On January 15, 2021 Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical company developing multifunctional biotherapeutics, reported new and updated clinical data for the HER2‑targeted bispecific antibody zanidatamab, in both HER2-expressing biliary tract cancer (BTC) and gastroesophageal adenocarcinoma (GEA) (Press release, Zymeworks, JAN 15, 2021, View Source [SID1234574037]). The data are being presented today at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium, taking place virtually January 15 – 17, 2021.

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"Data presented today at ASCO (Free ASCO Whitepaper) GI continue to demonstrate the potential of zanidatamab in advanced HER2-expressing cancers with high unmet need. The response rates and median duration of response in refractory BTC and GEA compare favorably to current standard of care and emerging treatments," said Diana Hausman, M.D., Chief Medical Officer at Zymeworks. "The BTC data were the basis of the recent Breakthrough Therapy designation granted by the FDA, a key step in helping zanidatamab become the first potential HER2‑targeted therapy approved in this indication. Furthermore, the activity in GEA supports our goal of establishing zanidatamab as the foundational HER2-targeted therapy for GEA and other HER2-positive cancers, not only in later stage disease, but also in earlier lines of treatment."

The following presentations are available to conference registrants on the ASCO (Free ASCO Whitepaper) conference website as well as to the general public at ir.zymeworks.com/events-and-presentations/.

Zanidatamab Monotherapy and Chemotherapy Combinations in HER2-Expressing Gastroesophageal Cancer – Clinical Results – Abstract #164

Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): Results from a Phase 1 study (Presenter: Funda Meric-Bernstam, MD, UT MD Anderson Cancer Center, TX; Rapid Abstract oral presentation on Friday, January 15, 11:30 am-12:15 pm ET)

HER2 is overexpressed in approximately 20% of GEA patients. For these patients, trastuzumab in combination with chemotherapy is the only approved HER2‑targeted therapy. Treatment options are currently limited if disease progression occurs after trastuzumab in combination with chemotherapy.

Findings from an ongoing Phase 1 study of zanidatamab in HER2-positive GEA were last presented in July 2020. New and updated results are being presented in a Rapid Abstract oral presentation today, January 15th, at 11:30 am ET at the ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium followed by a webcast at 5:00 pm ET to discuss the data, led by zanidatamab study investigator Dr. Funda Meric-Bernstam, MD.

The data being reported are from HER2-expressing GEA patients who received zanidatamab either as monotherapy (n=35) or in combination with chemotherapies (n=28). The groups had a median of two to three (range 0-7) prior therapies, with a high percentage (88-91%) having received prior HER2-targeted therapies. The data continue to demonstrate that zanidatamab is well tolerated with the majority of treatment-related AEs considered mild to moderate in severity (Grade 1 or 2) and manageable in the outpatient setting.

In 33 response-evaluable patients who received zanidatamab as monotherapy (10 mg/kg weekly or 20 mg/kg every two weeks), the objective response rate (ORR) was 39% (13/33), 11 (33%) of which were confirmed by a subsequent scan. The disease control rate (DCR) was 61% (20/33) and median duration of response (DOR) was six months.

In 10 response-evaluable patients who received zanidatamab (20 mg/kg every two weeks) plus paclitaxel, the ORR was 60% (6/10), five (50%) of which were confirmed by a subsequent scan including one patient who experienced a complete response. The DCR was 90% (9/10) for this group. In 14 response-evaluable patients who received zanidatamab (20 mg/kg every two weeks or 30 mg/kg every three weeks) plus capecitabine, the confirmed ORR was 57% (8/14) and the DCR was 71% (10/14). Overall the median DOR for zanidatamab plus chemotherapy was 8.9 months and the median progression-free survival (PFS) was 5.6 months with eight (29%) patients still on study at the time of data cut-off.

In 2019, Zymeworks initiated a global, multicenter Phase 2 clinical trial (NCT03929666) evaluating zanidatamab in combination with standard of care chemotherapy for the first-line treatment of HER2-positive metastatic GEA. Taken together, data from the Phase 1 and Phase 2 studies further support the company’s plans to initiate, with partner BeiGene, a pivotal study for zanidatamab plus chemotherapy +/- tislelizumab (anti-PD1), as first-line treatment for advanced HER2-positive GEA in mid-2021.

Zanidatamab Monotherapy in HER2-Amplified Biliary Tract Cancer – Clinical Results – Abstract #299

Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): Results from a Phase 1 study (Presenter: Funda Meric-Bernstam, MD, UT MD Anderson Cancer Center, TX)

Globally, more than 210,000 people are diagnosed with BTC every year and as many as one-fifth of these patients have tumors that express HER2. Currently no HER2‑targeted therapy has been approved for the treatment of BTC.

Findings from the ongoing Phase 1 study of zanidatamab in HER2-amplified BTC were last shared in July 2020. The updated and new results are being presented today in a poster session at the ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium.

Data were reported on 21 patients diagnosed with HER2-amplified BTC who received zanidatamab at the recommended dose of 20 mg/kg every two weeks. Patients received a median of two (range 1-8) prior therapies and five (24%) of the patients were previously treated with the HER2-targeted therapy trastuzumab.

Zanidatamab was well tolerated and demonstrated durable antitumor activity in these patients. All zanidatamab-related adverse events (AEs) were mild or moderate in severity (Grade 1 or 2). The confirmed objective response rate (ORR) in trastuzumab-naïve patients was 47% (7/15) and overall ORR was 40% (8/20). The overall disease control rate (DCR) was 65% (13/20), and median duration of response (DOR) was 7.4 months with several patients still on study at the time of data cut-off.

Based on these results, in July 2020 Zymeworks initiated a global pivotal Phase 2b trial (HERIZON-BTC-01; ZW25-203) [NCT04466891] of zanidatamab monotherapy in patients with HER2-amplified BTC that has been previously treated with at least one gemcitabine-containing systemic chemotherapy regimen. The US Food and Drug Administration (FDA) recently granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified BTC, based on evaluation of the Phase 1 data. This global pivotal Phase 2 study of zanidatamab in BTC may enable the submission of a Biologics License Application by Zymeworks in the United States as early as 2022.

Zanidatamab HERIZON-BTC-01 Trial in Progress Poster Presented Today – Abstract TPS352

A Phase 2b, Open-label, Single-arm Study of Zanidatamab (ZW25) Monotherapy in Patients with Advanced or Metastatic HER2-amplified Biliary Tract Cancers (BTC): HERIZON-BTC-01 Study (Lead Author: Shubham Pant, MD, UT MD Anderson Cancer Center, TX)

Zymeworks is presenting a trial in progress poster at ASCO (Free ASCO Whitepaper) GI for a global pivotal Phase 2 trial in HER2-amplified BTC (HERIZON-BTC-01; ZW25-03). Multiple clinical sites are now open to enrollment in the U.S., South Korea, Italy and Spain, with additional sites planned in Canada, Chile, China, France and the UK [Phase 2:NCT04466891]. This study is designed to support accelerated approval based on a primary endpoint of objective response rate, and key secondary endpoints of duration of response and safety.

About the Zanidatamab Phase 1 Clinical Trial

Zymeworks’ Phase 1 zanidatamab study has three parts. From part one of the study (the dose-escalation phase), the recommended single-agent dose was determined to be 20 mg/kg once every two weeks or 10 mg/kg weekly. In the second part of the study (the cohort expansion phase), additional patients are being enrolled to further assess zanidatamab’s single-agent tolerability and antitumor activity against a variety of cancer types in different settings. The third part of the study (the combination phase) is underway and evaluating zanidatamab in combination with selected chemotherapy agents in gastroesophageal and breast cancer patients with HER2 high or lower HER2 expression levels.

About Zanidatamab

Zanidatamab is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding, and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks is developing zanidatamab in multiple Phase 1, Phase 2, and pivotal clinical trials globally as a targeted treatment option for patients with solid tumors that express HER2. The FDA has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified BTC, and two Fast Track designations to zanidatamab, one as a single agent for refractory BTC and one in combination with standard of care chemotherapy, for first-line gastroesophageal adenocarcinoma (GEA). These designations mean zanidatamab is eligible for Accelerated Approval, Priority Review and Rolling Review, as well as intensive FDA guidance on an efficient drug development program. Zanidatamab has also received Orphan Drug designations for the treatment of biliary tract, gastric and ovarian cancers, as well as Orphan Drug designation for the treatment of gastric cancer from the European Medicines Agency.

On January 15, 2021 Isofol Medical AB (publ) ("Isofol"), (Nasdaq First North Premier Growth Market: ISOFOL) reported that a poster presentation is presented at ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI) (Press release, Isofol Medical, JAN 15, 2021, View Source [SID1234574046]). The abstract present results from the Phase I/IIa ISO-CC-005 study which shows a correlation between clinical benefit and gene expression of the folate pathway in patients with metastatic colorectal cancer treated with 5-FU-based chemotherapy in combination with arfolitixorin. Furthermore, Isofol gives an update of the timing of the interim analysis in the global Phase III AGENT study.

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In connection to ASCO (Free ASCO Whitepaper)-GI, Isofol together with QuartzBio, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, will present a poster with the title "Folate pathway gene expression in metastatic colorectal cancer patients treated with arfolitixorin/5-FU-based chemotherapy" on asco.org between 2.00 PM – 12.15 AM CET on January 15 (registration required). The poster is available at the same time on the website.

The poster present results from the ISO-CC-005 study where it was found that the gene expression levels of TYMS are significantly associated with clinical benefit (partial response or stable disease), in patients treated with 5-FU-based chemotherapy in combination with arfolitixorin.

Given the role of TYMS in the folate metabolic pathways, Isofol plan to further assess its predictive potential on a larger cohort which will provide additional cues on the use of this and other related genes as predictive markers for treatment outcome and their role in the mode of action of arfolitixorin, as part of the ongoing Phase III AGENT study.

The AGENT study was fully recruited in December 2020 with 440 patients and the company is currently awaiting the interim analysis, which was initiated when the 330th patients had been treated for 16 weeks and had two tumor evaluations.

Lockdowns due to COVID-19 of participating hospitals have had impact on timelines for gathering data. Data has been provided to third parties and is currently being reviewed, quality controlled, and prepared. Once that has been done the iDSMB (independent Data and Safety Monitoring Board) will analyze safety and efficacy (ORR, Overall Respons Rate and PFS, Progression-Free Survival) and give a recommendation. Recruitment will either be stopped after 440 patients or expanded to 660 patients, to further strengthen the statistical power for PFS). Based on the current available information, Isofols estimation is that the recommendation from iDSMB, based on the interim analysis, is expected during Q1 2021.

On January 15, 2021 AstraZeneca’s Imfinzi (durvalumab) reported that it has been approved in the European Union and the UK for an additional dosing option, a 1,500mg fixed dose every four weeks, in locally advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on at least 1% of tumour cells and whose disease has not progressed following platinum-based chemoradiation therapy (CRT) (Press release, AstraZeneca, JAN 15, 2021, View Source [SID1234574029]).

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Lung cancer is the leading cause of cancer death and 80-85% of patients with lung cancer have NSCLC.1-3 Approximately one third of patients are diagnosed in the Stage III setting and the majority of these have unresectable tumours and are treated with curative intent.3-5

This new dosing option is consistent with the approved Imfinzi dosing in extensive-stage small cell lung cancer (ES-SCLC) and is available to patients with locally advanced, unresectable NSCLC weighing more than 30kg.

The approval by the European Commission was based on data from several Imfinzi clinical trials. These include the PACIFIC Phase III trial which supported the two-week, weight-based dosing of 10mg/kg already approved in locally advanced, unresectable NSCLC, and the CASPIAN Phase III trial which used four-week, fixed dosing during maintenance treatment in ES-SCLC.

The approval follows an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, which recommended approval in December 2020. This CHMP recommendation and approval also apply to the UK.

Luis Paz-Ares, MD, PhD, Chair, Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain and principal investigator in the CASPIAN Phase III trial, said: "Less-frequent dosing is important for cancer patients, and may be particularly relevant right now for those suffering from lung cancer, who are especially vulnerable to complications from COVID-19. Patients with cancer should be able to focus on living their lives as much as possible and doctors can now offer them a more convenient dosing option that could reduce medical visits by half and help avoid unnecessary risk of exposure to infection in the healthcare setting."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "We are pleased to offer a four-week dosing option to lung cancer patients in Europe to meet an urgent need and help enable continuity of care during the pandemic. Cancer won’t wait, and it is our job to provide patients with treatment options that address the challenges the pandemic poses to their care."

Imfinzi was also recently approved for unresectable Stage III NSCLC after CRT in the US for the four-week, fixed-dose regimen. Imfinzi is approved in the curative-intent setting of unresectable, Stage III (locally advanced) NSCLC after CRT in the EU, US, Japan, China and many other countries, based on the PACIFIC Phase III trial. Additionally, it is approved in the EU, US, Japan and many other countries around the world for the treatment of ES-SCLC based on the CASPIAN Phase III trial.

Stage III NSCLC
Stage III (locally advanced) NSCLC is commonly divided into three subcategories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery.2 Stage III disease is different from Stage IV disease, when the cancer has spread (metastasised), as the majority of Stage III patients are currently treated with curative intent.2,3

Stage III NSCLC represents approximately one third of NSCLC incidence and in 2015 was estimated to affect nearly 200,000 patients in China, France, Germany, Italy, Japan, Spain, UK, and the US, with approximately 43,000 cases in the US alone.4,6 The majority of Stage III NSCLC patients are diagnosed with unresectable tumours.5 Prior to approval of Imfinzi in this setting, no new treatments beyond CRT had been available to patients for decades.7-9

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and several other countries.

As part of a broad development programme, Imfinzi is being tested as a monotherapy and in combinations including with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, oesophageal cancer, gastric and gastroesophageal cancer, cervical cancer, ovarian cancer, endometrial cancer and other solid tumours.

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 histologies, several stages of disease, lines of therapy and modes of action.

An extensive Immuno-Oncology (IO) development programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.10 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (POSEIDON and PEARL Phase III trials) and for patients in earlier stages of disease including potentially-curative settings (MERMAID-1, MERMAID-2, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC Phase III trials) both as monotherapy and in combination with tremelimumab and/or chemotherapy.

Imfinzi is also in development in the NeoCOAST, COAST and HUDSON Phase II trials in combination with potential new medicines from the early-stage pipeline including Enhertu (trastuzumab deruxtecan).

AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored in immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small, targeted molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

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 seven 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.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies – 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 January 15, 2021 Taiho Pharmaceutical Co., Ltd. reported its establishment of a new headquarters, Taiho Oncology Europe GmbH in Zug, Switzerland, as a clinical development and commercial base for its pharmaceutical business in Europe (Press release, Taiho, JAN 15, 2021, View Source [SID1234574014]).

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Taiho Oncology Europe is established as a subsidiary of Taiho Pharmaceutical. Together with Taiho Pharmaceutical, Taiho Oncology, Inc. (Princeton, New Jersey), a subsidiary of Taiho Pharmaceutical, will support its operation in Europe.

Taiho Oncology Europe will be responsible for the European commercialization of futibatinib (development code; TAS-120), an FGFR inhibitor currently under development as a new oral anti-cancer agent, after obtaining marketing approval. Futibatinib is not yet approved in any country worldwide.

Taiho Pharmaceutical will further promote its globalization through Taiho Oncology Europe, and will strive to continue its contribution to cancer patients and caregivers worldwide.

On January 14, 2021 Xspray Pharma AB (publ) (Nasdaq Stockholm: XSPRAY) reported results from the extra bioequivalence study in fasting healthy volunteers conducted with the Company’s leading product candidate HyNap-Dasa (Press release, Xspray, JAN 14, 2021, View Source [SID1234575598]). The results are in line with previous bioequivalence studies, but the results show that the study design is robust. Xspray Pharma will already next week start the previously communicated bioequivalence studies with modified formulations. Xspray Pharma has recently received positive results for an improved version of Sprycel, based on HyNap-Dasa, and will initiate registration studies for that product during Q1 2021 with the aim to submit for marketing approval according to the 505(b)(2) procedure during Q2 2021.

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The recently conducted bioequivalence study in fasting healthy volunteers was of the same size and design as the study reported under Q3 2020. The results show that the study was well conducted and included a sufficient number of subjects, but that formal bioequivalence was not achieved. In both studies, markedly poor absorption of dasatinib was observed in a few subjects given the reference product Sprycel which was not seen in subjects given the HyNap-Dasa formulation. While the EMA finalized guidance on dasatinib bioequivalence allows the exclusion of the data for these poorly absorbing subjects, US FDA does not.

"This confirms the results of the previous study and our primary focus is now on the two modified formulations of HyNap-Dasa. These are optimized to achieve bioequivalence and enable an ANDA submission. I am glad that we, as promised, can start the first of these studies already next week. At the same time, we are now expanding our product portfolio with an improved product based on the results of the successful study with omeprazole," says Per Andersson, CEO of Xspray Pharma. "We continue to work on commercial partnerships according to plan and can now offer both an improved and a generic version, which strengthens the value of our HyNap-Dasa product portfolio."

Xspray Pharma’s program for registration studies during H1 2021

Improved version of Sprycel – HyNap-Dasa 505(b)(2)
The study with the improved version of HyNap-Dasa, reported on December 30, 2020, proved that HyNap-Dasa can be taken concomitantly with omeprazole, which is not possible with Sprycel. Based on these positive results showing a clinically relevant improvement potential, Xspray Pharma will initiate a registration study during Q1 2021. The results will form the basis for submission for the improved product in accordance with the 505(b)(2) procedure planned during Q2 2021. Xspray Pharma has also begun work on an application for Orphan Drug Designation (ODD) for this product candidate.

Generic version of Sprycel – HyNap-Dasa ANDA
The work to achieve bioequivalence between HyNap-Dasa and Sprycel continues with two modified formulations of HyNap-Dasa developed together with an expert group of reputable external advisors.

The first formulation involves a minor modification, and a bioequivalence study is planned to start next week. No further stability studies are required for this formulation which, provided positive results, makes the ANDA submission during Q2 2021 possible.

The second formulation is slightly more modified for which reason some stability studies will need to be conducted. The Company expects to start bioequivalence studies with this formulation during Q2 2021 and provided positive results, submit an ANDA in Q3 2021 at the earliest.

Improved version of Nilotinib – HyNap-Nilo 505(b)(2)
As announced in December 2020, Xspray Pharma’s product candidate HyNap-Nilo has received Orphan Drug Designation (ODD) from the FDA for the treatment of chronic myeloid leukemia (CML). A clinical trial program with two different formulations has been initiated.