On September 10, 2017 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported updated data from its ongoing Phase 1 clinical trial of BLU-554, a potent and highly selective inhibitor of fibroblast growth factor receptor 4 (FGFR4) for the treatment of patients with advanced hepatocellular carcinoma (HCC) (Press release, Blueprint Medicines, SEP 10, 2017, View Source;p=irol-newsArticle&ID=2299574 [SID1234520491]). As of a data cutoff date of August 18, 2017, BLU-554 demonstrated a 16 percent objective response rate (ORR) in patients with FGFR4-driven HCC. In addition, 49 percent of patients with FGFR4-driven HCC had radiographic tumor reduction. BLU-554 was well-tolerated and most adverse events (AEs) reported by investigators were Grade 1 or 2. The data will be presented today in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain.

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"Patients with hepatocellular carcinoma face a very poor prognosis with few therapeutic options," said Richard Kim, M.D., Associate Professor, Moffit Cancer Center, an investigator for the study. "The new BLU-554 data announced today show that in heavily pre-treated patients, BLU-554 demonstrated encouraging clinical activity, with approximately half of patients with FGFR4-driven HCC having tumor shrinkage. These data compare well to historical data for currently approved agents showing response rates of approximately 10 percent or less, and BLU-554 has the potential to change the treatment paradigm for patients with FGFR4-driven HCC."

"We are encouraged by the updated BLU-554 Phase 1 data presented at ESMO (Free ESMO Whitepaper), which build on our prior clinical experience and suggest that BLU-554 may offer meaningful benefit to patients with FGFR4-driven HCC," said Andy Boral, M.D., Ph.D., Chief Medical Officer of Blueprint Medicines. "These data speak to BLU-554’s potential as the first biomarker-driven targeted therapy for liver cancer. The higher frequency of tumor reduction in patients with FGFR4-driven HCC confirm the importance of aberrantly activated FGFR4 signaling in driving a subset of patients’ disease and demonstrate BLU-554’s ability to modulate the FGFR4 pathway."

Updated Data from the Ongoing Phase 1 Clinical Trial

BLU-554 is currently being evaluated in a Phase 1 clinical trial in patients with advanced HCC. Following the completion of the dose escalation portion of the trial and determination of the maximum tolerated dose (MTD) of 600 mg once daily (QD), Blueprint Medicines initiated the expansion portion of the trial.

As of the data cutoff of August 18, 2017, 77 patients had been treated with BLU-554 in the dose escalation and expansion portions of the Phase 1 clinical trial at five dose levels (ranging from 140 mg QD to 900 mg QD), including 44 patients with FGFR4-driven HCC. FGFR4-driven HCC was defined as at least one percent tumor expression of FGF19, the FGFR4 ligand, as measured by an immunohistochemistry (IHC) assay. In general, the enrolled population was heavily pretreated: 82 percent received prior tyrosine kinase inhibitor (TKI) treatment, 23 percent received prior immunotherapy, and 91 percent received prior systemic therapy.

Pharmacokinetic (PK) analysis demonstrated rapid oral absorption across all dose levels, with a mean half-life of approximately 17 hours and exposure in the expected therapeutic range based on HCC xenograft models. Collectively, these data support a once-daily dosing regimen.

Safety Data

As of the data cutoff of August 18, 2017, the majority of AEs reported by investigators were Grade 1 or 2. Across all grades, the most common AEs reported by investigators related to BLU-554 included diarrhea (71%), nausea (42%), vomiting (36%), transaminase elevation (AST 34% and ALT 32%) and fatigue (29%). Grade 3 or higher AEs related to BLU-554 occurring in five or more patients included anemia, diarrhea and transaminase elevation (AST and ALT). Among all 77 patients treated with BLU-554, 58 patients discontinued treatment with BLU-554, including 42 patients due to disease progression, 11 patients due to treatment-related AEs, three patients who withdrew consent and two patients due to the investigator’s decision.

Clinical Activity Data

As of the data cutoff of August 18, 2017, 67 patients were evaluable for response assessment. An additional 10 patients were treated with BLU-554 as of the data cutoff date but were not evaluable for response assessment. Response was assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

In patients with FGFR4-driven HCC (n=38), the data showed an ORR of 16 percent (95 percent confidence interval 6-31 percent). In addition, 49 percent of patients had radiographic tumor reduction, and clinical activity was observed regardless of disease etiology or geography. As of the data cutoff date:

One patient had an unconfirmed complete response.
Five patients had a partial response, with four confirmed and one unconfirmed.
An additional 20 patients had stable disease, representing a disease control rate of 68 percent.
No responses were observed in patients without FGFR4 pathway activation (n=29).
Among all 77 patients treated with BLU-554, 19 remained on treatment as of the data cutoff date, including 15 patients with FGFR4-driven HCC. Median progression free survival was 3.7 months among patients with FGFR4-driven HCC.

In addition, five TKI-naïve patients with FGFR4-driven HCC were evaluable for response assessment as of the data cutoff date. Within this group, preliminary evidence of prolonged disease control was observed. Two TKI-naïve patients remain on treatment as of the data cutoff with a duration of treatment of 11.4 months and 12.3 months, respectively.

Clinical Development Plans for BLU-554

Blueprint Medicines plans to continue to enroll and follow the cohort of patients with FGFR4-driven HCC in the ongoing Phase 1 clinical trial to further evaluate the safety and clinical activity of BLU-554 in this population. In addition, the Company plans to initiate an additional cohort in this clinical trial in the first quarter of 2018 to evaluate BLU-554 in TKI-naïve patients with FGFR4-driven HCC. Blueprint Medicines also plans to explore opportunities to conduct a clinical trial to evaluate BLU-554 in combination with an immune checkpoint inhibitor.

About the 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. The dose-escalation portion of the Phase 1 clinical trial was completed, and the maximum tolerated dose (MTD) was determined to be 600 mg QD. Blueprint Medicines is currently enrolling the expansion portion of the Phase 1 clinical trial 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, as well as evaluating the PK of BLU-554 and pharmacodynamic markers of BLU-554 activity. The expansion portion of the Phase 1 clinical trial is designed to enroll approximately 60 patients in expansion cohorts with QD dosing, 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 percent. 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 typically providing time to progression of less than six months and overall survival of less than one year. FGF19 is the ligand that activates FGFR4, a receptor that promotes hepatocyte proliferation and regulates bile acid homeostasis in the liver. Blueprint Medicines estimates that approximately 30 percent of patients with HCC have tumors with aberrantly activated FGFR4 signaling.

About BLU-554

BLU-554 is an orally available, potent, irreversible inhibitor of FGFR4 discovered and being developed by Blueprint Medicines. BLU-554 was specifically designed by Blueprint Medicines to inhibit FGFR4 with exquisite selectivity, thereby sparing the paralogs FGFR1, FGFR2 and FGFR3. Blueprint Medicines is developing BLU-554, an investigational medicine, for the treatment of patients with FGFR4-driven HCC. The Company retains worldwide development and commercialization rights for BLU-554. In addition, Blueprint Medicines and Ventana Medical Systems, Inc. are developing an IHC assay as a companion diagnostic test for use with BLU-554 to identify HCC patients with aberrantly active FGFR4 signaling as indicated by FGF19 protein overexpression.

On September 10, 2017 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 1b trial of FP-1039/GSK3052230 (hereafter FP-1039) in mesothelioma patients were reported today in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain (Press release, Five Prime Therapeutics, SEP 10, 2017, View Source [SID1234520447]). The presentation titled "Multicenter, Nonrandomized, Open-Label Phase 1b Study of FP-1039/GSK3052230 with Chemotherapy: Results in Malignant Pleural Mesothelioma (MPM)" by Dr. Jose Trigo et al., is available at View Source

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"We are encouraged by the results of FP-1039 in the front-line treatment of malignant pleural mesothelioma, a rare aggressive cancer with a poor prognosis," said Helen Collins, M.D., Senior Vice President and Chief Medical Officer of Five Prime. "The majority of patients across all dose levels experienced tumor reduction. While this is single-arm data, we believe the findings compare favorably to historical data for chemotherapy alone. In addition to the safety and efficacy results, duration of progression-free survival correlated positively with increasing expression levels of tumoral FGF2."

The mesothelioma arm of the open-label Phase 1b trial evaluated weekly infusions of FP-1039, an FGF ligand trap, in combination with first-line pemetrexed and cisplatin chemotherapy in patients with untreated, unresectable MPM. Following the dose escalation portion of the trial, 15 mg/kg weekly was identified as the maximum tolerated dose (MTD) for FP-1039 and established as the dose for expansion in patients with MPM. The primary study endpoints are safety and overall response rate (ORR), disease control rate (DCR) at 6 months, progression free survival (PFS) and exploratory translational objectives. The poster includes data from MPM patients who had received FP-1039 as of the March 17, 2017 cut-off.

Safety Data

The most common adverse events across all dose levels (AEs; all grades) observed were: nausea (56%), decreased appetite (36%), fatigue (33%) and infusion reaction (36%)

The vast majority of events were Grades 1-2

Three dose-limiting toxicities (DLTs) were observed at the 20 mg/kg dose (Grade 5 bowel perforation/ischemia; Grade 3 elevated creatinine level and Grade 3 infusion reaction)

No DLTs were observed at the 15 mg/kg dose level and so MTD was established at 15 mg/kg

Toxicities associated with small-molecule FGFR inhibitors, such as hyperphosphatemia, retinal detachment and nailbed changes, have not been observed
Efficacy Data

In the 27 patients evaluable as of March 17, 2017, who had received FP-1039 at or below the 15 mg/kg MTD dose level:

Preliminary ORR was 48%, with six-month DCR of 81%, evaluated per mRECIST 1.1

– 13 confirmed Partial Responses (PRs) and 9 durable Stable Disease (SD) (lasting at least six months)

– Evaluable patients are defined as patients who enrolled at least 42 days (2 cycles) prior to the cutoff date

Median PFS at or below the 15 mg/kg MTD dose level was 7.4 months. Historical median time to progression for cisplatin/pemetrexed is 5.7 months.
FGF2 IHC Exploratory Biomarker Data

FGF2 overexpression is associated with worse prognosis in MPM

Statistically significant correlation between PFS and cytoplasmic FGF2 H-score was observed for the 15 mg/kg expansion group
About FP-1039

FP-1039 is a protein drug designed to intervene in FGF signaling. As a ligand trap, FP-1039 binds to FGF ligands circulating in the extracellular space (such as FGF2), preventing these signaling proteins from reaching FGFR1 on the surface of tumor cells. Treatment with FP-1039 treatment has not been shown to cause hyperphosphatemia, a side effect seen with small molecule inhibitors of FGF receptors, which block the activity of both cancer-associated FGFs and FGF-23. GlaxoSmithKline (GSK) was the sponsor of the trial.

On September 10, 2017 Pfizer Inc. (NYSE:PFE) reported positive findings from REFLECTIONS B327-02 (n=707), a pivotal Phase 3 randomized, double-blind comparative safety and efficacy study of the company’s investigational trastuzumab biosimilar (PF-05280014) versus Herceptin1 (trastuzumab), at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid (Press release, Pfizer, SEP 10, 2017, View Source [SID1234520449]). Positive data from a supplemental study, REFLECTIONS B327-04 (n=226), were also presented at the meeting. PF-05280014 is being developed by Pfizer as a potential biosimilar to Herceptin.

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"Biosimilars are poised to revolutionize the oncology treatment landscape by expanding patient access to high quality and effective therapies," said Dr. Mark Pegram, associate director for clinical research at the Stanford Comprehensive Cancer Institute, and director of the Breast Oncology Program at the Stanford Women’s Cancer Center. "These data are encouraging, and reinforce the future potential of Pfizer’s investigational trastuzumab biosimilar to help meet the needs of cancer patients and their treating physicians as a potentially lower cost option to Herceptin, across all indications."

The REFLECTIONS B327-02 study achieved the primary objective for equivalence in the objective response rate (ORR) of PF-05280014 versus Herceptin in patients receiving first-line treatment, in combination with paclitaxel, for HER2-positive metastatic breast cancer [risk ratio of 0.940; within the pre-specified equivalence margin of 0.8–1.25]. ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum period of time.2 Additionally, rates of one year progression-free survival and one year survival were similar across groups (56% and 88.84% vs. 52% and 87.96% for PF-05280017 and Herceptin, respectively).

The REFLECTIONS B327-04 study found there were no clinically meaningful differences between PF-05280014 and Herceptin in terms of efficacy, safety, immunogenicity, and noninferiority in pharmacokinetics, as neoadjuvant treatment taken in combination with docetaxel and carboplatin for patients with operable HER2-positive breast cancer.

"Pfizer is committed to driving significant improvements in patient care through the development of high quality, effective biosimilars. Including PF-05280014, Pfizer’s biosimilars pipeline consists of eight distinct biosimilar molecules in mid to late stage development, with three of these in oncology," said Salomon Azoulay, MD, Senior Vice President, Chief Medical Officer, Pfizer Essential Health. "By continuing to grow our oncology and supportive care presence through both novel therapies and biosimilars, we are able to provide an array of important treatment options for patients, physicians and healthcare systems."

As part of Pfizer’s commitment to expanding its oncology biosimilars pipeline, the company is progressing its biosimilar trastuzumab marketing applications, which have been accepted for review by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

About PF-05280014

PF-05280014 is a monoclonal antibody (mAb) that is in development as a potential biosimilar for all currently approved indications of Herceptin (trastuzumab).

Herceptin is currently approved in the U.S., EU and other markets for HER2-positive breast cancer and gastric cancer.

PF-05280014 is an investigational compound and has not received regulatory approval in any country. Biosimilarity has not yet been established by regulatory authorities and is not yet claimed.

On September 8, 2017 Sanofi and Regeneron Pharmaceuticals, Inc. reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation status to cemiplimab (REGN2810) for the treatment of adults with metastatic cutaneous squamous cell carcinoma (CSCC) and adults with locally advanced and unresectable CSCC, the second deadliest skin cancer after melanoma[i], Anchor[ii] (Press release, Sanofi, SEP 8, 2017, View Source [SID1234520415]). Cemiplimab is an investigational human, monoclonal antibody targeting PD-1.
Sanofi and Regeneron previously reported positive, preliminary results for cemiplimab from two expansion cohorts involving 26 advanced CSCC patients in a Phase 1 study of nearly 400 patients, at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2017. EMPOWER-CSCC 1, a Phase 2, potentially pivotal, single-arm, open label clinical trial of cemiplimab is currently enrolling patients for metastatic CSCC and locally advanced and unresectable CSCC. Cemiplimab is being jointly developed by Sanofi and Regeneron under a global collaboration agreement. Pending data results, the companies anticipate submitting a biologics license application for cemiplimab with the FDA in the first quarter of 2018.
CSCC is the second most common type of skin cancer in the United States. Although CSCC has a good prognosis when caught early, it can prove especially difficult to treat when it progresses to advanced stages. Patients at this stage can be disfigured due to multiple surgeries to remove CSCC tumors on the head, neck and other parts of the body.[iii] CSCC is responsible for the most deaths among non-melanoma skin cancer patients.ii
Breakthrough Therapy designation serves to expedite the development and review of drugs that target serious or life-threatening conditions. Drugs qualifying for this designation must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy. The designation includes all of the Fast Track program features, as well as more intensive FDA guidance and discussion. The Breakthrough Therapy designation is distinct from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.[iv]
Cemiplimab is currently under clinical development, and its safety and efficacy has not been fully evaluated by any regulatory authority.

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SurVaxM is a first-of-its-kind, patented peptide mimic immunotherapeutic vaccine (immunotherapy) that targets survivin, a cell-survival protein present in 95 percent of glioblastomas and many other cancers. It is engineered to recognize survivin-expressing cancer cells as foreign and stimulate patients’ own immune response to control tumor growth and recurrence.

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While vaccines are typically thought of as ways to prevent diseases, vaccines can also be used in a therapeutic mode (e.g., to treat cancer). SurVaxM is delivered through simple subcutaneous injection.
Malignant Glioma (GBM):

SurVaxM demonstrated safety and tolerability in a Phase I study in patients with recurrent or progressive malignant glioma (brain tumors). View press release

SurVaxM has now entered a Phase II clinical trial in adults with newly diagnosed glioblastoma. at leading cancer centers: Roswell Park Cancer Institute, Cleveland Clinic and Dana-Farber Cancer Institute. Please visit the Clinical Trials page for more information.

Although SurVaxM was first tested in brain cancer, survivin is present in most cancers, including multiple myeloma, melanoma, ovarian, renal, lymphoma, prostate and breast cancers. Thus SurVaxM could have broad applicability to these cancers.
Multiple Myeloma:

A Phase I clinical trial evaluating SurVaxM in combination with REVLIMID(lenalidomide) as a maintenance therapy for adults with multiple myeloma has been initiated with support from Celgene (marketer of REVLIMID). Please visit the Clinical Trials page for more information.

MimiVax has an exclusive license to globally commercialize SurVaxM, as well as an extensive worldwide patent portfolio for SurVaxM and other products in development.