 on tumor-infiltrating lymphocytes (TILs) and other immune infiltrating cells in both blood and tumor tissue will also be assessed. Following the dose-escalation stage of the study, dose expansion cohorts are planned to evaluate NKTR-214 in specific tumor types, including melanoma, renal cell carcinoma and non-small cell lung cancer.

For more information on the NKTR-214 Study, please visit the "Clinical Trials" section of www.mdanderson.org using identifier 2015-0573.

At MD Anderson Cancer Center, Patrick Hwu, M.D. serves as Head, Division of Cancer Medicine; Chair, Melanoma Medical Oncology and Chair, Sarcoma Medical Oncology and Adi Diab, M.D. serves as Assistant Professor, Department of Melanoma Medical Oncology and Division of Cancer Medicine. Mario Sznol, M.D., is Professor of Medicine (Medical Oncology) at Yale Cancer Center and also Co-Director of the Yale SPORE in Skin Cancer. Michael Hurwitz, M.D. serves as Assistant Professor of Medicine, Medical Oncology at Yale Cancer Center.

Findings Across a Range of Hematological Cancers Add to The Growing Breadth of KEYTRUDA® (pembrolizumab) Data

On December 8, 2015 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that new study findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, across a range of hematological cancers were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Merck & Co, DEC 8, 2015, View Source [SID:1234508490]).

New and updated data were presented that demonstrate a potential role for KEYTRUDA in multiple myeloma, Hodgkin lymphoma, B-cell lymphoma, and Richter’s transformation in chronic lymphocytic leukemia.

"As part of our commitment to helping people with cancer, Merck is leading a broad immuno-oncology clinical program to evaluate the role of KEYTRUDA across several types of blood cancer," said Roger Dansey, M.D., senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Despite the numerous advances in the treatment of blood cancers, there remains a significant unmet medical need. The findings presented at ASH (Free ASH Whitepaper) are encouraging, and reinforce the potential for KEYTRUDA in the treatment of these types of cancer."

KEYTRUDA data presented at ASH (Free ASH Whitepaper) included five presentations, with first-time findings in multiple myeloma and updated findings in classical Hodgkin lymphoma.

(Abstract #505) Oral Presentation: Pembrolizumab in Combination with Lenalidomide and Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM): Keynote-023. J. San Miguel. Monday, Dec. 7, 7:00 AM EST. Location: Hall E1 (Orange County Convention Center).

(Abstract #584) Oral Presentation: PD-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment. P. Armand. Monday, Dec. 7, 10:45 AM EST. Location: Hall E2 (Orange County Convention Center).

(Abstract #506) Oral Presentation: A Phase II Study of Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM). A. Badros. Monday, Dec. 7, 7:15 AM EST. Location: Hall E1 (Orange County Convention Center).

(Abstract #834) Oral Presentation: PD-1 Blockade with Pembrolizumab (MK-3475) in Relapsed/Refractory CLL including Richter Transformation: an early efficacy report from a phase 2 trial (MC1485). W. Ding. Monday, Dec. 7, 5:45 PM EST. Location: Valencia BC (Orange County Convention Center).

(Abstract #3986) Poster Presentation: Phase 1b Study of PD-1 Blockade with Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL). P. Zinzani. Monday, Dec. 7, 6:00 PM – 8:00 PM EST. Location: Hall A (Orange County Convention Center).

The KEYTRUDA program currently addresses more than 30 tumor types in more than 160 clinical trials, including more than 80 trials that combine KEYTRUDA with other cancer treatments. Within this program, there is a strong focus on hematological malignancies, with approximately 20 trials evaluating KEYTRUDA in blood cancers. This includes four registration-enabling studies in Hodgkin lymphoma and multiple myeloma, as well as more than 15 combinations of KEYTRUDA with other treatments for specific hematologic malignancies.

Registration-enabling trials of KEYTRUDA are also currently enrolling patients suffering from melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, and breast cancer, with further trials in planning for other malignancies.

About Blood Cancers

In most blood cancers, also called hematological malignancies, the normal blood cell development process is interrupted by uncontrolled growth of an abnormal type of cancerous blood cell. These cancerous cells prevent blood from performing many of its functions, like fighting off infections or preventing serious bleeding. There are three main types of blood cancer: leukemia, lymphoma and myeloma. In 2012, an estimated 916,000 people worldwide were diagnosed and 570,000 people died from one of the three main types of blood cancer.

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA 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 is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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 is also indicated at the same dosing for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. These indications are approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA. 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.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients with melanoma, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA. 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.

Hepatitis occurred in patients receiving KEYTRUDA. Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. 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.

Hypophysitis occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Hypophysitis occurred in 1 (0.2 %) of 550 patients with NSCLC, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients with melanoma, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients with melanoma, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%). Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) 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 Grade 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in 3 (0.7%) patients with melanoma, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. 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.

Other clinically important immune-mediated adverse reactions can occur. 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 of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients with melanoma treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

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.

Among the 411 patients with metastatic melanoma, KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

Among the 550 patients with metastatic NSCLC, KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), decreased appetite (25%), dyspnea (23%), and cough (29%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

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.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.