On June 2, 2018 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, reported interim clinical data from the LOXO-292 global Phase 1 LIBRETTO-001 (LOXO-292 Investigated to Block RET-altered Tumors) dose escalation trial (Press release, Loxo Oncology, JUN 2, 2018, View Source [SID1234527090]). LOXO-292 is an investigational, highly potent and selective RET inhibitor. These data are being presented today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (abstract 102).

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"The LOXO-292 Phase 1 data are striking," said Alexander Drilon, M.D., clinical director in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and presenting author. "The activity we reported is impressive and I am thrilled to see this promising efficacy with limited adverse events, especially in this heavily pre-treated patient population of RET fusion cancers, including those with brain metastases, and RET mutated MTC."

"We are very excited to share the initial LOXO-292 clinical experience with the oncology community at ASCO (Free ASCO Whitepaper)," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "We have long believed that patients with RET fusion cancers and RET mutated MTC needed a purpose-built medicine tailored to their tumors. We hope that LOXO-292 continues to deliver on that premise. Thank you to the patients, investigators and clinical trial teams who made possible today’s presentation."

Trial Background

The LIBRETTO-001 Phase 1 trial contains a dose escalation phase and a dose expansion phase. The dose escalation phase follows a "3+3" design. LOXO-292 is dosed orally in 28-day cycles. As dose cohorts are cleared, additional patients can enroll in these cleared cohorts. Intra-patient dose escalation is also permitted as dose cohorts are cleared. The primary endpoint of the trial is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by RECIST 1.1) and duration of response. The dose expansion phase is designed to further characterize the overall response rate, durability of response, and safety of LOXO-292 in predefined groups of patients with activating RET alterations.

Key Data Presented at ASCO (Free ASCO Whitepaper)

The data presented at ASCO (Free ASCO Whitepaper) were based on an April 2, 2018 data cut-off date. Eighty-two total patients had been enrolled to eight dose escalation cohorts: 20 mg QD (n=6), 20 mg BID (n=10), 40 mg BID (n=16), 60 mg BID (n=10), 80 mg BID (n=18), 120 mg BID (n=4), 160 mg BID (n=12) and 240 mg BID (n=6). RET alterations were identified by local laboratories either in tumor or plasma and included the following primary diagnoses:

38 patients with RET fusion-positive non-small cell lung cancer (NSCLC) (21 with prior MKI treatment, 17 without)
9 patients with RET fusion-positive thyroid cancer (8 with prior MKI treatment, 1 without)
2 patients with RET fusion-positive pancreatic cancer (1 with prior MKI treatment, 1 without)
29 patients with RET-mutated medullary thyroid cancer (MTC) (23 with prior MKI treatment, 6 without)
4 patients with no known activating RET alterations
In addition to many patients with prior MKI treatment, 46% of patients had received prior chemotherapy and 24% had received prior immunotherapy (47% of those with NSCLC).

Pharmacokinetic analyses during the dose escalation demonstrated dose-dependent increases in LOXO-292 exposure with increasing dose. Starting at the 40 mg BID dose and the 80 mg BID dose, respectively, LOXO-292 delivered sustained >IC90 RET fusion and >IC90 RET M918T-mutant target coverage, based on cell-based potencies.

The data presented at ASCO (Free ASCO Whitepaper), summarized below, are based on response assessments performed by each respective clinical trial site (local, investigator-assessed radiology).

1. Patients eligible for response evaluation include thyroid cancer (n=7), pancreatic cancer (n=2).
2. Excludes patients recently enrolled that remain on treatment, but have not had a first post-baseline response assessment.
3. Response status per RECIST 1.1. Overall response rate = CR+uCR+PR+uPR. Overall response rate, Confirmed overall response rate: all RET fusion-positive (30/39, 25/34), RET fusion-positive NSCLC (23/30, 20/27), RET fusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18).
4. Excludes patients with unconfirmed CR/PR pending confirmation at time of data cut-off.
5. Unconfirmed responses in patients that remain on treatment awaiting a confirmatory response assessment.
6. Patients that discontinued treatment prior to a first post-baseline response assessment.

Anti-tumor activity was observed regardless of RET fusion partner (including KIF5B), RET mutation (including M918T and V804M gatekeeper mutations), and prior MKI treatment. Twelve patients with RET fusion cancers had central nervous system (CNS) metastases at enrollment and all remained on study without progression. Three of these patients had RECIST target lesions in the CNS, and all three exhibited intracranial partial responses. In patients with RET-mutant MTC, LOXO-292 treatment resulted in significant reductions in the serum tumor markers calcitonin and carcinoembryonic antigen (CEA).

As of the data cutoff, LOXO-292 demonstrated early evidence of durable activity, with 90% of RET fusion-positive cancer patients and 93% of RET-mutant MTC patients remaining on therapy. All responding patients across all tumor types remained on therapy. The longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than ten months as of the data cut-off date.

Most treatment-emergent adverse events were Grade 1 in severity. The treatment-emergent adverse events observed in ≥10% of patients, regardless of relationship to LOXO-292, were fatigue (12% Grade 1, 7% Grade 2, 0% ≥Grade 3), diarrhea (10% Grade 1, 6% Grade 2, 0% ≥Grade 3), constipation (13% Grade 1, 1% Grade 2, 0% ≥Grade 3), dry mouth (12% Grade 1, 0% ≥Grade 2), nausea (9% Grade 1, 4% Grade 2, 0% ≥Grade 3), and dyspnea (7% Grade 1, 2% Grade 2, 1% ≥Grade 3). Only two adverse events ≥Grade 3 were attributed to LOXO-292 (Grade 3 tumor lysis syndrome, Grade 3 increased ALT). An MTD had not been reached. At the 240 mg BID dose level, one dose limiting toxicity (DLT) was reported (aforementioned Grade 3 tumor lysis syndrome).

LOXO-292 also demonstrated robust reduction and clearance of RET alterations as detected in patients’ plasma cell free DNA (cfDNA). These data will be presented in a separate poster presentation on June 3, 2018.

LIBRETTO-001 Trial Update

The expansion cohorts of the LIBRETTO-001 trial are now open and enrolling at the 160 mg BID dose. This dose was selected for initial expansion based on its promising activity and tolerability profile. Additional dose exploration above 160 mg BID is ongoing and patients enrolled to the expansion cohorts may dose escalate should a higher dose be advanced.

About the ASCO (Free ASCO Whitepaper) Presentations

LOXO-292 data are being presented in two presentations at ASCO (Free ASCO Whitepaper):

"A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers." This abstract is being presented in an oral presentation by Dr. Alexander Drilon, Memorial Sloan Kettering Cancer Center, during a Clinical Science Symposium session entitled, "Tumor Genomics: Finding the Target, Hitting the Target" from 8:00 – 9:30AM CT on Saturday, June 2, 2018 (Abstract 102).
"Detection and clearance of RET variants in plasma cell free DNA (cfDNA) from patients (pts) treated with LOXO-292." This abstract is being presented as a poster by Dr. Geoff Oxnard, Dana Farber Cancer Institute, during the Lung Cancer—Non-Small Cell Metastatic poster session from 8:00 – 11:30AM CT on Sunday, June 3, 2018 (Abstract 9048).
The presentations will be available online at View Source at the time of their scheduled presentation at ASCO (Free ASCO Whitepaper).

Conference Call and Webcast Information
Loxo Oncology management will host a conference call and live webcast with slides and Q&A today at 4:00 p.m. CT to discuss the LOXO-292 data. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 3597058. A live webcast of the presentation will be available at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the company’s website for 30 days following the call.

On June 2, 2018 AstraZeneca and MedImmune, its global biologics research and development arm, reported that results from the Phase III (‘1053’) clinical trial (Abstract #7004) that evaluated moxetumomab pasudotox in 80 patients with relapsed or refractory hairy cell leukemia (HCL) who had received at least two prior lines of therapy.1 (Press release, AstraZeneca, JUN 2, 2018, View Source [SID1234527107])

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Moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin, showed a 75% objective response (OR) rate, a 41% complete response (CR) rate, and a 30% durable CR rate (primary endpoint). The majority of patients with a complete response had a durable response (73%; 24/33) and achieved a negative minimal residual disease (MRD) status (82%; 27/33). Findings from this pivotal trial were presented for the first time during an oral session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "Moxetumomab pasudotox is an investigational, first-in-class immunotoxin which we believe has the potential to advance outcomes for patients with relapsed or refractory hairy cell leukemia, a condition with a high unmet need. It is also the first agent to be submitted for regulatory review from our Antibody Drug Conjugates platform, and as such demonstrates our commitment to developing novel treatments for blood cancer."

Robert J. Kreitman, MD, Senior Investigator, Head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, said: "Hairy cell leukemia is a rare, chronic blood cancer with no established standard of care for patients with relapsed or refractory disease following purine nucleoside analog therapy. With very few treatments available, there remains significant unmet medical need for people with relapsed or refractory disease. The response rates observed in this trial, and elimination of the residual leukemia cells that cause relapse in some patients, highlight the potential impact this potential new medicine could have on patients and the management of this disease."

Summary of key results from the Phase III ‘1053’ single arm, multicenter clinical trial in 80 patients with relapsed or refractory HCL (16.7 months median follow-up), as determined by a blinded independent central review:

The primary endpoint of the trial was durable CR, which is defined as CR with HR for >180 days. The median time to HR was 1 month. MRD refers to the small amounts of cancer cells that may remain after treatment.2 A high rate of negative MRD after therapy may further improve outcomes.3 The median duration of OR and median progression-free survival were not reached.

The most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%); 8% had infections and 3% had neutropenia deemed treatment-related. Three patient deaths occurred, none of which were determined to be treatment-related. Treatment-related AEs leading to discontinuation were hemolytic uremic syndrome (HUS; 4 [5%]), capillary leak syndrome (CLS; 2 [3%]), and increased blood creatinine (2 [3%]). Seven patients (9%) had CLS and seven (9%) had HUS; this includes four (5%) patients who had both CLS and HUS. CLS and HUS were manageable and reversible.

In April 2018, AstraZeneca announced that the US Food and Drug Administration (FDA) accepted the Biologics License Application (BLA) for moxetumomab pasudotox for the treatment of adult patients with HCL who have received at least two prior lines of therapy. The BLA is based on results from the Phase III ‘1053’ clinical trial. The FDA has granted Priority Review status with a Prescription Drug User Fee Act action date set for the third quarter of 2018.

NOTES TO EDITORS

About Moxetumomab Pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is an investigational anti-CD22 recombinant immunotoxin and a potential new medicine with the opportunity to be a first-in-class treatment in the US for patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior lines of therapy. Immunotoxins are a class of anticancer agents that combine the selectivity of antibodies to target drug delivery and the potency of toxins to kill target cancer cells.4 Moxetumomab pasudotox is composed of a binding portion of an anti-CD22 antibody fused to a toxin. CD22 is a B-lymphocyte restricted transmembrane protein with a higher receptor density in HCL cells relative to normal B cells, making it an attractive therapeutic target for the treatment of this cancer.5 After binding to CD22, the molecule is internalized, processed and releases its modified protein toxin that inhibits protein synthesis, leading to apoptotic cell death. Moxetumomab pasudotox has been granted Orphan Drug Designation by the FDA for the treatment of HCL.

About Hairy Cell Leukemia

HCL is a rare, incurable slow-growing leukemia in which the bone marrow overproduces abnormal B cells or lymphocytes.6 HCL can result in serious and life-threatening conditions, including infections, bleeding and anemia.7 Approximately 1,000 people are diagnosed with HCL in the US each year.8,9,10 While many patients initially respond to treatment, up to 40% will relapse.11 With no established standard of care and very few treatments available, there remains significant unmet medical need for people with relapsed or refractory HCL.12,13

About the ‘1053’ Phase III Trial

The ‘1053’ trial is a single-arm, multicenter Phase III clinical trial assessing the efficacy, safety, immunogenicity and pharmacokinetics of moxetumomab pasudotox monotherapy in patients with relapsed or refractory HCL who have received at least two prior therapies. The trial is being conducted in 80 patients across 34 sites in 14 countries.14 The primary endpoint was durable complete response (CR), defined as CR with hematologic remission (blood count normalization) for >180 days. Secondary outcome measures included overall response rate, relapse free survival, progression-free survival, time to response, safety, pharmacokinetic and immunogenic potential.14

On June 2, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 antagonists to improve immune cell trafficking to treat cancer and rare diseases, reported positive clinical results from the Phase 2 expansion of an ongoing Phase 1/2 study of X4P-001-IO in combination with Inlyta (axitinib) in patients with clear cell renal cell carcinoma (ccRCC).

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The results were the first from the Phase 2 portion of the study and demonstrated that the combination was well tolerated with a manageable safety profile and had encouraging response in heavily pretreated patients. In patients with ccRCC, the combination treatment of X4P-001-IO, a CXCR4 antagonist, and Inlyta, Pfizer’s VEGFR kinase inhibitor, showed an objective response rate (ORR) of 23%, including 1 patient with a confirmed complete response (CR). Nearly 75% of patients received at least two prior lines of therapy prior to entering the study. The data were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 2nd in Chicago, IL.

"X4P represents a novel targeted mechanism of action with demonstrated tolerability and promising efficacy in combination with axitinib in patients with pretreated renal cancer. The results from this study demonstrate that X4P-001-IO has the potential to enhance clinical responses to axitinib and other tyrosine kinase inhibitors that target tumor angiogenesis," said Ulka Vaishampayan, MD, Chair, Karmanos Cancer Center, Professor of Oncology at Wayne State University, and lead investigator of the study.

Results from the 65 patients with advanced ccRCC enrolled in the ongoing study (as of the data cutoff date of March 23, 2018) were presented at ASCO (Free ASCO Whitepaper) and highlights of the poster presentation include:

The combination of 400 mg X4P-001-IO administered once daily and 5 mg axitinib twice daily was well tolerated with a manageable safety profile. The most frequent treatment-related adverse events (AEs) were diarrhea, decreased appetite, fatigue, hypertension, nausea, headache and cough. No grade 4 or 5 AEs were observed.
In the 47 evaluable patients, the overall response rate (ORR) was 23% with one patient achieving a confirmed complete response (CR). Response data from the remaining 18 patients is pending.
Thirteen patients remain on study for 24 weeks or more; the median duration on treatment was 16 weeks (range 2 – 96 weeks).
"These interim results represent an important step in the continued development of X4P-001-IO. In this larger patient population, where many patients are still very early in treatment with the combination, we find promising signs of clinical efficacy. The tumor microenvironment modulating effect of X4P-001-IO is expected to increase and deepen responses over time, and we look forward to the maturation of the data in the coming months," said Sudha Parasuraman, MD, Chief Medical Officer of X4. "Our combined clinical experience continues to demonstrate the important role that CXCR4 antagonism may play in improving outcomes in combination with important cancer therapeutic modalities."

The Phase 2 portion of the study continues to follow patients on study to evaluate the clinical efficacy of X4P-001-IO as measured by objective response rate (ORR), duration of response (DOR), and progression free survival (PFS). (View Source)

About X4P-001-IO in Cancer

X4P-001-IO is an investigational selective, oral, small molecule antagonist of C-X-C receptor type 4 (CXCR4). CXCR4 is a chemokine receptor present in abundance on certain immune cells and cancer cells and it plays a critical role in immune cell trafficking, infiltration and activation in the tumor microenvironment. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment. X4P-001-IO has the ability to help restore immunity within the tumor microenvironment and has the potential to enhance the anti-tumor activity of approved and emerging oncology agents, such as checkpoint inhibitors and targeted therapies. X4P-001-IO is being investigated in several clinical studies in solid tumors.

On June 1, 2018 Advaxis, Inc. (NASDAQ:ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported preliminary data from the ongoing metastatic, castration resistant prostate cancer (mCRPC) Phase 1/2 KEYNOTE-046 study, conducted in conjunction with Merck (known as MSD outside the United States and Canada) evaluating ADXS-PSA, Advaxis’s Listeria monocytogenes (Lm)-based immunotherapy, alone and in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy (Press release, Advaxis, JUN 1, 2018, View Source [SID1234527023]).

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Findings will be highlighted in a poster discussion at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting underway in Chicago, on Saturday, June 2, from 4:45 pm to 6:00 p.m. CDT (Location: Hall A; Poster #246; Abstract #5019). Principal Investigator and author Naomi Haas, MD, Director of the Prostate and Kidney Cancer Programs and Associate Professor of Medicine at the Hospital of the University of Pennsylvania will be presenting.

ADXS-PSA was tested alone or in combination with KEYTRUDA in an advanced and heavily pretreated patient population who had progressed on androgen deprivation therapy. A total of 13 and 37 patients were evaluated on monotherapy and combination therapy, respectively. Overall, the safety profile was consistent with findings from prior clinical studies using the Lm platform. Treatment-related adverse events (TRAEs) were mostly mild or moderate constitutional symptoms such as fever, chills, rigors, hypotension, nausea and fatigue, consistent with immune activation and manageable with standard care. One patient in the monotherapy arm was discontinued from the study due to a grade 4 TRAE related to cytokine release, which resolved within 24 hours using medical management. There were no new toxicities observed with the combination therapy. In all treated patients, those who received the combination therapy experienced the longest overall survival (OS) at data cut-off, with the median not having been reached at 13 months of follow-up.

"Improvements in the care and treatment of highly refractory prostate cancer, a traditionally difficult type of cancer to treat, are vital. These early results show a safe and tolerable profile for ADXS-PSA alone or in combination with KEYTRUDA," said Dr. Haas. "Albeit the study was not designed to compare monotherapy to combination therapy, the survival rates in the combination therapy arm are encouraging, especially given the reduction in PSA levels observed in this group, and mature data in the following 6 months will help better define the role of ADXS-PSA in combination with KEYTRUDA in mCRPC."

Key Findings from KEYNOTE-046 (as of March 30, 2018):

The advanced patient population in the study had a median Gleason score of 8.3, and was heavily pretreated, with greater than 70% having received three or more prior lines of therapy.
Median overall survival had not been reached in the combination arm after 13 months of follow-up (95%CI 7.16-NR), and was 7.79 months (95%CI 3.52-11.9) in the monotherapy arm.
56.8% of patients on combination therapy and 38.5% of patients on monotherapy did not experience disease progression.
The percentage of patients with PSA declines from baseline in the combination therapy arm was 40.5%, and 15.4% in the monotherapy arm.
In all treated patients, an improvement in survival was observed in patients with PSA declines from baseline of 50% or greater vs. those with PSA declines of less than 50%. There were 7 patients in the combination arm with 50% or greater declines in PSA from baseline, and none in the monotherapy arm.
Previously presented immunologic data from the monotherapy arm of this trial showed that ADXS-PSA induced or enhanced T cell responses not only to PSA, but also to other prostate cancer antigens that were not expressed by the Lm-based vector, which is indicative of antigen cascade or antigen spreading (SITC 2017; Hayes et al. J Immunother Cancer. 2017;5(Suppl 2)86:P2). Correlative immunologic analyses and overall survival for the combination therapy patients are underway.

About KEYNOTE-046

KEYNOTE-046 (NCT02325557) is a Phase 1/2 open-label, multicenter dose determination and expansion trial that evaluates the safety, tolerability and preliminary clinical activity of ADXS-PSA as monotherapy (Part A; n=14 [13 treated]), and in combination with KEYTRUDA (Part B; n= 37) in heavily pretreated patients with progressive and refractory mCRPC. Patient accrual in the study is complete, with 5 patients still receiving treatment, all in Part B, and being followed for survival analysis.

About ADXS-PSA

ADXS-PSA, one of Advaxis’s Listeria monocytogenes (Lm) based immunotherapies, utilizes live, attenuated, bioengineered Lm as a vector to deliver PSA directly to antigen presenting cells. Development is being pursued in a clinical trial collaboration and supply agreement with Merck.

On June 1, 2018 Zymeworks Inc. (NYSE/TSX: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported the presentation of ZW25 clinical data by Funda Meric-Bernstam, MD, Principal Investigator for the ZW25 study at the University of Texas MD Anderson Cancer Center (Press release, Zymeworks, JUN 1, 2018, View Source [SID1234527042]). Data from the ongoing multi-center Phase 1 study showed single agent ZW25 induced anti-tumor activity and was well tolerated in heavily pretreated patients across a range of HER2-expressing cancers.

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"Since the first patient treated, ZW25’s compelling single agent activity has consistently exceeded our expectations," said Ali Tehrani, Ph.D., President and CEO of Zymeworks. "The expanded body of data presented today supports our confidence that ZW25 is an active agent with the potential to become an approved cancer treatment."

ZW25 Clinical Results Presented Today

To date, a total of 50 patients have been enrolled in the study; data from 42 patients were available as of the data cut-off date of April 18, 2018 for ASCO (Free ASCO Whitepaper) and presented today. Durable cytotoxin-free single agent activity was observed in patients with heavily pretreated HER2-expressing cancers across a range of tumor types.

The best overall response observed with ZW25 as a single agent therapy in 33 response-evaluable patients (defined as having measurable disease and at least one tumor restaging or clinical progression) was 12 partial responses (36%), six stable disease (18%) and 15 progressive disease (45%). Overall, 68% (21/31) of all patients with measurable disease (at least one restaging scan) had a decrease in target lesions.

In 18 breast cancer patients, with a median of six prior systemic regimens, including trastuzumab, pertuzumab, T-DM1, and lapatinib in the majority of patients, the disease control rate (DCR, percentage of patients with either a partial response or stable disease) was 50%. In nine gastroesophageal cancer patients, with a median of four prior systemic regimens, including trastuzumab in all cases, the DCR was 56%, and in six other HER2-expressing cancer patients, including colorectal cancer, the DCR was 67%. Anti-tumor activity was assessed per RECIST every eight weeks.

"Our hope is to bring these promising new therapies to patients who have run out of treatment options," said Dr. Meric-Bernstam, Professor and Chair of the Department of Investigational Cancer Therapeutics, Medical Director of the Institute for Personalized Cancer Therapy at University of Texas MD Anderson Cancer Center. "To see this level of single agent activity without any concomitant chemotherapy in these advanced heavily pretreated patients is encouraging."

In the study, ZW25 was well tolerated at all dose levels and schedules and there were no dose-limiting toxicities observed at any dose (n=42). Treatment-related adverse events were primarily Grade 1 or 2, and no treatment-related serious adverse events or discontinuations were seen.

"Given ZW25’s anti-tumor activity and safety profile, we are excited to expand the number of clinical trials we have underway for this program," said Diana Hausman, MD, Zymeworks’ Chief Medical Officer. "We believe ZW25 could be used as monotherapy or readily combined with a number of approved anti-cancer treatments to further leverage its activity."

Clinical Development Plans

Based on the clinical data generated to date, Zymeworks plans to focus development of ZW25 in three areas:

First, as a single agent treatment for advanced HER2 high gastroesophageal cancer in patients who have received prior trastuzumab therapy, as well as in other HER2 high cancers, such as colorectal, where a HER2-targeted agent has not yet been approved;
Second, in combination with chemotherapeutics in earlier lines of therapy for HER2 high gastroesophageal and breast cancers; and
Third, in combination with other anti-cancer agents in patients with lower HER2-expressing cancers.
Zymeworks’ top priority is to focus on advanced gastroesophageal cancer. A potential Phase 2/3 study could begin as early as the second half of 2019 pending discussion with the US Food and Drug Administration (FDA). In addition, new studies to evaluate combinations beyond those ongoing in the current Phase 1 study are planned to start later this year.

About the Trial

Zymeworks’ adaptive Phase 1 study has three parts. Enrollment in the first portion of the study (the dose-escalation phase) has been completed. The recommended single agent dose was determined to be 20 mg/kg once every two weeks. In the second part of the study (the cohort expansion phase) now underway, additional patients are being enrolled to further assess ZW25’s single agent tolerability and anti-tumor activity against a variety of cancer types in different settings. The third part of the study (the combination phase), which is also underway, is evaluating ZW25 in combination with selected chemotherapy agents in gastroesophageal and breast cancer patients with HER2 high or lower HER2 expression levels.

June 4, 2018 Webcast and Conference Call

Zymeworks will host a webcast and conference call on June 4th, at 8:30 a.m. ET (5:30 a.m. PT) to review the ZW25 clinical data presented at ASCO (Free ASCO Whitepaper) and discuss next steps.

Interested parties can access a live webcast of the presentation via a link from Zymeworks’ website at View Source A recorded replay will also be available on the website shortly after the call concludes.

The live call and Q&A may be accessed by dialing 1-800-319-4610 for North American callers, or 1-604-638-5340 for international callers. Callers should dial in five to 10 minutes prior to the scheduled start time and ask to join the "Zymeworks call".

About ZW25

ZW25 is being evaluated in a Phase 1 clinical trial in the United States and Canada. It 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 and has led to encouraging anti-tumor activity in patients. Zymeworks is developing ZW25 as a HER2-targeted treatment option for patients with any solid tumor that expresses HER2. The FDA has granted Orphan Drug Designation to ZW25 for the treatment of both gastric and ovarian cancers.

About the Azymetric Platform

The Azymetric platform enables the transformation of monospecific antibodies into bispecific antibodies, giving them the ability to simultaneously bind two different targets. Azymetric bispecific technology enables the development of multifunctional biotherapeutics that can block multiple signaling pathways, recruit immune cells to tumors, enhance receptor clustering and degradation, and increase tumor-specific targeting. These features are intended to enhance efficacy while reducing toxicities and the potential for drug-resistance. Azymetric bispecifics have been engineered to retain the desirable drug-like qualities of naturally occurring antibodies, including low immunogenicity, long half-life, and high stability. In addition, they are compatible with standard manufacturing processes with high yields and purity with the potential to significantly reduce drug development costs and timelines.