On September 15, 2021 Thermo Fisher Scientific reported that The U.S. Food and Drug Administration (FDA) has granted premarket approval to it’s Oncomine Dx Target Test as a companion diagnostic (CDx) to identify patients with epidermal growth factor receptor (EGFR) Exon20 insertion mutation-positive metastatic non-small cell lung cancer (mNSCLC) who are candidates for EXKIVITY (mobocertinib), a targeted drug developed by Takeda Pharmaceutical Company Limited ("Takeda") (Press release, Thermo Fisher Scientific, SEP 15, 2021, View Source [SID1234587776]).

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EXKIVITY is a small-molecule tyrosine kinase inhibitor (TKI) designed to selectively target EGFR Exon20 insertion mutations. It received approval by the FDA on September 15, 2021 for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR Exon20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. This indication is approved under Accelerated Approval based on overall response rate and duration of response demonstrated in the platinum-pretreated population of the Phase 1/2 trial of EXKIVITY. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

"Without proper and timely diagnoses, patients with EGFR Exon20 insertion mutations don’t have access to therapies that can most effectively treat their disease," said Dion Warren, vice president, head of U.S. Oncology Business Unit at Takeda Oncology. "We’re pleased to partner with Thermo Fisher to identify and address the unmet needs of patients with this rare cancer."

Lung cancer is the leading cause of cancer death among both men and women in the United States, and non-small cell lung cancer accounts for about 80 to 85 percent of all lung cancer cases.[i] Additionally, EGFR-positive mutations are observed in up to 18 percent of lung cancer cases in the U.S., offering an opportunity to identify and group patients based on this biomarker.[ii] While EGFR mutations are an important therapeutic target, there is a gap in therapies available for EGFR Exon20 insertion mutations,[iii] which affects approximately 1-2 percent of patients with NSCLC.[iv]

Conventional PCR methods can miss 50 percent or more of EGFR Exon20 insertion mutations[v],[vi], thus prompting diagnostic molecular testing with next-generation sequencing (NGS) technology. Testing with NGS is important for early identification and appropriate characterization of tested patients.

"EXKIVITY offers new hope to previously treated patients with mNSCLC and EGFR Exon20 insertion mutations, who usually do not respond well to other available treatments," said Garret Hampton, president, clinical next-generation sequencing and oncology at Thermo Fisher Scientific. "FDA approval of the Oncomine Dx Target Test as a companion diagnostic for EXKIVITY will allow clinicians to identify key biomarkers in patients who could benefit from this targeted therapy. Working closely with Takeda to scale the clinical adoption of the test as a companion diagnostic for EXKIVITY is an important next step to enabling precision medicine and potentially improving outcomes of lung cancer patients."

Oncomine Dx Target Test simultaneously evaluates 23 genes associated with NSCLC. The FDA first approved the test as a CDx in 2017 and it is now approved for five targeted therapies for NSCLC and one targeted therapy for cholangiocarcinoma in the U.S. The test has also been approved by Japan’s Ministry of Health, Labour and Welfare (MHLW) as a CDx for five biomarkers – EGFR, ALK, ROS1, BRAF, and RET – associated with 10 targeted therapies for NSCLC. The test is currently approved and reimbursed by government and commercial insurers in more than 15 countries, including the U.S., multiple European nations, Japan, South Korea and the Middle East, and covering more than 550 million lives globally.

On September 15, 2021 Obsidian Therapeutics, a biotechnology company pioneering engineered cell and gene therapies, reported that the Company will present data highlighting its cytoTIL15 program at the upcoming European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, which will be hosted virtually September 16-21, 2021 (Press release, Obsidian Therapeutics, SEP 15, 2021, View Source [SID1234587803]).

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The abstract for the poster describes how Obsidian’s cytoTIL15 product (TIL engineered with membrane-bound IL15, or mbIL15) demonstrates enhanced in vitro potency and phenotype and in vivo persistence in the absence of IL-2, paving the way for more durable efficacy and improved safety in patients with solid tumor malignancies. The abstract has been published in ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2021 Abstract Book.

Details of the poster presentation:

Title: cytoTIL15: A novel TIL therapy for melanoma with superior potency and enhanced persistence without IL2 to improve safety & efficacy and expand patient eligibility

Abstract Number: 1008P

Session: Investigational Immunotherapy

Abstract Summary: Tumor-infiltrating lymphocytes (TILs) have generated promising data in clinical trials as therapy for heavily pretreated patients with solid tumor malignancies, such as metastatic melanoma. TIL therapy currently requires IL2 for in vivo maintenance of TILs, significantly limiting its application due to patient safety and eligibility hurdles. Obsidian’s cytoTIL product is comprised of TILs engineered with mbIL15 that is regulatable using a drug responsive domain (DRD) designed via our cytoDRiVE platform. Our cytoTIL15 product displays a favorable cytotoxic CD8+ T cell phenotype while maintaining TCR Vbeta repertoire diversity during manufacturing. cytoTIL15 exhibit superior in vitro anti-tumor cytotoxicity as well as polyfunctionality, compared to conventional TILs + IL2. In vivo, cytoTIL15 demonstrate greater antigen-independent expansion and persistence compared to conventional TILs treated with IL2.

Jan ter Meulen, M.D., Ph.D., Chief Scientific Officer of Obsidian, commented, "We are very excited about the superior persistence and cytotoxicity profile exhibited by cytoTIL15 in our preclinical models, and are eager to continue to advance our mission to translate these benefits to patients with metastatic melanoma and other solid tumor malignancies."

About cytoTIL15

cytoTIL15 is Obsidian’s lead cytoTIL program, currently in preclinical development for the treatment of patients with metastatic melanoma and other solid tumors. cytoTIL15 is a novel engineered tumor infiltrating lymphocyte therapy engineered with regulated membrane-bound IL15 that does not require patients to receive concomitant IL2 therapy, a toxic and costly requirement for conventional TILs. The Company expects to submit an IND for cytoTIL15 in mid-2022.

On September 15, 2021 4D pharma plc (AIM: DDDD, NASDAQ: LBPS), a pharmaceutical company leading the development of Live Biotherapeutic products (LBPs), a novel class of drug derived from the microbiome, reported new biomarker analyses from two ongoing clinical trials of its lead immuno-oncology single strain Live Biotherapeutic, MRx0518, in both neoadjuvant and refractory solid tumor settings, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, September 16-21, 2021 (Press release, 4d Pharma, SEP 15, 2021, View Source [SID1234590217]).

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"At the core of 4D pharma’s platform is the importance of understanding the impact of Live Biotherapeutics on human biology to rationally select and develop candidates, predict and measure response. These new biomarker data provide us with critical guidance on the biological and mechanistic impact of MRx0518 therapy in patients with various solid tumors," said Dr. Alex Stevenson, Chief Scientific Officer, 4D pharma. "These new findings indicate the potential to predict patients most likely to respond to MRx0518 therapy based on tumor biology."

"Furthermore, the monotherapy data demonstrates that a short course of MRx0518 treatment is able to positively modulate prognostic indicators of immunotherapy response," he added. "We look forward to utilizing and implementing these important new findings as we work to progress this novel oncology Live Biotherapeutic through development towards approval."

Highlights of the two ESMO (Free ESMO Whitepaper) 2021 poster presentations:

Baseline biomarkers associated with clinical benefit in patients with solid tumors refractory to immune checkpoint inhibitors (ICIs) treated with live biotherapeutic MRx0518 in combination with pembrolizumab

Presentation Number: 1024P

●Tumor biomarkers were assessed in patients with evaluable baseline samples (N = 12) in the ongoing Phase I/II study of MRx0518 in combination with anti-PD-1 immune checkpoint inhibitor (ICI) Keytruda (pembrolizumab)

●At baseline, patients who achieved complete response, partial response or stable disease for at least six months (collectively ‘responders’, N=4) from the combination of MRx0518 with Keytruda (pembrolizumab) had significantly greater densities of CD3+FOXP3+CD8- regulatory T cells (Tregs) and CD3+KI67+ proliferating T cells in tumors at baseline, compared to patients with progressive disease (PD, N=8), p=0.0381 and p=0.0048, respectively.

●In addition, significantly lower densities of CD68+ macrophages at baseline were observed in the tumor microenvironment of responders compared to patients with progressive disease, p=0.0303.

These data indicate the potential for MRx0518 to overcome Treg-mediated acquired resistance to cancer treatment, and presents a biomarker potentially able to identify patients most likely to respond to immunotherapy based on MRx0518. Further tumor sample analysis is ongoing for additional patients recruited into the study.

Neoadjuvant MRx0518 treatment is associated with significant gene and metagene signature changes in solid tumours

Presentation Number: 543P

●Gene expression profiling of paired tumor samples pre- and post-MRx0518 monotherapy across multiple solid tumor types (N=15) showed that treatment with MRx0518 for two to four weeks was associated with anti-tumor immune activity including antigen presentation, innate immune processes, and interferon response.

●Analysis of paired tumor samples also identified significant increases in mast cells, Th1, CD8+ T cell, neutrophil, endothelial cell and inflammatory chemokine metagene signatures following MRx0518 monotherapy.

●Effects were particularly pronounced in the cohort of breast cancer patients (N=7), with significant increases observed in total and activated dendritic cells, CD8+ T cells and cytotoxic cells in the tumor micro-environment.

●Functional metagene analysis also identified positive changes in prognostic indicators and metagene signatures predictive of immunotherapy response in patients with breast cancer, including inflammatory chemokines, cytotoxicity, lymphoid scores, and the Tumor Inflammation Signature (TIS)1 – demonstrated to retrospectively predict clinical benefit of anti-PD-(L)1 ICI therapy efficacy in various cancer types.

The immune biomarker data from this study of MRx0518, as a monotherapy dosed over a short period of just two to four weeks, demonstrates the potent activity of this oral Live Biotherapeutic directly on the human immune system, and the positive implications for clinical outcomes. This study is being conducted in collaboration with Imperial College London.

Both ePosters will be available under the "Posters and Publications" section of the 4D pharma website at www.4dpharmaplc.com at 7:30 GMT on Thursday 16th September 2021.

1 Ayers M, et al. J Clin Invest. 2017;127:2930–40

About MRx0518

MRx0518 is single strain Live Biotherapeutic product in development for the treatment of cancer. It is delivered as an oral capsule and stimulates the body’s immune system, directing it to produce cytokines and immune cells that are known to attack tumours. It is currently being evaluated in three clinical trials in cancer patients. MRx0518-I-001 is a neoadjuvant monotherapy study in a variety of solid tumours and is being conducted at Imperial College (London, UK). MRx0518-I-002 is in combination with KEYTRUDA (pembrolizumab) in patients who have previously progressed on anti PD-1 therapies. The Coordinating Investigator of the study is at The University of Texas MD Anderson Cancer Center, Houston, USA, with multiple additional sites in the US. The study is being conducted in collaboration with MSD, the tradename of Merck & Co., Inc., Kenilworth, NJ, USA. MRx0518-I-003 is in combination with preoperative radiotherapy in resectable pancreatic cancer. A fourth clinical trial, in collaboration with Merck KGaA and Pfizer Inc., of BAVENCIO (avelumab) in combination with MRx0518 as a first-line maintenance therapy for patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy, is expected to commence in Q4 2021.

On September 14, 2021 Sanofi reported the completion of its acquisition of Translate Bio, further accelerating the company’s efforts to develop transformative vaccines and therapies using mRNA technology (Press release, Sanofi, SEP 14, 2021, View Source [SID1234587675]). The acquisition adds a critical pillar to the company’s mRNA Center of Excellence which aims to unlock the potential of next-generation mRNA vaccines and other strategic areas such as immunology, oncology, and rare diseases.

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The tender offer for all of the outstanding shares of Translate Bio common stock expired as scheduled at one minute after 11:59 p.m., Eastern Time, on Monday, September 13, 2021. The minimum tender condition and all of the other conditions to the offer have been satisfied and on September 14, 2021, Sanofi accepted for payment and will promptly pay for all shares validly tendered and not validly withdrawn.

Following its acceptance of the tendered shares, Sanofi completed its acquisition of Translate Bio through the merger of a wholly owned subsidiary of Sanofi with and into Translate Bio, pursuant to Section 251(h) of the General Corporation Law of the State of Delaware, with Translate Bio continuing as the surviving corporation and becoming an indirect, wholly owned subsidiary of Sanofi.

In connection with the merger, all Translate Bio shares not validly tendered in the tender offer have been converted into the right to receive the same $38 per share in cash, without interest thereon and net of any applicable withholding taxes, that would have been paid had such shares been validly tendered in the tender offer. As of September 14, 2021, Translate Bio common stock will cease to be traded on the NASDAQ Global Select Stock Market.

Morgan Stanley & Co. International plc acted as exclusive financial advisor to Sanofi while Weil, Gotshal & Manges LLP acted as legal counsel. Centerview Partners acted as lead financial advisor to Translate Bio in the transaction, while Paul, Weiss, Rifkind, Wharton & Garrison LLP acted as legal counsel. Evercore also acted as a financial advisor in this transaction to Translate Bio. MTS Health Partners, LP also gave financial advice to Translate Bio.

On September 14, 2021 Specialised Therapeutics reported that AUSTRALIAN patients with an aggressive form of lung cancer (metastatic Small Cell Lung Cancer) can now access a new therapy that may improve outcomes (Press release, Specialised Therapeutics Asia, SEP 14, 2021, View Source [SID1234587691]).

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The therapy, ZEPZELCA (lurbinectedin) has been approved by the Therapeutic Goods Administration (TGA) "for the treatment of patients with metastatic small cell lung cancer (SCLC) that has progressed on or after prior platinum-containing therapy".1

This means patients who have failed other existing treatment options will now be able to access another line of therapy.

ZEPZELCA is the first new therapy approved by the TGA to treat second-line SCLC in more than two decades.

Australian lung cancer oncologist Professor Paul Mitchell from the Olivia Newton-John Cancer and Wellness and Research Centre said SCLC was particularly aggressive and more than two-thirds of patients were diagnosed with extensive stage disease. He said fewer than 5% of these patients currently survived more than five years post diagnosis. 3,4

"The new availability of ZEPZELCA will be welcomed by patients, families and the medical community, as we strive to improve patient outcomes for this disease," Professor Mitchell said.

"With this approval, we now have another option for patients who have progressed after prior platinum-based treatments. This provides an opportunity for them to continue treatment and potentially, improve outcomes."

The TGA approval of ZEPZELCA has been granted under a provisional regulatory pathway. The US Food and Drug Administration (FDA) and Australia’s Therapeutic Goods Administration (TGA) collaborated via ‘Project Orbis’ to accelerate availability to Australian patients.

ZEPZELCA’s approval is based on clinical data from an open-label, multi-centre, single-arm phase II study in 105 adult patients with SCLC who had disease progression after treatment with platinum-based chemotherapy.2

The data, which appeared in The Lancet Oncology May 2020 issue, demonstrated that in patients with relapsed SCLC, ZEPZELCA provided an Overall Response Rate (ORR) of 35% and a median duration of response of 5.3 months as measured by investigator assessment (30% and 5.1 months respectively, as measured by an independent review committee (IRC).2

The provisional approval is the subject of a further confirmatory study in more than 700 patients with 2nd line SCLC including some Australian sites. This study is expected to be completed in 2025.

ZEPZELCA is being made available in Australia by the independent pharmaceutical Company, Specialised Therapeutics (ST), under exclusive license from international partner, PharmaMar.

ST Chief Executive Officer Mr Carlo Montagner said the approval of ZEPZELCA would potentially make a difference for around 400 Australian patients annually who had run out of treatment options.

"We are delighted to be able to provide a new therapy option for patients with this difficult to treat cancer," he said.

"While patients may initially respond to traditional chemotherapy, they often experience an aggressive recurrence that is historically resistant to treatment.

"Our mission has always been to provide therapies in areas of unmet need and SCLC is certainly one of these areas. We look forward to making a difference for these patients and their families."

PharmaMar president José María Fernández Sousa-Faro, PhD, said the Company was delighted Australian patients would now be provided access to ZEPZELCA.

"We are pleased to bring a new treatment choice to relapsed SCLC patients. "The accelerated approval of ZEPZELCA underscores its potential to fill an unmet need in this often-overlooked SCLC community."

ZEPZELCA is currently available in Australia via a Special Access Program.

Commercial supplies of ZEPZELCA will commence early 2022.

About Small Cell Lung Cancer (SCLC)

SCLC is a particularly aggressive type of lung cancer that represents approximately 10-15% of all lung cancers,3 accounting for more than 275,000 new cases worldwide every year. In Australia, around 1,900 patients are diagnosed annually with the disease,4 which is characterised by rapid growth, early dissemination that is often asymptomatic and with acquired resistance to drugs2. SCLC is staged into limited-stage or extensive-stage disease. Limited-stage disease is potentially curable with aggressive therapy consisting of concurrent chemoradiotherapy, prophylactic cranial irradiation, and occasionally, surgery. However, nearly two-thirds of SCLC patients have extensive-stage disease at diagnosis, which is not curable, and patients are currently treated with palliative intent, with a median survival of 7 to 11 months after diagnosis and with less than 5% survival at 2 years.5,6

About ZEPZELCA (lurbinectedin)

ZEPZELCA also known as PM1183, is an alkylating drug that binds guanine residues within DNA. This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.1

ZEPZELCA 4 mg is a prescription medicine used to treat adults with a kind of lung cancer called small cell lung cancer (SCLC) that has spread to other parts of the body (metastatic) and who have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working. ZEPZELCA is approved based on response rate and how long the response lasted. Additional studies will further evaluate the benefit of ZEPZELCA for this use.

About the Phase II Monotherapy Trial
The Phase II trial of ZEPZELCA was an open-label, single-arm study, which enrolled a total of 105 SCLC patients at 26 hospitals in six European countries and the U.S.2 In the trial, platinum-sensitive and platinum-resistant patients were treated with ZEPZELCA 3.2 mg/m2, administered as a 60-minute IV infusion repeated every 21 days until disease progression or unacceptable toxicity. The primary endpoint, ORR, was 35% and the median duration of response was 5.3 months as measured by investigator assessment (30% and 5.1 months respectively, as measured by an IRC).2 Serious adverse reactions in ≥3% of patients included pneumonia, febrile neutropenia, neutropenia, respiratory tract infection, anaemia, dyspnoea, and thrombocytopenia. ZEPZELCA was discontinued in 1.9% of patients and was delayed in 30.5% of patients due to an adverse reaction. Dose reductions for an adverse reaction occurred in 25 percent of patients.2