On November 28, 2016 OncoPep, Inc. reported the initiation of a Phase 1b clinical trial evaluating PVX-410, a multi -peptide therapeutic cancer vaccine, in patients with moderate or high -risk for progression smoldering multiple my eloma (SMM) , an asymptomatic precursor to multiple myeloma , which is a cancer of the plasma cells (Press release, OncoPep, NOV 28, 2016, View Source [SID1234516818]). The study, led by Noopur Raje, M.D. at Massachusetts General Hospital, will assess the safety and tolerability of PVX-410 in combination with durvalumab with or without lenalidomide. The trial initiation follows the successful completion of a Phase 1/2a dose escalation study of P VX -410 in patients with SMM, the results of which will be presented at the 58 th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), being held from December 3-6, 2016 in San Diego, California.

"We are encouraged by the results of the Phase 1/2a clinical trial, which demonstrated that PVX-410 is well -tolerated and may elicit a memory T cell response in patients with smoldering multiple myeloma," said Dr. Raje, Director of the Cente r for Multiple Myeloma at the Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School . "In the Phase 1b trial, we are looking to further evaluate the safety and tolerability of PVX-410 in combination with the checkpoint inhibitor, durvalumab, and the immunomodulatory drug, lenalidomide, in hopes that the combination will further augment a tar geted immune-mediated attack against SMM cells and ultimately prevent progression to multiple myeloma .

" The open label Phase 1b study is designed to evaluate the safety and tolerability of PVX-410 and durvalumab with and without lenalidomide in patients w ith SMM. Patients will receive either durvalumab alone, PVX -410 + durvalumab, or PVX -410 + durvalumab + lenalidomide over a three -month treatment phase. The study is expected to enroll approximately 26 patients at multiple trial sites, including Massachuse tts General Hospital. More information on the trial can be found at clinicaltrials.gov , identifier number NCT02886065.

Details of the Phase 1/2a data presentation at ASH (Free ASH Whitepaper) are as follows:

Title: "Final Results of a Phase 1/2a, Dose Escalation Study of PVX -410 Multi -Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM) " Session: Myeloma: Therapy, excluding Transplantation: Poster I Date: Saturday, December 3, 2016 Time: 5:30pm – 7:30pm PST Location: Hall GH, San Diego Convention Center
Results of the Phase 1/2a clinical trial demonstrated that PVX-410 was well -tolerated , with a treatment-emergent adverse event (TEAE) profile that was consistent with that expected . PVX-410 was immunogenic as a monotherapy and in combination with lenalidomide , with the immune response to PVX -410 being enhanced by the addition of lenalidomide.

A total of 22 patients with moderate or high -risk SMM received six bi -weekly subcutaneous injections of PXV-410 at eit her a low dose, target dose, or target dose plus lenalidomide. All patients experienced at least one TEAE, the majority of which were Grade 1 in intensity and occurred within 2 days of PVX-410 injection. No deaths or study drug-related serious adverse events were reported.

An immune response to PVX -410 was demonstrated by an increase in the percentage of tetramer – and interferon- gamma -positive cells in the CD3 + CD8 + T cell population and increases from baseline in interleukin -2 -, tumor necrosis factor -alpha -, and CD137 -positive CD8 + T cells . Moreover , an increase in the effector memory T cell population was seen post -vaccination, a response that was enhanced by the addition of lenalidomide. Among the 12 monot herapy patients, five (two low -dose, three target -dose) experienced progression to active disease withi n nine months post -treatment, and seven had stable disease (SD) at follow -up month 12. Among the nine evaluable PVX ‑ 410 + lenalidomide patients, five achieved at least a minimal response, with 1 patient achieving a partial response . One of these five patients then progressed to multiple myeloma by month five post -treatment. Fou r patients had SD at follow -up month 12.

About Smoldering Multiple Myeloma
Smoldering multiple myeloma (SMM) is a plasma cell proliferative disorder with a high risk of progression to multiple myeloma (MM). It is estimated that SMM accounts for approximately 15% of all newly diagnosed cases of MM, and the annual risk of progressi on from SMM to symptomatic MM requiring treatment is estimated to be 10%. The current standard of care for SMM is watchful waiting, and approaches that intend to delay or prevent progression to symptomatic MM are needed.

About PVX -410
PVX -410 is a novel t herapeutic cancer vaccine currently in Phase 1b clinical trials in smoldering multiple myeloma and triple negative breast cancer. PVX -410 consists of four peptides from unique regions of three multiple myeloma -associated antigens and is designed to elicit an immune response to the targeted tumor antigens. PVX -410 was granted orphan drug designation from the U.S. Food and Drug Administration in 2013

On November 28, 2016 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported data from its ongoing Phase 1 trial evaluating BLU-554, an investigational medicine for the treatment of advanced hepatocellular carcinoma (HCC) (Press release, Blueprint Medicines, NOV 28, 2016, View Source [SID1234516817]). Blueprint Medicines is developing BLU-554 as a potent, highly selective inhibitor of fibroblast growth factor receptor 4 (FGFR4). The data are being presented on Tuesday, November 29, 2016, at the 28th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany.

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!

"We desperately need new treatment options for patients with liver cancer, the second leading cause of cancer deaths worldwide," said Richard Kim, M.D., Moffitt Cancer Center, an investigator for the study. "Unlike many other tumor types, there are no biomarker-driven targeted therapies currently approved for HCC, the most common form of liver cancer. These preliminary data are exciting as they suggest BLU-554 may offer the first targeted therapy in a biomarker-defined group of patients with advanced HCC. I am excited to evaluate BLU-554 in the expansion portion of the Phase 1 clinical trial, where we are prospectively selecting patients for FGFR4 pathway activation."

"We are very encouraged to see early anti-tumor activity in patients with confirmed FGF19 overexpression and consistent evidence of FGFR4 pathway modulation during the dose escalation part of this first-in-human clinical trial," said Andy Boral, M.D., Chief Medical Officer of Blueprint Medicines. "Now that we have demonstrated proof-of-concept, determined the maximum tolerated dose (MTD), and implemented FGF19 biomarker screening globally, we can move rapidly to enroll patients in the expansion part of the study to more fully evaluate the activity of BLU-554 in patients with advanced HCC."

Data from the Ongoing Global Phase 1 Clinical Trial

BLU-554 was evaluated in the dose escalation stage of a Phase 1 clinical trial in patients with advanced HCC. As of the data cutoff date of November 7, 2016, 25 patients had been treated in the dose escalation portion of the Phase 1 clinical trial at five dose levels (ranging from 140 mg once daily (QD) to 900 mg QD), with the majority of patients having previously received sorafenib. The study was designed to retroactively assess patient biopsies for FGFR4 pathway activation after enrollment by evaluating levels of FGF19, the protein that activates FGFR4, using an investigational immunohistochemistry (IHC) assay. Prospective screening of patients with the investigational IHC assay was implemented during dose escalation, enabling enrollment of enrichment patients with confirmed FGF19 overexpression which resulted in a larger number than anticipated of biomarker positive patients being enrolled. Blueprint Medicines has initiated the expansion portion of the Phase 1 clinical trial, and enrollment is ongoing.

Pharmacokinetic (PK) data across all dose levels showed rapid oral absorption, a mean half-life of approximately ten hours, and exposure in the expected therapeutic range based on HCC xenograft models.

Pharmacodynamic (PD) data demonstrated FGFR4 pathway inhibition with BLU-554, as evidenced by effects on metabolic pathways downstream of FGFR4, with increases in the bile acid precursor C4, decreases in cholesterol, and feedback upregulation of the ligand FGF19 in blood.

Preliminary Safety Data

As of the data cutoff date of November 7, 2016, the majority of adverse events (AEs) reported by investigators were Grade 1 or 2 and most commonly included diarrhea (72%), nausea (44%), abdominal pain (40%), vomiting (40%), fatigue (36%), transaminase elevation (ALT 32% and AST 28%) and decreased appetite (24%). Treatment with BLU-554 demonstrated acceptable tolerability below 900mg. Investigators reported Grade 3 or higher AEs in 17 patients. Grade 3 or worse AEs occurring in three or more patients included anemia, elevated transaminases (AST and ALT), abdominal pain and decreased lymphocytes. Two patients experienced dose-limiting toxicities at 900 mg (Grade 3 abdominal pain and Grade 3 fatigue), defining 600 mg QD as the MTD. Only two patients discontinued treatment with BLU-554 due to drug-related toxicities, including Grade 4 increased AST and Grade 3 hemorrhage. The case of Grade 3 hemorrhage occurred in a patient treated at 900 mg, above the MTD.

Preliminary Clinical Activity Data

As of the data cutoff date of November 7, 2016, 25 patients in the first five cohorts of the dose escalation portion of the clinical trial (at doses ranging from 140 mg QD to 900 mg QD) were evaluable for clinical activity.

One patient had a confirmed partial response (PR), and remained on the clinical trial for eight 28-day dosing cycles. Twelve patients had stable disease (SD), including seven who had tumor reduction but did not reach the threshold for a PR.
Of ten evaluable patients with FGF19 overexpression in their tumors, five had radiographic tumor reduction, including one patient with a confirmed PR. Seven of the ten patients with FGF19 overexpression remain on treatment as of the data cutoff.
Among all 25 evaluable patients, seven patients remain on treatment as of the data cutoff, with a duration of treatment ranging from 0.8 to 7.6 months.
Eighteen patients discontinued treatment with BLU-554, including 15 patients due to disease progression, two patients due to treatment-related AEs and one patient due to the investigator’s decision.
Clinical Development Plans for BLU-554

Blueprint Medicines has initiated enrollment of the biomarker-selected expansion cohorts at the maximum tolerated dose of 600 mg QD. In the expansion, patients will be prospectively evaluated for tumor expression of FGF19 using an investigational IHC assay. We plan to enroll approximately 45 patients in three subsets. Two subsets of patients will be selected to have tumors that overexpress FGF19 (confirmed by IHC), which indicates autocrine physiology, where FGF19 is produced by the tumor cells in the liver. One of the patient subsets with tumors that overexpress FGF19 will also have FGF19 gene amplification (confirmed by fluorescence in situ hybridization). The third subset of patients will be selected to have tumor FGF19 expression less than 1% by the IHC assay, which indicates normal endocrine physiology, where FGF19 is produced by the intestine.

Conference Call Information

Blueprint Medicines will host a conference call and webcast on Thursday, December 1, 2016 at 12:30 p.m. ET (6:30 p.m. CET) to discuss the preliminary clinical data for BLU-554 in HCC. The data will be presented on Tuesday, November 29, 2016 by Richard Kim, M.D., Moffitt Cancer Center, in a poster presentation, "First-in-Human Study of BLU-554, a Potent, Highly-Selective FGFR4 Inhibitor Designed for Hepatocellular Carcinoma (HCC) with FGFR4 Pathway Activation," (Abstract 105A) at the 28th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany (EORTC-NCI-AACR) (Free EORTC-NCI-AACR Whitepaper). The poster is included in the Molecular Targeted Agents I session from 5:45 a.m. – 12:30 p.m. ET (11:45 a.m. – 6:30 p.m. CET). As part of the conference call and webcast, Blueprint Medicines will also be discussing the preliminary data from the dose escalation portion of its Phase 1 clinical trial for BLU-285 in unresectable PDGFRα-driven and treatment-resistant KIT-driven gastrointestinal stromal tumors, which will be presented in a late-breaking oral presentation at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) on December 1, 2016, and the abstract and data will remain embargoed until December 1, 2016 at 12:01 a.m. CET (November 30, 2016 at 6:01 p.m. ET).

To participate in the conference call, please dial 1-855-728-4793 (domestic) or 1-503-343-6666 (international) and refer to conference ID 10770449. A live webcast of the presentation will also be available under "Events and Presentations" in the Investors section of Blueprint Medicines’ website at View Source A replay of the webcast will be available approximately two hours after the conference call and will be available for 30 days following the call.

About the Global Phase 1 Clinical Trial for BLU-554 in Advanced HCC

Blueprint Medicines’ Phase 1 clinical trial for BLU-554 is designed to evaluate the safety and tolerability of BLU-554 in multiple ascending doses in patients with advanced HCC. Enrollment in the dose-escalation portion of the Phase 1 clinical trial has been completed, and the maximum tolerated dose (MTD) has been determined to be 600 mg QD. Blueprint Medicines has initiated enrollment of the expansion portion of the Phase 1 clinical trial in three defined cohorts at the MTD. The primary objective of the expansion portion of the Phase 1 clinical trial is to continue to evaluate the safety and tolerability of BLU-554. Secondary objectives include assessing clinical activity by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria, as well as evaluating the pharmacokinetics of BLU-554 and pharmacodynamic markers of BLU-554 activity. The expansion portion of the Phase 1 clinical trial is designed to enroll approximately 45 patients in expansion cohorts, at multiple sites in the United States, European Union and Asia. Please refer to www.clinicaltrials.gov for additional details related to this Phase 1 clinical trial. For more information, please contact the study director for this Phase 1 clinical trial at [email protected].

About HCC

Liver cancer is the second leading cause of cancer-related deaths worldwide, with HCC accounting for most liver cancers. In the United States, HCC is the fastest rising cause of cancer-related death. Over the past two decades, the incidence of HCC has tripled while the five-year survival rate has remained below 12%. The highest incidence of HCC occurs in regions with endemic hepatitis B virus, including Southeast Asia and sub-Saharan Africa. Treatment options for patients with advanced HCC are limited, with the currently approved first line therapy providing a time to progression that is less than six months and overall survival that is typically less than one year. FGF19 is the ligand that activates FGFR4, which Blueprint Medicines estimates is aberrantly activated in approximately 30% of patients with HCC. FGF19 and FGFR4 promote hepatocyte proliferation and regulate bile acid homeostasis in the liver.

About BLU-554

BLU‑554 is an orally available, potent, highly selective and irreversible inhibitor of the kinase FGFR4, while sparing the other three FGFR paralogs. Blueprint Medicines is initially developing BLU-554, an investigational medicine, for the treatment of patients with advanced HCC. BLU-554 was discovered by Blueprint Medicines’ research team, and Blueprint Medicines retains worldwide development and commercialization rights for BLU-554.

On November 28, 2016 MabVax Therapeutics Holdings, Inc. (NASDAQ: MBVX), a clinical stage immuno-oncology drug development company, reported that the first patients have been treated with MVT-5873, the company’s therapeutic antibody, in combination with a standard of care chemotherapy in a previously untreated pancreatic cancer patient population (Press release, MabVax, NOV 28, 2016, View Source [SID1234516816]). The company recently reported that it had established sufficient safety and tolerability utilizing MVT-5873 as a monotherapy in relapsed or refractory locally advanced or metastatic pancreatic cancer patents to initiate the expansion into first line treatment.

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 November 14th of this year the company reported that the safety of MVT-5873 has been established during administration as monotherapy at three incremental dose levels in relapsed or refractory locally advanced or metastatic pancreatic cancer patents. As specified in the protocol, once safety and tolerability have been established, the second part of the phase I trial investigating MVT-5873 in combination with a standard of care chemotherapy using nab-paclitaxel plus gemcitabine could be initiated. Patients are now being enrolled in the first of successive incremental dose levels to access safety and tolerability when used in combination with chemotherapy and to ultimately establish a recommended phase II dose (RP2D) when used in combination.

In addition patients continue to be recruited into the monotherapy portion of the trial to establish the RP2D in monotherapy in relapsed or refractory locally advanced or metastatic pancreatic cancer patents. Since the announcement in mid-November, three monotherapy patients have been treated with the next incremental dose.

"From the outset we have been working toward expanding our clinical program into treatment of newly diagnosed patients in combination with a standard of care chemotherapy," stated President and CEO J. David Hansen. He added, "Pancreatic cancer is an extraordinarily difficult disease to treat and our evaluation of MVT-5873 in combination with a front line chemotherapy provides a potential new opportunity for treatment of the disease. We designed our preclinical studies to assess the synergistic effect of adding MVT-5873 to a standard chemotherapy treatment regimen. We reported positive results from those studies and demonstrated a dose dependent positive response. We are looking forward to presenting the results from both the dose expansion portions of the monotherapy and combination with chemotherapy trials mid-year 2017."

On November 28, 2016 Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective drug candidates for the treatment of cancer, reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has granted full approval to Erivedge (vismodegib) for the treatment of adult patients with symptomatic metastatic basal cell carcinoma (BCC) or locally advanced BCC inappropriate for surgery or radiotherapy (Press release, Curis, NOV 28, 2016, View Source [SID1234516815]). Erivedge is also approved in the U.S. for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. Erivedge was developed and is marketed by Roche and Genentech, a member of the Roche Group, under a collaboration agreement between Curis and Genentech.

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!

Erivedge was originally granted ‘conditional approval’ in July, 2013 in the European Union (EU) and the authorization has now been converted from ‘conditional’ to ‘full approval’ based on the results from the STEVIE study that included 1215 patients with advanced BCC. STEVIE (MO25616) is a single-arm, open-label, Phase II, multicenter study that was conducted by Roche to assess the safety of vismodegib in patients with locally advanced and metastatic BCC. The safety and efficacy results of the STEVIE trial were consistent with the results of the pivotal study ERIVANCE BCC (SHH4476g) that supported the initial conditional approval of the drug in the EU.

About Basal Cell Carcinoma and the Hedgehog Pathway

According to the American Cancer Society, BCC accounts for approximately 80 percent of all diagnosed skin cancers. The disease is generally considered curable if the cancer is restricted to a small area of the skin. However, in a small group of people, if the disease is left untreated or recurs in the same location after surgery or radiotherapy, it may become locally advanced and invade further into surrounding areas such as sensory organs (ears, nose and eyes), bone, or other tissues. Depending on the location of the lesion, some cases of advanced BCC can be disfiguring, and treatment with surgery or radiation can lead to the loss of sensory organs and their functions such as eyesight or hearing. In a small proportion of patients, BCC can metastasize, spreading to other parts of the body. Abnormal signaling in the Hedgehog pathway is implicated in more than 90 percent of BCC cases.

About Erivedge

Erivedge is designed to selectively inhibit signaling in the Hedgehog pathway by binding to a protein called Smoothened. The Hedgehog signaling pathway plays an important role in regulating proper growth and development in the early stages of life and normally becomes less active in adults. The Hedgehog signaling pathway is implicated in the development of certain types of cancer, including BCC.

In January 2012, Erivedge became the first licensed medicine for patients with advanced basal cell carcinoma when the U.S. Food and Drug Administration (FDA) approved it under the priority review program that provides for an expedited six-month review of drugs that offer major advances in treatment. Erivedge is approved in the U.S. for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. Erivedge is currently approved and marketed in multiple countries worldwide.

Erivedge is currently in development by Roche and Genentech in other diseases including idiopathic pulmonary fibrosis and myelofibrosis.

About the Curis-Genentech Collaboration

Under the ongoing collaboration agreement between Genentech, a wholly owned member of the Roche Group, and Curis, Erivedge (vismodegib, GDC-0449, RG3616) was discovered by Genentech and was jointly validated by the parties through a series of preclinical studies. Pursuant to this collaboration, Genentech and Roche are responsible for clinical development, and Genentech (U.S.), Roche (Ex-U.S. excluding Japan) and Chugai Pharmaceuticals (Japan) are responsible for commercialization of Erivedge. Curis receives royalties on sales of Erivedge by Genentech/Roche.

On November 28, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) accepted for review the supplemental Biologics License Application (sBLA) for KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of previously treated patients with advanced microsatellite instability-high (MSI-H) cancer (Press release, Merck & Co, NOV 28, 2016, View Source [SID1234516812]). The FDA granted Priority Review with a PDUFA, or target action date, of March 8, 2017; the sBLA will be reviewed under the FDA’s Accelerated Approval program based on tumor response rate and durability of response. The FDA recently granted Breakthrough Therapy Designation to KEYTRUDA for unresectable or metastatic MSI-H non-colorectal cancer, and previously granted it for the treatment of patients with unresectable or metastatic MSI-H colorectal 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!

"The FDA’s acceptance of this application represents an important advance for the field of immuno-oncology and is further evidence of Merck’s commitment to identifying patients most likely to benefit from KEYTRUDA treatment," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "We believe that patients whose tumors harbor DNA repair defects may be especially responsive to KEYTRUDA, and we look forward to working with the FDA to bring this important new therapy to these very challenging treatment situations."

The application, which is seeking approval for KEYTRUDA at a fixed dose of 200 mg every three weeks, is based on data from five uncontrolled, open-label, multi-cohort, multi-site phase I/II trials investigating the activity of KEYTRUDA in MSI-H cancer.

About Microsatellite Instability

Microsatellites are short repetitive sequences of DNA found throughout the genome. Microsatellite instability – or MSI – is caused by a deficiency in the cell’s ability to repair errors in the DNA sequence (mismatch repair) that occur during cell division leading to a characteristic change in microsatellite repeats. MSI-H is already an established biomarker in certain types of cancer. The presence of MSI is generally determined by an analytical test that compares the length of DNA from several microsatellite markers in tumor and normal cells, and produces a hallmark profile that distinguishes MSI-high, MSI-low, or microsatellite-stable tumor samples.

About KEYTRUDA (pembrolizumab)

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 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 use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA 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 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 (pembrolizumab).

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.

Head and Neck Cancer

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

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

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

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

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

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

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

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

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

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 (pembrolizumab) 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.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, 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.

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

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

In KEYNOTE-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 (pembrolizumab)), 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 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 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%).

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.

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.

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 360 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.