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Curis and Aurigene Announce CA-170 Program Update Following Data Presented at ESMO 2017

On September 11, 2017 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective therapeutics for the treatment of cancer, reported preliminary data from the initial 34 patients with cancer treated in the dose escalation stage of the Phase 1 trial of CA-170 conducted in the U.S., South Korea and Spain, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress (Press release, Curis, SEP 11, 2017, View Source [SID1234520460]). As a result of the initial safety data and preliminary evidence of clinical benefit observed in the trial, Curis’s collaborator and discoverer of CA-170, Aurigene Discovery Technologies Limited, a specialized biotechnology company engaged in discovery and early clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases, reported plans to initiate a Phase 2 trial of CA-170 to be conducted at sites in India.

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"We are pleased with these early results. Based on evidence of tumor shrinkage, multiple patients remaining on drug treatment for extended periods, and compelling signals for biomarkers of immune modulation in patient blood and tumor samples, we remain highly confident that the CA-170 program is moving in the right direction. We plan to continue with the dose escalation and continued analysis of patient biopsy samples in the Phase 1 trial," said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. "We expect to provide additional updates at upcoming conferences including the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting in November."

"The ability for cancer patients to administer a potential checkpoint inhibitor on their own as a once daily oral drug is a significant and unique opportunity in our field," added Adil Daud, M.D., investigator in the CA-170 Phase 1 trial and director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center. "These initial clinical results are encouraging and merit continued development."

"These results are consistent with the observations made in the preclinical setting and further affirm CA-170’s mechanism of action as an oral small molecule checkpoint inhibitor," commented Mr. CSN Murthy, Chief Executive Officer of Aurigene. "Based on these initial clinical results, we are excited for the opportunity to expand testing of CA-170, possibly in earlier lines of treatment and in a greater number of immunotherapy treatment-naïve cancer patients." Added Mr. Murthy, "Together with Curis, we have designed a Phase 2 trial in selected populations of patients of interest to be treated at major cancer centers in India. Aurigene’s decision to sponsor and fund this trial is further affirmation of our commitment to CA-170 and a reflection of the successful collaboration we have with Curis in multiple development programs."

CA-170 is an oral small molecule targeting the immune checkpoints PDL1 and VISTA. Data presented at the ESMO (Free ESMO Whitepaper) 2017 conference represent the initial 34 patients treated to date in the dose escalation Phase 1 trial. 30 patients were naïve to prior immunotherapy treatment, while four patients had experienced prior treatment with approved anti-checkpoint antibodies. No dose limiting toxicities were observed at doses ranging from 50 mg to 800 mg once daily dosing examined thus far. CA-170 demonstrated good oral bioavailability and plasma drug levels were shown to increase in a near-linear manner with increasing doses. Evidence of immune modulation, including an increase in activated CD8+ T cells, was observed in patient blood and tumor biopsy samples examined following treatment. Of the 21 patients evaluable for disease assessment, 13 patients experienced disease stabilization. Four immunotherapy treatment-naïve patients treated with CA-170 experienced shrinkage of their tumors. Six patients remained on drug treatment beyond three months, including all four patients with tumor shrinkages. In addition, seven of the 34 patients remain on study and are continuing with treatment.

Tucatinib Data in Multiple Tumor Types Presented at the European Society for Medical Oncology (ESMO) 2017 Congress

On September 11, 2017 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported tucatinib data in multiple tumor types were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress being held September 8-12, 2017 in Madrid, Spain (Press release, Cascadian Therapeutics, SEP 11, 2017, View Source [SID1234520458]). Results from the pooled analysis of Phase 1b combination studies support the potential utility of tucatinib for patients with HER2-positive (HER2+) metastatic breast cancer with brain metastases, including untreated or progressive brain metastases after radiation therapy. HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and brain metastases.

"Approximately 30-to-50 percent of patients with metastatic HER2+ breast cancer will develop brain metastases over time and, historically, patients with HER2+ brain metastases have had poorer outcomes compared to those without," said Stacy L. Moulder, MD, Associate Professor, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. "The results from this pooled analysis of tucatinib combination studies suggesting that patients with HER2+ brain metastases, including those with untreated or progressing disease, have similar progression-free survival compared to those without brain metastases is promising and supports inclusion of patients with brain metastases into ongoing clinical trials. There remains a clinical need for safe and effective HER2-targeted therapies that are active both systemically and in the brain."

Luke Walker, MD, Senior Vice President, Clinical Development of Cascadian Therapeutics, added, "These data from our Phase 1b trials further support the inclusion of patients with brain metastases in our ongoing registrational trial of tucatinib in combination with capecitabine and trastuzumab. This trial, known as HER2CLIMB, is enrolling patients with all types of brain metastases, including untreated, previously treated or progressing brain metastases. Approximately half of patients enrolled in HER2CLIMB to date have had brain metastases at study entry, which will allow us to assess activity in that subpopulation in a statistically meaningful way."

Progression-free survival (PFS) and site of first progression in HER2+ metastatic breast cancer patients with or without brain metastases: A pooled analysis of tucatinib phase I studies (Poster 264)

In this poster (264), data from two Phase 1b combination studies of tucatinib were pooled to analyze baseline characteristics and outcomes of patients with and without brain metastases: tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) in heavily pre-treated patients with advanced HER2+ breast cancer with or without brain metastases (ONT-380-005/Triplet study), and tucatinib in combination with T-DM1 (ONT-380-004). Of the 77 patients in the pooled analysis, 47 percent (n=36) of patients are without brain metastases and 53 percent (n=41) with brain metastases, including patients with untreated or progressive brain metastases after radiation therapy. Four subgroups were identified retrospectively based on historical data and then compared with respect to baseline characteristics, progression-free survival and site of progression. Data from pooled tucatinib studies suggest the PFS of patients with and without brain metastases were similar, regardless of whether brain metastases were untreated or progressed after radiation therapy.

In addition, the following nonclinical poster supports the clinical evaluation of tucatinib for the treatment of other HER2+ tumor types.

Tucatinib, a HER2 selective kinase inhibitor, is active in patient derived xenograft (PDX) models of HER2-amplified colorectal, esophageal and gastric cancer (Poster 1639)

In this poster, data are presented that show tucatinib is active as a single agent in nonclinical models of HER2+ gastrointestinal cancers, including colorectal, esophageal and gastric cancers. The data also demonstrate that tucatinib combined with trastuzumab displayed superior anti-tumor activity compared with either single agent, producing a higher proportion of partial and complete tumor regressions. These nonclinical data support the clinical evaluation of tucatinib for the treatment of HER2+ gastrointestinal cancers. Tucatinib is currently being evaluated in an open label Phase 2 study combining tucatinib with trastuzumab in HER2+/RAS wild type metastatic colorectal cancer (MOUNTAINEER: NCT03043313).

Scott Peterson, Ph.D., Chief Scientific Officer of Cascadian Therapeutics, commented, "We are pleased to share this update regarding the potential versatility of tucatinib in combination for other tumor types beyond breast cancer."

To access these poster presentations, please visit www.cascadianrx.com.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without inhibition of EGFR. Inhibition of EGFR has been associated with clinical toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 (HER2+) are more aggressive and historically have been associated with poor overall survival, compared with HER2-negative cancers.

About HER2CLIMB Pivotal Trial

HER2CLIMB is a randomized (2:1), double-blind, placebo-controlled pivotal clinical trial comparing tucatinib vs. placebo, each in combination with capecitabine and trastuzumab and without loperamide or budesonide prophylaxis, in patients with locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine, also known as T-DM1. The primary endpoint is progression-free survival (PFS) based upon independent radiologic review. Key objectives related to assessing activity in brain metastases include a key secondary endpoint of PFS in a subset of patients with brain metastases. All patients will be followed for overall survival. HER2CLIMB is currently enrolling patients in the United States, Canada, Western Europe and Australia. Additional information is available at www.HER2CLIMB.com.

About HER2+ Metastatic Breast Cancer

Patients with HER2+ breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. The American Cancer Society estimates that 20-25 percent of the approximately 246,660 annual new cases of breast cancer diagnoses in the U.S. are HER2+. Historically, HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and CNS disease (brain metastases). Up to 50 percent of patients with HER2+ metastatic breast cancer experience brain metastases over time.3 Over the past two decades, the approvals of four targeted treatments (trastuzumab, pertuzumab, lapatinib, and T-DM1) have led to improved time to progression and survival rates of patients with HER2+ breast cancer. Despite these advances, there is still a significant need for new therapies that can impact metastatic disease, including brain metastases, and be tolerated for longer periods of time.

Blueprint Medicines Announces New Data from Ongoing Phase 1 Clinical Trial of BLU-554 in Patients with Advanced Hepatocellular Carcinoma

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.

"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.

Five Prime Presents Preclinical Research Data on Novel B7-H4 Therapeutic Antibody at ESMO 2017 Congress

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 an oral poster discussion featuring data related to FPA150, Five Prime’s novel B7-H4 antibody, was presented today 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 [SID1234520464]). The poster titled "FPA150, a Novel B7-H4 Therapeutic Antibody with Checkpoint Blockade and ADCC Activities" by Charles Kaplan et al. is available at View Source

"B7-H4 represents an ideal target for a therapeutic antibody," said Bryan Irving, Ph.D., Senior Vice President of Research at Five Prime. "B7-H4 is expressed in several solid tumor types not typically associated with PD-L1 expression and its expression negatively correlates with patient outcome. Moreover, B7-H4 represents a T cell checkpoint ligand that is not currently targeted by other immuno-oncology agents. As such, we feel that our monoclonal B7-H4 antibody, FPA150, which appears to possess both T cell checkpoint blockade activity and enhanced ADCC, has the potential to be an effective therapeutic by improving anti-tumor immune responses in cancer patients who may not respond well to PD-1 or PD-L1-targeted agents."

B7-H4 shares significant homology with other B7 family members, including PD-L1 and PD-L2. B7-H4 is expressed in several human tumors such as carcinomas of the breast, ovary and endometrium, and its expression tends to correlate with poor prognosis. While the receptor for B7-H4 is unknown, it is believed to be expressed on T cells because B7-H4 is described as a ligand capable of directly inhibiting T cell activity.

FPA150 is a high affinity, afucosylated B7-H4 monoclonal antibody that has demonstrated potent antibody-dependent cell-mediated cytotoxicity (ADCC) and T cell checkpoint blockade activity in vitro and significant dose-dependent anti-tumor efficacy in vivo.

Five Prime is currently developing FPA150 and IND-enabling studies are ongoing.

Roche announces phase III study results of Zelboraf for adjuvant treatment of BRAF V600 mutation-positive melanoma

On September 10, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported data for the phase III BRIM8 study, which was designed to investigate the efficacy and safety of Zelboraf (vemurafenib) in the adjuvant (after surgery) treatment of people with completely resected, BRAF V600 mutation-positive melanoma. The study assessed two cohorts; stage IIC-IIIB (cohort 1) and stage IIIC (cohort 2) melanoma patients (Press release, Hoffmann-La Roche, SEP 10, 2017, View Source [SID1234520462]). The study did not meet its primary endpoint of significantly reducing the risk of recurrence (disease-free survival; DFS) in patients with stage IIIC melanoma (cohort 2); however, a 46% reduction in recurrence risk was observed in stage IIC-IIIB patients (cohort 1). The safety profile was consistent with that seen in previous studies of Zelboraf in advanced melanoma.
People in cohort 2 had a median DFS of 23.1 months with Zelboraf vs. 15.4 months with placebo (HR=0.80; 95% CI 0.54-1.18, p=0.2598).

For people in cohort 1, median DFS was not reached with Zelboraf compared with median DFS of 36.9 months with placebo, (HR=0.54; 95% CI 0.37-0.79). Due to the pre-specified statistical design of the study, the results for cohort 1 cannot be formally tested for significance.

"While results in people with stage IIIC melanoma were not what we had hoped, the reduction in the risk of recurrence in people with stage IIC-IIIB disease is encouraging and suggests Zelboraf may play a role in this earlier setting," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development.
Full data will be presented today at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) annual meeting in Madrid, Spain as part of Presidential Symposium III (Abstract #LBA7) from 4.30pm to 5.45pm CET.
The results will also be featured in ESMO (Free ESMO Whitepaper)’s official press program.

About BRIM8
BRIM8 is a multicentre, randomized, double-blind, two-cohort, placebo-controlled study that investigated the efficacy and safety profile of Zelboraf for the adjuvant treatment of people with completely resected, BRAF V600 mutation-positive melanoma at high risk for recurrence. The primary endpoint was disease-free survival. The study had a Special Protocol Assessment and was designed with two cohorts with a hierarchical analysis where cohort 2 was required to meet the primary endpoint before cohort 1 analysis. People in cohort 1 had completely resected Stage IIC, IIIA or IIIB melanoma; people in cohort 2 had completely resected Stage IIIC melanoma. In the study, 498 people were randomised to receive either oral Zelboraf 960mg or placebo twice daily for 52 weeks.

About melanoma
Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer.1,2 BRAF is mutated in approximately half of melanomas.3 More than 232,000 people worldwide are currently diagnosed with melanoma each year.4 In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.5