On September 17, 2021 AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) reported Detailed results from the positive Phase II DESTINY-Gastric02 trial showed that Enhertu (trastuzumab deruxtecan), the HER2-directed antibody drug conjugate (ADC), provided a clinically meaningful and durable tumour response in patients with HER2-positive metastatic and/or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma previously treated with a trastuzumab-containing regimen (Press release, AstraZeneca, SEP 17, 2021, View Source [SID1234587871]). Results were presented during a late-breaking mini-oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021.

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Gastric cancer is associated with a poor prognosis, particularly in the advanced stages of the disease, with only 5% to 10% of metastatic patients surviving five years globally.1,2 Approximately one in five gastric cancers are HER2-positive.3,4

In the primary analysis of DESTINY-Gastric02, the first trial of Enhertu specifically in Western patients with HER2-positive metastatic gastric cancer or GEJ adenocarcinoma, Enhertu (6.4 mg/kg) demonstrated a confirmed overall response rate (ORR) of 38% as assessed by independent central review (ICR). Three (3.8%) complete responses (CR) and 27 (34.2%) partial responses (PR) were observed in patients treated with Enhertu.

These results were consistent with those from the registrational DESTINY-Gastric01 Phase II trial previously published in The New England Journal of Medicine.

After a median follow-up of 5.7 months, the median duration of response (DoR) of Enhertu was 8.1 months (95% CI 4.1-NE). The median progression-free survival (PFS) was 5.5 months (95% CI 4.2-7.3). An exploratory endpoint of confirmed disease control rate (DCR) of 81% (95% CI; 70.6-89.0) was seen.

Eric Van Cutsem, MD, PhD, University Hospitals Leuven, said: "While the benefit of a HER2-targeted therapy in the first-line metastatic gastric cancer setting has been well-established, the disease will eventually progress. The positive results of DESTINY-Gastric02 show a strong response rate and reinforce the established efficacy and safety profile of Enhertu in patients who are in need of additional therapeutic options."

Susan Galbraith, Executive Vice President, Oncology R&D, said: "The data from DESTINY-Gastric02 reaffirm the clinical significance of the potential benefit of Enhertu in patients with advanced gastric cancer. Patients often experience disease progression following initial therapies, and then face limited treatment options, so today’s news brings hope to both patients and treating physicians."

Gilles Gallant, Senior Vice President, Global Head, Oncology Development, Daiichi Sankyo, said: "The encouraging results from DESTINY-Gastric02 are consistent with those previously seen in the pivotal DESTINY-Gastric01 trial. This additional data will support our ongoing discussions with global health authorities as we work toward Enhertu becoming an option for patients with HER2-positive metastatic gastric cancer."

Summary of Results

Efficacy Measure

Total Evaluable (n=79)i,ii

Confirmed ORR (%) (95% CI)ii,iii

38.0% (27.3-49.6)

Complete response (%)

3.8%

Partial response (%)

34.2%

Stable disease (%)

43.0%

DCR (95% CI)iv

81% (70.6-89.0)

Median DoR (months) (95% CI)

8.1 months (4.1-NE)

Median PFS (months) (95% CI)

5.5 months (4.2-7.3)

i Enhertu 6.4 mg/kg; median duration of follow-up was 5.7 months.
ii As assessed by independent central review
iii ORR is (CR + PR)
iv DCR is (CR + PR +SD)

The overall safety profile of Enhertu in DESTINY-Gastric02 was consistent with that seen in DESTINY-Gastric01. The most common Grade 3 or higher drug-related treatment-emergent adverse events seen in DESTINY-Gastric02 were anaemia (7.6%), neutropenia (7.6%), nausea (3.8%) and fatigue (3.8%).

There were six cases (7.6%) of treatment-related interstitial lung disease (ILD) or pneumonitis reported, as determined by an independent adjudication committee. The majority (83%) were low Grade (Grade 1 or Grade 2), with one Grade 5 (ILD or pneumonitis-related death).

Enhertu is approved in Israel, Japan and the US for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

Enhertu is being further assessed in a comprehensive clinical development programme evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers.

Several presentations featured during the ESMO (Free ESMO Whitepaper) Congress 2021 will showcase the strength and depth of Enhertu data across multiple tumour types, including gastric, lung and breast cancers, reinforcing the transformational potential of this medicine in the treatment of HER2-targetable cancers.

Gastric cancer
Gastric (stomach) cancer is the fifth most common cancer worldwide and the fourth highest leading cause of cancer mortality, with a five-year survival rate of 5% to 10% for advanced or metastatic disease.1,5 There were approximately one million new cases of gastric cancer and 768,000 deaths reported worldwide in 2020.6

Incidence rates for gastric cancer are markedly higher in eastern Asia, where approximately half of all cases occur.1,6,7 Gastric cancer is typically diagnosed in the advanced stage but even when diagnosed in earlier stages of the disease the survival rate remains modest.8-10

Approximately one in five gastric cancers are HER2-positive.3,4 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers.4 HER2 overexpression may be associated with a specific HER2 gene alteration known as HER2 amplification.4

Recommended first-line treatment for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy.7 For patients with metastatic gastric cancer that progresses following initial treatment with a trastuzumab-based regimen, treatment options are limited, and in many regions of the world, there are no additional HER2-directed medicines available.1,8,11

DESTINY-Gastric02
DESTINY-Gastric02 is a global, open-label, single-arm, Phase II trial evaluating the safety and efficacy of Enhertu (6.4mg/kg) in patients with HER2-positive metastatic and/or unresectable gastric or GEJ adenocarcinoma with disease progression on or after a trastuzumab-containing regimen.

The primary endpoint of DESTINY-Gastric02 is objective response rate (ORR), confirmed by Independent Central Review (ICR). Secondary endpoints include progression-free survival (PFS) confirmed by ICR, investigator assessed PFS, investigator assessed ORR, overall survival (OS) and duration of response (DoR).

DESTINY-Gastric02 enrolled 79 patients at multiple sites in North America and Europe. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

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

Enhertu (6.4mg/kg) is also approved in Israel, Japan and the US for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

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

Enhertu was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the "ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers," based on data from both the DESTINY-CRC01 and DESTINY-Gastric01 trials, as well as one of the targeted therapy advances of the year in non-small cell lung cancer (NSCLC), based on the interim results of the HER2-mutated cohort of the DESTINY-Lung01 trial.

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

Daiichi Sankyo collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in gastrointestinal cancers
AstraZeneca has a broad development programme for the treatment of gastrointestinal (GI) cancers across several medicines spanning a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented over five million new cancer cases leading to more than 3.5 million deaths.12 Within this programme, the Company is committed to improving outcomes in gastric, liver, oesophageal, pancreatic, and colorectal cancers.

The Company aims to understand the potential of Enhertu in the two most common GI cancers, colorectal and gastric cancers. Imfinzi (durvalumab) is being assessed as both monotherapy and in combinations including with tremelimumab across the two main types of liver cancer, hepatocellular carcinoma and biliary tract cancer, and in oesophageal and gastric cancers.

Lynparza (olaparib) is a first-in-class PARP inhibitor with a broad and advanced clinical trial programme across multiple GI tumour types including pancreatic and colorectal cancers. Lynparza is development and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On September 17, 2021 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Pfizer Inc. (NYSE: PFE) reported ahead of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 that XTANDI (enzalutamide) improved overall survival (OS) in the ARCHES study in men with metastatic hormone-sensitive prostate cancer (mHSPC, also known as metastatic castration-sensitive prostate cancer) (Press release, Astellas, SEP 17, 2021, View Source [SID1234587870]). The Phase 3, randomized, double-blind, placebo-controlled trial compared XTANDI plus androgen deprivation therapy (ADT) versus placebo plus ADT in men with mHSPC and OS was a key secondary endpoint.

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In the study, XTANDI plus ADT reduced the risk of death by 34% (n=1,150; hazard ratio [HR]=0.66; [95% confidence interval [CI]: 0.53-0.81]; p<0.0001) compared to placebo plus ADT. Median OS, which represents the time from randomization to death due to any cause, was not reached in either treatment group. The safety profile in both study arms was consistent with findings from the primary analysis.

Pfizer-Astellas-Logo

Pfizer-Astellas-Logo
Results from the final analysis of the ARCHES trial will be presented virtually at ESMO (Free ESMO Whitepaper) by Andrew Armstrong, M.D., Professor of Medicine, Surgery, Pharmacology and Cancer Biology, and Director of Research in the Duke Cancer Institute’s Center for Prostate and Urologic Cancers in Durham, North Carolina, U.S. (Abstract LBA25; September 18, 14:20 CEST).

"Overall survival benefit has been observed in patients treated with enzalutamide in three stages of advanced prostate cancer – metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, and now in metastatic hormone-sensitive prostate cancer," said Dr. Armstrong. "The results from ARCHES provide valuable data on the clinical profile of enzalutamide in this earlier disease setting."

The primary results from the ARCHES trial were published in the Journal of Clinical Oncology in 2019. The study met its primary endpoint of radiographic progression-free survival (rPFS) as assessed by independent central review, finding that treatment with XTANDI plus ADT demonstrated a 61% reduction in the risk of radiographic disease progression or death compared with ADT alone in men with mHSPC (HR=0.39; [95% CI: 0.30-0.50]; p<0.001).1 The median follow-up time was 14.4 months. Median rPFS was not reached (NR) with XTANDI plus ADT (95% CI: NR to NR) versus 19.0 months (95% CI: 16.6-22.2 months) with placebo plus ADT. At the time of the primary analysis, OS data were not mature.

In the ARCHES primary analysis, Grade 3 or greater adverse events (AEs; defined as severe/disabling or life-threatening) were similar for patients receiving both XTANDI plus ADT and those who received placebo plus ADT (24.3% vs. 25.6%). Common AEs (occurring in at least 5% of patients) that were reported more often in patients treated with XTANDI plus ADT versus those treated with ADT alone included hot flush, fatigue, arthralgia, hypertension, nausea, musculoskeletal pain, diarrhea, asthenia and dizziness.

These data supported global regulatory approvals, including European Commission marketing authorization for mHSPC earlier this year.

About Metastatic Hormone-Sensitive Prostate Cancer
Prostate cancer is considered metastatic once it has spread outside of the prostate gland to other parts of the body, such as the lymph nodes, bones, lungs, and liver.2 Men are considered hormone- (or castration-) sensitive if their disease still responds to medical or surgical treatment to lower testosterone levels.3 Metastatic hormone-sensitive prostate cancer (mHSPC) has a median survival of approximately 3-4 years for men starting treatment with ADT.4

ARCHES Trial
The company-sponsored, Phase 3, randomized, double-blind, placebo-controlled ARCHES trial (NCT02677896) enrolled 1,150 patients with metastatic hormone-sensitive prostate cancer (mHSPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. Patients in the trial were randomized to receive XTANDI 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or had a history of bilateral orchiectomy.

The primary endpoint of the trial was radiographic progression-free survival (rPFS) assessed by blinded independent central review. Radiographic progression-free survival was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after study drug discontinuation. Radiographic disease progression was defined by identification of two or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. Patients were stratified by volume of disease (low vs. high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1-5 cycles, or 6 prior cycles).

E.U.: About XTANDI (enzalutamide) and Important Safety Information
Enzalutamide is an androgen receptor signaling inhibitor indicated in the European Union for the treatment of adult men with:

Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with ADT.
High-risk non-metastatic castration-resistant prostate cancer (CRPC).
Metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. It is also indicated in adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.
For Important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: View Source

U.S.: About XTANDI (enzalutamide) and Important Safety Information
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures occurred in patients receiving XTANDI. 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. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.

Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI.

Adverse Reactions (ARs)
In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for additional safety information.

About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of people living with cancer. Today, we have an industry-leading portfolio of 24 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood and lung cancers, as well as melanoma.

On September 17, 2021, AIM ImmunoTech Inc. (the "Company") reported a Company Presentation On September 17, 2021, AIM ImmunoTech Inc. (the "Company") posted a Company Presentation

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On September 17, 2021 VBL Therapeutics (NASDAQ: VBLT) reported that the independent Data Safety Monitoring Committee (DSMC) of the ongoing OVAL Phase 3 registration-enabling study of VB-111 in ovarian cancer has conducted its fifth pre-planned review and has provided clearance to proceed with further clinical research as planned with no changes to the protocol (Press release, VBL Therapeutics, SEP 17, 2021, View Source [SID1234587867]).

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The independent DSMC for the OVAL trial is tasked with setting standards of safety, monitoring these standards’ implementation for the trial participants and treatment efficacy data, and acting on behalf of patients whenever necessary as the committee continues to monitor progress.

"We continue to be very pleased to learn that data collected to date in the OVAL clinical trial has passed independent DSMC review as we progress toward our enrollment goal," said Prof. Dror Harats, M.D., chief executive officer of VBL Therapeutics. "We thank the DSMC for its ongoing diligence, guidance and support."

The OVAL trial is planned to enroll approximately 400 adult patients globally and more than 320 patients (>80 percent) have already been recruited. The trial has two primary endpoints: progression free survival (PFS) and overall survival (OS). Successfully meeting either primary endpoint has the potential to support a biologics license application (BLA). Meeting the PFS endpoint, with a readout anticipated in the second half of 2022, could accelerate BLA submission by approximately one year, subject to discussions with the U.S. Food and Drug Administration (FDA), compared to original projections based on the readout of the OS primary endpoint that remains anticipated in 2023.

About VB-111 (ofranergene obadenovec; `ofra-vec`)
VB-111 is an investigational anti-cancer, gene-therapy agent in development to treat a wide range of solid tumors. VB-111 is a unique biologic agent designed to use a dual mechanism to target solid tumors. Its mechanism combines the blockade of tumor vasculature with an anti-tumor immune response. VB-111 is administered as an IV infusion once every 6-8 weeks. It has been observed in past clinical research to be generally well-tolerated in >300 cancer patients and demonstrated activity signals in an "all comers" Phase 1 trial as well as in three tumor-specific Phase 2 studies. VB-111 has received orphan designation for the treatment of ovarian cancer by the European Commission. VB-111 has also received orphan drug designation in both the United States and Europe, and fast track designation in the United States, for prolongation of survival in patients with recurrent glioblastoma. VB-111 demonstrated proof-of-concept and survival benefit in Phase 2 clinical trials in radioiodine-refractory thyroid cancer (NCT01229865) and platinum-resistant ovarian cancer (NCT01711970).

About the OVAL Trial (NCT03398655)
OVAL (VB-111-701/GOG-3018) is an international Phase 3 randomized, pivotal registration-enabling clinical trial comparing a combination of VB-111 and paclitaxel to placebo plus paclitaxel, in adult patients with recurrent platinum-resistant ovarian cancer. OVAL is conducted in collaboration with the GOG Foundation, Inc., an independent international non-profit organization with the purpose of promoting excellence in the field of gynecologic malignancies.

On September 17, 2021 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported four e-poster presentations at the ESMO (Free ESMO Whitepaper) Congress 2021 (Press release, Deciphera Pharmaceuticals, SEP 17, 2021, View Source [SID1234587866]). The presentations include updated preliminary results from the ongoing Phase 1b/2 study of rebastinib in combination with paclitaxel in patients with PROC and updated preliminary results from the ongoing Phase 1/2 study of vimseltinib in patients with TGCT. A long-term update on the Phase 3 INVICTUS study of QINLOCK (ripretinib) in patients with advanced gastrointestinal stromal tumors (GIST), and results from the expansion phase of the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma will also be presented.

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All e-poster presentations are now available on-demand via the ESMO (Free ESMO Whitepaper) website and on the Company’s website at www.deciphera.com/presentations-publications. Deciphera will also host an investor event featuring key opinion leaders to discuss the rebastinib and vimseltinib data today, September 17, 2021, at 10 AM ET. A live webcast of the event may be accessed through the "Investors" section of Deciphera’s website at www.deciphera.com. A replay of the webcast will be available following the event.

"We are excited to present strong results at this year’s ESMO (Free ESMO Whitepaper) Congress, which support both our plans to initiate a Phase 3 pivotal study for rebastinib pending regulatory feedback, and our plans to initiate a Phase 3 pivotal study for vimseltinib. The updated safety and efficacy results for rebastinib in combination with paclitaxel show highly encouraging results, including a median progression free survival of 9.1 months, in heavily pretreated patients with PROC where additional treatment is heterogeneous and single agent paclitaxel retreatment has historically shown only 3-4 months of PFS. Based on these impressive results in patients with a significant unmet medical need, we have begun planning for a pivotal Phase 3 study that we plan to initiate in 2022 following regulatory feedback," said Matthew L. Sherman, MD, Executive Vice President and Chief Medical Officer of Deciphera. "We are equally encouraged by the tolerability and efficacy data presented today from the Phase 1/2 study of vimseltinib in TGCT. The data presented today with vimseltinib in TGCT reinforce its potential to be a best-in-class treatment for this disease. We are rapidly moving forward with this program and we expect to initiate our Phase 3 study, MOTION, in the fourth quarter of this year."

Dr. Sherman continued, "In addition to rebastinib and vimseltinib, we presented positive results from the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma, and a long-term update from the Phase 3 INVICTUS study of QINLOCK, which shows further prolonged clinically meaningful median overall survival among patients receiving QINLOCK. Finally, we look forward to our Phase 3 INTRIGUE readout later this year in patients with second-line GIST."

Updated Preliminary Data from the Ongoing Phase 1b/2 Study of Rebastinib in Combination with Paclitaxel in PROC

The Phase 1b/2 study of rebastinib in combination with paclitaxel is a two-part, open-label, multicenter study assessing the safety, tolerability, anti-tumor activity, and pharmacokinetics of rebastinib in patients with advanced or metastatic solid tumors. The data presented today is from the second stage of Part 2 of the Simon two-stage design in PROC.

As of the June 22, 2021 cutoff date, 38 patients with PROC initiated treatment with rebastinib and paclitaxel and are included in the safety population and 34 patients that met the criteria for the modified intent-to-treat population (mITT) are included in the efficacy analysis.

The median progression-free survival (PFS) was 9.1 months.
There were 13 patients with objective responses (10 confirmed) for an objective response rate (ORR) of 38% (confirmed and unconfirmed) and 29% (confirmed only) with a median duration response of 5.5 months.
The clinical benefit rate at 16 weeks was 76%.
A CA-125 response occurred in 19 of 26 patients (73%).
Rebastinib in combination with paclitaxel was generally well tolerated at 50 mg BID, and most common (≥15%) treatment-emergent adverse events (TEAEs) were Grade 1 or 2.
Four patients experienced serious adverse events (SAEs) at least possibly related to rebastinib including reversible muscular weakness (n=2), constipation (n=1), fatigue (n=1), and urinary tract infection (n=1).
Based on the strength of these findings, the Company has begun planning for a pivotal study in PROC that is anticipated to start in 2022, subject to feedback from regulators.

Updated Preliminary Data from the Ongoing Phase 1/2 Study of Vimseltinib in TGCT

The Phase 1/2 study of vimseltinib is an open-label, multicenter study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of vimseltinib in patients with solid tumors and TGCT. The data today is from patients with TGCT in both the Phase 1 dose escalation portion of the study and from cohort A in the Phase 2 expansion portion of the study. Cohort A includes TGCT patients with no prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib is allowed) and cohort B includes patients with prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib are not eligible).

As of the June 7, 2021 cutoff date, 68 TGCT patients were treated with vimseltinib and included in the safety population, including 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 36 TGCT patients enrolled in cohort A in the Phase 2 portion of the study. Efficacy data presented today is from 51 TGCT patients, including all 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 19 TGCT patients enrolled in cohort A in the Phase 2 portion of the study that were evaluable for efficacy as of the cutoff date.

Dose Cohorts and Demographics:

32 patients enrolled in Phase 1 (dose escalation) and 36 patients enrolled in Phase 2 cohort A (expansion):
Phase 1 cohort 5 (n=8): 30 mg loading dose daily for five days followed by a maintenance dose of 30 mg twice a week.
Phase 1 cohort 8 (n=12): 30 mg loading dose daily for three days followed by a maintenance dose of 10 mg daily.
Phase 1 cohort 9 (n=12): 20 mg loading dose daily for three days followed by a maintenance dose of 6 mg daily.
Phase 2 cohort A (n=36): 30 mg twice weekly (no loading dose).
12 out of 32 patients (38%) in Phase 1 and 32 out of 36 patients (89%) in Phase 2 cohort A had at least one prior surgery; five patients (16%) in Phase 1 and two patients (6%) in Phase 2 cohort A had received at least one prior systematic therapy.
51 patients were evaluable for efficacy by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 at the data cutoff in Phase 1 across all dose cohorts and in Phase 2 cohort A; response data is based on independent central radiologic review with the exception of one patient who had a local assessment, and for whom no central assessment was performed.
Updated Preliminary Efficacy and Duration of Treatment:

Of the 51 efficacy-evaluable patients in Phase 1 across all dose cohorts and in the Phase 2 cohort A, 24 patients had a response resulting in an ORR of 47%.
Of the 32 patients in Phase 1, 16 patients achieved an objective response for an ORR of 50% with durable responses observed across all dose cohorts, including one complete response in cohort 5. The median duration of treatment for all patients was 10.1 months. 72% of patients remain active in the study as of the data cutoff date.
Of the 36 patients enrolled in Phase 2 cohort A, 19 patients were evaluable for efficacy, of which there were eight patients with an objective response for an ORR of 42%. Of the 19 patients, 10 had more than one follow-up imaging assessment and two responses occurred at later scans. The median duration of treatment for all patients was 1.9 months. The study is ongoing and follow-up evaluation is continuing with 83% of patients remaining active as of the data cutoff date.
Safety and Tolerability:

In both Phase 1 and Phase 2 cohort A, treatment with vimseltinib was generally well tolerated in patients with TGCT. Two patients (6%) discontinued treatment due to a TEAE in Phase 1 and one patient (3%) discontinued treatment due to an TEAE in Phase 2 cohort A.
Two patients experienced SAEs at least possibly related to vimseltinib, including metabolic encephalopathy and vaginal hemorrhage in Phase 1; no treatment-related SAEs were reported in Phase 2 cohort A.
The majority of the common (≥15%) TEAEs were Grade 2 or lower.
Observed transaminase, pancreatic, and creatine phosphokinase enzyme elevations were mostly low grade, asymptomatic, and consistent with mechanism of action of CSF1R inhibitors.
No abnormalities in bilirubin levels were reported.
Phase 3 MOTION Study

Based on the positive results of the ongoing Phase 1/2 study, the Company plans to advance vimseltinib into a pivotal Phase 3 study in patients with TGCT. The MOTION study is two-part, randomized, double-blind, placebo-controlled study of vimseltinib to assess the efficacy and safety in patients with symptomatic TGCT who are not amenable to surgery. In Part 1 of the study, eligible study participants will be assigned to receive either vimseltinib or matching placebo for 24 weeks. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib for Part 2 of the study. Part 2 is a long-term treatment phase in which all participants receive open-label vimseltinib. The primary endpoint of the study is ORR at 25 weeks as measured by RECIST v1.1 by blinded independent central review. The Company expects to initiate the MOTION study in the fourth quarter of this year.

Long-term Update from Phase 3 INVICTUS Study of QINLOCK in Patients with Advanced GIST

The INVICTUS Phase 3 clinical study is a randomized (2:1), double-blind, placebo-controlled, international, multicenter study to evaluate the safety, tolerability, and efficacy of QINLOCK compared to placebo in patients with advanced GIST whose previous therapies have included at least imatinib, sunitinib, and regorafenib. The Company previously reported primary results from the randomized portion of the INVICTUS study, in which QINLOCK significantly improved PFS and showed a clinically meaningful overall survival (OS) benefit.

An exploratory evaluation of primary and secondary endpoints in the Phase 3 INVICTUS study, with a cutoff date of January 15, 2021, an additional 19 months after the primary analysis, demonstrates consistent PFS with no change since the primary data cut off, and improved median OS among patients receiving ripretinib.

Median PFS was 6.3 months with QINLOCK compared to 1.0 month with placebo.
Median OS was 18.2 months with QINLOCK compared to 6.3 months with placebo.
Median OS was 10 months in placebo patients who crossed over to QINLOCK.
Median ORR was 11.8% with QINLOCK compared to 0% with placebo.
Median duration of response with QINLOCK was 14.5 months.
Safety findings were consistent with the primary analysis results and most TEAEs were Grade 1 or 2. Increases in TEAEs and TEAEs leading to dose modifications in the additional 19 months of follow up were minimal.

These more mature results continue to support the clinically meaningful benefit in PFS and OS for QINLOCK with an acceptable safety profile in patients with advanced GIST treated with three or more prior lines of therapy.

Phase 1 Study of Ripretinib in Patients with KIT-altered Metastatic Melanoma

As part of the expansion phase of the Phase 1 study, 26 patients with KIT-altered metastatic melanoma were treated with ripretinib at the recommended Phase 2 dose of 150 mg daily in repeated 28-day cycles. Tumor progression was assessed by the investigator using computed tomography/magnetic resonance imaging according to RECIST v1.1 on day 1 of cycles 3, 5, 7, and every three cycles thereafter, and a final study visit. ORR was confirmed with follow-up imaging approximately 28 days later. Patients who had disease progression at ripretinib 150 mg daily were allowed to dose escalate to 150 mg twice daily.

Ripretinib demonstrated encouraging efficacy in patients with KIT-altered metastatic melanoma with a confirmed ORR of 23%, median duration of response of 9.1 months, and median PFS of 7.3 months. In addition, there were two unconfirmed partial responses resulting in an ORR of 31% (confirmed and unconfirmed).
Tyrosine kinase inhibitor (TKI)-naïve patients had a greater response (confirmed ORR of 29% and median PFS of 10.2 months) to ripretinib than those with prior TKI treatment (confirmed ORR of 11% and median PFS of 2.9 months).
Ripretinib had an acceptable safety profile in KIT-altered metastatic melanoma consistent with the approved indication in GIST.