Preliminary results confirm that the addition of bone-protecting agents to Radium-233 (Ra-233) treatment can limit fractures in metastatic castration resistant prostate cancer patients

On May 31, 2019 Interim results from the EORTC 1333/PEACE phase III trial were reported at ASCO (Free ASCO Whitepaper) 2019 annual meeting in Chicago, USA (Press release, EORTC, MAY 31, 2019, View Source [SID1234536753]). This phase III study evaluates the benefit of combine Radium-233 (Ra-233) to enzalutamide in early asymptomatic or mildly symptomatic. The trial was amended, following the publications of the ERA223, to impose the co-administration bone protecting agents such as zoledronic acid or denosumab. The safety analysis of 146 patients with or without the addition of these agents was shown.

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Ra-223, enzalutamide, and abiraterone are the cornerstone modern treatment of mCRPC. They are usually used sequentially, enzalutamide and abiraterone being used usually in asymptomatic or mildly-symptomatic patients and Ra-223 being prescribed when the patients become more symptomatic from bone metastases. There is a strong rationale for combined RA-223 earlier with abiraterone or enzalutamide. Two trials were thus conducted: the ERA223 trial1 comparing the combination of RA-223 and abiraterone to abiraterone only and the EORTC-GUCG-1333(PEACE 3) trial comparing the combination of enzalutamide and RA-233 to enzalutamide alone. The ERA 223 was unfortunately unblinded in December 2017 following the demonstration of a significant increase of the risk of fracture and death in the RA-223/abiraterone combination arm.

It was recommended not to use this combination. Following these results, the ESMO (Free ESMO Whitepaper) clinical guidelines were adapted to include that mCRPC patients treated with Ra233 must also be given bone-protecting agents. In the EORTC 1333/PEACE phase III trial, it was seen that this guideline was not followed; therefore when the ERA trial was unblinded an amendment was made to enforce the use of bone protecting agents.

Overall, so far, 45% of the patients were treated without bone protecting agents and their median follow-up is 20 months, and 55% were treated with bone protection. The median follow-up of this group is only 13 months. At one year, the there was a 12.4% cumulative risk of fracture with enzalutamide that increased to 37.4% when Ra223 is added to enzalutamide. However, with mandatory continuous administration of bone protecting agents starting at least 6 weeks before the first injection of Ra223, the cumulative risk at one year was almost abolished with 0 fractures on enzalutamide alone and 2.2% with the combination.

"This safety analysis confirms the importance of complying to international recommendations when treating mCRPC patients, and especially about the importance of preventing skeletal complications in patients with bone metastases," says Professor Bertrand Tombal, leading investigator and urologist from Cliniques Universitaires Saint-Luc in Brussels, Belgium.

"These early results strongly suggest that the risk of fractures is very well controlled in both arms when patients receive bone-protecting agents. The study is closely monitored as recruitment and follow-up continues," says Laurence Collette, leading study statistician and Head of the Statistics Department, EORTC Headquarters, Brussels, Belgium

Abstract number: #5007: Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone; an interim safety analysis.

Bertrand F. Tombal, Yohann Loriot, Fred Saad, Raymond S. McDermott, Tony Elliott, Alejo Rodriguez Vida, Franco Nole, Beatrice Fournier, Laurence Collette, Silke Gillessen

1Smith, M. et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol; 20: 408–19 (2019).

BERGENBIO ASA: INVITATION TO ASCO UPDATE CALL

On May 31, 2019 BerGenBio ASA (OSE:BGBIO), reported that it will share its latest updates and data on an investor call on 4 June 2019, during the annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting (Press release, BerGenBio, MAY 31, 2019, View Source [SID1234536747]). BerGenBio’s senior management team will be hosting the call at 15:30 CET.

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Dial-in details are:

Standard International Dial-In: +44 (0) 2071 928000
United States Dial-In: 16315107495
Participant Code: 4352428
The call will focus on two peer reviewed abstracts on Phase II clinical data with bemcentinib in the treatment of Non-Small Cell Lung Cancer and Acute Myeloid Leukemia.

Iovance Biotherapeutics Expands Partnership with WuXi Advanced Therapies Business

On May 31, 2019 Iovance Biotherapeutics, a late-stage biotechnology company developing novel cancer immunotherapies based on tumor-infiltrating lymphocyte (TIL) technology, reported that it has expanded its relationship with WuXi AppTec’s Advanced Therapies Business Unit (WuXi ATU) (Press release, Iovance Biotherapeutics, MAY 31, 2019, View Source [SID1234536741]). WuXi will increase capacity for Iovance’s innovaTIL-01 and innovaTIL-04 studies, which offer lifileucel and LN-145 for treatment of metastatic melanoma and recurrent, metastatic, or persistent cervical cancer, respectively.

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"We are excited to continue our partnership with WuXi," said Maria Fardis, Ph.D., MBA, President and Chief Executive Officer of Iovance. "Being able to expand our relationship in order to broaden patient access to our treatments is very important to us. WuXi has been a strong partner in developing the Iovance TIL product and we look forward to further expansion of our ongoing relationship."

Felix Hsu, SVP and Global Head of WuXi Advanced Therapies, said, "We are pleased to expand our relationship and manufacturing partnership with Iovance, and look forward to helping to accelerate and expand their clinical trials where possible, so more patients get access to their treatments and the benefits they provide." WuXi manufactures TIL products for Iovance at its Commerce Center 3 facility, a 55,000-square-foot late phase and commercial manufacturing facility for cell therapies. It is one of three facilities in the Philadelphia Navy Yard supporting the development, manufacturing and quality control testing of cell and gene therapies.

MEI Pharma to Present at the Jefferies 2019 Global Healthcare Conference

On May 31, 2019 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported that Daniel P. Gold, Ph.D., president and chief executive officer, will present at the Jefferies 2019 Global Healthcare Conference on Friday, June 7, 2019 at 1:00 p.m. ET (Press release, MEI Pharma, MAY 31, 2019, View Source [SID1234536740]). The conference will take place June 4-7, in New York, N.Y.

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A live audio webcast of the event can be accessed on the Events & Presentations page of the Investors section of MEI Pharma’s website at View Source

An archived replay of the webcast will be available on MEI Pharma’s website for at least 30 days after the live event concludes.

Daiichi Sankyo Presents Preliminary Phase 1 Data for HER3 Targeting ADC U3-1402 in Patients with EGFR Mutated Non-Small Cell Lung Cancer at 2019 ASCO Annual Meeting

On May 31, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that preliminary results from the dose escalation part of the phase 1 study with U3-1402, an investigational and potential first-in-class HER3 targeting antibody drug conjugate (ADC), in 23 patients with metastatic EGFR mutated, TKI resistant non-small cell lung cancer (NSCLC), will be presented today during an Oral Symposium at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL. (Abstract #9010) (Press release, Daiichi Sankyo, MAY 31, 2019, https://www.prnewswire.com/news-releases/daiichi-sankyo-presents-preliminary-phase-1-data-for-her3-targeting-adc-u3-1402-in-patients-with-egfr-mutated-non-small-cell-lung-cancer-at-2019-asco-annual-meeting-300859635.html [SID1234536739])

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Preliminary efficacy data for 16 evaluable patients at the time of data cut-off who received U3-1402 at dose levels from 3.2 mg/kg to 6.4 mg/kg showed that a reduction in tumor size was observed in all 16 evaluable patients across all doses, with a median best percentage change of -29 percent (range -3 to -80 percent). All 16 patients had received prior treatment with an EGFR tyrosine kinase inhibitor (TKI), including 15 with osimertinib. Seven patients also had prior chemotherapy. A total of 16 patients remained on treatment at the time of data cut-off on February 25, 2019.

"These initial clinical data demonstrate activity with U3-1402, including early tumor shrinkage in patients who had developed resistance to approved EGFR TKIs," said Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, and a trial investigator. "There is a need for new treatment approaches for EGFR mutated non-small cell lung cancer that develops resistance to TKIs, especially osimertinib, and preliminary results from this study indicate that targeting HER3 with U3-1402 is a strategy that may be effective across multiple different resistance mechanisms."

HER3 expression has been reported in up to 75 percent of non-small cell lung cancers.1 In study patients, all tumors available for assessment in retrospective immunohistochemistry (IHC) analysis (n=19) showed some level of HER3 expression.

Preliminary safety data in 23 evaluable patients showed a manageable safety profile for U3-1402 with median treatment exposure of 105 days. A maximum tolerated dose has not yet been reached. The most common treatment-emergent adverse events of any grade (in ≥30 percent of patients) included nausea (60.9 percent), fatigue (39.1 percent), vomiting (34.7 percent), decreased appetite (30.4 percent) and platelet count decrease (30.4 percent). One treatment-emergent adverse event grade ≥3 occured in >10 percent of patients (platelet count decrease, 26.1 percent). The following dose-limiting toxicities were observed in four patients: grade 4 platelet count decrease (4 patients) and grade 3 febrile neutropenia (1 patient). Six patients (26.1 percent) experienced treatment-emergent serious adverse events regardless of causality, with three patients (13.0 percent) experiencing treatment-emergent serious adverse events that were related to study treatment. One patient experienced a treatment-emergent adverse event leading to treatment discontinuation (4.3 percent).

"U3-1402 was designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver chemotherapy inside cancer cells that express HER3 as a cell surface antigen," said Dalila Sellami, MD, Vice President, U3-1402 Global Team Leader, Global Oncology Research and Development, Daiichi Sankyo. "These findings provide evidence of promising activity of U3-1402 in non-small cell lung cancer and add to our previous preliminary research demonstrating its potential use in HER3 positive metastatic breast cancer."

About the Study
The global, phase 1, open label, two-part study is enrolling patients with metastatic or unresectable EGFR mutated NSCLC that has progressed while taking an EGFR TKI. This includes patients who either experienced disease progression on erlotinib, gefitinib, dacomitinib or afatinib and tested negative for the T790M mutation or who experienced disease progression on osimertinib regardless of T790M status. The primary objectives of the study are to assess the safety and tolerability of U3-1402 and determine the recommended dose for expansion. The secondary objectives are to characterize the pharmacokinetics of U3-1402 and to evaluate preliminary efficacy by measuring antitumor activity of U3-1402. The study is expected to enroll more than 60 patients at approximately 17 sites globally. For more information about the study, visit ClinicalTrials.gov.

About U3-1402
Part of the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise, U3-1402 is an investigational and potential first-in-class HER3 targeting ADC. 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. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, U3-1402 is comprised of a human anti-HER3 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

U3-1402 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

Unmet Need in Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide; there were an estimated 2.1 million new cases of lung cancer in 2018 and 1.8 million deaths.2 Most lung cancers are diagnosed at an advanced or metastatic stage.3 Non-small cell lung cancer (NSCLC) accounts for 80 to 85 percent of all lung cancers.4 The introduction of targeted therapies and checkpoint inhibitors in the past decade has improved the treatment landscape for patients with advanced or metastatic NSCLC; however, for those who are not eligible for current treatments, or whose cancer continues to progress, new therapeutic approaches are needed.5

For patients with advanced EGFR mutated NSCLC, EGFR TKIs offer higher response rates and progression free survival compared to chemotherapy; however, most patients eventually develop resistance to the drugs, usually within a year, at which point treatment options become more limited.6

HER3 is a member of the human epidermal growth factor receptor family of tyrosine kinase receptors, which are associated with aberrant cell growth.7 HER3 is overexpressed in several types of cancers and has been linked to tumor progression and worse overall survival.8 HER3 expression is associated with increased metastases and reduced survival in patients with non-small cell lung cancer, where frequency has been reported as high as 75 percent.1 In recent years, researchers have recognized potential for HER3 as a therapeutic target.7 Currently, no HER3 targeting agents are approved for NSCLC or any cancer.