On September 5, 2018 Iovance Biotherapeutics, Inc presented the Corporate Presentation (Presentation, Iovance Biotherapeutics, SEP 5, 2018, View Source [SID1234529316]).

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On September 5, 2018 Eureka Therapeutics, Inc., a clinical stage biopharmaceutical company with the goal of curing cancer by developing novel T-cell therapies that harness the evolutionary power of the immune system, reported preliminary safety and clinical results from its ongoing proof-of-concept study of ET140202 T-cell therapy in AFP-positive patients with hepatocellular carcinoma (HCC), the most prevalent form of liver cancer (Press release, Eureka Therapeutics, SEPT 5, 2018, View Source [SID1234529300]). The data was presented today in the late-breaking abstracts session of the CAR-TCR Summit in Boston, Massachusetts.

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The findings from the proof-of-concept first-in-human study, which is being conducted at the First Affiliated Hospital of Xi’An Jiaotong University in China, demonstrated a favorable safety profile of ET140202 T-cell therapy in six patients with no observed cytokine release syndrome (CRS) or drug-related neurotoxicity. In addition, one patient in the i.v. arm of the study had a complete response. Overall, tumor regression was observed in three out of six patients.

"We are encouraged by the safety profile and the potential efficacy of ET140202 for AFP-positive liver cancer," said Cheng Liu, Ph.D., President and Chief Executive Officer of Eureka Therapeutics. "Combining T-cell therapy with a TCR-mimic antibody to target intracellular antigens is a novel approach and can potentially represent a powerful way to treat solid tumors, and in particular, liver cancer, an area of significant unmet medical need. The initial results represent an important milestone in T-cell therapy against solid tumors, and we intend to continue to study and rapidly advance ET140202 into Phase 1 clinical trials in the United States."

Commenting on the data, liver cancer surgeon and researcher Yuman Fong, M.D. said "Hepatocellular carcinoma is a cancer where we have had great difficulties finding effective treatments. The study shows early but important data in the possibility of targeting solid tumors using T-cell therapy." Dr. Fong, the Sangiacomo Family Chair in Surgical Oncology and Chair and Professor of the Department of Surgery at City of Hope National Medical Center in Duarte, California, continued "ET140202 has demonstrated a large therapeutic window with the potential of repeat dosing, combination therapy, as well as a higher dosing level than we have seen with other T-cell programs. I look forward to seeing future data on this study."

Data from Ongoing Proof of Concept Study

As of the data cutoff date of July 2018, six patients who had previously failed multiple lines of therapy had been treated in one of three treatment arms of ET140202: intravenous (i.v.), intra-hepatic artery (i.a.) infusion or intratumoral (i.t.) injection. All patients enrolled in this study were AFP-expressing HCC patients carrying at least one HLA-A2 allele. All six patients had pre-existing cirrhosis.

In vivo T-cell expansion, which indicates T-cell activation, was observed in all six patients. Reduction of serum AFP was observed in four out of the six patients. A complete response was observed in one patient at the five-month assessment, with tumor regression observed in both the primary liver tumors and distal lung metastases after multiple treatment doses. In addition, the serum AFP of this patient returned to normal levels at the five-month assessment. The complete response was maintained at the seven-month assessment. Among other patients with one to three months of follow-up, two patients showed partial tumor regression, two patients showed stable disease and one patient showed progressive disease. Of the six patients, three died due to non-drug-related complications of liver disease. Two of these three patients showed a partial response at the one-month follow-up assessment.

Across all evaluable patients, ET140202 was generally well-tolerated. All drug-related adverse events reported by investigators were limited to Grades 1 or 2, with the most common being fever and fatigue.

About Liver Cancer

Liver cancer is the second most common cause of cancer-related deaths, with roughly 600,000 patient deaths every year worldwide, with incidence rates on the rise and limited treatment options. Between 2000 and 2016, mortality rates in liver cancer have increased 43% in the United States. Hepatocellular carcinoma is the predominant type of liver cancer with approximately 31,500 cases per year occurring in the United States. Alpha-fetoprotein (AFP) is overexpressed, specifically in liver cancer, making it an ideal target for T-cell immunotherapy. However, AFP is intracellularly expressed and secreted, and therefore, not targetable by conventional antibody-based therapies.

About ET140202 Study

ET140202 utilizes Eureka’s proprietary ARTEMIS T-cell receptor platform engineered with a proprietary human TCR-mimic (TCRm) antibody to target an AFP-peptide/HLA-A2 complex on HCC cancer cells. Using its proprietary E-ALPHA antibody discovery platform, Eureka discovered and developed a TCRm antibody to selectively bind upon fragments or peptides of the AFP protein that are broken down within the cancer cell proteasome and displayed on the cell surface by the major histocompatibility complex (MHC). Once engaged onto this complex, the ET140202 engineered T-cell is designed to be activated to kill the cancer cell. The ET140202 clinical proof-of-concept study was sponsored by Aeon Therapeutics (Shanghai) Co., Ltd. at the First Affiliated Hospital of Xi’An Jiaotong University.

About ARTEMIS T-cell Receptor Platform

Eureka’s proprietary ARTEMIS T-cell receptor platform was designed to create potentially safer and more effective T-cell therapies. In pre-clinical studies against CD19-positive malignancies, Eureka’s ARTEMIS T-cells matched the cancer killing potency of CAR-T therapies but with a dramatic reduction in the levels of inflammatory cytokines released. Cytokine release syndrome (CRS) and neurotoxicity are serious side effects associated with CAR-T therapies.

On September 5, 2018 Quanterix Corporation (NASDAQ:QTRX), a company digitizing biomarker analysis with the goal of advancing the science of precision health, reported that Kevin Hrusovsky, Chief Executive Officer, President and Chairman of Quanterix, will present at the Wells Fargo Securities 2018 Healthcare Conference on Thursday, Sept. 6, 2018 at 9:45 a.m., EDT at The Westin Copley Place in Boston, Mass (Press release, Quanterix, SEPT 5, 2018, View Source [SID1234529299]). Hrusovsky will also be attending Citi’s 13th Annual Biotech Conference on the same day at the Four Seasons Boston, where he is scheduled to meet privately with leading healthcare investors.

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On September 5, 2018 TP Therapeutics, a privately held, clinical-stage biopharmaceutical company developing oncology therapies with a focus on addressing drug resistance, reported that updated interim data from its ongoing Phase 1/2 TRIDENT-1 study of Repotrectinib (TPX-0005) will be presented in an oral presentation at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer to be held Sept. 23-26, 2018, in Toronto (Press release, TP Therapeutics, SEPT 5, 2018, View Source [SID1234529298]).

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The presentation will provide an updated interim analysis of the Phase 1 study in ROS1 fusion-positive non-small-cell lung cancer (NSCLC) patients across multiple doses of Repotrectinib, TP Therapeutics’ investigational next-generation tyrosine kinase inhibitor (TKI) designed to effectively target ROS1, TRKA-C and ALK fusion proteins, and overcome clinical resistance due to secondary kinase domain mutations. Preclinical and early clinical findings have shown Repotrectinib to be a potent and selective inhibitor for ALK, ROS1, and TRK family.

World Conference on Lung Cancer
Presentation Title: Safety and Preliminary Clinical Activity of Ropotrectinib1 (TPX-0005), a Next-Generation ROS1/TRK/ALK Inhibitor, in Advanced ROS1 Fusion-Positive Non-Small Cell Lung Cancer
Topic: Targeted Therapy
Date: Monday, Sept. 24, 2018
Session: Novel Therapies in ROS1, HER2 and rare EGFR Mutations (10:30 a.m. to Noon)
Abstract: 14217
Presenter: Jessica J. Lin, M.D., Massachusetts General Hospital Cancer Center

Initial preliminary data from the ongoing Phase 1 portion of the TRIDENT-1 study were presented in June 2018 at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper). In addition, the preclinical and clinical proof-of-concept data for Repotrectinib were recently published in the journal Cancer Discovery (The Cancer Discovery article may be found online at: View Source).

About repotrectinib (TPX-0005)

Repotrectinib (TPX-0005) is a potent and orally bioavailable investigational small molecule kinase inhibitor for ALK, ROS1, and TRK family. The clinical benefits of targeting ALK, ROS1, or TRK fusion kinase have been demonstrated with multiple kinase inhibitors already approved for the treatment of ALK+ non-small cell lung cancer (NSCLC), in addition to crizotinib for ROS1+ NSCLC, and larotrectinib and entrectinib in clinical studies for TRK+ cancers. The successes of these therapies are overshadowed by the development of acquired resistance. The acquired solvent front mutations including ALK G1202R, ROS1 G2032R, TRKA G595R and TRKC G623R render a common clinical resistance to the current ALK, ROS1, and TRK inhibitors.

Repotrectinib has demonstrated potency against wildtype and mutated ALK, ROS1 and TRK family kinases, especially the clinically significant solvent front mutations, gatekeeper mutations, and emerging compound mutations after multiple line treatments. Repotrectinib may provide a new opportunity to inhibit the abnormal signaling of ALK, ROS1, or TRK family in solid malignancies, and overcome multiple resistance mechanisms seen in refractory patients. Repotrectinib is currently being evaluated in a Phase 1/2, open-label, multi-center, first-in-human study of the safety, tolerability, pharmacokinetics and anti-tumor activity in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements TRIDENT-1 study (www.clinicaltrial.gov number NCT03093116). Interested patients and physicians can also contact the TP Therapeutics Oncology Clinical Trial Hotline at 1-858-276-0005 or email [email protected].

1Note: TPX-0005 had an initial generic name of "ropotrectinib," which was later changed to repotrectinib and is now the accepted name by USAN and WHO INN.

On September 5, 2018 Checkmate Pharmaceuticals (Checkmate), reported that it has entered into a clinical trial collaboration and supply agreement with the alliance between Merck KGaA, Darmstadt, Germany, and Pfizer to evaluate CMP-001, a TLR9 agonist, in combination with avelumab*, a human anti-PD-L1 antibody (Press release, Checkmate Pharmaceuticals, SEPT 5, 2018, View Source [SID1234529297]). The collaboration will evaluate the safety and effectiveness of CMP-001 administered in combination with avelumab in patients with advanced squamous cell cancer of the head and neck (SCCHN) resistant to a prior PD-1/PD-L1 inhibitor.

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"This collaboration is an important next step in advancing our clinical development program for CMP-001 into indications beyond melanoma, where we already have demonstrated proof-of-concept,’’ said Art Krieg, CEO of Checkmate. "Merck KGaA, Darmstadt, Germany, and Pfizer are ideal partners for Checkmate given their commitment to developing avelumab broadly in the immuno-oncology field."

"Early data suggest CMP-001 exhibits clinically encouraging activity and we are looking forward to investigating this compound in combination with avelumab in advanced head and neck cancer," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "Our collaboration with Checkmate further demonstrates the alliance’s commitment to explore novel combinations with avelumab to potentially improve patient outcomes."

"Combining avelumab with CMP-001 adds to our clinical development strategy of IO combinations in different hard-to-treat cancers," said Alise Reicin, Head of Global Clinical Development at the Biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "We look forward to working with Checkmate to explore how the combination of these agents can potentially advance care for these patients."

Avelumab has received accelerated approval** by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic Merkel cell carcinoma (MCC) and previously treated patients with locally advanced or metastatic urothelial carcinoma (mUC), and is under further clinical evaluation across a range of tumor types under a global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer.

*Avelumab is under clinical investigation for treatment of SCCHN in combination with CMP-001 and has not been demonstrated to be safe and effective for this use. There is no guarantee that avelumab will be approved for SCCHN by any health authority worldwide.

About CMP-001

CMP-001 is a first-in-class CpG-A Toll-like receptor 9 (TLR9) agonist that is encapsulated in a virus-like particle (VLP). CMP-001 is designed to induce both innate and adaptive anti-tumor immune responses, thereby converting immunologically "cold" tumors into immunologically "hot" tumors, with the potential to mediate tumor regression. It is the only CpG-A class TLR9 agonist in clinical trials and differs from other CpG classes in clinical development by having a native DNA backbone that induces the highest levels of type I IFN. Based on analyses of gene expression in human tumors showing that increased IFN and related immune gene expression is associated with better response to PD-1 inhibition, it is believed that this mechanism of action may restore, enable or improve responses to anti-PD-1/PD-L1 therapeutics.

CMP-001 is being evaluated in multiple tumor types to assess its safety, activity, alternative routes of administration and combination with other immunotherapies and modalities. For information on CMP-001 trials that are currently recruiting patients, please visit www.clinicaltrials.gov.

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.1-3 Avelumab has also been shown to induce NK cell mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.3-5 In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Avelumab is currently being evaluated in the JAVELIN clinical development program, which involves at least 30 clinical programs, including seven Phase III trials, and more than 8,600 patients across more than 15 different tumor types. For a comprehensive list of all avelumab trials, please visit clinicaltrials.gov.

Approved Indications in the US**

The US Food and Drug Administration (FDA) granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information from the US FDA Approved Label

The warnings and precautions for avelumab (BAVENCIO) include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions), infusion-related reactions and embryo-fetal toxicity.

Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO for mMCC and patients with locally advanced or metastatic UC include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash.