On June 4, 2019 Asuragen, Inc., a molecular diagnostics company delivering easy-to-use products for complex testing in genetics and oncology, reported publication of a study demonstrating a single next-generation sequencing (NGS) workflow for the sensitive and accurate detection of DNA and RNA variants associated with non-small cell lung cancer (NSCLC) in the journal Translational Oncology (View Source) (Press release, Asuragen, JUN 4, 2019, View Source [SID1234536880]). The article, titled "An Integrated Next-Generation Sequencing System for Analyzing DNA Mutations, Gene Fusions, and RNA Expression in Lung Cancer," describes the targeted analysis of 190 loci from low-input and low-quality NSCLC specimens using a rapid and standardized NGS procedure that is compatible with existing laboratory instrumentation.

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!

Lung cancer is the leading cause of cancer-related death worldwide and NSCLC accounts for approximately 85% of all lung cancer cases. A number of targeted therapies for DNA and RNA variants in NSCLC are now available, but their timely detection is complicated by segregated NGS methods for DNA versus RNA and by limitations in biopsy tissue and nucleic acid quality to support split workflows. To address these challenges, the publication describes a unified DNA/RNA NGS assay that covers hotspot mutations in 20 genes, including EGFR, KRAS, BRAF, and PIK3CA, as well as 107 RNA fusion variants recurrent in NSCLC, such as ALK, RET, ROS1, and NTRK1, and MET exon 14 skipping events. RNA quantification also includes 23 transcripts with prognostic and theranostic value, such as PD-L1, PD-L2, INFG, and CTLA4 that are important in assessing T-cell-inflamed phenotypes and the impact of immune checkpoint inhibitor therapies. Analysis is achieved using proprietary software to automate variant calls from total nucleic acid, resulting in quantification of SNVs, INDELs, CNVs, fusions, splice variants, and expression targets – all within a single, harmonized NGS run. By querying functional input copies, sequence quality, sample-specific error rates, local sequence complexity, and coverage depth, the software is an essential component of the overall system and helps ensure robust and accurate results.

In the study, over 200 formalin-fixed, paraffin-embedded (FFPE) surgical resections and core needle biopsies provided by collaborators at MD Anderson Cancer Center were tested. The results were consistent with variant prevalence established by large, international consortia such as TCGA, demonstrating mutual exclusivity between driver events and distinct molecular subtypes for adenocarcinoma and squamous cell carcinoma. Sequence variants in fine needle aspirate (FNA) smears from BATTLE-2 clinical trial subjects were in 97% agreement with matched FFPE specimens tested by the FoundationOne NGS Assay, even though the FNA biopsies had substantially fewer cells available for analysis.

"Our study with Asuragen demonstrates the continued evolution of NGS methods to reliably quantify different types of cancer-associated variants across both DNA and RNA that are relevant to precision medicine," commented Ignacio I. Wistuba, MD, professor and chair, Department of Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center. "This integrated and rapid approach may help clinicians and laboratories maximize the actionable information they can recover from small patient biopsies, and accelerate turnaround times for results and decision-making."

This study was funded in part by a Cancer Prevention and Research Institute of Texas (CPRIT) Product Development Research grant.

On June 4, 2019 VBI Vaccines Inc. (NASDAQ: VBIV) ("VBI"), a commercial-stage biopharmaceutical company developing next-generation infectious disease and immuno-oncology vaccines, reported a poster on Sunday, June 2, 2019, at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting that exhibited expanded clinical data from Part A of the Phase 1/2a study of VBI-1901 in recurrent Glioblastoma (GBM) patients (Press release, VBI Vaccines, JUN 4, 2019, View Source [SID1234536896]).

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!

The poster presented data on a total of 18 patients enrolled in Part A of the study, which was a multi-center, open-label, dose-escalation study across three dose cohorts of VBI’s vaccine immunotherapeutic, VBI-1901 – 0.4 µg, 2.0 µg, and 10.0 µg. Part A was designed to evaluate the safety and tolerability of VBI-1901, and to define the optimal immunogenic dose level to test in the Part B extension phase of the study, which is expected to initiate enrollment mid-year 2019. Part B of the trial will further assess immunologic responses and potential correlations with tumor and clinical responses.

Andrew B. Lassman, M.D., Chief of Neuro-oncology at Columbia University Irving Medical Center and Associate Director for Clinical Infrastructure at Herbert Irving Comprehensive Cancer Center, and principal investigator of the study commented, "Though early, the data we’ve seen to-date in this Phase 1/2a study of VBI-1901 are intriguing, yet of course require confirmation in later phase and additional trials. The patients in this study, and more generally in the recurrent GBM setting, are immunocompromised and have very few effective treatment options available to them. Any treatment that could demonstrate even some benefit would be incredibly meaningful for these patients and their families. I look forward to seeing additional data from Part B of the study."

Highlights from Poster Presentation (Poster #237, Abstract #2048)

Safety:

The vaccine immunotherapeutic was well-tolerated at all doses, with no safety signals observed
Grade 2, 3, or 4 adverse events occurred in 66%, 22%, and 11% of participants, respectively – none were related to the vaccine immunotherapeutic

Immunogenicity and Tumor/Clinical Responses:

Six (6) patients immunologically responded to VBI-1901, with evidence of robust boosting of cytomegalovirus (CMV)-specific immune responses against both glycoprotein B (gB) and pp65 antigens.
Median progression-free survival (PFS) was longer among responders (14.5 weeks) vs. non-responders (6 weeks).
Three out of six (3/6) patients in the high-dose, 10 µg, cohort had evidence of stable disease (SD) by magnetic resonance imaging (MRI), compared to one out of six (1/6) in the low-dose cohort and zero out of six (0/6) in the intermediate-dose cohort.

"The tumor responses seen in three of the six patients in the high-dose cohort are promising, with all three having immunologic responses to VBI-1901 as well," said David E. Anderson, Ph.D., VBI’s Chief Scientific Officer. "In Part B of the study, we are narrowing the enrollment criteria to ensure a more homogenous patient population that may better assess the potential correlation between immunogenicity and tumor and clinical responses to VBI-1901. Enrollment of 10 patients in Part B, all first-recurrent GBM patients, is expected to initiate mid-year this year, 2019."

The full poster can be viewed on the "Events/Presentations" page in the Investor Section of the VBI Vaccines website.

VBI Press Release

About the Phase 1/2a Study Design

VBI’s two-part Phase 1/2a study is a multi-center, open-label, dose-escalation study of VBI-1901 in up to 28 patients with recurrent GBM:

Part A: Dose-escalation phase to define the safety, tolerability, and optimal dose level of VBI-1901 in recurrent GBM patients. This phase enrolled 18 patients across three dose cohorts.
Part B: A subsequent extension of the optimal dose level, as defined in the dose escalation phase. This phase is expected to enroll an expanded cohort of approximately 10 additional patients.

VBI-1901 is administered intradermally and is adjuvanted with granulocyte-macrophage colony-stimulating factor (GM-CSF), a potent adjuvant that mobilizes dendritic cell function. Patients in both phases of the study will receive the vaccine immunotherapeutic every four weeks until tumor progression.

Additional information, including a detailed description of the study design, eligibility criteria, and investigator sites, is available at ClinicalTrials.gov using identifier NCT03382977.

On June 3, 2019 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer, autoimmune diseases, asthma and allergic diseases, reported that the first patient has been dosed in a Phase 1 clinical study to evaluate the safety and tolerability of XmAb22841, both as a monotherapy and in combination with pembrolizumab, in patients with advanced solid tumors (Press release, Xencor, JUN 3, 2019, View Source [SID1234536793]). XmAb22841 is a bispecific antibody that simultaneously targets the immune checkpoint receptors CTLA-4 and LAG-3.

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!

"Our TME activators seek to improve the tolerability and clinical benefit of immunotherapy by activating T cells specifically in the tumor microenvironment, where many checkpoint receptors are highly expressed on immune cells. Toward that goal, XmAb22841 is designed with XmAb bispecific technology to target those cytotoxic T cells that simultaneously co-express the immune checkpoints CTLA-4 and LAG-3," said Paul Foster, M.D., senior vice president and chief medical officer at Xencor. "We intend to advance XmAb22841 in combination with anti-PD1 immunotherapy to potentially drive better responses through triple checkpoint blockade."

The Phase 1 dose-escalation and expansion study, which explores XmAb22841 as a monotherapy and in combination with pembrolizumab will characterize the safety and tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of intravenous administration in patients with select advanced solid tumors. For more information about the study, please visit View Source (identifier: NCT03849469).

About XmAb22841

XmAb22841 is a bispecific antibody that simultaneously targets immune checkpoint receptors CTLA-4 and LAG-3 and is designed to promote tumor-selective T-cell activation. Xencor’s XmAb bispecific Fc domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture. XmAb bispecific Fc domains have been engineered to eliminate Fc gamma receptor (FcγR) binding, with the intent to prevent activation and/or depletion of T cells via engagement by FcγR-expressing cells. XmAb22841 is being evaluated in a Phase 1 study for the treatment of advanced solid tumors, as a monotherapy and in combination with pembrolizumab.

On June 3, 2019 Oncopeptides AB (Nasdaq Stockholm: ONCO), a pharmaceutical company focused on the development of targeted therapies for difficult-to-treat hematological cancers, reported new data presented at the the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from its Phase 1/2 O-12-M1 clinical study of lead candidate melflufen (Press release, Oncopeptides, JUN 3, 2019, View Source [SID1234536810]). The data demonstrate that melflufen may offer positive disease stabilization and favorable time to next treatment (TTNT) outcomes in heavily-pretreated patients with relapsed/refractory multiple myeloma (RRMM).

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!

Overall conclusions from the data presented include:

Melflufen plus dexamethasone treatment results in disease stabilization in 76% of RRMM patients, which translates to a median TTNT of 7.9 months (10.6 months when censoring at time of death), which compares favorably with other relevant trials.
A median OS of 20.7 months in an advanced RRMM population, suggesting that melflufen therapy is associated with a long?term benefit and allows patients to receive further treatment to control disease.
Results support those of previous data showing the promising efficacy profile of melflufen for the treatment of RRMM.
The data is presented by Professor Paul G. Richardson, MD, RJ Corman Professor of Medicine at Harvard Medical School and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, USA.

Oncopeptides recently announced that, following discussions with the U.S. Food & Drug Administration (FDA), the company has initiated the preparation for submitting a New Drug Application (NDA) for accelerated approval of melflufen for the treatment of patients with triple-class refractory multiple myeloma. The company targets to submit the application in the first quarter of 2020 based on the positive data from the ongoing Phase 2 HORIZON clinical trial.

"We are committed in helping patients with myeloma get access to melflufen given the safety and efficacy profile that is emerging from our clinical trials," said Jakob Lindberg, CEO of Oncopeptides. "In addition to the data presented at ASCO (Free ASCO Whitepaper), data from the melflufen clinical programs have also been selected for four presentations at the 2019 EHA (Free EHA Whitepaper) Annual Congress, including updated data from the HORIZON Phase 2 pivotal clinical trial that will serve as the foundation for our NDA submission."

The full poster presented at the 2019 ASCO (Free ASCO Whitepaper) Annual Meeting can be found on the company webpage under:

www.oncopeptides.com / Investors & Media / Presentations / 2019 ASCO (Free ASCO Whitepaper) Annual Meeting – poster

About the O-12-M1 Clinical Trial
O?12?M1 is a Phase 1/2 study with melflufen plus dexamethasone in 62 patients with RRMM who had ≥2 prior lines of therapy, prior exposure to at least an IMiD and a proteasome inhibitor, and disease progression on last line of therapy. Final study results were presented at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

Summary of O-12-M1 Data
At the time of data cutoff on November 9, 2017, 45 patients had been treated with 40 mg melflufen and dexamethosone. Median age was 66 years (47-78). 60% of patients were ISS stage II/III and 44% were high-risk cytogenetics. Patients had four median prior lines of therapy, with 91% of patients being single refractory, 67% of patients double refractory and 7% triple refractory. Further, 53% of patients were alkylator refractory. At data cutoff, 44 pts (98%) discontinued melflufen + dexamethasone, mainly due to adverse events (40%) and PD (31%). 27 patients received subsequent therapy. Median time from start of melflufen and dexamethasone to first subsequent therapy or death (TTNT), whichever occurred first, was 7.9 months (95% CI: 5.68-11.01). The majority of patients’ (52%) next therapy was single-agent with or without steroid therapy, and approximately half of patients receiving subsequent therapy (44%) received at least two subsequent lines of therapy.

Table: TTNT with Melflufen in O-12-M1 and Other Agents in RRMM

TTNT with Melflufen in O-12-M1

For further information, please contact:
Jakob Lindberg, CEO of Oncopeptides
E-mail: [email protected]
Telephone: +46 (0)8 615 20 40

Rein Piir, Head of Investor Relations at Oncopeptides
E-mail: [email protected]
Cell phone: +46 (0)70 853 72 92

This information was submitted for publication at 15.00 CET, June 3, 2019

About melflufen
Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. It belongs to the novel class Peptidase Enhanced Cytotoxics (PEnC), which is a family of lipophilic peptides that exhibit increased activity via peptidase cleavage and have the potential to treat many cancers. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and immediately cleaved by peptidases to deliver an entrapped hydrophilic alkylator payload. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the peptidase cleavage, and induces irreversible DNA damage and apoptosis. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.

On June 3, 2019 Merck, a leading science and technology company, reported updated results from the potentially registrational Phase II VISION study, showing durable anti-tumor clinical activity for the investigational targeted therapy tepotinib* across different lines of treatment in advanced non-small cell lung cancer (NSCLC) patients harboring MET exon 14 skipping mutations detected by liquid biopsy (LBx) or tissue biopsy (TBx) (Press release, Merck & Co, JUN 3, 2019, View Source [SID1234536831]). Data were shared in an oral presentation today at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL, US.

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!

"Tepotinib has been designed to potentially improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations," said Luciano Rossetti, Global Head of Research & Development for the Biopharma business of Merck. "Tepotinib is an important part of our strategic focus on precision medicine, and both the proportion of patients responding and the duration of anti-tumor clinical activity demonstrate the potential of this investigational therapy."

Discovered in-house at Merck, tepotinib is an investigational, highly potent and selective1 oral MET kinase inhibitor that is designed to inhibit the oncogenic signaling caused by MET (gene) alterations, including both MET exon 14 skipping mutations and MET amplifications, or MET protein overexpression. Alterations of the MET signaling pathway are found in various cancer types, including 3-5% of NSCLC cases, and correlate with aggressive tumor behavior and poor clinical prognosis.2-4

"Patients with this NSCLC molecular subtype lack treatment options that have the potential to significantly improve clinical outcomes," said Paul K. Paik, M.D., primary study investigator and Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center. "It is noteworthy to see data that are consistent with tepotinib’s previously reported efficacy findings in this patient population, and that also provide valuable new insight into its durable clinical activity across various treatment lines."

Results from the ongoing Phase II VISION study in 73 efficacy-evaluable patients with NSCLC with MET exon 14 skipping mutations identified by LBx or TBx demonstrate overall objective response rate (ORR) of 50.0% for LBx-identified patients as assessed by Independent Review Committee (IRC), and 55.3% as assessed by investigators. The ORR for TBx-identified patients was 45.1% and 54.9%, respectively. The overall median duration of response (DOR) was 12.4 months and 17.1 months among LBx-identified patients, as assessed by IRC and investigators, respectively, while among TBx-identified patients, 15.7 and 14.3 months were observed, respectively.

Most treatment-related adverse events (TRAEs) were Grade 1 and 2. No Grade 4 or 5 TRAEs were observed. Any grade TRAEs reported by ≥10% of 87 patients evaluable for safety were peripheral edema (48.3%), nausea (23.0%) diarrhea (20.7%) and increased blood creatinine (12.6%). Other relevant TRAEs of any grade include increased lipase (4.6%), fatigue (3.4%) and vomiting (3.4%). TRAEs led to permanent discontinuation in four patients (two patients due to peripheral edema, one due to interstitial lung disease, one due to diarrhea and nausea).

The use of both liquid and tissue biopsies to identify patients for the VISION trial is intended to support improved patient selection and is consistent with the company’s focus on patient-centric drug development.

Tepotinib is currently being investigated in NSCLC in two different settings: in NSCLC harboring MET alterations (MET exon 14 skipping mutations and MET amplifications) as monotherapy, as well as in combination with the tyrosine kinase inhibitor (TKI) osimertinib in epidermal growth factor receptor (EGFR) mutated MET amplified NSCLC having acquired resistance to prior EGFR TKI. Additional information on these clinical trials can be found at ClinicalTrials.gov using the identifiers NCT02864992 and NCT03940703, respectively. Merck is also actively assessing the potential of investigating tepotinib in combination with novel therapies for other tumor indications.

*Tepotinib is the recommended International Nonproprietary Name (INN) for the MET kinase inhibitor (MSC2156119J). Tepotinib is currently under clinical investigation and not approved for any use anywhere in the world.

Notes to Editors
Tepotinib oral session:

Title

Lead Author

Abstract #

Presentation
Date / Time
(CDT)

Location

Tepotinib

Oral Session

Phase II study of
tepotinib in
NSCLC patients with

METex14 mutations

P.K. Paik

9005

Mon, Jun 3, 8:00

AM – 11:00 AM
(9:24 AM – 9:36
AM lecture time)

Hall B1

About Non-Small Cell Lung Cancer
With 2 million cases diagnosed annually, lung cancer (including trachea, bronchus, and lung) is the most common type of cancer worldwide, and the leading cause of cancer-related death, with 1.7 million mortality cases worldwide.5 Alterations of the MET signaling pathway, including MET exon 14 skipping mutations and MET amplifications, occur in 3-5% of NSCLC cases.2-4

About Tepotinib
Tepotinib, discovered in-house at Merck, is an investigational oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations, including both MET exon 14 skipping mutations and MET amplifications, or MET protein overexpression. It has been designed to have a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations.

Tepotinib is currently being investigated in NSCLC and Merck is actively assessing the potential of investigating tepotinib in combination with novel therapies and in other tumor indications.

All Merck press releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to www.merckgroup.com/subscribe to register online, change your selection or discontinue this service.