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.

On May 31, 2019 Vanda Pharmaceuticals Inc. (Vanda) (Nasdaq: VNDA) reported that Mihael H. Polymeropoulos, co-founder and Chief Executive Officer, will present at the Jefferies 2019 Global Healthcare Conference in New York City on Tuesday, June 4, 2019 (Press release, Vanda Pharmaceuticals, MAY 31, 2019, View Source [SID1234536738]). A corporate presentation is scheduled for 11:00 a.m. Eastern Time.

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The corporate presentation given at the Jefferies 2019 Global Healthcare Conference will be available live on Vanda’s corporate website, where it also will be archived for 30 days. To access the presentation, go to Vanda’s website at www.vandapharma.com and click on the Presentations tab on the Investor Relations page. Please connect to the website several minutes prior to the start of the live presentation.

On May 31, 2019 Apexian Pharmaceuticals, Inc., a clinical stage drug development company focused on advancing APX3330 for the treatment of diseases mediated by the APE1/Ref-1 protein, reported that it will report clinical data from its clinical study, APX-CLN-0011: A Phase 1 Study of APX3330 in Patients with Advanced Solid Tumors in a poster being presented on June 1 at the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois (Press release, Apexian Pharmaceuticals, MAY 31, 2019, View Source [SID1234536737]).

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"We look forward to presenting data on the use of APX3330 in patients with advanced cancers and to discuss the opportunities for clinical advancement of our selective APE1/Ref-1 inhibitor that these trial data provide," said Dr. Mark Kelley, Chief Scientific Officer of Apexian. "Our study enrolled patients across a range of tumor indications, allowing us to identify molecular signals of activity in response to administration of APX3330 as a single agent."

Dr. Richard Messmann, Chief Medical Officer of Apexian added, "These data have also enabled us to confirm the safety of chronic dosing of APX330 and to begin correlating our clinical findings with the molecular activities mediated by targeting the redox component of the APE1/Ref-1 protein. These findings will guide us through the next steps in the development path for APX3330."

On May 31, 2019 AIVITA Biomedical, a biotech company specializing in innovative stem cell applications, reported that it will be presenting at the upcoming Bio International Convention taking place June 3-6 in Philadelphia, Pennsylvania (Press release, AIVITA Biomedical, MAY 31, 2019, View Source [SID1234536736]). AIVITA CEO Dr. Hans Keirstead will deliver a corporate presentation highlighting the company’s clinical and commercial programs.

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The BIO International Convention is an annual event hosting more than 16,000 attendees from around the globe seeking opportunities in partnering, education, and networking with global biotech and pharma leaders. Details of the company presentation are as follows:

Date: Monday June 3, 2019
Time: 2:15 PM EDT
Location: Pennsylvania Convention Center, Philadelphia, Theater 3

In his presentation Dr. Keirstead will highlight new predictive efficacy clinical efficacy data from AIVITA’s ongoing 8-center Phase 2 immunotherapy clinical trial in patients with glioblastoma. The trial is investigating AIVITA’s platform cancer technology, a next generation immunotherapy targeting the tumor-initiating stem cell. Dr. Keirstead will also share recent developments and international distribution partnerships for its ROOT of SKIN line of consumer skincare products, all of the proceeds of which support the treatment of women with ovarian cancer.

On May 31, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported findings from the investigational Phase 3 TITAN study, which showed the addition of ERLEADA (apalutamide) to androgen deprivation therapy (ADT) compared with placebo plus ADT significantly improved the dual primary endpoints of overall survival (OS) and radiographic progression-free survival (rPFS) in patients with metastatic castration-sensitive prostate cancer (mCSPC) (Press release, Johnson & Johnson, MAY 31, 2019, View Source [SID1234536735]).1 The study included patients with mCSPC regardless of extent of disease or prior docetaxel treatment history.1 Results were presented in an oral session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (abstract #5006), and simultaneously published online in The New England Journal of Medicine.The data were selected for the Best of ASCO (Free ASCO Whitepaper) 2019 Meetings, which highlight cutting-edge science and reflect leading research in oncology.

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ERLEADA plus ADT significantly extended OS compared to placebo plus ADT with a 33 percent reduction in the risk of death (HR=0.67; 95 percent CI, 0.51-0.89; P=0.0053).1 ERLEADA plus ADT also significantly improved rPFS compared to placebo plus ADT with a 52 percent reduction in risk of radiographic progression or death compared to placebo plus ADT (HR=0.48; 95 percent CI, 0.39-0.60; P<0.0001).1 The two-year OS rates, after a median follow-up of 22.7 months, were 82 percent for ERLEADA plus ADT compared to 74 percent for placebo plus ADT.1

These data formed the basis of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) seeking approval of a new indication for ERLEADA for the treatment of patients with mCSPC, which is currently under review through the Real-Time Oncology Review (RTOR) program.

"Patients with metastatic castration-sensitive prostate cancer typically have a poor prognosis, with a median overall survival of less than five years. Despite advances in treatment, there is still a critical need to improve outcomes for these patients," said Dr. Kim Chi, Medical Oncologist at BC Cancer – Vancouver and principal investigator of the study. "These data suggest that apalutamide prolongs overall survival and delays disease progression in patients with metastatic castration-sensitive prostate cancer."

In addition to meeting the primary dual endpoints of OS and rPFS, the secondary endpoint of prolonged time to cytotoxic chemotherapy in patients treated with ERLEADA plus ADT was also met, with a 61 percent risk reduction compared with placebo plus ADT (HR=0.39; 95 percent CI, 0.27-0.56; P<0.0001).1 In exploratory endpoints, median time to PSA progression was more favorable following ERLEADA plus ADT, compared with placebo plus ADT, and prostate-specific antigen (PSA) reached undetectable levels in 68 percent of patients in the ERLEADA plus ADT arm and 29 percent of patients in the placebo plus ADT arm.1 Additionally, ERLEADA plus ADT, compared with placebo plus ADT, achieved a 34 percent risk reduction in median time to second progression-free survival (PFS2), defined as time from randomization to either disease progression on first subsequent anticancer therapy or death, whichever occurred first (HR=0.66; 95 percent CI, 0.50-0.87).1 Although time to pain progression was tested, it did not reach statistical significance. Due to a hierarchical statistical design, no formal testing for further secondary endpoints, including median time to chronic opioid use and median time to skeletal-related events, were conducted at this time.1

Adverse events were generally consistent with the known ERLEADA safety profile. The most common Grade 3/4 adverse events (AEs) for ERLEADA plus ADT, versus placebo plus ADT were similar (42 percent vs. 41 percent).1 The most common Grade 3 AEs for ERLEADA plus ADT versus placebo plus ADT were hypertension (8.4 percent vs. 9.1 percent) and skin rash (6.3 percent vs. 0.6 percent).1 Additional reported Grade 3 AEs for ERLEADA plus ADT versus placebo plus ADT were back pain (2.3 percent vs. 2.7 percent), blood alkaline phosphatase increased (0.4 percent vs. 2.5 percent) and anemia (1.7 percent vs. 3.2 percent).1 Treatment discontinuation due to AEs was 8 percent in the ERLEADA arm compared to 5 percent in the placebo arm.1 Rash of any grade was more common among patients treated with ERLEADA plus ADT, versus placebo plus ADT (27 percent vs. 9 percent, respectively).1

"The TITAN study results demonstrate that the addition of ERLEADA to ADT improves clinical outcomes without compromising health-related quality of life for a broad range of patients with metastatic castration-sensitive prostate cancer," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "These data suggest that ADT alone should no longer be considered the standard of care for metastatic castration-sensitive prostate cancer and support Janssen’s investigation of ERLEADA in earlier stages of prostate cancer."

About the TITAN Study1
TITAN (NCT02489318) is a Phase 3 randomized, placebo-controlled, double-blind study in men with mCSPC regardless of extent of disease or prior docetaxel treatment history. The study included 1,052 patients included in intention-to-treat (ITT) population in 23 countries across 260 sites in North America, Latin America, South America, Europe and Asia Pacific. Patients with mCSPC were randomized 1:1 and received either ERLEADA (240 mg) plus continuous ADT (n=525), or placebo plus ADT (n=527). The recruitment period for the study spanned from December 2015 to July 2017. The study included mCSPC patients with both low- and high-volume disease, those who were newly diagnosed, or those who had received prior definitive local therapy or prior treatment with up to six cycles of docetaxel or up to six months of ADT for mCSPC. Participants were treated until disease progression or the occurrence of unacceptable treatment-related toxicity. An Independent Data-Monitoring Committee was commissioned by the sponsor to monitor safety and efficacy before unblinding and to make study conduct recommendations. Dual primary endpoints of the study were OS and rPFS. Secondary endpoints included time to cytotoxic chemotherapy, time to pain progression, time to chronic opioid use and time to skeletal-related event. Exploratory endpoints included time to PSA progression, time to PFS2 and time to symptomatic progression.1 For additional study information, visit ClinicalTrials.gov.

About Metastatic Castration-Sensitive Prostate Cancer
Metastatic castration-sensitive prostate cancer (mCSPC) refers to prostate cancer that still responds to ADT and has spread to other parts of the body.2,3 Patients with mCSPC tend to have a poor prognosis, with a median OS of less than five years, underscoring the need for new treatment options.2,3,4

About ERLEADA
ERLEADA (apalutamide) is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). It became the first treatment to receive FDA approval for nmCRPC on February 14, 2018.5 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide as a treatment option for patients with non-metastatic (M0) CRPC with a category 1 recommendation for those with a PSA doubling time ≤10 months*.6 Additionally, the American Urological Association (AUA) Guidelines for Castration-Resistant Prostate Cancer (CRPC) were updated to include apalutamide (ERLEADA) with continued ADT as a treatment option that clinicians should offer to patients with asymptomatic nmCRPC. It is included as one of the options clinicians should offer to patients with nmCRPC who are at high risk for developing metastatic disease (Standard; Evidence Level Grade A)**.7

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer V.2.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 23, 2019. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

**Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.

**Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.

ERLEADA IMPORTANT SAFETY INFORMATION5

CONTRAINDICATIONS

Pregnancy — ERLEADA (apalutamide) can cause fetal harm and potential loss of pregnancy.

WARNINGS AND PRECAUTIONS

Falls and Fractures — In a randomized study (SPARTAN), falls and fractures occurred in 16% and 12% of patients treated with ERLEADA compared to 9% and 7% treated with placebo, respectively. Falls were not associated with loss of consciousness or seizure. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents.

Seizure — In a randomized study (SPARTAN), 2 patients (0.2%) treated with ERLEADA experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

ADVERSE REACTIONS

Adverse Reactions — The most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

Laboratory Abnormalities — All Grades (Grade 3-4)

Hematology — anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (2%), placebo 21% (2%)

Chemistry — hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (2%), placebo 22% (0.5%)
Rash — Rash was most commonly described as macular or maculo-papular. Adverse reactions were 24% with ERLEADA versus 6% with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (5%) versus placebo (0.3%).

The onset of rash occurred at a median of 82 days. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four percent of patients treated with ERLEADA received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA.

Hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

DRUG INTERACTIONS

Effect of Other Drugs on ERLEADA — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA on Other Drugs — ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.

P-gp, BCRP or OATP1B1 substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.