On April 20, 2016 Exelixis, Inc. (NASDAQ: EXEL) reported that new data for cabozantinib, cobimetinib and XL888 will be presented at the upcoming 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, June 3 – 7, 2016 (Press release, Exelixis, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158762 [SID:1234511169]).

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!

An oral presentation will include pivotal overall survival data from the METEOR study, the randomized phase 3 trial of cabozantinib versus everolimus in patients with previously treated advanced renal cell carcinoma (RCC). These data were submitted to the U.S. Food and Drug Administration (FDA) in the New Drug Application (NDA) for cabozantinib for patients with advanced RCC who have received one prior therapy. On January 28, 2016 Exelixis announced that the FDA accepted the NDA for cabozantinib. The FDA granted Priority Review to the filing and assigned a Prescription Drug User Fee Act action date of June 22, 2016. Additional presentations at ASCO (Free ASCO Whitepaper) will highlight results from early and mid-stage trials of cabozantinib in other disease settings, including metastatic colorectal cancer, endometrial cancer and metastatic urothelial carcinomas.

"The overall survival data for cabozantinib from the METEOR trial represent an important milestone in the treatment of advanced renal cell carcinoma," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "When taken alongside data from the trial’s other endpoints, this result makes cabozantinib the first therapy to demonstrate improvements in the three key measures of efficacy in a large randomized phase 3 trial of patients with this advanced form of cancer. Exelixis is committed to ongoing clinical research for patients who need new treatment options, and the slate of data for Exelixis-discovered compounds at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting speaks to the urgency with which we and our collaborators are working to improve care and outcomes for patients with cancer."

Cabozantinib will be the subject of nine presentations. The full schedule of cabozantinib presentations expected at the meeting is as follows (all times are in Central Daylight Time):

Oral Presentations:
[4506] "Overall survival (OS) in METEOR, a randomized phase 3 trial of cabozantinib (Cabo) versus everolimus (Eve) in patients (pts) with advanced renal cell carcinoma (RCC)."
Dr. Toni K. Choueiri, Dana Farber Cancer Institute, Boston, Massachusetts
Oral Abstract Session: Genitourinary (Nonprostate) Cancer: 8 – 11 a.m.
Sunday, June 5, 10:12 – 10:24 a.m.

Poster Presentations
[9068] "MDM2 amplification (Amp) to mediate cabozantinib resistance in patients (Pts) with advanced RET-rearranged lung cancers."
Romel Somwar, Memorial Sloan Kettering Cancer Center, New York, New York
Poster Session: Lung Cancer—Non-Small Cell Metastatic
Poster presented Saturday, June 4, 8 – 11:30 a.m., Hall A (Poster #391)
Note: This is an Investigator-Sponsored Trial.

[3548] "Phase Ib study of cabozantinib plus panitumumab in KRAS wild-type (WT) metastatic colorectal cancer (mCRC)."
Dr. John Strickler, Duke University Medical Center, Durham, North Carolina
Poster Session: Gastrointestinal (Colorectal) Cancer
Poster presented Saturday, June 4, 8 – 11:30 a.m., Hall A (Poster #245)
Note: This is an Investigator-Sponsored Trial.

[2565] "Population pharmacokinetic (PopPK) and exposure-response (ER) modeling of cabozantinib (C) in patients (pts) with renal cell carcinoma (RCC) in the phase 3 METEOR study."
Dr. Steve Lacy, Exelixis, Inc., South San Francisco, California
Poster Session: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Poster presented Sunday, June 5, 8 – 11:30 a.m., Hall A (Poster #265)

[1093] "Effect of cabozantinib treatment on circulating immune cell populations in patients with metastatic triple-negative breast cancer (TNBC)."
Dr. Dan G. Duda, Massachusetts General Hospital, Boston. Massachusetts
Poster Session: Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
Poster presented Sunday, June 5, 8 – 11:30 a.m., Hall A (Poster #198)
Note: This is an Investigator-Sponsored Trial.

[4534] "A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC)."
Dr. Andrea Borghese Apolo, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Washington, D.C.
Poster Discussion Session: Genitourinary (Nonprostate) Cancer
Poster presented Monday, June 6, 1 – 4:30 p.m., Hall A; discussed at 4:45 – 6 p.m. in Arie Crown Theater
Note: This is a National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) study.

[4558] "Efficacy of cabozantinib (C) vs everolimus (E) in patients (pts) with advanced renal cell carcinoma (RCC) and bone metastases (mets) from the phase III METEOR study."
Dr. Bernard Escudier, Institut Gustave Roussy, Villejuif, France
Poster Session: Genitourinary (Nonprostate) Cancer
Poster presented, Monday, June 6, 1 – 4:30 p.m., Hall A (Poster #180)

[4557] "Outcomes based on prior VEGFR TKI and PD-1 checkpoint inhibitor therapy in METEOR, a randomized phase 3 trial of cabozantinib (C) vs everolimus (E) in advanced renal cell carcinoma (RCC)."
Dr. Thomas Powles, Barts Cancer Institute, Queen Mary University, London, England
Poster Session: Genitourinary (Nonprostate) Cancer
Poster Presented Monday, June 6, 1 – 4:30 p.m., Hall A (Poster #179)

[5586] "Phase II study of cabozantinib in recurrent/metastatic endometrial cancer (EC): a study of the Princess Margaret, Chicago and California Phase II Consortia."
Dr. Neesha Dhani, Princess Margaret Cancer Centre, University Health Network, Chicago, Illinois
Poster Session: Gynecologic Cancer
Poster Presented Monday, June 6, 1 – 4:30 p.m., Hall A (Poster #409)
Note: This is an NCI-CTEP study.

Investor/Analyst Briefing to Review Cabozantinib Data

Exelixis will host a live investor/analyst briefing on Sunday, June 5, 2016, from 7:30-9:30 p.m. EDT / 6:30-8:30 p.m. CDT / 4:30-6:30 p.m. PDT. During the briefing, Exelixis management and invited guest speakers will review and provide context for cabozantinib data presented at the ASCO (Free ASCO Whitepaper) Annual Meeting. The briefing will be webcasted. To access the webcast, log onto www.exelixis.com and proceed to the Event Calendar page under Investors & Media. Please connect to the company’s website at least 15 minutes prior to the webcast to ensure adequate time for any software download that may be required to listen to the webcast. An archived replay of the webcast will be available on the Event Calendar page under Investors & Media at www.exelixis.com for one year. A telephone replay of the webcast will be available until 11:59 p.m. EDT on June 7, 2016; please visit the Event Calendar page for details on phone replay access when available.

XL888 Data to be Presented in a Poster
In addition, investigational compound XL888 will be the subject of the following poster presentation (in Central Daylight Time):

[9544] "Phase I study of vemurafenib and heat shock protein 90 (HSP90) inhibitor XL888 in metastatic BRAF V600 mutant melanoma."
Dr. Zeynep Eroglu, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
Poster Session: Melanoma/Skin Cancers
Poster presented Saturday, June 4, 1 – 4:30 p.m., Hall A (Poster #149)
Note: This is an Investigator-Sponsored Trial.

Cobimetinib to be Featured in Eight Presentations
Also at the meeting, Exelixis’ collaborator Genentech, a member of the Roche Group, will present data on cobimetinib, an Exelixis-discovered compound, in disease settings including colorectal cancer, triple-negative breast cancer, and BRAF-mutant melanoma. The full schedule of cobimetinib presentations expected at the meeting is as follows (all times are in Central Daylight Time):

Oral Presentation:
[3502] "Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC)."
Dr. Johanna Bendell, Sarah Cannon Research Institute, Nashville, Tennessee
Oral Abstract Session: Gastrointestinal (Colorectal) Cancer
Oral presentation on Sunday, June 5, 8 – 11 a.m., Hall B1 (abstract scheduled for 8:24 – 8:36 a.m.)

Poster Discussion:
[9510] Extended follow-up results of a phase 1B study (BRIM7) of cobimetinib and vemurafenib in BRAF-mutant melanoma
Dr. Adil Daud, University of California, San Francisco, San Francisco, California
Poster Session: Melanoma/Skin Cancers
Poster presentation from Saturday, June 4, 1 – 4:30 p.m. (Poster #115) in Hall A; discussion on Saturday, June 4, 4:45 – 6 p.m. in room E354b

Poster Presentations:
[9528] "Clinical predictors of response for coBRIM, a phase 3 study of cobimetinib (C) in combination with vemurafenib (V) in advanced BRAF-mutated melanoma (MM)."
Dr. James Larkin, The Royal Marsden Hospital, London, UK
Poster Session: Melanoma/Skin Cancers
Saturday, June 4, 1 – 4:30 p.m., Hall A (Poster #133)

[9530] "Efficacy of cobimetinib (C) and vemurafenib (V) in advanced BRAF-mutated melanoma patients (pts) with poor and favorable prognosis in the coBRIM phase 3 study."
Dr. Grant A McArthur, Peter MacCallum Cancer Centre, East Melbourne, Australia and University of Melbourne, Parkville, Australia
Poster Session: Melanoma/Skin Cancers
Saturday, June 4, 1 – 4:30 p.m., Hall A (Poster #135)

[9533] "Adverse event (AE) incidence rates with cobimetinib (C) plus vemurafenib (V) treatment: extended follow-up (f/u) of the phase 3 coBRIM study."
Dr. Brigitte Dréno, Nantes University, Nantes, France
Poster Session: Melanoma/Skin Cancers
Saturday, June 4, 1 – 4:30 p.m., Hall A (Poster #138)

[9536] "Identifying prognostic subgroups for outcomes in BRAFV600-mutated metastatic melanoma patients (pts) treated with vemurafenib (V) ± cobimetinib (C): A pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM."
Dr. James Larkin, The Royal Marsden Hospital, London, UK
Poster Session: Melanoma/Skin Cancers
Saturday, June 4, 1 – 4:30 p.m., Hall A (Poster #141)

[1074] "Cobimetinib (C) + paclitaxel (P) as first-line treatment in patients (pts) with advanced triple-negative breast cancer (TNBC): updated results and biomarker data from the phase 2 COLET study."
Dr. Adam Brufsky, NRG Oncology/NSABP and Magee Women’s Hospital, Pittsburgh, PA
Poster Session: Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
Sunday, June 5, 8 – 11:30 a.m., Hall A (Poster #179)

[TPS1100] "COLET (NCT02322814): A multistage, phase 2 study evaluating the safety and efficacy of cobimetinib (C) in combination with paclitaxel (P) as first- line treatment for patients (pts) with metastatic triple-negative breast cancer (TNBC)."
Dr. David Miles, Mount Vernon Cancer Centre, London, UK
Poster Session: Breast Cancer —Triple-Negative/Cytotoxics/Local Therapy
Sunday, June 5, 8 – 11:30 a.m., Hall A (Poster #203a)

About the METEOR Phase 3 Pivotal Trial

METEOR is an open-label, event-driven trial with the primary endpoint of progression-free survival (PFS). The target enrollment for METEOR was 650 patients, and 658 patients were ultimately randomized. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia. Patients were randomized 1:1 to receive 60 mg of cabozantinib daily or 10 mg of everolimus daily, and were stratified based on the number of prior VEGF receptor TKI therapies received, and on commonly applied RCC risk criteria developed by Motzer et al. No cross-over was allowed between the study arms.

Secondary endpoints for METEOR include overall survival (OS) and objective response rate. The secondary endpoint of OS assumed a median of 15 months for the everolimus arm and 20 months for the cabozantinib arm. The study was designed to observe 408 deaths in the entire intent-to-treat population of 650 planned patients, providing 80% power to detect a HR of 0.75. An interim analysis of OS at the 2-sided 0.0019 level employing a Lan-DeMets O’Brien-Fleming alpha-spending function was planned at the time of the primary analysis for PFS, if the trial met the primary PFS endpoint. This analysis showed a strong trend in OS favoring cabozantinib (HR=0.67, 95% CI 0.51-0.89, p=0.005), although the p-value of 0.0019 to achieve statistical significance was not reached at that time. Based upon these results and after consulting with the FDA and EMA, a second interim analysis was undertaken; the results of this second interim analysis crossed the boundary for early declaration of statistical significance.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2016 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.1 Approximately 17,000 patients in the U.S. and 37,000 globally require second-line or later treatment.3

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.4,5 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.6-9 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.5,6

About Cabozantinib

Cabozantinib targets include MET, AXL and VEGF-1, -2 and -3 receptors. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are associated with tumor angiogenesis, invasiveness, metastasis and drug resistance.

On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

About the Cobimetinib and Vemurafenib Combination

Cobimetinib is a selective inhibitor that blocks the activity of MEK, a protein kinase that is part of a key pathway (the RAS-RAF-MEK-ERK pathway) that promotes cell division and survival. This pathway is frequently activated in human cancers including melanoma, where mutation of one of its components (BRAF) causes abnormal activation in about 50% of cases. Tumors with BRAF mutations may develop resistance and subsequently progress after treatment with a BRAF inhibitor. About 50% of patients with BRAF mutation positive melanoma experience a tumor response when treated with a BRAF inhibitor, however development of resistance and subsequent tumor progression limits treatment benefit. Clinical and preclinical analyses indicated that reactivation of the MEK-ERK pathway may underlie development of resistance to BRAF inhibitors in many progressing tumors, and that co-treatment with a BRAF and MEK inhibitor delays the emergence of resistance in the preclinical setting, providing the rationale for testing the combination of vemurafenib and cobimetinib in clinical trials. In addition to the combination with vemurafenib in melanoma, cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types, including non-small cell lung cancer, colorectal cancer, triple-negative breast cancer and melanoma.

On April 20, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported the presentation of data demonstrating that selective HDAC6 inhibition results in dosedependent increases in cell killing as a single treatment and in combination with Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica), in patient-derived cell lines and preclinical models of chronic lymphocytic leukemia (CLL) (Press release, Acetylon, APR 20, 2016, View Source [SID:1234511168]). The studies were completed in collaboration with the laboratory of Javier Pinilla-Ibarz, M.D., Ph.D. at the Moffitt Cancer Center and the data were presented by Moffitt investigator, Eva Sahakian, Ph.D., in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans.

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 CLL, malignant B cells evade immune detection and lead to immune suppression. Recently, histone deacetylases (HDACs) have been shown to play an active role in the regulation of pathogenesis and immune-related pathways in CLL, although their role in B-cell receptor signaling remains unknown. Previously, aberrant overexpression of HDAC6 has been demonstrated in CLL cell lines and patient samples, and the authors sought to understand the mechanistic role of HDAC6 in CLL.

In collaboration with Acetylon scientists, the authors demonstrated that selective HDAC6 inhibition in CLL cell lines resulted in dose-dependent reductions in IL-10, a cytokine that regulates cell proliferation in CLL, as well as dose-dependent increases in cell death and a synergistic reduction in cell viability in combination with the BTK inhibitor, ibrutinib. Genetic knockdown of HDAC6 in CLL cells reduced expression of PD-L1 and other immune checkpoint markers, while increasing markers related to antigen presentation, including MHC II. Using an animal model of CLL, the authors then demonstrated with systemic administration of a selective HDAC6 inhibitor, a reduction in disease burden and increased survival in parallel with diminished expression of immune checkpoint markers on T-cells and B-cells, as well as a reduction in the number of immunosuppressive T-cells (Tregs).

"The preclinical findings presented at AACR (Free AACR Whitepaper) today demonstrate that selective HDAC6 inhibition may provide a successful combination immunotherapeutic strategy for the treatment of CLL," said Steven Quayle, Ph.D., Senior Scientist at Acetylon.
"Overall these data further support the broad versatility and immunomodulatory capability of our selective HDAC6 inhibitors in multiple drug combinations across a breadth of oncology applications, including hematologic as well as solid tumor indications," said Simon S. Jones, Ph.D., Senior Vice President, Head of Research and Preclinical Development at Acetylon.

Details of the presentation are as follows:

Date: Wednesday, April 20, 2016
Time: 7:30 AM -11:00 AM CDT
Location: Section 4
Session: Epigenetic Biomarkers and Therapies
Poster Board Number: 29
Abstract Number: 4485
Title: Regulation of chronic lymphocytic leukemia (CLL) immunobiology by histone deacetylase 6 (HDAC6)

About HDAC6 Inhibition
Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and may enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy.
©2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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!

On April 20, 2016 Mirna Therapeutics, Inc. (Nasdaq:MIRN), a clinical stage biopharmaceutical company developing a broad pipeline of microRNA-based oncology therapeutics, reported the presentation of new preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Mirna Therapeutics, APR 20, 2016, View Source [SID:1234511166]). Researchers reported results in two poster presentations from experiments demonstrating that the Company’s lead microRNA therapeutic, MRX34 (miR-34), is synergistic with widely used cancer chemotherapies and next-generation tyrosine kinase inhibitors (TKIs).

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!

"These in vitro data suggest that MRX34 has strong potential in combination with other cancer drugs," commented Miguel Barbosa, Ph.D., Mirna’s Chief Scientific Officer. "The ability of miR-34 to control multiple oncogenic pathways may overcome both primary and acquired resistance when used in combination with chemotherapy or TKIs."

In a poster (#4829) entitled, "miRNA Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Cytotoxic Chemotherapy (CT) in NSCLC," researchers from Mirna and the University of Texas Health Science Center at San Antonio reported:

Synergistic anticancer effects were observed between miR-34a and platinum and other commonly used cytotoxic chemotherapy drugs, across a range of non-small cell lung cancer (NSCLC) cell lines with varying degrees of resistance.
The synergy observed suggests the potential for lower, less toxic doses of chemotherapy than currently used in the clinic when in combination with miR-34a.
In a second poster (#4814) entitled, "MicroRNA (miRNA) Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Next Generation EGFR Tyrosine Kinase Inhibitors (TKIs) in NSCLC," researchers from Mirna reported:

Synergistic anticancer effects were shown between miR-34a and next-generation EGFR TKIs afatinib and rociletinib against a range of wild-type and mutant NSCLC cell lines. These results extend similar findings with the first-generation EGFR TKI erlotinib (Zhao et al, PLoS ONE 9(2):e89105).
Results support the potential of MRX34 and EGFR TKI combinations to overcome both primary and acquired resistance to EGFR TKIs in patients with NSCLC.
Mirna is a grant recipient of the Cancer Prevention Research Institute of Texas (CPRIT) for preclinical and clinical testing of microRNA and targeted drug combination therapies, and also of the National Institutes of Health (NIH) for the study of combination molecular therapies for lung cancer, as well as miRNAs in combination with standard of care chemotherapy.

The posters may be accessed from the Events & Presentations section of the Company’s website.

On April 20, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of preclinical data relating to its KTN3379 and KTN0073 drug development programs at the AACR (Free AACR Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana, April 16-20, 2016 (Press release, Kolltan Pharmaceuticals, APR 20, 2016, View Source [SID:1234511164]).

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!

"This new preclinical data with KTN3379, along with emerging clinical results to date, support our plans to initiate a Phase 2 study in squamous cell tumors of the head and neck. Separately, we have identified KTN0073 as a unique antibody targeting the Met receptor tyrosine kinase with novel mechanisms of action. We are actively seeking a partner for the KTN0073 program to assist in the development of this novel and differentiated antibody drug candidate," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

"KTN3379 has shown broad anti-tumor activity in preclinical models, is potent, and binds to a unique epitope on ErbB3 or HER3. We presented scientific data supporting the potential use of KTN3379 for treatment of squamous cell tumors of the head and neck (HNSCC) and we continue to explore additional tumor indications where ErbB3 plays a role in driving the tumor or limiting therapies due to pathway resistance. The data presented shows anti-tumor activity of KTN3379 in HNSCC models in combination with the standard of care, cetuximab and radiation, and the anti-tumor activity correlated with several measurable parameters related to activation of the ErbB3 or EGF receptors. HNSCC cancer enriches for these parameters, and we are measuring these endpoints in ongoing and future clinical studies to guide patient selection and drug effectiveness," said Theresa LaVallee, Ph.D., Senior Vice President, Translational Medicine and Product Development at Kolltan.

Following are key data and results from the four poster presentations at AACR (Free AACR Whitepaper) relating to KTN3379 and KTN0073:

KTN3379
KTN3379 is an IgG1 monoclonal antibody that effectively locks ErbB3 in an inactive conformation by binding to a unique epitope, which may contribute to the antibody’s high potency and dual mechanism of action.

On Monday, April 18, "Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN" (Abstract Number 1196) was presented in a poster session.

The poster presentation reported the following data and results:

ErbB3 and its ligand neuregulin (NRG) are highly expressed in HNSCC and HER2, not EGFR, catalyzes ErbB3 activation in the presence of NRG;

Database analyses of HNSCC patient samples indicated that NRG expression is highly correlated with the expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα), but not other EGFR ligands;

Using NRG-positive cell lines, KTN3379 anti-tumor activity correlated with the level of secreted AREG and TGFα and EGFR homodimer levels; and

The combined measurement of NRG with EGFR activation is a potential biomarker for KTN3379 activity.
On Tuesday, April 19, "Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC" (Abstract Number 2979) was presented in a poster session.

The poster presentation featured the following data and results:

Combined administration of KTN3379 and BYL719, a PIK3Cα inhibitor, enhanced anti-tumor activity over single agent administration in HNSCC models;

Inhibition of PI3K led to upregulation of ErbB3 activity;

ErbB3 upregulation attenuated PI3K inhibition suggesting ErbB3 is playing a role in resistance as a compensatory pathway; and
Dual targeting of the ErbB3 and PI3K pathways led to synergistic anti-tumor activity in vitro and in vivo.

On Tuesday, April 19, "Inhibition of heregulin-mediated ErbB3 signaling as a radiosensitization therapy for head and neck cancers" (Abstract Number 3053) was presented in a poster session.

The poster presentation reported the following data and results:

Two different HNSCC models of cetuximab resistance were generated using A431 and FaDu cell lines by exposure to increasing doses of cetuximab over 14 weeks;

In these models, ErbB3 levels and signaling were upregulated and KTN3379 effectively blocked elevated ErbB3 signaling and overcame the cetuximab resistance in the A431 and FaDu models;

In a panel of six HNSCC cell lines, KTN3379 enhanced the anti-tumor activity of radiation alone or the combination of radiation and cetuximab in most of the cell lines; and

These results suggest that combining KTN3379 with standard of care treatments in HNSCC, including cetuximab and radiation, may enhance anti-tumor activity and may overcome resistance.

KTN0073
KTN0073 is a humanized, IgG2 monoclonal antibody that inhibits Met-dependent tumor growth in preclinical models when activated by HGF, Met gene amplification, or mutations in exon 14.

On Tuesday, April 19, "An anti-Met IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth" (Abstract Number 3835) was presented in a poster session.

The poster presentation highlighted the following data and results:
KTN0073 was identified as a potent anti-Met antibody with broad anti-tumor activity in HGF-driven and Met amplified tumors;

KTN0073 induced potent degradation of oncogenic exon 14-mutant Met, which propagates prolonged Met signaling due to a defect in receptor degradation;

Conversion of the antibody from IgG1 to IgG2 surprisingly resulted in enhanced anti-tumor activity in vitro and in vivo; and

KTN0073 demonstrated broad anti-tumor activity through multiple mechanisms of action in HGF-driven, Met-amplified, and exon 14-mutated tumors.

The posters are available on the Kolltan website.

About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), a receptor tyrosine kinase (RTK) that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers, including head and neck, breast, lung, gastric, and melanoma. Kolltan is conducting multiple clinical trials evaluating KTN3379 in the treatment of solid tumors (NCT02014909, NCT02456701, and NCT02473731).