On May 29, 2020 EORTC reported that the long-term results of the MINDACT (EORTC 10041/BIG3-04) study were presented today in the ASCO (Free ASCO Whitepaper) virtual meeting (Press release, EORTC, MAY 29, 2020, View Source [SID1234558776]). MINDACT tests the 70-gene signature MammaPrint to help identifying breast cancer patients who would do not need adjuvant chemotherapy . In 2016, the results of the primary endpoint (distant metastasis free survival (DMFS)) at 5 years median follow up were presented . Dr Fatima Cardoso, the principle investigator of the study, presented the updated results with 8.7 years of median follow-up, with more than 90% of patients followed for at least 5 years. 6693 patients were enrolled in the randomised MINDACT study between 2007-2011. The DMFS was assessed at 5 years for 644 clinical high and genomic low risk patients who were randomised to follow the genomic risk assessment and received no chemotherapy. In addition, a secondary analysis was conducted to evaluate DMFS and overall survival in the same population of clinical high and genomic low population depending on whether chemotherapy was administered or not.

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The present analysis confirms that MINDACT is a positive de-escalation study, as the primary DMFS endpoint at 5 years is continually met in clinical high and genomic low risk patients who receive no chemotherapy. The outcome of the "intention to treat" population are shown in the table below.

At 8 years, the estimated DMFS gain for chemotherapy administration in Clinical-High/Genomic-Low is 2.6% and must be balanced with the treatment’s harmful side effects.

A subgroup analyses was performed regarding the effect of chemotherapy per age group. This analysis showed that: a) omitting chemotherapy in Clinical-High/Genomic-Low postmenopausal women continues to be safe, (DMFS gain 0.2% ± 2.3%), and a fully preserved performance of MammaPrint to forego adjuvant chemotherapy is demonstrated; b) in premenopausal women the difference seen might be clinically relevant (DMFS gain 5% ± 2.8%); importantly, this effect may possibly be related to chemotherapy-induced ovarian function suppression.

"The present analysis clearly proves that chemotherapy can safely be avoided for postmenopausal women, classified as high risk of relapse by traditional clinico-pathological factors, but with a MammaPrint test of low risk, confirming the clinical utility of this genomic test, " said Dr Fatima Cardoso, Principal Investigator of the Study and Director of the Breast Unit at the Champalimaud Clinical Centre, Lisbon, Portugal.

Research Funding:
MINDACT was supported by grants from the European Commission Framework Programme VI (FP6-LSHC-CT-2004-503426, "TRANSBIG Network of Excellence"), the Breast Cancer Research Foundation, the U.S. National Cancer Institute, the European Breast Cancer Council-, Pharmaceutical/Biotech Company, U.S. National Institutes of Health

Session Type: Oral Abstract Session
Session Title: Breast Cancer—Local/Regional/Adjuvant
Track: Breast Cancer—Local/Regional/Adjuvant
Subtrack: Adjuvant Therapy
Abstract #: 506
Clinical Trial Registry Number: NCT00433589
Citation: J Clin Oncol 38: 2020 (suppl; abstr 506)
DOI: 10.1200/JCO.2020.38.15_suppl.506
Research support: Funding

MINDACT was supported by grants from the European Commission Framework Programme VI (FP6-LSHC-CT-2004-503426, "TRANSBIG Network of Excellence"), the Breast Cancer Research Foundation, Novartis, F. Hoffman La Roche, Sanofi-Aventis, Eli Lilly, Veridex, the U.S. National Cancer Institute, the European Breast Cancer Council-Breast Cancer Working Group (BCWG grant for the MINDACT biobank), the Jacqueline Seroussi Memorial Foundation (2006 JSMF award), Prix Mois du Cancer du Sein (2004 award), Susan G. Komen for the Cure (SG05-0922-02), Fondation Belge Contre le Cancer (SCIE 2005-27), Dutch Cancer Society (KWF), The Netherlands Genomics Initiative – Cancer Genomics Centre (2008-2012), Association Le Cancer du Sein, Parlons-en!, the Brussels Breast Cancer Walk-Run and the American Women’s Club of Brussels, NIF Trust, German Cancer Aid, the Grant Simpson Trust and Cancer Research UK, La Ligue Nationale Contre Le Cancer. This trial was also supported by the EORTC Cancer Research Fund. Whole genome analysis was provided in kind by Agendia.

Role of the funding sources

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Acknowledgments

We are grateful to all patients and families who participated in this study.

We are grateful to the European Commission Sixth Framework Programme (FP6-LSHC-CT-2004-503426), the European Community Seventh Framework Programme (HEALTH-F2-2009-223175 to the Collaborative Oncological Gene-environment Study), the Breast International Group (BIG) AISBL, F. Hoffmann-La Roche, Novartis, Sanofi-Aventis, for supporting this independent EORTC Study.

On May 29, 2020 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported updated data from the dose escalation portion of the company’s Phase 1/2 clinical trial of ARV-110 in men with metastatic castration-resistant prostate cancer (mCRPC), to be shared as an oral presentation at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on May 29, 2020 (Press release, Arvinas, MAY 29, 2020, View Source [SID1234558660]). ARV-110 is a potent, selective, orally available androgen receptor (AR) degrader, and the ASCO (Free ASCO Whitepaper) presentation highlights promising clinical activity, including both efficacy and AR degradation, in a heavily pretreated patient population. ­

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"For ARV-110 to show signs of efficacy in these patients at this early stage of development is strong validation of our PROTAC technology," said John Houston, Ph.D., President and Chief Executive Officer at Arvinas. "In addition, seeing AR degradation demonstrates that ARV-110 is acting on-mechanism to achieve this result, and we are excited to continue clinical development in the hope of bringing a new therapeutic option to patients with significant unmet need."

"The responses we see are the first powerful examples in patients of the potential benefits of protein degradation pharmacology compared to classic inhibition or antagonism, which failed in these patients while degradation showed clinical benefit," added Ron Peck, M.D., Chief Medical Officer at Arvinas. "This is a patient population where other therapies would be expected to have little to no benefit, and we are very pleased with the early clinical efficacy data and safety profile we are seeing and think it bodes well for both ARV-110 and the PROTAC platform."

The dose escalation portion of Arvinas’ Phase 1/2 clinical trial of ARV-110 is designed to assess safety, tolerability, and pharmacokinetics (PK) in men with mCRPC who have progressed on standard of care therapies, as well as to identify a recommended Phase 2 dose. To date, ARV-110 has shown a favorable safety profile, and PK have been generally dose proportional, reaching exposures associated with tumor inhibition in preclinical models at 140 mg. In the data released today, Arvinas also shared evidence of in-tumor AR reduction, the first demonstration of successful targeted protein degradation by a PROTAC protein degrader in humans.

ARV-110 has demonstrated evidence of activity at doses and in AR mutational backgrounds in which responses would be expected based on preclinical data. As of the April 20, 2020 data cut-off, 20 patients were evaluable for prostate-specific antigen (PSA) response, including 12 patients treated at 140 mg or higher (these 12 patients exclude one patient who received two weeks of therapy prior to discontinuing due to a rosuvastatin-related dose limiting toxicity).

Of those 12 patients treated at 140 mg and above, circulating tumor DNA (ctDNA) analysis of five patients showed AR forms not degradable by ARV-110 in preclinical studies (i.e., L702H point mutations and AR-V7 splice variants). In the group of seven remaining patients who had forms of AR degradable by ARV-110 (other AR point mutations, AR amplification, and wildtype AR), two patients achieved confirmed PSA responses that remain ongoing with additional follow-up since the abstract was submitted.

One of these patients had a 74% decline from baseline in PSA and remained without progression after 30 weeks, as of the data cut-off. This patient did not have measurable disease at baseline for assessment by Response Evaluation Criteria in Solid Tumors (RECIST). The second patient had both a deep PSA response (97% decline from baseline) and a confirmed RECIST response (80% decrease from baseline in tumor mass) and remains without progression after 18 weeks. Both responses, which were in patients at the 140 mg dose, were achieved by ARV-110 despite prior enzalutamide, abiraterone, chemotherapy, and other therapies. Tumors from both patients have H875Y and T878A point mutations in AR, which are known to drive resistance to current standard of care treatments and have been degraded by ARV-110 in preclinical studies. In addition to these two patients, PSA reductions were observed in other patients but did not meet a 50% reduction in PSA threshold at data cutoff, and four patients remain on ARV-110 without radiographic progression for at least 20 weeks.

A potential drug-drug interaction between ARV-110 and rosuvastatin (ROS) was identified during the trial. Of the 22 patients enrolled, two had concurrent use of ROS. One patient receiving 280 mg ARV-110 experienced a Grade 4 dose-limiting toxicity (DLT) of elevated aspartate transaminase/alanine transaminase (AST/ALT) followed by acute renal failure. The second patient, receiving 70 mg ARV-110, experienced a Grade 3 AST/ALT elevation, which resolved after the removal of ROS, and the patient was retreated with ARV-110. Follow-up exploratory findings indicate that ROS concentrations were elevated in both patients who had liver function test (LFT) increases. Subsequent in vitro transport pump studies indicate that ARV-110 inhibits breast cancer resistant pump (BCRP) transporter, of which ROS is a substrate. Following the initial data that supported a potential interaction with ROS, concomitant use of ROS was precluded, and no other related Grade 3 or 4 adverse events have since been reported. Six other patients have received concomitant non-ROS statins without AST/ALT adverse events.

Dose escalation and enrollment continues, with the most recent cohort initiating dosing in May 2020 at 420 mg. The expansion portion of the Phase 1/2 trial is expected to begin once the recommended Phase 2 dose has been determined and will evaluate the anti-tumor activity of ARV-110 through assessment of PSA response, using the Prostate Cancer Working Group 3 Criteria, and overall RECIST response rate in patients with measurable disease. The expansion will further investigate a link between AR genomic profile and efficacy, which could inform an enrichment strategy. Arvinas plans to provide updated information on the ARV-110 Phase 1/2 study by the end of 2020.

Arvinas Webcast Investor Meeting
The company will host a conference call and webcast at 8:30 AM ET today to discuss these data. Participants are invited to listen by dialing (844) 467-7654 (domestic) or (602) 563-8497 (international) five minutes prior to the start of the call and providing the passcode access code 8069179. A listen-only webcast of the conference call can also be accessed through the "Investors + Media" tab on the Arvinas website, www.arvinas.com, and a replay will be available for six weeks following the call.

About ARV-110
ARV-110 is an orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR). ARV-110 is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer.

ARV-110 has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies.

About Metastatic Castration-Resistant Prostate Cancer (mCRPC)

In the United States, prostate cancer is both the second most prevalent cancer in men and the second leading cause of cancer death in men. The American Cancer Society predicts that one in nine men will be diagnosed with prostate cancer in his lifetime. Metastatic castration-resistant prostate cancer (mCRPC) is defined by disease progression despite androgen deprivation therapy and is often correlated with rising levels of prostate-specific antigen (PSA).

Current AR-targeted standard of care treatments for mCRPC are less effective in patients whose disease has increased levels of androgen production, AR gene or gene enhancer amplification, or AR point mutations. Up to 25 percent of patients do not respond to second-generation hormone therapies like abiraterone and enzalutamide, and the vast majority of responsive patients will ultimately become resistant, resulting in poor prognoses for men diagnosed with this devastating condition.

On May 29, 2020 AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) reported that Results from the ongoing Phase II DESTINY-Lung01 trial showed Enhertu (trastuzumab deruxtecan) achieved a clinically meaningful tumour response in patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) whose disease had progressed following one or more systemic therapies (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558676]).

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Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1 There are currently no medicines approved specifically for the treatment of HER2m NSCLC, which affects approximately 2-4% of patients with NSCLC.2,3

The primary endpoint of confirmed objective response rate (ORR), assessed by independent central review, was 61.9% for patients treated with Enhertu monotherapy (6.4mg/kg). Patients achieved a disease control rate (DCR) of 90.5% with an estimated median progression-free survival (PFS) of 14.0 months. Median duration of response (DoR) and overall survival (OS) had not yet been reached at the time of data cut-off.

Egbert F. Smit, MD, PhD, Professor, Department of Thoracic Oncology at the Netherlands Cancer Institute, Amsterdam, Netherlands and principal investigator in the Phase II DESTINY-Lung01 trial, said: "While there have been important advances in the treatment of lung cancer over the past decade, there are still patients whose tumours continue to progress despite treatment with newer targeted agents or immunotherapies. Understanding additional molecular targets for treatment, such as HER2, is critical to advancing treatment options for these patients, and the results seen in the DESTINY-Lung01 trial are very encouraging."

José Baselga, Executive Vice President, Oncology R&D, said: "The results seen with Enhertu in patients with metastatic HER2-mutant non-small cell lung cancer are very exciting and highlight the role Enhertu may have as a new treatment option for patients facing a devastating prognosis. Further, the results demonstrate the potential of Enhertu to treat another tumour type among patients with extremely high unmet need."

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "While the role of anti-HER2 treatment is well-established in breast and gastric cancers, there are no HER2-directed therapies specifically approved for lung cancer. These results validate HER2 mutations as actionable targets in lung cancer and offer further evidence that Enhertu has the potential to transform outcomes for these patients."

Summary of results

CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable
i. Enhertu 6.4 mg/kg.
ii. As assessed by independent central review.
iii. ORR is (CR + PR).
iv. DCR is (CR + PR + SD).

Patients were treated with a median of two prior lines of therapy (1-6) with most receiving platinum-based chemotherapy (90.5%) and anti-PD-1 or PD-L1 treatment (54.8%). Median treatment duration was 7.76 months (0.7-14.3) with a median duration of follow-up of 8.0 months (1.4-14.2). As of data cut-off on 25 November 2019, 45.2% of patients with HER2m metastatic NSCLC remained on treatment with Enhertu.

The overall safety and tolerability profile of Enhertu in DESTINY-Lung01 was consistent with that seen in the Phase I lung cancer trial and previously reported Enhertu trials.4 The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (26.2%) and anaemia (16.7%). There were five cases (11.9%) of confirmed treatment-related interstitial lung disease (ILD) and pneumonitis as determined by an independent adjudication committee. All ILD and pneumonitis cases were Grade 2. One Grade 1 ILD is still undergoing adjudication.

Results from the DESTINY-Lung01 trial were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on 29 to 31 May 2020. Several other presentations featured during the meeting will showcase AstraZeneca’s leadership in lung cancer across early and late-stage disease and reinforce the Company’s biomarker-driven approach.

Enhertu was recently granted Breakthrough Therapy Designation in the US for the treatment of HER2m metastatic NSCLC.

HER2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers. In some tumours, HER2 overexpression is associated with a specific HER2 gene alteration known as amplification and is often associated with aggressive disease and poorer prognosis.5

Other HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets.3,6 These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis.2,3,6

NSCLC

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths globally.1

Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC. Within NSCLC, patients are classified as squamous, representing 25-30% of patients, or non-squamous, the most common type representing approximately 70-75% of NSCLC patients. Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.7 For these patients with metastatic disease, prognosis is particularly poor, only 6-10% will be alive five years after diagnosis.8,9 The introduction of targeted therapies and checkpoint inhibitors in recent years has improved outcomes for patients with advanced NSCLC; however, new approaches are needed for those who are not eligible for available treatments, or whose cancer continues to progress.10 Currently, no medicine is specifically approved to treat patients with HER2m NSCLC.

DESTINY-Lung01

DESTINY-Lung01 is a global, Phase II, open-label, multi-centre, two-cohort trial testing the safety and efficacy of Enhertu in 170 patients with HER2m or HER2-overexpressing, defined as IHC3+ or IHC2+, unresectable and/or metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is confirmed ORR by independent central review. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappears. Key secondary endpoints include DoR, DCR, PFS and OS.11

Enhertu

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed antibody drug conjugate (ADC) and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Enhertu (5.4 mg/kg) is approved in the US and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

In May 2020, Enhertu received BTD from the US FDA for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab and Orphan Drug Designation for patients with gastric cancer, including gastroesophageal junction cancer. In March 2018, Enhertu received a SAKIGAKE designation for potential use in the same HER2-positive gastric cancer patient population and a supplemental New Drug Application was recently submitted to the Japan Ministry of Health, Labour and Welfare.

In May 2020, Enhertu also received a BTD for the treatment of patients with metastatic NSCLC whose tumours have a HER2 mutation and with disease progression on or after platinum-based therapy.

Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histology, several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and its ongoing Phase III trials LAURA, and FLAURA2.12-14 We are also committed to addressing tumour mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines. Enhertu, a HER2-directed ADC, is in development for HER2m metastatic non-squamous NSCLC including trials in combination with other anticancer medicines.11

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.15 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON and PEARL) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the Phase II trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline including Enhertu.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and ADCs – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On May 29, 2020 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), currently developing pelareorep, an intravenously delivered immuno-oncolytic virus, reported the publication of an electronic-poster (ePoster) with clinical proof-of-concept data from the Company’s phase 1b study in carfilzomib-refractory multiple myeloma patients treated with pelareorep in combination with carfilzomib (Kyprolis) (Press release, Oncolytics Biotech, MAY 29, 2020, View Source [SID1234558692]). Data presented in the ePoster demonstrates that the pelareorep-carfilzomib combination treatment results in selective replication of pelareorep in cancer cells and beneficial induction of an inflamed tumor environment associated with clinical responses. The ePoster was published this morning and will be presented this weekend as part of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Annual Meeting.

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"We are excited by the data showing an association between clinical and anti-tumor inflammatory response induced with pelareorep-carfilzomib treatment in this extremely difficult to treat patient population," said Dr. Douglas W. Sborov, MD, co-author. "The induction of cytokine release syndrome, which can be effectively monitored and managed via treatment with tocilizumab and steroids, is particularly interesting as it highlights the ability of the treatment to induce robust immune cell activation and tumor lysis. Taken together with earlier results from this study demonstrating pelareorep-induced upregulation of PD-L1 expression, the current data strongly support the potential of the ongoing trial investigating pelareorep, carfilzomib, and immune checkpoint inhibitor combination. This ongoing study could ultimately result in the development of a new treatment option for this high-need indication."

The ePoster, Oncolytic virus Pelareorep [P] plus Carfilzomib & Dexamethasone [Kd] phase 1 trial in Carfilzomib-refractory patients (NCI9603): responses with cytokine storm was co-authored by Dr. Douglas W. Sborov MD, MS, Assistant Professor, Division of Hematology and Hematologic Malignancies, University of Utah – Huntsman Cancer Institute, and Craig Hofmeister, M.D., MPH, Associate Professor, Department of Hematology and Medical Oncology Emory University School of Medicine, as well as several other colleagues at institutions across the United States. Key data and conclusions from six patients in the study are presented in the ePoster and include:

•Pelareorep targets and selectively replicates in multiple myeloma tumor cells
•Pelareorep, when combined with carfilzomib, activates a profound inflammatory response accompanied by a 50% ORR (overall response rate) and 83% CBR (clinical benefit rate)
•Three partial responses (PRs), one minimal response (MR), one stable disease (SD), and one progressive disease (PD) were achieved among patients with advanced and difficult-to-treat carfilzomib-refractory disease
•Significant and rapid T cell activation led to a single incidence of cytokine storm associated with tumor response after treatment with pelareorep and carfilzomib

"The exciting clinical proof-of-concept data demonstrate that pelareorep induces an inflammatory response in multiple myeloma, which is an unusual lymphoid tumor with immunosuppressive properties," said Dr. Rita Laeufle, Chief Medical Officer of Oncolytics Biotech. "The study examines the relationship between pelareorep-induced tumor inflammation and response to treatment. These findings reveal that induction of inflammation within the multiple myeloma tumor microenvironment may augment the effectiveness of checkpoint inhibitors, which to date have had little success against multiple myeloma."

The ePoster was presented as part of the Hematologic Malignancies-Plasma Cell Dyscrasia session at the ASCO (Free ASCO Whitepaper) Virtual Annual Meeting. A copy of the ePoster can be found on the Posters & Publications page of the company’s website: View Source

About Pelareorep
Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.

On May 29, 2020 Myovant Sciences (NYSE: MYOV), a healthcare company focused on redefining care for women and for men, reported additional results from its Phase 3 HERO study of once-daily, oral relugolix (120 mg) in men with advanced prostate cancer in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program and simultaneous publication in the New England Journal of Medicine (NEJM) (Press release, Myovant Sciences, MAY 29, 2020, https://investors.myovant.com/news-releases/news-release-details/myovant-sciences-announces-additional-positive-efficacy-and [SID1234558710]). The data expand on earlier findings from the HERO study, demonstrating the superiority of relugolix to leuprolide acetate across multiple endpoints, and further show that treatment with relugolix was associated with a lower risk of major adverse cardiovascular events compared to leuprolide acetate.

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Relugolix met the primary endpoint and demonstrated superiority to leuprolide acetate across six key secondary endpoints, all with p-values < 0.0001. In the primary endpoint responder analysis, 96.7% of men receiving once-daily, oral relugolix achieved sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks, compared to 88.8% of men treated with leuprolide acetate.

Detailed secondary endpoint data, presented and published today, showed notable differences in the rapid and profound suppression of testosterone, PSA response, and testosterone recovery after discontinuation of treatment. In the relugolix group, testosterone suppression to less than 50 ng/dL was achieved in 56.0% of men by Day 4 and 98.7% by Day 15, compared to 0.0% by Day 4 and 12.1% by Day 15 for men in the leuprolide acetate group. Additionally, in the relugolix group, profound testosterone suppression to less than 20 ng/dL was achieved in 78.4% of men at Day 15, compared to 1.0% at Day 15 for men in the leuprolide acetate group. A higher proportion of men in the relugolix group achieved a 50% reduction in PSA by Day 15 and confirmed at Day 29 compared to those in the leuprolide acetate group (79.4% vs. 19.8%, respectively). Within 90 days of treatment discontinuation, 54% of men in the relugolix group achieved normal testosterone levels (≥ 280 ng/dL) with a mean testosterone level of 288.4 ng/dL, compared to 3% of men in the leuprolide acetate group with a mean testosterone level of 58.6 ng/dL.

"A faster effect in lowering testosterone for prostate cancer patients can be clinically significant – likewise, a more rapid testosterone recovery after stopping treatment, could potentially improve a patient’s quality of life," said Neal Shore, M.D., medical director of the Carolina Urologic Research Center, HERO program steering committee member, presenter of the ASCO (Free ASCO Whitepaper) data, and lead author on the NEJM paper. "Both of these findings could make a meaningful difference in the treatment journey for men with advanced prostate cancer."

Men in the relugolix group had a 54% lower risk of major adverse cardiovascular events compared to men in the leuprolide acetate group (2.9% vs. 6.2%, respectively). Additionally, in men with a history of these events, the relugolix group had 80% fewer major adverse cardiovascular events reported compared to the leuprolide acetate group (3.6% vs. 17.8%, respectively). More than 90% of men in the HERO study had at least one cardiovascular risk factor, including lifestyle risk factors such as tobacco use and obesity, comorbidities such as diabetes and hypertension, and prior history of a major adverse cardiovascular event.

"Cardiovascular disease is the leading cause of death in men with prostate cancer," said Dr. Shore. "An oral therapeutic option with strong efficacy that also reduces cardiovascular risk compared to that of conventional GnRH agonist therapy would be a critical achievement for men with advanced prostate cancer."

As previously reported, the incidence of adverse events in the HERO study was comparable for relugolix and leuprolide acetate groups (92.9% vs. 93.5%, respectively). The most frequently reported adverse events, reported in at least 10% of men in the relugolix group, were hot flashes, fatigue, constipation, mild to moderate diarrhea, and arthralgia.

"Relugolix has the potential to be an important new treatment option for men with prostate cancer and would represent significant progress in our company’s commitment to redefine care for men," said Lynn Seely, M.D., chief executive officer of Myovant Sciences. "We are grateful to have the opportunity to share these additional data through presentation and publication in such highly-respected venues as the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the New England Journal of Medicine. We have already submitted our New Drug Application to the FDA with the goal of bringing this oral, once-daily potential treatment to men with prostate cancer as expeditiously as possible, especially given the current environment with the COVID-19 pandemic and the difficulties and risks men face traveling to hospitals and clinics to receive injections."

Myovant submitted a New Drug Application (NDA) to the FDA for relugolix in April 2020, which, if approved, would be the first and only oral gonadotropin-releasing hormone (GnRH) receptor antagonist treatment for men with advanced prostate cancer.

The ASCO (Free ASCO Whitepaper) presentation (#5602), "HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer," is available for on-demand viewing.

Conference Call
Myovant will hold a conference call to discuss these data on Monday, June 1, 2020 at 8:30 a.m. Eastern Time / 5:30 a.m. Pacific Time. Myovant management will be joined by Neal Shore, M.D. To participate in the live conference call, please dial 1-800-532-3746 for domestic callers and +1-470-495-9166 for international callers. A live webcast of the conference call will also be available on the investor relations page of Myovant’s website at investors.myovant.com and will remain archived on Myovant’s website for at least 30 days.

About the Phase 3 HERO Program in Advanced Prostate Cancer
Myovant’s Phase 3 clinical program for advanced prostate cancer consisted of a randomized, open-label, parallel-group, multinational clinical study designed to evaluate the safety and efficacy of relugolix in men with androgen-sensitive advanced prostate cancer who required at least one year of continuous androgen deprivation therapy. Men enrolled in the study were randomized 2:1 to receive a single loading dose of relugolix 360 mg followed by relugolix 120 mg once daily, or to treatment with leuprolide acetate 3-month depot injection, respectively.

Data from an additional key secondary endpoint, castration resistance-free survival, are expected in the third quarter of 2020.

About Prostate Cancer
Prostate cancer is the second most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the U.S. Cardiovascular mortality is the leading cause of death in men with prostate cancer and accounts for 34% of deaths in men with prostate cancer in the U.S. Approximately three million men in the U.S. are currently living with prostate cancer, and approximately 170,000 men are estimated to be newly diagnosed in 2019. Advanced prostate cancer is prostate cancer that has spread or come back after treatment and may include men with biochemical recurrence (rising PSA in the absence of metastatic disease on imaging), locally advanced disease, or metastatic disease. Treatment for advanced prostate cancer typically involves androgen deprivation therapy, which reduces testosterone to very low levels, commonly referred to as castrate levels. GnRH receptor agonists, such as leuprolide acetate, or slow-release injections are the current standard of care for androgen deprivation therapy. However, GnRH receptor agonists may be associated with mechanism-of-action limitations, including the potentially detrimental initial rise in testosterone levels that can exacerbate clinical symptoms, which is known as clinical or hormonal flare, and delayed testosterone recovery after the drug is discontinued. Approximately 200,000 men are treated with androgen deprivation therapy with a GnRH agonist or antagonist each year.

About Relugolix
Relugolix is a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist that reduces testicular testosterone production, a hormone known to stimulate the growth of prostate cancer, and ovarian estradiol production, a hormone known to stimulate the growth of uterine fibroids and endometriosis. Myovant is developing relugolix as a monotherapy tablet (120 mg once daily) for men with advanced prostate cancer. Myovant is also developing a relugolix combination tablet (relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) for women with uterine fibroids and for women with endometriosis.