On April 4, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the first presentation of preclinical data on the Company’s novel fully human anti-PD-L1 monoclonal antibody at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, being held this week, April 1-5, 2017, at the Walter E. Washington Convention Center in Washington, D.C (Press release, TG Therapeutics, APR 4, 2017, View Source [SID1234518469]).

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The following poster was presented today, April 4, 2017, during the Immunoconjugates and Antibodies Session in Halls A-C.

Preclinical Characterization of a Novel Fully Human lgG1 Anti-PD-L1 mAb CK-301

Based on the various assays performed, the poster concluded:

CK-301 is a high affinity PD-L1 specific fully humanized lgG1 antibody which blocks binding of PD-L1 to PD-1.
Activity of CK-301 in all assays tested was similar to anti-PD-L1’s used as active controls (surrogates of avelumab, atezolizumab, or durvalumab).
Similar to the approved anti-PD-L1, avelumab, CK-301 has the potential to induce ADCC (antibody-dependent cell-mediated cytotoxicity).
A first-in-human Phase 1 study of CK-301 is planned to commence this year.

Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer stated, "The team has worked hard to develop a high quality anti-PD-L1 antibody which we believe is the cornerstone of any proprietary immune-oncology (I/O) strategy. While anti-PD-1/PD-L1 therapy has been broadly explored in solid tumors, we are still in the very early days of understanding their utility and best applications in B-cell malignancies. As a company, we have been highly focused on developing best-in-class combination therapies for patients with B-cell malignancies and believe the next generation of combinations will include both targeted therapies, like TG-1101 and TGR-1202, plus I/O agents like our anti-PD-L1 antibody presented here today. We look forward to commencing the first-in-human study this year."

On April 4, 2017 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported that updated interim clinical data from its Phase 2b Selinexor Against Diffuse Aggressive Lymphoma (SADAL) study evaluating lead product candidate, selinexor (KPT-330), an oral Selective Inhibitor of Nuclear Export / SINE compound, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) was presented today in a late-breaking poster at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in Washington, DC (Press release, Karyopharm, APR 4, 2017, View Source [SID1234518468]). In the SADAL study, selinexor achieved a 28.6% overall response rate (ORR) in patients with relapsed or refractory DLBCL. Importantly, the responses were shown to be durable with a median duration of response (DOR) of greater than seven months, including prolonged complete responses (CRs).

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"Data from the ongoing SADAL study demonstrate robust single-agent activity of selinexor and prolonged response rates in this heavily pretreated DLBCL patient population, including against both the GCB and non-GCB (ABC) subtypes," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "The observed response rates were consistent across both the 60mg and 100mg treatment arms, but greater durability and tolerability was observed in the 60mg arm. Based on these results and following agreement with FDA, a study amendment is underway to discontinue the 100mg treatment arm and focus solely on the 60mg treatment arm where we plan to add approximately 90 patients. We look forward to reporting top-line data from the SADAL study in mid-2018. Should the data confirm the current results, we plan to apply for accelerated approval for the treatment of relapsed / refractory DLBCL."
Updated Phase 2b SADAL Clinical Data in Relapsed or Refractory DLBCL

In a late-breaking poster presentation titled, "A Phase 2b randomized study of selinexor in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) demonstrates durable responses in both GCB and non-GCB subtypes," Marie Maerevoet, MD of the Institute Jules Bordet in Belgium presented updated clinical data from the ongoing Phase 2b SADAL study.

A summary of the efficacy data as presented at AACR (Free AACR Whitepaper) 2017 is outlined in the following table and described below.


Targeting Disease at the Nuclear Pore

Best Responses* in Patients as of 1 March 2017

Category
N ORR (%) DCR (%) CR (%) PR (%) SD (%) PD (%) NE (%)
All patients
63 18 (28.6 %) 27 (42.9 %) 7 (11.1 %) 11 (17.5 %) 9 (14.3 %) 29 (46.0 %) 7 (11.1 %)
60 mg
32 9 (28.1 %) 12 (37.5 %) 4 (12.5 %) 5 (15.6 %) 3 (9.4 %) 17 (53.1 %) 3 (9.4 %)
100 mg
31 9 (29.0 %) 15 (48.4 %) 3 (9.7 %) 6 (19.4 %) 6 (19.4 %) 12 (38.7 %) 4 (12.9 %)
GCB-Subtype
32 8 (25.0 %) 14 (43.8 %) 3 (9.4 %) 5 (15.6 %) 6 (18.8 %) 13 (40.6 %) 5 (15.6 %)
Non-GCB-Subtype
31 10 (32.3 %) 13 (41.9 %) 4 (12.9 %) 6 (19.4 %) 3 (9.7 %) 16 (51.6 %) 2 (6.5 %)

* Responses were adjudicated according to the Lugano Classification (Cheson, 2014) by an independent central radiological review committee. ORR=Overall Response Rate (CR+PR), CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease, DCR=Disease Control Rate (CR+PR+SD), NE=Not Evaluable for Response. Responses as of March 1, 2017 based on interim unaudited data.

Based on the intention-to-treat analysis of the first 63 patients (median of 3 prior treatment regimens (range 2-5)), as adjudicated by an independent central radiological committee, 18 patients responded (7 patients with a CR and 11 patients with a PR) for an ORR 28.6%. An additional 9 patients experienced SD, for a DCR of 42.9%. The median overall survival was 8 months for all patients, consistent with published data in this population. As of the data cutoff date, median survival for the responders had not been reached and is over 9 months. The median DOR across all patients was greater than 7 months and responses tended to occur rapidly with a median of 2 months to onset. Among patients who responded, the median time on treatment was 9 months with a follow up of 13 months. As of the data cutoff date, 9 patients who responded remained on treatment, including 6 patients with a CR.

Selinexor showed similar activity against GCB and non-GCB subtypes of DLBCL: Of the 32 patients with DLBCL of the GCB-subtype, 8 responded (3 patients with a CR, 5 patients with a PR and 6 patients with SD) for an ORR of 25.0% and DCR of 43.8%. Of the 31 patients with DLBCL of the non-GCB-subtype (ABC), 10 responded (4 patients with a CR, 6 patients with a PR and 3 patients with SD) for an ORR of 32.3% and DCR of 41.9%.

Among the 72 patients evaluated for safety, the most common adverse events (AEs) across both dosing groups were fatigue (65%), thrombocytopenia (54%), nausea (51%), anorexia (49%), vomiting (35%) and anemia (32%), and were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care. As expected, the most common grade 3 and 4 AEs in the 60mg arm were thrombocytopenia (32%), neutropenia (16%), anemia (14%), and fatigue (11%) and were manageable with dose modifications and/or standard supportive care.

Dr. Maerevoet commented, "With the impressive and durable responses observed to date, including in both the GCB and non-GCB subtypes of DLBCL, single-agent selinexor is demonstrating the potential to become a new oral option for this difficult to treat patient population who are not candidates for transplantation and whose disease is unlikely to respond to further chemotherapy or targeted agents."

Planned Development Path for Selinexor in DLBCL

As a result of the interim data and in consultation with FDA, Karyopharm is amending the SADAL study protocol to become a single-arm study focusing solely on single-agent selinexor dosed at 60mg twice weekly, eliminating the 100mg arm. The study is also being amended to reduce the 14-week treatment-free period to 8 weeks in patients who achieved at least a PR on their most recent therapy. Patients who were refractory or did not achieve at least a PR on their prior therapy will continue with the 14-week treatment-free period. The FDA agreed that the modification to a single-arm study was reasonable and that the proposed trial design and indication appear appropriate for accelerated approval, though eligibility for accelerated approval will depend on the complete trial results and available therapies at the time of regulatory action. The Company plans to enroll up to an additional 90 patients to the new 60mg single-arm cohort and expects to report top-line results from the SADAL study in mid-2018.

Title: A Phase 2b randomized study of selinexor in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) demonstrates durable responses in both GCB and non-GCB subtypes
Presenter: Marie Maerevoet, Institute Jules Bordet
Poster Board #: 13
Session: Phase I-III Clinical Trials and Pediatric Clinical Trials
Location: Convention Center, Halls A-C, Poster Section 33
Date and Time: Tuesday, April 4, 2017 from 1:00 PM – 5:00 PM ET
LOGO
Targeting Disease at the Nuclear Pore

About Selinexor
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 1,900 patients have been treated with selinexor and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Karyopharm plans to initiate a pivotal randomized Phase 3 study of selinexor in combination with bortezomib (Velcade) and low-dose dexamethasone (BOSTON) in patients with multiple myeloma in early 2017. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the Company’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

On April 4, 2017 Roche (SIX: RO, ROG; OTCQX:RHHBY) reported it has received 510(k) clearance from the U.S. Food and Drug Administration (FDA) for the CINtec Histology test (Press release, Hoffmann-La Roche, APR 4, 2017, View Source [SID1234518467]). This test is the only clinically validated p16 biomarker test that, when used in conjunction with hematoxylin & eosin (H&E) staining, helps pathologists determine which women should receive treatment for cervical pre-cancer. This test is a part of the Roche Cervical Cancer Portfolio, which includes the cobas HPV Test and the CINtec PLUS Cytology3 test.

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"The CINtec Histology test will help physicians make informed decisions as to the best course of care for patients with high-grade pre-cancerous cervical disease," said Roland Diggelmann, CEO, Roche Diagnostics. "By improving the consistency of diagnosis across pathologists, it can help ensure the right patients are receiving the best possible treatment for this highly preventable disease."

As women positive for HPV are at greater risk for having or developing pre-cancerous cervical lesions, cervical cancer screening can help physicians find and treat these pre-cancerous lesions before they develop into invasive cancers. The CINtec Histology test plays a key role when a cervical tissue biopsy is taken as a result of an abnormal cervical cancer screening result, as it provides conclusive visual confirmation of the presence or absence of pre-cancerous lesions. These lesions, if untreated, could eventually lead to cervical cancer.

FDA clearance was based on the results generated in the CERTAIN4 (Cervical Tissue Adjunctive Analysis) study, which now joins the landmark ATHENA5 and PALMS6 trials in demonstrating the effectiveness of the products within the Roche Cervical Cancer Portfolio. Additionally, the use of p16 immunohistochemistry is recommended by the World Health Organization (WHO), the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) to improve the detection of pre-cancerous cervical disease.

On April 4, 2017 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has presented the latest research data regarding a mechanism of action that led to increased anti-tumor activity in mouse models which had been dosed with a combination of the in-house developed anticancer agent lenvatinib mesylate (lenvatinib) and an anti-mouse PD-1 antibody, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 108th Annual Meeting (Press release, Eisai, APR 4, 2017, View Source [SID1234518466]).

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The results presented at the AACR (Free AACR Whitepaper) meeting 1 showed that when syngeneic model mice inoculated with mouse liver cancer, melanoma or colon cancer cell lines were dosed with a combination of lenvatinib (10 mg/kg, once daily) and an anti-mouse PD-1 antibody (500 g/mouse, twice a week), lenvatinib alone or an anti-mouse PD-1 antibody alone, a substantial inhibitory effect on tumor growth was observed in mice that had been dosed with the combination therapy compared to the single treatments.
Additionally, an increased number of mice in the combination therapy group showed Complete Response (CR) of tumor compared to the single treatment group. Specifically, in the combination therapy group, 7 out of 30 mice showed CR (colon cancer models: 2/10, melanoma models: 2/10, liver cancer models: 3/10), whereas in each single treatment group, 1 out of 30 mice showed CR (colon cancer models: 1/10, melanoma models: 0/10, liver cancer models: 0/10).

Furthermore, in the liver cancer mouse model, even when identical cancer cell lines were re-inoculated into mice with complete tumor remission, no in vivo growth was observed.

RNA analysis of the cancer tissue and other tests confirmed a reduction in immunosuppressive tumor associated macrophages, a reduction in immunosuppressive signal receptors, and an increase in the ratio of memory T cells in model mice dosed with lenvatinib.

This non-clinical research suggested synergistic anti-tumor activity when combining lenvatinib with an anti-mouse PD-1 antibody in the mouse models, based on an immunostimulatory response due to the reduction in tumor associated macrophages and the enhancement of the ratio of memory T cells by lenvatnib.

Eisai has positioned oncology as a key therapeutic area of focus and remains committed to providing further evidence for lenvatinib as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.


1. About lenvatinib mesylate (generic name, "lenvatinib", product name: Lenvima / Kisplyx) Discovered and developed in-house, lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.
Currently, Eisai has obtained approval for lenvatinib as a treatment for refractory thyroid cancer in over 50 countries including in the United States, Japan, in Europe, Korea, Mexico, and Brazil, and is undergoing regulatory review in other countries including South Africa and Indonesia. Specifically, Eisai has obtained approval for the agent in the United States for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in Japan for the treatment of unresectable thyroid cancer, and in Europe for the treatment of adult patients with progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine, respectively.
Lenvatinib was also approved in the United States in May 2016 for an additional indication in combination with everolimus for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Furthermore, lenvatinib was approved in combination with everolimus for the treatment of adult patients with advanced RCC following one prior vascular endothelial growth factor (VEGF) targeted therapy in Europe in August 2016. Lenvatinib has been launched in Europe under the brand name Kisplyx for this indication.
Additionally, in January 2017, a Phase III clinical trial of lenvatinib as a first-line treatment for patients with unresectable hepatocellular carcinoma has achieved its primary endpoint.
A Phase III study of lenvatinib in separate combinations with everolimus and pembrolizumab in renal cell carcinoma (first-line) was initiated and is underway. Additionally, a Phase Ib/II study to investigate the agent in combination with pembrolizumab in select solid tumors including endometrial cancer, renal cell carcinoma, head and neck cancer, and urothelial cancer is also underway.


2. About memory T cells After being activated by an antigen presented on cancer cells or infected cells, CTL (cytotoxic T lymphocyte) cells turn into effector T cells, which can attack and eliminate the antigen. Afterwards, the majority of the effector T cells will die, but a portion of them remain in the body as memory T cells, which retain the "experience" of fighting off cancer cells or infection. If the same cancer cells or infection appear again, they will once again become effector T cells, and attack the invader with high efficiency

On April 4, 2017 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, reported two presentations of preclinical results on the Company’s proprietary dual-switch technology for use in CAR-T and TCR product candidates at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, D.C (Press release, Bellicum Pharmaceuticals, APR 4, 2017, View Source [SID1234518465]).

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"We’re excited to report compelling preclinical data on the first dual-switch technology designed to provide control over both the activity and safety of cell-based therapies," said Rick Fair, Chief Executive Officer of Bellicum Pharmaceuticals. "These data in both CAR-T and TCR constructs support our objective to continue leading the industry in developing novel, controllable cell therapies. We look forward to advancing product candidates incorporating this dual-switch technology into the clinic."

The Company’s dual molecular switch is designed to increase efficacy, durability and safety of adoptive cell therapies. T-cell proliferation is triggered by an inducible MyD88/CD40 (iMC) costimulatory switch, which when activated by the presence of both a target antigen and rimiducid, leads to enhanced T-cell activation and survival. A novel suicide switch, called RapaCIDeTM, is also engineered into the cell for use in the event of severe toxicities. RapaCIDe is activated via infusion of rapamycin, triggering immediate apoptosis of the modified cells. The dual-switch technology has been incorporated into the Company’s GoCAR-T and GoTCR platforms.

In a late-breaking poster presentation titled "Dual-switch HER2 CAR-T cells: Small molecule-regulated GO and STOP switches to target solid cancer in vivo," Bellicum scientists tested the novel dual-switch platform in solid tumors by combining both the iMC costimulatory and RapaCIDe apoptotic signaling switches inside a first-generation CAR targeting HER2. Results showed that the novel RapaCIDe switch was as effective as the Company’s CaspaCIDe switch at activating apoptosis, while the iMC costimulatory switch enhanced tumor killing and T-cell proliferation. This study demonstrated that the Company’s dual-switch GoCAR-T technology effectively controlled tumor growth, T-cell proliferation/persistence and elimination in a solid tumor model.

Additional data were reported in a second presentation on the Company’s dual-switch technology in a TCR targeting the cancer antigen PRAME (preferentially expressed antigen in melanoma). The TCR was engineered with the rimiducid-driven iMC costimulatory switch and the RapaCIDe suicide switch. Results reported in a poster presentation titled "Dual-switch TCR: A two-ligand system to control PRAME TCR-modified T-cell proliferation and death using inducible MyD88/CD40 and caspase-9," showed that T cells transduced with the dual-switch technology effectively enhanced T-cell proliferation/persistence in the presence of rimiducid, and exposure to rapamycin effectively triggered the RapaCIDe switch and induced apoptosis, eliminating the cells. This is the first reported prototype of a dual-switch TCR designed to increase efficacy, durability and safety of adoptive T-cell therapies.

The posters will be available in the Abstracts & Presentations section of the Bellicum website after the presentations.

AACR Presentation Details

Late-Breaking Presentation:

Abstract Number: LB-184 / 7
Presentation Title: "Dual-switch HER2 CAR-T cells: Small molecule-regulated GO and STOP switches to target solid cancer in vivo"
Presentation Date: Tuesday, April 4, 2017
Presentation Time: 8:00 AM – 12:00 PM ET
Section: 35
Additional Presentation:

Abstract Number: 3745 / 1
Presentation Title: "Dual-switch TCR: A two-ligand system to control PRAME TCR-modified T cell proliferation and death using inducible MyD88/CD40 and caspase-9"
Presentation Date: Tuesday, April 4, 2017
Presentation Time: 8:00 AM – 12:00 PM ET
Section: 30