On June 23, 2021 AstraZeneca and HUTCHMED reported that its Orpathys (savolitinib) has been granted conditional approval in China to treat patients with non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy (Press release, AstraZeneca, JUN 23, 2021, View Source [SID1234584265]).

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This approval follows a priority review designation by the Center for Drug Evaluation of China’s National Medical Products Administration (NMPA) and marks the first global regulatory approval for the oral, potent, and highly selective MET tyrosine kinase inhibitor (TKI).

More than a third of the world’s lung cancer patients are in China and, among those with NSCLC, approximately 2-3% have tumours with MET exon 14 skipping alterations, a targetable mutation in the MET gene.1-3 This mutation is more common (13-22%) among patients with pulmonary sarcomatoid carcinoma (PSC), a rare and aggressive subtype of NSCLC usually resistant to chemotherapy.1,4

The approval by the NMPA was based on positive results from a single-arm Phase II trial conducted in China in patients with NSCLC with this mutation, including patients with the PSC subtype. Orpathys demonstrated robust anti-tumour activity based on an independent review of objective response rate (ORR) in the trial’s primary endpoint and its disease control rate (DCR). Continued approval is contingent upon the successful completion of a confirmatory trial in this patient population.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "This approval makes Orpathys the only targeted medicine approved for these biomarker-selected patients in China, and it adds another novel medicine to our already diverse lung cancer portfolio. We are proud that this first-ever regulatory approval of Orpathys is in China, where we have a long-standing commitment to improving patient outcomes and working with the right partners to achieve that goal. Alongside HUTCHMED, we look forward to the continued development of this medicine across a range of cancers where MET alterations and amplification are drivers of tumour growth and treatment resistance."

Christian Hogg, Chief Executive Officer, HUTCHMED, said: "It is with great pleasure that today we announce the first regulatory approval of Orpathys globally, HUTCHMED’s third self-discovered oncology drug to be commercialized. Our collaboration with AstraZeneca in 2011 has been an important driver in the development of this novel targeted oncology drug, involving both a China-based biotech and a global pharmaceutical company. This approval is a testament to the perseverance and scientific ingenuity of this long-standing alliance, and we are hopeful that this is only the beginning of the progress we can achieve for patients with MET-altered tumours."

In the Phase II trial, at a median follow up of 17.6 months, Orpathys demonstrated an ORR of 42.9% (95% confidence interval [CI] 31.1-55.3) and median progression-free survival (PFS) of 6.8 months (95% CI 4.2-9.6) in the overall trial population. PFS was clinically meaningful across subgroups, and ORR results were consistent regardless of prior treatment or tumour histology, including in patients with the PSC subtype (40.0%, 95% CI 21.1-61.3) and patients with other NSCLC subtypes (44.4%, 95% CI 29.6-60.0). DCR in the overall trial population was 82.9% (95% CI 72.0-90.8).

The safety and tolerability profile of Orpathys was consistent with previous trials, and no new safety signals were identified. Most adverse events (AEs) were Grade 1–2 and resolved with dose modification or discontinuation. Grade 3 or higher AEs occurred in 45.7% of patients, and treatment-related serious AEs occurred in 24% of patients. One treatment-related death was reported from tumour lysis syndrome in a patient with PSC.

Results from the Phase II trial were presented during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program in May 2020, and updated results were published in The Lancet Respiratory Medicine in June 2021.

As part of the joint global development programme with HUTCHMED, Orpathys is being evaluated in combination with Tagrisso and other medicines to address tumour mechanisms of resistance in NSCLC in the ORCHARD and SAVANNAH Phase II trials for the combinations to provide longer duration of benefit, and as a treatment for other MET-driven tumours, including papillary renal cell carcinoma, and gastric and gastroesophageal junction cancers.

NSCLC, PSC and MET aberrations
Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths.2 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.5 The majority of NSCLC patients are diagnosed with advanced disease.6

PSC is a rare subtype of NSCLC, comprising 0.3-3% of all lung malignancies.7 Compared with other NSCLC subtypes, PSC patients have a poorer prognosis and limited treatment options.4,8-9

MET is a tyrosine kinase receptor.10 While MET genetic alterations are common in many solid tumours, MET exon 14 skipping alterations are more frequently associated with lung cancer, occurring in approximately 2-3% of patients with NSCLC and 13-22% of patients with PSC.1,4,11 MET amplification or overexpression is one of the mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) TKIs for metastatic EGFR-mutated NSCLC.10

NCT02897479
The single-arm, open-label Phase II trial NCT02897479 assessed the efficacy and safety of Orpathys in the treatment of Chinese patients with locally advanced or metastatic PSC or other NSCLC subtypes with MET exon 14 skipping alterations who progressed on prior treatment or were unable to receive chemotherapy.

Patients were treated with weight-based dosing of Orpathys once-daily oral tablets (600mg/day or 400mg/day for patients weighing less than 50kg). Treatment continued until disease progression, death, intolerable toxicity, or discontinuation. The trial enrolled 70 patients across multiple centres in China. The primary endpoint was ORR, and key secondary endpoints were PFS, DCR and safety assessment.

Orpathys
Orpathys (savolitinib) is an oral, potent, and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumours. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations) or gene amplification.

Orpathys is currently under clinical development for multiple tumour types, including lung, kidney, and gastric cancers, as a single treatment and in combination with other medicines.

AstraZeneca and HUTCHMED collaboration
In 2011, AstraZeneca and HUTCHMED entered a global licensing agreement to jointly develop and commercialise Orpathys. HUTCHMED is responsible for the manufacturing and supply of Orpathys, and AstraZeneca is responsible for its commercialisation in China and worldwide. Sales of Orpathys will be recognised by AstraZeneca.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and assessing innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On June 23, 2021 Alentis Therapeutics reported that it will present data at the European Association for the Study of the Liver (EASL) International Liver Congress 2021, being held virtually from June 23-26, 2021 (Press release, Alentis Therapeutics, JUN 23, 2021, View Source [SID1234584264]).

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Data to be presented includes research from Alentis and academic collaborators that provides preclinical proof-of-concept in patient-derived cell-based and mouse models of CLDN1-specific mAbs for treatment of advanced liver fibrosis and prevention and treatment of hepatocellular carcinoma (HCC).

Presentations at the Digital International Liver Congress are listed below

Oral Presentation GS-2069: Claudin-1 is a target for treatment of advanced liver fibrosis and cancer prevention

Presenter: Natascha Roehlen, Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France
Presentation Date and Time: June 24, 2021, 4:00 p.m. CEST

Oral Presentation OS-2190: A humanized Claudin-1 specific monoclonal antibody for treatment of hepatocellular carcinoma

Presenter: Natascha Roehlen, Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France
Presentation Date and Time: June 25, 2021, 3:15 pm CEST

On June 23, 2021 Rubius Therapeutics, Inc. (Nasdaq:RUBY), a clinical-stage biopharmaceutical company that is genetically engineering red blood cells to create an entirely new class of cellular medicines called Red Cell Therapeutics, reported that the first patient has been dosed in a new Phase 1 arm of the ongoing Phase 1/2 clinical trial of RTX-240 in combination with KEYTRUDA (pembrolizumab)1 for the treatment of patients with relapsed/refractory or locally advanced solid tumors (Press release, Rubius Therapeutics, JUN 23, 2021, View Source [SID1234584708]). To be eligible for the trial, patients must have disease that is relapsed or refractory to an anti-PD-1 or PD-L1 therapy.

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"RTX-240 is designed to activate and expand a patient’s own immune cells to mount a broad and potent anti-tumor response. Combining an immune agonist with a PD-1 checkpoint inhibitor has the potential to prevent the cancer from evading the immune response. The RTX-240 and pembrolizumab combination is anticipated to drive activated T cells and NK cells into the tumor microenvironment with the potential to overcome resistance to PD-1 inhibition," said Christina Coughlin, M.D., Ph.D., chief medical officer at Rubius Therapeutics. "Given the favorable emerging safety profile and promising initial clinical activity reported as part of our initial clinical results from the ongoing Phase 1 monotherapy trial of RTX-240 in advanced solid tumors, we believe that the combination with pembrolizumab has the potential to provide significant benefit to patients with disease that is relapsed or refractory to prior anti-PD-1 or PD-L1 therapy."

"Despite recent advances in cancer immunotherapy, there remains a need for new combination approaches that broaden the benefits of immunotherapy in patients with solid tumors following treatment with checkpoint inhibition," said Omid Hamid, M.D., Chief of Translational Research and Immunotherapy, Director of the Phase 1 Immuno-Oncology Program of The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, and RTX-240 investigator. "The exciting initial safety and efficacy data from the ongoing monotherapy Phase 1 clinical trial make RTX-240 a potentially promising candidate for the treatment of cancer, and we are excited to work with Rubius to evaluate RTX-240 in combination with pembrolizumab."

RTX-240 is engineered to express a co-stimulatory molecule, 4-1BB ligand, and a cytokine, IL-15TP, on the cell’s surface, and is designed to broadly stimulate the immune system by activating and expanding both natural killer (NK) cells and T cells to generate a potent anti-tumor response. Pembrolizumab is a humanized monoclonal immunoglobulin G4 antibody (IgG4 mAb) with high specificity of binding to the programmed cell death protein-1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab is indicated for the treatment of patients across several indications as monotherapy and in combination with numerous therapies.

About the RTX-240 Phase 1/2 Clinical Trial
This is a Phase 1/2 open label, multicenter, multidose, first-in-human dose-escalation and expansion study designed to determine the safety and tolerability, pharmacokinetics, maximum tolerated dose and a recommended Phase 2 dose and dosing regimen of RTX-240. The trial will also assess the pharmacodynamics of RTX-240 measured by changes in T and NK cell number and function relative to baseline and anti-tumor activity. The trial has three separate Phase 1 arms: an ongoing monotherapy dose escalation arm in adults with relapsed/refractory or locally advanced solid tumors, an ongoing monotherapy dose escalation arm in adults with relapsed/refractory acute myeloid leukemia, and a combination therapy dose escalation arm with pembrolizumab in adults with relapsed/refractory or locally advanced solid tumors. The monotherapy arm of the trial in advanced solid tumors includes a Phase 2 expansion in specified tumor types.

On June 23, 2021 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has obtained manufacturing and marketing approval for the EZH2 inhibitor "Tazverik Tablets 200 mg" (tazemetostat hydrobromide) in Japan with the indication of relapsed or refractory EZH2 gene mutation-positive follicular lymphoma (only when standard treatment is not applicable) (Press release, Eisai, JUN 23, 2021, View Source [SID1234584266]).

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This approval is based on the results of a multicenter, open-label, single-arm clinical phase II trial (Study 206)1 in Japan conducted by Eisai and other studies2 conducted by Epizyme, Inc. (Headquarters: Massachusetts, United States) outside Japan. Study 206 enrolled patients with EZH2 gene mutation-positive, primarily follicular lymphoma, who had relapsed or were refractory. The primary endpoint of this study was objective response rate (ORR), and secondary endpoints included safety. This study achieved the primary endpoint target and exceeded a prespecified tumor response threshold with statistical significance: ORR in patients with EZH2 mutation-positive relapsed or refractory follicular lymphoma (n=17) was 76.5% (90% confidence interval (CI): 53.9-91.5) as measured by independent review. Treatment-emergent adverse events (incidence of 25% or more) observed in this study were dysgeusia (52.9%), nasopharyngitis (35.3%), lymphopenia (29.4%) and blood creatine phosphokinase increased (29.4%). Eisai will conduct a post-marketing special use results survey (all-case surveillance) in all patients who are administered "Tazverik" until a pre-determined number of patients has been reached in accordance with an approval condition imposed by the MHLW.

Created by utilizing Epizyme’s proprietary product platform, "Tazverik" is a first-in-class small molecule inhibitor of the epigenetic enzyme EZH2. It is one of the histone methyltransferases in the epigenetics-related protein group, and is thought to regulate the expression of cancer-related genes and suppress the growth of cancer cells by specifically targeting EZH2, which contributes to the cancer growth process.3 Eisai is responsible for the development and commercialization of this agent in Japan, while Epizyme, Inc. is responsible for all regions outside of Japan. In the United States, "Tazverik" received accelerated approval for the indication of epithelioid sarcoma in January 2020, and follicular lymphoma in June 2020 (Notes to editors 1).

Follicular lymphoma is a low-grade B-cell lymphoma that accounts for 10-20% of non-Hodgkin’s lymphomas. Follicular lymphoma is generally indolent and sensitive to chemotherapy. However, development of a new treatment strategy is required for follicular lymphoma which still remains difficult to cure, as recurrence often occurs repeatedly. 7-27% of follicular lymphomas are reported to have gain-of-function mutations in the EZH2 gene,4,5 and it is estimated that there are approximately 600 to 2,400 patients with follicular lymphoma with EZH2 gene mutations in Japan. A companion diagnostic test for EZH2 gene mutations, "cobas EZH2 Mutation Test" by Roche Diagnostics K.K. (Headquarters: Tokyo) was approved in May 2021.
　

Eisai aims to make continuous efforts to meet the diversified needs of and increase the benefits provided to patients with cancer, their families, and healthcare professionals, by delivering "Tazverik" as a new treatment option for EZH2 gene mutation-positive follicular lymphoma.

On June 23, 2021 Celsion Corporation (NASDAQ: CLSN), a clinical-stage company focused on DNA-based immunotherapy and next-generation vaccines, reported that its new wholly owned subsidiary, Celsion GmbH, will manage all current and future investigator-sponsored development of ThermoDox, the Company’s proprietary heat-activated liposomal encapsulation of doxorubicin (Press release, Celsion, JUN 23, 2021, View Source [SID1234584283]). Andreas Voss, M.D., a leading oncology researcher, has been named Managing Director of Celsion GmbH and will step down from Celsion’s board of directors later this year to head the subsidiary, which is based in Zug, Switzerland.

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Establishing Celsion GmbH allows Celsion’s management to focus solely on GEN-1, its DNA-mediated IL-12 immunotherapy currently in Phase I/II development for the treatment of advanced ovarian cancer, and PLACCINE, its nucleic acid vaccine platform. In addition to clinical and regulatory advice, Celsion’s ongoing investment in ThermoDox will be limited to providing clinical drug supply and modest financial support.

ThermoDox is currently under investigator-sponsored development for several cancer indications, including:

A Phase I study led by the University Medical Center Utrecht in the Netherlands to determine the safety, tolerability and feasibility of ThermoDox in combination with Magnetic Resonance Guided High Intensity Focused Ultrasound hyperthermia and cyclophosphamide therapy for the local treatment of the primary tumor in metastatic breast cancer.
A Phase I study led by Oxford University in the UK to assess intravenous delivery of ThermoDox in combination with High Intensity Focused Ultrasound in pancreatic cancer.
A clinical project at the National Institutes of Health to evaluate ThermoDox plus the chemotherapy drug mitomycin in bladder cancer.
Commenting on his new role in leading Celsion GmbH, Dr. Voss said, "I am excited to spearhead this effort and to work with investigators around the world who are interested in pursuing further clinical development of ThermoDox. Building upon encouraging preclinical results in several cancer indications, we have been fielding numerous requests from investigators to conduct their own studies. We know that doxorubicin is one of the most active cytotoxic drugs with no known specific resistance mechanism. Furthermore, the ability of ThermoDox to deliver high doses into tumor tissue is proven and its mechanism of action is well understood. Celsion GmbH’s long-term objective is to seek partnerships that will maximize the potential of ThermoDox, ultimately providing value to the parent company."

Michael H. Tardugno, Celsion’s chairman, president and chief executive officer, said, "Despite the bitter disappointment and surprise with our Phase III OPTIMA study of ThermoDox in primary liver cancer, many investigators are undaunted by various anomalies related to that data and see value in the drug’s continued study. We owe patients and the scientific community the opportunity to investigate ThermoDox while removing the financial obligation from our stockholders. Celsion is now solely focused on the significant opportunity we face with GEN-1 and PLACCINE in advanced ovarian cancer and SARS-CoV-2 vaccines, respectively. I am delighted that Celsion GmbH is in the experienced hands of Dr. Voss, who will pursue other collaborations and partnerships with the intent to monetize this asset."

Andreas Voss, M.D. joined Celsion’s board of directors in 2015. Dr. Voss has more than 25 years of research and drug development expertise. He previously served as Vice President of Clinical Affairs for Europe at Caris Life Sciences, a biotechnology company focused on implementing personalized medicine in oncology through its liquid biopsy technology. Prior to joining Caris in 2010, he was responsible for the global clinical development of Avastin and was a member of the Corporate Drug Safety Board at F. Hoffmann-La Roche. Before joining Roche in 2006, he was Medical Director for the Lung Cancer Disease Area at AstraZeneca, and from 2000 to 2003 he was Medical Director for Anti-infectives and Oncology at Bayer GmbH. From 1996 to 2000, Dr. Voss was Head of Medical Research, Oncology at Asta Medica AG. Dr. Voss received his M.D. from the University of Hamburg Medical School and was a postdoctoral fellow at the University of California San Diego.