1stOncology™: Cancer Intelligence Service – Page 15682 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Data on Verastem’s Focal Adhesion Kinase Inhibitor Defactinib Presented at the 2017 American Association for Cancer Research Annual Meeting

On April 2, 2017 Verastem, Inc. (NASDAQ: VSTM), focused on discovering and developing drugs to treat cancer, reported the oral presentation of data for its lead focal adhesion kinase (FAK) inhibitor, defactinib, by the Company’s scientific collaborator David G. DeNardo, PhD, Assistant Professor of Medicine, Division of Oncology, Department of Immunology, Washington University School of Medicine in St. Louis, at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in Washington, DC (Press release, Verastem, APR 2, 2017, View Source [SID1234518406]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

In an oral presentation titled, "Reprogramming the tumor microenvironment to improve responses to therapy," Dr. DeNardo described data demonstrating that FAK inhibition can enable efficacy of PD-1 inhibition in preclinical models of pancreatic cancer that, like the clinical disease, are otherwise refractory to checkpoint inhibition. As described in Dr. DeNardo’s presentation, a clinical trial is in progress, which combines Verastem’s FAK inhibitor defactinib with Merck’s PD-1 inhibitor pembrolizumab together with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Initial analysis of immune biomarkers from matched pairs of metastatic biopsies, taken either pre or post treatment, from patients with PDAC has been conducted in this study.

"Immunotherapeutic agents have shown little clinical benefit in pancreatic cancer and this is likely due, at least in part, to the presence of an immunosuppressive tumor microenvironment including a dense stroma which may prevent T cell entry into, or function within, tumor tissues," said Dr. DeNardo. "Our initial biomarker data, indicating an increase in activated proliferating cytotoxic T cells together with a reduction in tumor-associated macrophages (TAMs) appear promising. We are extremely interested to see whether these immune changes that may shift the balance from immunosuppressive to immunoreactive tumors, may translate into a clinical benefit for pancreatic cancer patients who have few effective treatment options."

Jonathan Pachter, PhD, Verastem’s Chief Scientific Officer, added, "Pancreatic cancer has the highest mortality rate of all major cancers, and the disease is still considered largely incurable. The data presented today by Dr. DeNardo at AACR (Free AACR Whitepaper) 2017 provide important support and rationale for the ongoing clinical study evaluating Verastem’s lead FAK inhibitor defactinib in combination with pembrolizumab and gemcitabine in patients with pancreatic cancer."
The ongoing Phase 1 clinical trial is being conducted at the Washington University School of Medicine in St. Louis under the direction of Andrea Wang-Gillam, MD, PhD, Clinical Director of the Gastrointestinal Oncology Program with financial support from the Precision Medicine Research Associates and the BJH Foundation. The trial, which is expected to enroll approximately 50 patients, is currently completing its dose-escalation portion.

Details for the oral symposium presentation at AACR (Free AACR Whitepaper) 2017 are:
Title: Reprogramming the Tumor Microenvironment to Facilitate Responses to Immunotherapy
Session: Major Symposium; SY14 – Myelomonocytic Cells and Stroma as Therapeutic Targets
Location: Room 206 – Level 2 Washington Convention Center
Date and time: Sunday, April 2, 2017 from 2:05-2:30pm ET
A copy of the oral presentation slides will be available here following the conclusion of Dr. DeNardo’s presentation and a webcast will be available from AACR (Free AACR Whitepaper) beginning on April 26, 2017.

About the Tumor Microenvironment
The tumor microenvironment encompasses multiple tumor and non-tumor cell populations and an extracellular matrix that support cancer cell survival. This includes immunosuppressive regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, cancer-associated fibroblasts and extracellular matrix proteins that can hamper the entry and therapeutic benefit of cytotoxic T cells and anti-cancer drugs. In addition to targeting the proliferative and survival signaling of cancer cells, Verastem’s product candidates, including duvelisib and defactinib, also target the tumor microenvironment to potentially improve a patient’s response to therapy.

About Defactinib
Defactinib is an investigational inhibitor of FAK, a non-receptor tyrosine kinase encoded by the PTK-2 gene that mediates oncogenic signaling in response to cellular adhesion and growth factors.1 Based on the multi-faceted roles of FAK, defactinib is used to treat cancer through modulation of the tumor microenvironment, enhancement of anti-tumor immunity, and reduction of cancer stem cells.2,3 Defactinib is currently being evaluated in combination with immunotherapy for the treatment of pancreatic cancer, ovarian cancer, non-small cell lung cancer, and mesothelioma, in three combination clinical trials with pembrolizumab or avelumab from Merck & Co. and Pfizer/Merck KGaA, respectively.4,5,6 Information about these and additional clinical trials evaluating the safety and efficacy of defactinib can be found on www.clinicaltrials.gov.

Kite Presents Ongoing Response Rate in Plenary Session from its Pivotal CAR-T Trial of Axicabtagene Ciloleucel in Patients with Aggressive Non-Hodgkin Lymphoma at the 2017 American Association of Cancer Research Annual Meeting

On April 2, 2017 Kite Pharma, Inc., (Nasdaq:KITE) reported two plenary presentations of positive data from the primary analysis of ZUMA-1 for its lead CAR-T candidate, axicabtagene ciloleucel, in patients with refractory aggressive B-cell non-Hodgkin lymphoma (NHL) at the 2017 American Association of Cancer Research Annual Meeting in Washington, D.C (Press release, Kite Pharma, APR 2, 2017, View Source [SID1234518399]). Both presentations were given by Frederick L. Locke, M.D., the ZUMA-1 Co-Lead Investigator, and Director of Research for the Immune Cell Therapy Program at Moffitt Cancer Center in Tampa, Florida.

The study met the primary endpoint of objective response rate (ORR) recorded after a single infusion of axicabtagene ciloleucel, with 82 percent (p < 0.0001). These results demonstrate the treatment effect of axicabtagene ciloleucel in diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL), which are types of aggressive NHL.

ZUMA-1 enrolled 111 patients of whom 101 were successfully treated with axicabtagene ciloleucel. ZUMA-1 patients were heavily pretreated and representative of those in the SCHOLAR-1 pooled analysis of refractory aggressive NHL. The key ZUMA-1 patient characteristics are below:

Stage III/IV disease (85 percent)
Refractory to chemotherapy, no prior autologous stem cell transplant (ASCT) (79 percent)
Relapsed within 12 months of ASCT (21 percent)
Received three or more lines of prior therapy (69 percent)
Refractory to two consecutive lines of prior therapy (54 percent)
The following table shows response data including the month 6 ORR and CR as well as ongoing response rates at the primary analysis data cut-off.

DLBCL (n=77) TFL/PMBCL (n=24) Combined (n=101)
ORR (%) CR (%) ORR (%) CR (%) ORR (%) CR (%)
ORR 82 49 83 71 82 54
Month 6 36 31 54 50 41 36
Ongoing 36 31 67 63 44 39

ORR was generally consistent in key subgroups. ORR in patients who are refractory to second or greater line of therapy was 83 percent and 76 percent in patients who relapsed within 12 month of ASCT.

With a median follow-up of 8.7 months, the median overall survival (OS) has not yet been reached. The overall duration of response (DOR) was 8.2 months and has not yet been reached for patients with a CR. In the SCHOLAR-1 pooled analysis, the median OS was estimated to be 6.6 months with only 8 percent achieving CR with currently available therapies.

As previously reported, the most common grade 3 or higher adverse events included anemia (43 percent), neutropenia (39 percent), decreased neutrophil count (32 percent), febrile neutropenia (31 percent), decreased white blood cell count (29 percent), thrombocytopenia (24 percent), encephalopathy (21 percent) and decreased lymphocyte count (20 percent). As compared to the interim analysis, grade 3 or higher cytokine release syndrome (CRS) decreased from 18 percent to 13 percent and neurologic events decreased from 34 percent to 28 percent. There were three deaths throughout the course of the trial not due to disease progression. Two events, one hemophagocytic lymphohistiocytosis (HLH) and one cardiac arrest in the setting of CRS, were deemed related to axicabtagene ciloleucel. The third case, a pulmonary embolism, was deemed unrelated. There were no cases of cerebral edema.

The accompanying plenary presentation reviewed the product characteristics and biomarker analysis from ZUMA-1. Axicabtagene ciloleucel was successfully manufactured (99 percent) from heavily pretreated patients with a broad range of baseline T cell numbers. Objective responses were observed across a wide range of product CD4:CD8 ratios, and were associated with higher levels of anti-CD19 CAR T cells in the blood. Immune signatures of CRS and neurological events were identified.

"We are excited to present the data from the primary analysis of ZUMA-1 at AACR (Free AACR Whitepaper). Close to half of patients treated remained in response, which represents a remarkable result in this heavily treated population with refractory aggressive NHL who previously faced a dismal outlook," said Jeff Wiezorek, M.D., Senior Vice President of Clinical Development. "We believe the rates of CRS and neurologic events decreased over the course of the study as clinicians gained experience in the management of adverse events. Biomarker analysis advances our understanding of product characteristics and immune signatures associated with clinical outcomes and provides us further opportunity to potentially improve the safety profile."

Kite recently announced completion of its rolling submission of the Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA). Kite plans to submit a marketing authorization application (MAA) for axicabtagene ciloleucel for the treatment of relapsed or refractory DLBCL, PMBCL and TFL with the European Medicines Agency (EMA) in 2017.

Sattva S. Neelapu, M.D., Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center served as a co-lead investigator in the ZUMA-1 trial.

ZUMA-1 is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program.

About axicabtagene ciloleucel

Kite’s lead product candidate, axicabtagene ciloleucel, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. Axicabtagene ciloleucel has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

Puma Biotechnology Presents Interim Results of Phase Ib/II FB-10 Trial of PB272 in Combination with Trastuzumab Emtansine (T-DM1) in HER2-Positive Metastatic Breast Cancer at the 2017 AACR Annual Meeting

On April 2, 2016 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that interim results from the Phase Ib/II FB-10 clinical trial of Puma’s investigational drug PB272 (neratinib) given in combination with the antibody drug conjugate T-DM1 (Kadcyla, ado-trastuzumab emtansine) were presented at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper) that is currently taking place in Washington, D.C (Press release, Puma Biotechnology, APR 2, 2017, View Source [SID1234518392]). The presentation entitled, "NSABP FB-10: Phase Ib dose-escalation study evaluating trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer" was selected for an oral presentation.

The trial enrolled patients with HER2-positive metastatic breast cancer who had previously been treated with chemotherapy and the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta). Study treatment consisted of the standard dose of T-DM1 at 3.6 mg/kg administered intravenously every 3 weeks and neratinib administered orally at escalating doses of 120, 160, 200 and 240 mg per day continuously. Primary diarrhea prophylaxis with high dose loperamide was administered.

For the 16 patients who were evaluable for efficacy, the objective response (CR/PR) rate was 56%. More specifically, the efficacy results from the trial demonstrated that 3 patients had a complete response (CR) lasting 17.1 months, 11.9 months and 12+ months; 6 patients had a partial response (PR); 3 patients had stable disease (SD); and 4 patients had progressive disease (PD). The number and types of response per dose cohort are summarized in the table below.

Neratinib Dose
(mg/day)
No. of Objective Responses (CR/PR)
/ No. of Evaluable (CR/PR/SD/PD)
120 5/5 (CR 2, PR 3)
160 2/4 (CR 1, PR 1, PD 2)
200 1/5 (PR 1, SD 2, PD 2)
240 1/2 (PR 1, SD 1)

The waterfall plot for the trial, % Change in Size of Target Lesions," is shown in Figure 1, which is attached to this news release. In addition, the slides from the presentation are available on the Puma Biotechnology website.

The safety results of the study showed that the most frequently observed grade 3 adverse events were diarrhea, nausea, thrombocytopenia and hypertension. More specifically, for the 21 patients with available safety assessments, grade 3 diarrhea was reported in 4 patients (19%), grade 3 nausea was reported in 3 patients (14%), grade 3 thrombocytopenia was reported in 3 patients (14%), and grade 3 hypertension was reported in 2 patients (10%). There was 1 dose limiting toxicity (DLT) at the 120 mg dose (1 of 6 patients), 3 DLTs at the 200 mg dose (3 of 8) and 2 DLTs at the 240 mg dose (2 of 3). Additional patients are currently being accrued at the 160 mg dose in order to define the recommended Phase II dose.

Dr. Jame Abraham, Director of the Breast Oncology Program at Taussig Cancer Institute, Professor of Medicine at Cleveland Clinic, and principal investigator of the study, said, "We are encouraged by these initial findings and we will continue to enroll patients at the 160 mg dose to further evaluate the impact in this patient population."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the high response rate of the combination of T-DM1 and neratinib in this patient population who were previously treated with both pertuzumab and trastuzumab in this study. We look forward to completing enrollment in the current cohort and moving this combination into Phase II trials."

Five Prime Presents Preclinical Research Data on Novel Tetravalent Anti-GITR Antibody at 2017 AACR Annual Meeting

On April 2, 2017 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that a poster featuring data related to FPA154, Five Prime’s novel tetravalent anti-GITR antibody, was presented today at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, D.C (Press release, Five Prime Therapeutics, APR 2, 2017, View Source [SID1234518391]). The poster titled "Development of FPA154, a Novel Tetravalent Anti-GITR Antibody, for the Treatment of Solid Tumors" is available at View Source

"Our differentiated tetravalent anti-GITR antibody, FPA154, demonstrates activity that appears to be superior to conventional bivalent antibodies," said Luis Borges, Ph.D., Senior Vice President of Research at Five Prime. "These findings suggest our GITR agonist antibody has potent anti-tumor activity for the treatment of cancer, including in combination with PD-1 blockade, which suggests the potential for combination therapy."

Five Prime is developing a novel anti-GITR antibody with enhanced agonist activity for the treatment of solid tumors. Preclinical studies have indicated that GITR-targeting agents inhibit tumor growth via two mechanisms: depletion and possibly suppression of Treg cells and direct agonism of effector T cells. FPA154 recruits antibody-dependent cellular cytotoxicity (ADCC) activity against cells that express high levels of GITR, such as Treg cells within the tumor microenvironment.

A single dose of a mouse-reactive surrogate cmFPA154 molecule demonstrated its ability to induce tumor T cell infiltration and inhibit tumor growth in multiple models. In addition, the surrogate cmFPA154 molecule demonstrated potent anti-tumor activity in combination with PD-1 blockade, even in the absence of Fc effector function, which suggests potential for combination therapy.

Cyclacel’s Second-Generation CDK2/9 Inhibitor, CYC065, Elicits Marked Antineoplastic Effects in Lung Cancer by Engaging Anti-Metastatic Pathways

On April 2, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) ("Cyclacel" or the "Company"), reported the presentation by independent investigators of preclinical data demonstrating therapeutic potential of CYC065, the Company’s second-generation, cyclin-dependent kinase (CDK) 2/9 inhibitor, as a targeted anti-cancer agent (Press release, Cyclacel, APR 2, 2017, View Source [SID1234518375]). The data show that CYC065 substantially inhibited growth, triggered apoptosis, and induced anaphase catastrophe in murine and human lung cancer cells with known high metastatic potential. This was in marked contrast to effects in immortalized pulmonary epithelial murine and human cells. CYC065 markedly inhibited migration and invasion of lung cancer cells and affected distinctive pathways involved in DNA damage response, apoptosis, cell cycle regulation and cell migration. The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017, April 1 – 5, 2017, in Washington, D.C.

"This study adds to the growing evidence of the value of CDK inhibition as an approach to treating cancer," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "CYC065 is in a Phase 1, first-in-human trial to evaluate safety, tolerability and pharmacokinetics in patients with solid tumors. The trial is at an expanded sixth dose escalation level with the objective of determining maximum tolerated dose and recommended dosing for Phase 2. Evidence of target engagement with prolonged Mcl-1 suppression in peripheral blood cells has been observed in patient samples from the study. We believe that CYC065 is one of the first medicines to demonstrate this in a human trial and look forward to pursuing this lead as part of our transcription regulation program."

In the preclinical study, a group of researchers led by Professor Ethan Dmitrovsky, M.D., including Masanori Kawakami M.D., Ph.D., from The University of Texas MD Anderson Cancer Center, Houston, Texas, explored whether CYC065’s antineoplastic effects engaged anti-metastatic pathways. In vitro migration and invasion assays showed that CYC065 markedly inhibited migration and invasion of lung cancer cell lines, including KRAS mutant line. Reverse Phase Protein Arrays (RPPA) interrogated nearly 300 growth-regulatory proteins in murine and human lung cancer.

CYC065 treatment resulted in up-regulation of proteins involved in DNA damage and apoptosis, and down-regulation of ones involved in mTOR- and integrin pathways. Ingenuity pathway analysis (IPA) revealed up-regulation of pathways that engaged ATM signaling, G2/M DNA damage checkpoint regulation, or apoptosis signaling, down-regulation of pathways involved in mTOR signaling, cell cycle regulation, or integrin—mediated cell migration.

Data presented at AACR (Free AACR Whitepaper) show CYC065’s potential to cause anaphase catastrophe and to inhibit migration and invasion of lung cancer cells including the one with mutant KRAS. Anaphase catastrophe is a novel mechanism of action which offers an innovative approach to combat aneuploid cancer cells containing abnormal numbers of chromosomes. The data highlight CYC065’s potential to target key molecular features of cancers.

The study concluded that CYC065 elicits marked antineoplastic effects in lung cancers despite presence of KRAS mutations through anaphase catastrophe and also inhibited migration and invasion of lung cancer cells.

Abstract: 128
Title: The next generation CDK2/9 inhibitor CYC065 elicits marked antineoplastic effects in lung cancer by engaging anti-metastatic pathways
Date/time: Sunday, April 2, 2017 1:00 — 5:00 p.m. ET
Location: Section 5, Poster Board 24
Session Title:
Novel Agents
Authors: Masanori Kawakami1, Jason Roszik2,3, Lin Zheng1, Jonathan Kurie1, Lisa Maria Mustachio1, Xi Liu1, Ethan Dmitrovsky1 1. Department of Thoracic/Head and Neck Medical Oncology, 2. Genomic Medicine, 3.Cancer Biology; The University of Texas MD Anderson Cancer Center, Houston, Texas.
The abstract can be accessed through the AACR (Free AACR Whitepaper) website, www.aacr.org.

About CYC065

Cyclacel’s second generation CDK2/9 inhibitor, CYC065, is being evaluated in an ongoing, first-in-human, Phase 1 trial in patients with advanced solid tumors. In addition to determining safety and recommended dosing for Phase 2, the study aims to investigate CYC065’s effects on the Mcl-1 biomarker, which is implicated in the evolution of resistance in cancer. Evidence of target engagement with prolonged Mcl-1 suppression in peripheral blood cells was observed in patient samples from the study, as well as decreases in kinase substrate phosphorylation and increases in PARP cleavage, consistently with the Company’s preclinical data. CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, and improved metabolic stability than seliciclib, Cyclacel’s first generation CDK inhibitor. Similar to palbociclib, the first CDK inhibitor approved by FDA in 2015, CYC065 may be most useful as a therapy for patients with both liquid and solid tumors in combination with other anticancer agents, including Bcl-2 antagonists, such as venetoclax, or HER2 inhibitors, such as trastuzumab.