On June 5, 2016 Mirati Therapeutics, Inc. (NASDAQ: MRTX) reported an update on three current ongoing clinical programs in patients with non-small cell lung cancer (NSCLC) and other solid tumors (Filing, 8-K, Mirati, JUN 6, 2016, View Source [SID:1234513142]).

"We are making significant progress in the development of our pipeline as our ongoing clinical programs are showing meaningful results," said Charles M. Baum, M.D., Ph.D., president and CEO. "We have confirmed responses including sustained activity in our glesatinib program, and encouraging signs of early efficacy from sitravatinib. These data demonstrate our ability to advance our targeted oncology drug candidates through our differentiated development approach. Today we also announced the start of our mocetinostat combination trial, our first in immuno-oncology. We are excited about the potential to deliver meaningful data points on all three of our clinical programs in 2016 and into 2017."

Glesatinib Program Update

Glesatinib Phase 1b Trial

As of May 20, 2016, 28 patients with MET and AXL alterations were enrolled in the Phase 1b trial across multiple tumor types, including 22 NSCLC patients. A majority of these patients were heavily pretreated with multiple lines of prior therapy including radiation and/or surgery. Eleven of the NSCLC patients had genetic driver alterations comparable to the criteria in our ongoing Phase 2 trial, including two NSCLC patients with MET amplifications, eight NSCLC patients with MET exon14 deletion mutations, and one NSCLC patient with AXL amplification.

The results demonstrate tumor regression in the majority of patients including confirmed responses to glesatinib:

· 3 of 11 NSCLC patients had partial responses (PRs) confirmed per RECIST, including patients with a MET amplification, MET exon14 deletion mutation and AXL amplification
· Patients with confirmed responses were on study for 39 weeks, 23 weeks and 56 weeks, with the 23 and 56 week patients continuing on study
· Tumor regression was seen in 10 of the 11 patients, three of which had confirmed PRs

During the course of the Phase 1b trial, the majority of the NSCLC patients (nine of 11) experienced dose reductions and/or dose interruptions. These events may have resulted in decreased exposure levels needed to fully inhibit MET throughout the treatment cycle.

Of the nine patients whose doses were reduced during the trial, two had a second dose reduction; four patients had dose interruptions and three had multiple dose interruptions while on study. Of the patients no longer on trial, five discontinued due to disease progression, two were related to AEs (one incidence of nausea and vomiting and one diarrhea) and one patient withdrew consent.

The dose reductions and interruptions were due primarily to episodes of diarrhea, potentially associated with the original miglyol (an oil-based excipient similar to castor oil) formulation of glesatinib administered during the trial, which may have contributed to or exacerbated diarrhea.

A new formulation of glesatinib is being implemented in the ongoing Phase 2 trial to reduce dose reductions and interruptions and to optimize exposure levels throughout the treatment regimen. The new spray-dried dispersion (SDD) formulation of glesatinib was evaluated in a dose escalation arm of the Phase 1b study and a recommended Phase 2 dose of 750mg BID was established.

The patient with a MET exon14 deletion and confirmed PR has shown significant tumor regression as well as improved tolerability after moving to the new formulation at a dose of 500mg BID. Following two full cycles of treatment with the new formulation, the patient experienced a deepening PR, from 45% to 66%, and remains on study.

Data from the Phase 1b trial has shown the SDD formulation to have several advantages including: (i) fewer tablets per dose; (ii) better relative bioavailability than the original formulation supporting full target inhibition; (iii) improved tolerability; and (iv) manufacturing advantages.

"We believe that the combination of improved tolerability and bioavailability of the new formulation will allow patients to remain on the intended dose, extend the duration of treatment and possibly increase response rates," continued Baum. "Because development of the new formulation was already in process for integration into the Phase 2 trial for use commercially, the change has already been discussed with the FDA and is moving forward."

Glesatinib Phase 2 Trial

The Phase 2 trial for glesatinib continues in NSCLC patients with MET genetic alterations of interest who were previously treated with platinum-based chemotherapy and those who may also have had prior treatment with a checkpoint inhibitor. Enrollment is ongoing and the new formulation is being introduced this month. Patients who started on the original formulation will be transitioned to the new formulation. An interim update on response rates in patients from the Phase 2 study on the new formulation will be provided once a meaningful number of patients have been treated and are evaluable.

Patient screening continues to increase and 55 clinical sites are active globally, with approximately 130 sites planned in total. In addition to clinical screening at study sites, unique patient finding and outreach collaborations with Foundation Medicine and Guardant Health have identified more than 160 additional patients with MET amplification and exon14 deletion in the first three months. Our experience confirms the prevalence of these patient populations and the value of these collaborations, which expand our clinical reach beyond our dedicated trial sites.

The Company is exploring development of glesatinib for patients with AXL genetic alterations based upon the NSCLC AXL amplification patient who has now had a durable confirmed response to glesatinib for over a year and continues on trial.

Sitravatinib Program Update

Initial data from the Phase 1b trial of sitravatinib show early signs of clinical activity, including a confirmed PR in a Renal Cell Carcinoma (RCC) patient, as well as durable tumor regressions in multiple other tumor types, including NSCLC patients with RET mutations. The Phase 1b trial in sitravatinib continues to enroll patients with RET, CHR4q12, CBL, TRK and DDR genetic alterations in NSCLC and other solid tumors at sites in the U.S. and Korea.

A poster entitled, "A first in human Phase 1 study of receptor tyrosine kinase (RTK) inhibitor MGCD516 in patients with advanced solid tumors" presented at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting includes this initial clinical data, which further demonstrates the safety and tolerability of sitravatinib. The poster can be found at www.mirati.com.

The Phase 1b trial includes multiple cohorts to explore the safety and efficacy of sitravatinib in genetically selected patients with NSCLC, as well as cohorts in certain solid tumors where the profile of sitravatinib may provide clinical benefit. Based upon our experience to date, sitravatinib is generally well tolerated at the recommended Phase 2 dose of 150mg, administered once daily (QD).

An additional update on this trial is expected by the end of the year, when a greater number of patients have been enrolled.

Mocetinostat Program Update

The Company has initiated a trial for the combination study of mocetinostat, an HDAC (histone deacetylase) inhibitor, with the AstraZeneca/MedImmune anti-PD-L1 checkpoint inhibitor, durvalumab, in patients with NSCLC.

This trial is exploring the potential of mocetinostat to enhance the effectiveness of checkpoint inhibitors in NSCLC. The dual effect of Class I HDACs on tumor cells, as well as on immune cells, may enhance the effect of checkpoint inhibitors in all indications where checkpoint inhibitors have demonstrated efficacy.

The Company plans to provide an update on this Phase 2 trial as progress continues, with the potential to see initial signals of activity by early 2017.

About Glesatinib (MGCD265)

Glesatinib (MGCD265) is a tyrosine kinase inhibitor that potently and selectively targets tumors in patients with driver alterations in MET (mutations and gene amplification) and Axl (rearrangements and gene amplification) that occur in approximately 8% of patients with non-small cell lung cancer (NSCLC). Genetic alterations in these targets have been implicated as drivers of tumor growth and disease progression in NSCLC and other solid tumors. Glesatinib is being evaluated in a Phase 2 trial in NSCLC patients with MET genetic alterations to confirm and extend the data that supports the clinical benefit of glesatinib in patients with driver mutations in MET. Mirati retains worldwide rights to glesatinib.

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About Sitravatinib (MGCD516)

Sitravatinib (MGCD516) is being evaluated in a Phase 1b dose expansion cohort in selected patients with specific genetic alterations that are drivers of tumor growth, with an initial focus on NSCLC and in other solid tumors where sitravatinib may confer a benefit. Sitravatinib is a tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4q12, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression. Mirati retains worldwide rights to sitravatinib.

About Mocetinostat (MGCD103)

Mocetinostat (MGCD103) is an orally-bioavailable, spectrum-selective Class I & IV HDAC inhibitor currently being studied in a Phase 2 trial as a combination therapy with durvalumab, targeting the programmed death ligand 1 (PD-L1) pathway, which has been implicated in advanced lung cancers. In preclinical models, mocetinostat with durvalumab demonstrated significant reduction in tumor volume compared to either agent alone.

About Durvalumab

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 expression enables tumors to evade detection from the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks PD-L1 interaction with both PD-1 and CD80 on T cells, countering the tumour’s immune- evading tactics. Durvalumab is being developed alongside other immunotherapies to activate the patient’s immune system to attack the cancer. Durvalumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination with tremelimumab, in NSCLC, bladder, head and neck, gastric, pancreatic, HCC and blood cancers. In 2015, durvalumab received Fast Track Designation for the treatment of patients with PD-L1—positive metastatic SCCHN, and in 2016, durvalumab was granted Breakthrough Designation by the U.S. Food and Drug Administration as a potential treatment for metastatic urothelial bladder cancer.

On June 6, 2016 Kite Pharma, Inc. (Nasdaq:KITE) ("Kite") reported updated durability of complete responses in the Phase 1 portion of the ZUMA-1 trial (Press release, Kite Pharma, JUN 6, 2016, View Source [SID:1234513026]). The study is evaluating KTE-C19 in patients with chemorefractory diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma (NHL). KTE-C19 is an investigational therapy in which a patient’s T-cells are genetically modified to express a chimeric antigen receptor (CAR) that is designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. The results will be presented today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #7559).

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"Three reported complete remissions in patients with chemorefractory DLBCL after a single treatment with CAR T-cell therapy are still ongoing at nine months. This is remarkable given that single-digit complete response rates are historically observed in patients who do not respond to chemotherapy," said Sattva S. Neelapu, Associate Professor and Director of Translational Research, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center. "These results are extremely important as CAR engineered T-cells have the potential to transform the treatment landscape for chemorefractory DLBCL."

The Phase 1 portion of ZUMA-1 treated a total of 7 patients with chemorefractory DLBCL. The results showed that treatment with KTE-C19 achieved rapid and durable responses in patients with chemorefractory disease (objective response rate 71%, complete response rate 57%). Ongoing complete responses were observed in 3 patients after nine months of follow-up. KTE-C19 related adverse events consisted predominantly of cytokine release syndrome (CRS) and neurotoxicity, which were generally reversible. Grade 3 or higher CRS was observed in 14% and neurotoxicity in 57%; all were reversible except in one patient with dose-limiting toxicity.

KTE-C19, currently in Phase 2 clinical studies, has received Breakthrough Therapy Designation and Orphan Drug status from the U.S. Food and Drug Administration for the treatment of patients with chemorefractory DLBCL, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. The European Medicines Agency has also granted KTE-C19 access to regulatory support under its Priority Medicines (PRIME) initiative for the treatment of DLBCL and Orphan Drug Designation for various hematological indications.

About Diffuse Large B-Cell Lymphoma

According to the American Cancer Society, NHL accounts for about four percent of all cancers in the United States, making it one of the most common cancers diagnosed. DLBCL is the most common form of the disease, accounting for one out of every three cases of NHL.1 It is estimated that 26,000 people will be diagnosed with DLBCL in the United States in 2016. DLBCL is an aggressive and fast growing lymphoma, but considered curable in patients who respond to initial treatment with a chemotherapy-based regimen. Patients with chemorefractory DLBCL face limited treatment options and historically poor outcomes.

About Kite’s ZUMA Clinical Programs for KTE-C19

KTE-C19 is an investigational therapy in which a patient’s T-cells are genetically modified to express a CAR that is designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. Kite is currently enrolling four pivotal studies (also known as ZUMA studies) for KTE-C19 in patients with various B-cell malignancies.

Study Phase Indication Status
ZUMA-1
NCT02348216 Phase 2 Pivotal
(N=112)
Chemorefractory DLBCL, PMBCL, TFL
Phase 2 enrolling
ZUMA-2
NCT02601313 Phase 2 Pivotal
(N=70) Relapsed/refractory MCL Phase 2 enrolling
ZUMA-3
NCT02614066 Phase 1/2 Pivotal
(N=75) Relapsed/refractory Adult ALL Phase 1/2 enrolling
ZUMA-4
NCT02625480 Phase 1/2 Pivotal
(N=75) Relapsed/refractory Pediatric ALL Phase 1/2 enrolling

DLBCL = diffuse large B-cell lymphoma
PMBCL = primary mediastinal B-cell lymphoma
TFL = transformed follicular lymphoma
MCL = mantle cell lymphoma
ALL = acute lymphoblastic leukemia

On June 06, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that two analyses demonstrating the utility of the Myriad myRisk Hereditary Cancer test will be featured in oral presentations at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, Myriad Genetics, JUN 6, 2016, View Source [SID:1234513049]). These presentations demonstrate the importance of using a 25-gene panel to evaluate risk for hereditary breast and ovarian cancers.

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"Risk assessment for hereditary cancer is expanding with the use of the myRisk Hereditary Cancer 25-gene panel, approximately doubling the rate of mutation detection over BRCA1/2 testing alone. However, in these studies we sought to understand the magnitude of risk across 25 genes," said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. "We discovered that mutations in eight genes are associated with a two- to six-fold increase in breast cancer risk and mutations in 11 genes confer a two- to 40-fold increased risk for ovarian cancer. These important findings clarify the risk across diverse genes and support the use of myRisk as part of a clinical risk assessment for patients."

Results of the studies to be presented are described below and abstracts are available at: abstracts.asco.org. Follow Myriad on Twitter via @MyriadGenetics to stay informed about news and updates from the Company.

myRisk Hereditary Cancer Podium Presentations
Title: Magnitude of invasive breast cancer (BC) risk associated with mutations detected by multiple-gene germline sequencing in 95,561 women.
Presenter: Michael Hall, Stanford University Cancer Institute
Date: Monday, June 6, 2016, 8:00 — 11:30 a.m.; Discussion 1:15 — 2:30 p.m.
Location: S404, Abstract 1512, Poster Board 335

This study evaluated the magnitude of invasive breast cancer (BC) risk associated with mutations across a 25-gene panel test. A total of 95,561 patients underwent clinical testing with the myRisk Hereditary Cancer test. Seven percent of patients tested positive for a deleterious mutation. The majority of mutations occurred in BRCA1/2 genes (44 percent) or other genes associated with BC risk (40 percent). There was a significant association with personal BC history and mutations in BRCA1/2, PTEN, TP53, PALB2, CHEK2, BARD1 and ATM. Specifically, estimates ranged from two (ATM, CHEK2, BARD1) to six (BRCA1, PTEN) times increased risk for breast cancer. These findings demonstrate the BC risk across the diverse panel of 25 genes in the myRisk test.

Title: Ovarian cancer risk associated with mutations detected by multiple-gene germline sequencing in 95,561 women.
Presenter: Allison Kurian, Stanford University Cancer Institute
Date: Monday, June 6, 2016, 9:45 — 11:15 a.m.
Location: E450ab, Abstract: 5510

This study evaluated the magnitude of ovarian cancer (OC) risk with mutations across the 25 genes included in the myRisk Hereditary Cancer panel. Data from 95,561 patients were analyzed to examine the association between deleterious mutations and personal history of OC. The results showed that seven percent of patients tested positive for a deleterious mutation. Among 5,020 women affected by OC, 14 percent had a deleterious mutation (63 percent with BRCA1/2, 9.4 percent in Lynch Syndrome genes and 11.2 percent in other genes associated with OC). In this study, 11 genes were associated with a significant risk of OC, including the first report of OC risk associated with the ATM gene. Importantly, one-third of mutations in patients with OC were in non-BRCA and non-Lynch genes, demonstrating that panel testing with the myRisk test identified a broader spectrum of associated cancers.

About Myriad myRisk Hereditary Cancer Testing
The Myriad myRisk Hereditary Cancer test uses an extensive number of sophisticated technologies and proprietary algorithms in an 850 step laboratory process to evaluate 25 clinically significant genes associated with eight hereditary cancer sites including: breast, colon, ovarian, endometrial, pancreatic, prostate and gastric cancers and melanoma. For more information visit: View Source

On June 6, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reporteded new data with KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy from two studies (KEYNOTE-012 and KEYNOTE-055) in heavily pre-treated patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) (Press release, Merck & Co, JUN 6, 2016, View Source [SID:1234513071]). Data are being presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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In KEYNOTE-012, for the primary endpoint, findings showed an overall response rate (ORR) of 18 percent (n=34/192) (95% CI, 13-24). At the time of analysis, 65 percent of responders (n=22/34) were continuing to respond – with responses observed in some patients for more than 30 months; median duration of response had not yet been reached. The secondary endpoint results showed a median overall survival (OS) rate of eight months (95% CI, 6-10) (Abstract #6012). The phase 1b KEYNOTE-012 study was the first clinical study investigating the role of a PD-1 inhibitor in recurrent or metastatic HNSCC. Based on the results of KEYNOTE-012, Merck is seeking approval for KEYTRUDA (200 mg fixed dose every three weeks) for previously treated recurrent or metastatic HNSCC. The U.S. Food and Drug Administration (FDA) granted Priority Review with a PDUFA, or action date, of August 9, 2016. The application will be reviewed under the FDA’s Accelerated Approval program.

For the second study, KEYNOTE-055, which enrolled patients regardless of PD-L1 tumor status, an analysis based on the first 50 patients showed an ORR (confirmed, partial responses) in nearly one in five, or 18 percent (n=9/50) (95% CI, 9-31) of patients treated with KEYTRUDA (Abstract #6011). Findings from 92 patients with six months of follow-up or more are also being presented. KEYNOTE-055 is a phase 2 study evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA (pembrolizumab) as a monotherapy (200 mg fixed dose every three weeks) in patients with recurrent or metastatic HNSCC with disease progression on platinum-based and cetuximab therapy.

"Head and neck cancer is an extremely difficult disease to treat – and despite our best efforts, bringing forward meaningful treatment advances has been challenging," said Dr. Ranee Mehra, chief of head and neck oncology, Fox Chase Cancer Center. "To see this level of response with pembrolizumab in patients with head and neck cancer is encouraging and provides further evidence of the potential for pembrolizumab in the treatment of this disease."

The KEYTRUDA clinical development program includes more than 30 tumor types in more than 270 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments. With four registration-enabling studies, Merck currently has the largest immuno-oncology clinical development program in head and neck cancer, encompassing all stages of advanced disease, and is conducting research investigating OS and progression-free survival (PFS) endpoints with KEYTRUDA as a monotherapy, as well as in combination with chemotherapy compared to standard of care.

"In Merck’s immuno-oncology clinical development program, we are rapidly evaluating the potential for KEYTRUDA to play a role in managing a range of difficult-to-treat cancers, and these data being presented at ASCO (Free ASCO Whitepaper) are the result of this effort," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We look forward to bringing KEYTRUDA to more patients with our application for advanced head and neck cancer."

Findings from the KEYNOTE-012 Study (Abstract #6012)

KEYNOTE-012 is an ongoing multicenter, non-randomized, open-label, multi-cohort phase 1b trial evaluating KEYTRUDA as a monotherapy (10 mg/kg every two weeks or 200 mg fixed dose every three weeks) in patients with various advanced cancers, including head and neck. The head and neck cohorts include patients with recurrent or metastatic HNSCC, regardless of tumor human papilloma virus (HPV) status (23% positive; 77% negative). One cohort includes 60 patients who were considered PD-L1 positive; a second cohort includes 132 patients, regardless of PD-L1 tumor status. The primary endpoints include overall safety, tolerability, and ORR (as measured by RECIST v1.1); secondary endpoints include PFS, OS, and duration of response.

Findings presented at ASCO (Free ASCO Whitepaper) were based on long-term follow-up of a pooled analysis of the total population of patients across the two head and neck cohorts (n=192). Data showed an ORR (confirmed) of 18 percent (n=34/192) (95% CI, 13-24) – including eight complete responses and 26 partial responses. Thirty-three patients had stable disease and 93 patients had progressive disease. In total, 60 percent of patients experienced a decrease in their target lesions at the time of analysis. The median time to response was two months (range, 2-17 months). While median duration of response had not yet been reached (range, 2+ to 30+ months), 65 percent of responders (n=22/34) were continuing to respond at the time of analysis (85 percent of responses lasted for six months or more with 71 percent lasting for 12 months or more). An analysis of the survival measurements showed a median PFS of two months (95% CI, 1.9-2.1) – with a six-month PFS rate of 25 percent and 12-month PFS rate of 17 percent. The median OS was eight months (95% CI, 6-10) – with a six-month OS rate of 58 percent and a 12-month OS rate of 38 percent.

The safety profile was consistent with that observed in previously reported KEYTRUDA (pembrolizumab) studies. The treatment-related adverse events observed in this trial (any grade occurring in 5 percent or more of patients) were fatigue (n=42), hypothyroidism (n=19), rash (n=18), pruritus (n=16), decreased appetite (n=16), pyrexia (n=12), and nausea (n=11). Grade 3-4 treatment-related adverse events observed (occurring in 2 or more patients) were ALT increase (n=3), AST increase (n=3), fatigue (n=2), decreased appetite (n=2), hyponatremia (n=2), pneumonitis (n=2), facial swelling (n=2), and hypothyroidism (n=2). Twelve patients discontinued due to a treatment-related adverse event; there were no treatment-related deaths.

These data are being presented today, June 6, in an oral session by Dr. Ranee Mehra of Fox Chase Cancer Center from 12:18 – 12:30 p.m. CDT (Location: S100bc).

Findings from the KEYNOTE-055 Study (Abstract #6011)

KEYNOTE-055 is an ongoing multicenter phase 2 trial evaluating KEYTRUDA as a monotherapy (200 mg fixed dose every three weeks) in patients with advanced HNSCC, regardless of PD-L1 status, who have progressed on platinum-based and cetuximab therapy. The primary endpoints include overall safety, tolerability, and ORR (as measured by RECIST v1.1); secondary endpoints include PFS, OS, and duration of response.

Data presented at ASCO (Free ASCO Whitepaper) were based on an early analysis conducted on the first 50 patients enrolled in the study to receive KEYTRUDA and on an analysis of 92 patients with six months of follow-up or more. The first analysis (n=50) showed an ORR (confirmed, partial responses) of 18 percent (n=9/50) (95% CI, 9-31); nine patients had stable disease and 30 had progressive disease.

The analysis of the results observed in patients with six or more months follow-up (n=92) showed an ORR (confirmed, partial responses) of 17 percent (n=16/92) (95% CI, 10-27); 17 patients had stable disease and 51 had progressive disease. Analysis of results based on tumor HPV status showed an ORR of 22 percent (n=4/18) (95% CI, 6-48) in HPV-positive patients and 16 percent (n=12/74) (95% CI, 9-27) in HPV-negative patients. An analysis based on PD-L1 expression showed an ORR of 17 percent (n=13/76) (95% CI, 9-28) in patients whose tumors expressed PD-L1 and eight percent (n=1/13) (95% CI, 0.2-36) in patients whose tumors did not express PD-L1. Overall, 54 percent experienced a decrease in their target lesions. The median time to response was two months (range, 2-5 months). Median follow-up duration was seven months (range, 0-14 months) with 75 percent of responders remaining in response at the time of analysis. An analysis of the survival measurements showed a median PFS of 2.1 months (95% CI, 2.0-2.3), with a six-month PFS rate of 24 percent, and a median OS of eight months (95% CI, 8-11), with a six-month OS rate of 65 percent.

The safety profile was consistent with that observed in previously reported

KEYTRUDA (pembrolizumab) studies. The treatment-related adverse events observed in this trial (any grade occurring in five percent or more of patients) were fatigue (n=20), hypothyroidism (n=13), diarrhea (n=10), decreased appetite (n=9), nausea (n=9), AST increase (n=9), and rash (n=9). Grade 3-5 treatment-related adverse events observed (occurring in 2 or more patients) were anemia (n=2), AST increase (n=2), Alkaline Phosphatase increase (n=2), and hepatitis (n=2). There was one treatment-related death due to pneumonitis; three additional patients discontinued due to a treatment-related adverse event.

These data are being presented today, June 6, in an oral session by Dr. Joshua Bauml of the University of Pennsylvania from 12:06 – 12:18 p.m. CDT (Location: S100bc).

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 for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA (pembrolizumab) is also indicated 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. This indication is 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 this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients with melanoma, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. 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 and more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). 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.

Immune-mediated colitis occurred in 31 (2%) of 1567 patients with melanoma, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis. Immune-mediated colitis occurred in 4 (0.7%) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) 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.

Immune-mediated hepatitis occurred in patients receiving KEYTRUDA. Hepatitis occurred in 16 (1%) of 1567 patients with melanoma, including Grade 2 (0.1%), 3 (0.7%), 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.

Hypophysitis occurred in 13 (0.8%) of 1567 patients with melanoma, including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis. 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 clinically indicated. Withhold KEYTRUDA (pembrolizumab) for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 51 (3.3%) of 1567 patients with melanoma, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1567 patients with melanoma, including Grade 3 (0.1%) hypothyroidism. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. 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 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. 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.

Immune-mediated nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in 7 (0.4%) of 1567 patients with melanoma including, Grade 2 (0.2%), 3 (0.2%), 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.

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 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 1567 patients with melanoma: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, 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: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab).

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 Trial 6, 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 Trial 2, 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 maculo-papular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA (pembrolizumab).

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients with NSCLC. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported at least 2% 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%), cough (29%), decreased appetite (25%), and dyspnea (23%).

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.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, 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 270 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 prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

On June 6, 2016 Aeterna Zentaris Inc. (NASDAQ: AEZS; TSX: AEZ) (the "Company") reported its commitment to LHRH-receptor targeted therapy and its expectation that the pivotal, phase 3 trial for Zoptrex (zoptarelin doxorubicin) in women with advanced, recurrent endometrial cancer, is expected to be completed in the third quarter of 2016 (Press release, AEterna Zentaris, JUN 6, 2016, View Source [SID:1234513119]). During the 2016 Annual Meeting of the American Society of Clinical Oncologists ("ASCO"), the Company also discussed its plans to develop Zoptrex for additional indications, based upon achieving a positive outcome in the current clinical program.

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Zoptrex (zoptarelin doxorubicin), a novel synthetic peptide carrier linked to doxorubicin as a New Chemical Entity (NCE), is the Company’s lead oncology compound. Zoptrex is currently in a fully-enrolled Phase 3 clinical trial in endometrial cancer. The Company expects to complete the Phase 3 clinical trial in the third quarter of 2016 and, if the results of the trial warrant doing so, to file a new drug application for Zoptrex in the first half of 2017.

Commenting on the significance of Zoptrex to oncologists and their patients, Dr. Richard Sachse, the Company’s Chief Scientific Officer, explained, "Zoptrex is the first targeted oncological therapy using a peptide as the targeting agent and, therefore, it represents potentially a new tool in the treatment of tumors that overexpress the LHRH receptor. The design of the compound allows for the specific binding and selective uptake of the cytotoxic conjugate by LHRH receptor-positive tumors, typically found in gynecological cancers, prostate cancer and some forms of breast cancer. Potential benefits of this targeted approach may include enhanced efficacy and a more favorable safety profile with lower incidence and severity of adverse events, as compared to doxorubicin. If Zoptrex is approved as a therapy for endometrial cancer, we intend to develop it for these additional indications. In addition, based on the results of Phase 2 studies, we believe that Zoptrex holds promise to prove its efficacy for the treatment of ovarian and prostate cancer."

During the ASCO (Free ASCO Whitepaper) Annual Meeting, the Company provided an update regarding its progress with Zoptrex during one-on-one meetings with oncological key opinion leaders. Dr. Sachse described his interactions with ASCO (Free ASCO Whitepaper) attendees as promising, stating as follows: "I’m pleased and gratified by the continuing expressions of support for our work on Zoptrex. The oncologists with whom we met were pleased to learn of our progress toward the completion of our Phase 3 clinical trial and seemed to be as excited as we are about the contribution that our new targeted oncology therapy could make to the treatment of one of the most severe forms of cancer."