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 Foundation Medicine, Inc. (NASDAQ:FMI) reported new data in two presentations at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2016 that underscore the critical importance of integrating comprehensive genomic profiling into clinical care programs for the treatment of advanced breast cancer (Press release, Foundation Medicine, JUN 6, 2016, View Source [SID:1234513069]). Data presented from two separate studies showed:

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Molecular information elucidated from FoundationOne led physicians to change their recommended course of therapy for 41 percent of patient cases;
77 percent of patients profiled with FoundationOne harbored an alteration matched to an FDA-approved therapy;
98 percent of patients with advanced breast cancer had genomic alterations that matched therapeutics being studied in clinical trials; and
20 percent of advanced breast cancers possess high tumor mutational burden, suggesting a potential role for FoundationOne as a predictive biomarker for immune checkpoint inhibition.
"It’s no longer sufficient to classify or treat breast cancer as a single disease, and we must continue to acknowledge and understand its vast, complex genomic variability in order to provide individuals with every opportunity for improved outcomes," said Vincent Miller, M.D., chief medical officer, Foundation Medicine. "In a striking example of the importance of genomic information in breast cancer treatment, data presented at ASCO (Free ASCO Whitepaper) show that comprehensive genomic profiling led to physician-recommended therapy changes, matches with FDA-approved therapeutic agents that otherwise may have been overlooked or missed, and links to clinical trials for investigational targeted agents. This data is significant for the approximately 40,000 individuals in the United States who present with metastatic breast cancer annually, and it underscores opportunity with precision medicine to improve outcomes by matching patients with the right therapies."

Key Data Highlights:

The poster "Decision impact analysis of comprehensive genomic profiling (CGP) in advanced breast cancer: A prospective study," presented by Raquel E. Reinbolt, M.D., assistant professor, internal medicine, college of medicine, The Ohio State University, presented data that demonstrated that comprehensive genomic profiling in advanced breast cancer provides therapy or clinical trial recommendations for more than 70 percent of patients screened. A prospective, single center, single arm study enrolled advanced breast cancer patients who were within 10 weeks of starting therapy and who had an estimated survival of ≥ 3 months. Key findings include:

Comprehensive genomic profiling noted the existence of an FDA approved drug for 77 of 83 patients, with everolimus (n=72), temsirolimus (n=70), ponatinib (n=23) and pazopanib (n=20) being the most frequently selected by physicians
At least one clinical trial was identified for 98 percent of patients
A change in therapy was recommended by the treating physician for 34 of 83 patients (41 percent), and of these, 17 patients (50 percent) pursued the suggested treatment
A second poster "Biomarkers of Immune Checkpoint Inhibitor Response in Metastatic Breast Cancer: PD-L1 Protein Expression, PD-L1 Gene Amplification and Total Mutational Burden," presented by Jeffrey S. Ross, M.D., medical director, Foundation Medicine and Chair of the Department of Pathology, Albany Medical College, studied potential predictive biomarkers for immune checkpoint inhibitors in more than 6,000 breast cancer tumor samples at Foundation Medicine, and 84 breast cancer cases at Albany Medical Center. In the study, comprehensive genomic profiling using FoundationOne was performed on a cohort of 6,751 metastatic breast cancer tumor samples which were also evaluated for tumor mutational burden. PD-L1 expression detected by immunohistochemistry was used to predict patient survival in the 84 case Albany Medical Center cohort.

Key findings include:

PD-L1 protein expression in infiltrating immunocytes was found to be a significant favorable prognostic factor, which significantly correlated with increased overall survival whereas lack of PD-L1 staining in both tumor cells and immunocytes was a significant adverse prognostic factor associated with decreased patient survival
PD-L1 gene amplification was identified in only 57 of 6,751 (0.1 percent) metastatic breast cancer tumor samples, correlating with the potential for response to immune checkpoint inhibitors
High tumor mutational burden was found in 1,351 of 6,643 (20 percent) metastatic breast cancer cases underscoring the potential for further studies measuring tumor mutational burden with FoundationOne to identify breast cancer patients as candidates for immunotherapy
Breast cancer is the most common type of cancer among women in the United States, excluding non-melanoma cancers of the skin. The American Cancer Society estimates that approximately 246,660 women will be diagnosed with breast cancer in 20161. Although the majority of these patients will be cured of their disease in the primary treatment setting, the more than 40,000 cases of relapsed and metastatic breast cancer make this disease the second leading cause of death from cancer in American women2. The matching of patients with advanced breast cancer to personalized therapies holds significant promise to improving clinical outcomes for these patients.

On June 6, 2016 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that updated data from the ongoing Phase 1 trial of FPA144 was featured today in an oral presentation during the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Five Prime Therapeutics, JUN 6, 2016, View Source [SID:1234513068]). Dr. Jeeyun Lee from the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, gave the presentation, titled Antitumor Activity and Safety of FPA144, an ADCC-enhanced, FGFR2b Isoform-Selective Monoclonal Antibody, in Patients with FGFR2b+ Gastric Cancer and Advanced Solid Tumors (Abstract 2502). The presentation is available on the Five Prime website: View Source

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Part 1 of the trial evaluated escalating doses of FPA144 as a single agent in 27 patients, 19 with advanced solid tumors in Part 1a and 8 with advanced gastric cancer in Part 1b, including 6 with FGFR2b-overexpressing tumors. Enrollment is underway in Part 2 of the trial, evaluating the safety, pharmacokinetics (PK) and efficacy (objective response rate and duration of response) of biweekly 15 mg/kg infusions of FPA144 across multiple cohorts: gastric cancer patients whose tumors have high, moderate and low levels of FGFR2b protein overexpression and gastric cancer patients whose tumors do not have FGFR2b protein overexpression. Five Prime plans to expand the scope of this trial further by the end of 2016 to include a cohort of patients with a tumor type (other than gastric) that overexpresses FGFR2b.

Safety findings presented in this update are consistent with initial data presented during the ASCO (Free ASCO Whitepaper) Gastrointestinal Symposium in January 2016. Data across 40 patients in the full safety population of this trial (all gastric and solid tumor patients receiving any portion of at least one dose of FPA144) suggest that FPA144 has an acceptable safety profile in doses up to 15 mg/kg:

No dose-limiting toxicities (DLTs); maximum-tolerated dose (MTD) was not reached
No treatment-related serious adverse events (SAEs); 17 reported SAEs across 9 patients
No treatment-related adverse events (AEs) resulting in treatment discontinuation
No treatment-related hyperphosphatemia or retinal toxicity (differentiated from small molecule kinase inhibitors targeting FGF receptor tyrosine kinases)
The most common treatment-related AEs ( > 5%) were all grades 1 or 2: fatigue (22.5%), nausea (20%) and vomiting (12.5%)
One transient treatment-related Grade 3 AE of decreased neutrophil count
Comparable safety between gastric cancer patients and full safety population

FPA144 monotherapy demonstrated early evidence of anti-tumor efficacy in the 9 gastric cancer patients with FGFR2b protein overexpression (6 from Part 1b of the trial; 3 from Part 2) that were available for analysis as of the April 1, 2016 data cutoff. These patients were heavily pre-treated, having received between 1 and 6 prior therapies with a median of 2 prior therapies. The activity observed includes:

3 confirmed partial responses (PRs) out of 9 gastric cancer patients treated (33%) (one of these three PRs confirmed after the April 1, 2016 data cutoff)
7 of 9 gastric cancer patients with disease control (3 PRs + 4 stable disease), disease control rate (DCR) = 77%
12-week progression-free survival (PFS) in 6 of 9 gastric cancer patients (67%)
Median duration of treatment of 112 days (range 42-182 days), with 2 of 9 gastric cancer patients still on study
1 complete response (CR) in a patient with metastatic bladder cancer
In addition to the 3 PRs noted above, there was an additional unconfirmed PR in the 10th gastric cancer patient with FGFR2b protein overexpression (the 4th patient in the 15 mg/kg cohort). This 10th patient’s scan became available after the data cutoff of April 1, 2016, and the patient remains on treatment.

"The data suggest that FPA144 is an active drug that warrants further clinical development. The initial single-agent efficacy and safety data seen during the dose escalation portion of the study is encouraging," said Dr. Charles Fuchs, Director of the Center for Gastrointestinal Cancer, Dana Farber Cancer Institute. "Patients with advanced gastric cancer have a significant unmet medical need, and the literature suggests that those with tumors that overexpress FGFR2b have an even worse prognosis. New treatments options are needed for these patients."

"We are pleased with the data from this ongoing trial," said Lewis T. "Rusty" Williams, M.D., Ph.D., president and chief executive officer of Five Prime. "The data we have observed in this trial suggest that FPA144 has an acceptable safety profile and can be dosed biweekly. FPA144 monotherapy also showed evidence of clinical activity in the first nine FGFR2b+ gastric cancer patients that were available for analysis, with a disease control rate of 77% and a 12-week progression free survival of 67%. We were also pleased to see an unexpected complete response in a patient with bladder cancer in part 1a of the trial. We look forward to continuing the study and to further exploring FPA144 in gastric cancer with varying levels of FGFR2b protein overexpression as well as additional FGFR2b+ tumors."

About the FPA144 Phase 1 Trial
Parts 1a and 1b of the Phase 1 study evaluated the safety and pharmacokinetics (PK) of escalating doses of FPA144 in 27 patients with solid tumors, including gastric cancer patients. Enrollment is underway in Part 2 of the trial, evaluating the safety, PK and efficacy (response rate and duration of response) of biweekly 15 mg/kg infusions of FPA144 across multiple cohorts: gastric cancer patients with high, moderate and low levels of FGFR2b protein overexpression, FGFR2b- gastric cancer patients, and FGFR2b+ patients with other tumor types. Up to 30 patients may be enrolled in each tumor setting. Tumors will be biopsied pre- and post-treatment in order to determine levels of FGFR2b protein overexpression and FGFR2 gene amplification, and to detect PD-L1 and immune infiltrate changes within the tumor. Testing for FGFR2b protein overexpression is being conducted centrally, using a proprietary immunohistochemistry assay.

About FPA144
FPA144 is an anti-FGF receptor 2b (FGFR2b) humanized monoclonal antibody in clinical development as a targeted immune therapy for tumors that over-express FGFR2b, as determined by a proprietary immunohistochemistry (IHC) diagnostic assay. FGFR2 gene amplification (as identified by FISH) is found in a number of tumors, including in approximately 5% of gastric cancer patients, and is associated with poor prognosis.

FPA144 is designed to block tumor growth through two distinct mechanisms. First, it has been engineered to drive immune-based killing of tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and the recruitment of natural killer (NK) cells and T cells. Second, it binds specifically to FGFR2b and prevents the binding of certain fibroblast growth factors that promote tumor growth. When combined with PD-1 blockade, FPA144 has shown an additive effect in tumor growth inhibition in preclinical models. Five Prime retains global development and commercialization rights to FPA144.

On June 6, 2016 Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize liposomal delivery and antisense technology to develop a portfolio of targeted nucleic acid cancer and autoimmune drugs, reported that data from the Phase I study of BP1001 (Liposomal Grb2 Antisense) as a treatment for acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) and the safety segment of the Phase II combination therapy of BP1001 and low-dose cytarabine (LDAC) as a treatment for advanced AML were presented by Dr. Maro Ohanian, Assistant Professor at the University of Texas MD Anderson Cancer Center, during a poster presentation at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in a poster titled, "Phase I Study of BP1001 (Liposomal Grb2 Antisense) in Patients with Hematologic Malignancies (Filing, 8-K, Bio-Path Holdings, JUN 6, 2016, View Source [SID:1234513067])."

"While a small dataset, we are still very excited by these robust data showing that five of six evaluable patients demonstrated activity, especially for these refractory and resistant patients. We are also encouraged by the lack of toxicity as our Phase II efficacy segment will be in de novo fragile patients, for whom the drug side effect profile is particularly important," stated Peter H. Neilson, Chief Executive Officer of Bio-Path Holdings. "In addition, we were very pleased with BP1001’s pharmacokinetics, particularly its 30-hour half-life. The final analysis of these data, along with the demonstrated reductions in bone marrow blasts, suggests that 60 mg/m2 is the appropriate dose going forward."

The Phase I study of BP1001 comprised Cohorts 1 through 6 of the dose-finding monotherapy at doses up to 90 mg/m2 in refractory/relapsed leukemia patients. The safety segment of the Phase II study evaluated the toxicity of BP1001 in Cohorts 7 and 8 in doses of 60 mg/m2 and 90 mg/m2, combined with LDAC chemotherapy in refractory/relapsed patients with advanced AML.

Data from the safety segment of the Phase II combination therapy of BP1001 and LDAC showed no dose limiting toxicities. Of the six evaluable patients, four patients completed more than two cycles of treatment, three patients achieved complete remission and two patients achieved partial remission. BP1001 levels decreased bi-exponentially in plasma and the pharmacokinetics of BP1001 demonstrated a half-life at 60 mg/m2 of 30 hours.

As previously reported, data from the Phase I study demonstrated that BP1001 was well tolerated in refractory/relapsed leukemia patients at doses up to 90 mg/m2 with no drug related adverse events. It also decreased target Grb2 expression by an average of 50% in the 21 evaluable patients on BP1001 monotherapy. Of these patients in the Phase I study, seven patients completed more than two cycles of treatment, 10 patients had more than a 50% reduction in peripheral or bone marrow blasts and six patients had transient decline in blasts (n=3) and/or stable disease (n=3), with two patients experiencing transient improvement in leukemia cutis lesions.

About BP1001

BP1001 is a neutral-charge, liposome-incorporated antisense drug substance designed to inhibit Grb2 protein expression. The protein Grb2 is essential to cancer cell signaling because it is utilized by oncogenic tyrosine kinases to induce cancer progression. Suppressing the function or expression of Grb2 should interrupt its vital signaling function and have a therapeutic application in cancer.

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On June 6, 2016 Array BioPharma (Nasdaq: ARRY) reported full results at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Abstract No. 9500) from the pivotal Phase 3 NEMO (NRAS MELANOMA AND MEK INHBITOR) trial of binimetinib (Press release, Array BioPharma, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175437 [SID:1234513066]). The study found binimetinib significantly extended median progression-free survival (PFS), the study’s primary endpoint, at 2.8 months, as compared with 1.5 months observed with dacarbazine [hazard ratio (HR)=0.62 (95% CI 0.47-0.80), p<0.001] – the first trial to ever meet a PFS endpoint in patients with advanced NRAS-mutant melanoma. In the pre-specified subset of patients who received prior treatment with immunotherapy, including ipilimumab, nivolumab or pembrolizumab, patients who received binimetinib experienced 5.5 months of median PFS (95% CI, 2.8–7.6), compared with 1.6 months for those receiving treatment with dacarbazine (95% CI, 1.5–2.8).

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Array BioPharma. (PRNewsFoto/Array BioPharma Inc.)
"The NEMO findings are promising and suggest binimetinib may provide a new treatment option for the thousands of patients who are diagnosed with NRAS-mutant melanoma," said lead study investigator Reinhard Dummer, M.D., Professor, Dept. of Dermatology, University of Zurich Hospital. "Particularly compelling are the results in the pre-specified sub-group of patients who had received prior treatment with immunotherapy, which is now recognized as the standard of care for first-line treatment in this patient population."

In addition to improving PFS, binimetinib also demonstrated significant improvement in overall response rate (ORR) and disease control rate (DCR). While there was no statistically significant difference demonstrated in overall survival, the median overall survival (mOS) favored the binimetinib arm.

Confirmed ORR was 15 percent (95% CI, 11-20 percent) in patients receiving binimetinib vs. 7 percent (95% CI, 3-13 percent) in patients receiving dacarbazine.
DCR for patients receiving binimetinib was 58 percent (95% CI, 52-64 percent) vs. 25 percent (95% CI, 18-33 percent) for patients receiving dacarbazine.
mOS was estimated at 11.0 months in patients receiving binimetinib vs. 10.1 months for patients treated with dacarbazine [(HR) = 1.0 (95% CI 0.75-1.33), p=0.499].
"NRAS-mutant melanoma impacts one out of five advanced melanoma patients, yet there are currently no treatment options indicated specifically for these patients," said study investigator Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital and Professor of Medicine, Harvard Medical School. "There remains a need for additional effective treatments for patients with NRAS–mutant disease. Binimetinib may provide another important treatment option for this patient population."

Binimetinib was generally well-tolerated and the adverse events (AEs) reported were consistent with previous results in NRAS-mutant melanoma patients. Grade 3/4 AEs reported in greater than or equal to 5 percent of patients receiving binimetinib included increased creatine phosphokinase (CPK) and hypertension.

"The NEMO trial results demonstrate the potential of binimetinib to help slow disease progression in this patient population, an often overlooked subset without treatment options beyond immunotherapy," explained Victor Sandor, M.D., Chief Medical Officer, Array BioPharma. "Based on the strength of these data, we plan to submit our regulatory filing for binimetinib in NRAS-mutant melanoma later this month."

About NEMO
The NEMO trial, (NCT01763164), is an international, randomized Phase 3 study in patients with advanced NRAS-mutant melanoma. 402 patients were randomized 2:1 to receive continuous 45 mg BID binimetinib or 1,000 mg/m2 dacarbazine dosed every three weeks. Prior immunotherapy treatment was allowed. The primary endpoint of the study is progression-free survival, and overall survival is a key secondary endpoint. Patients underwent radiographic assessment of disease status every six weeks, and assessment of progression was determined by blinded central review. Over 100 sites across North America, Europe, South America, Asia and Australia participated in the study.

About NRAS-Mutant Melanoma
Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with more than 76,000 new cases and nearly 10,000 deaths from the disease projected in 2016. Activating NRAS mutations are present in up to 20 percent of patients with metastatic melanoma, and is a poor prognostic indicator for these patients. Treatment options for this population remain limited beyond immunotherapy, and patients face poor clinical outcomes and high mortality.

About Binimetinib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, non-small cell lung, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor, which targets key enzymes in this pathway.

Binimetinib is currently being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the recently initiated BEACON trial that will study encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant colorectal cancer. Array projects COLUMBUS top-line results availability during the third quarter of 2016.