On September 15, 2024 TORL BioTherapeutics, LLC ("TORL Bio" or "the Company"), a clinical stage biotechnology company discovering and developing new antibody-based immunotherapies to improve and extend the lives of patients with cancer worldwide, reported the presentation of additional results from the ongoing Phase 1 study of TORL-1-23, the Company’s Claudin 6 (CLDN6) targeted antibody-drug conjugate (ADC) in patients with advanced cancer at the 2024 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO 2024) in Barcelona, Spain (Press release, TORL Biotherapeutics, SEP 15, 2024, View Source [SID1234646628]). This mini-oral presentation (ESMO Presentation #721MO) included updated results from the TORL123-001 (TRIO-049) trial up to the 4.0 mg/kg dose level of TORL-1-23. The data were presented by the Global Principal Investigator, Gottfried E. Konecny, M.D. of the University of California, Los Angeles (UCLA) Medical Center.

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"The latest efficacy and safety data from this Phase 1 study continue to support the potential of TORL-1-23 as a new treatment option for patients with Claudin 6 positive ovarian cancer," said Global Principal Investigator, Gottfried E. Konecny, M.D. of UCLA Medical Center.

In this ongoing Phase 1 study, 81 patients with CLND6 positive (CLDN6+), heavily pretreated ovarian, testicular, endometrial, non-small cell lung cancer (NSCLC), and other cancers were enrolled and are evaluable for safety and efficacy across 11 dose cohorts ranging from 0.2 mg/kg to 4.0 mg/kg administered intravenously every 3 weeks. Patients had an average of 4 prior therapeutic regimens.

Key study findings include the following:

At doses from 0.2 mg/kg to 2.4 mg/kg every 3 weeks, TORL-1-23 is generally well tolerated. The most common adverse events were grade 1 or 2 fatigue, peripheral neuropathy, and alopecia. The most frequent grade 3+ adverse event was neutropenia. Febrile neutropenia, interstitial lung disease, and ocular toxicities were not observed.
Prophylactic pegfilgrastim was implemented at doses 3.0 mg/kg or higher and was effective at mitigating neutropenia. The maximum tolerated dose (MTD) has yet to be identified.
Encouraging antitumor activity was observed in this heavily pretreated population during dose finding across all enrolled cancer histologies and dose levels.
At doses of 2.4 mg/kg and 3.0 mg/kg every 3 weeks, there were deep and durable confirmed responses in 9/20 (45%) patients with CLDN6+ platinum-resistant/refractory ovarian cancer (PROC). Median duration of response exceeded 6 months at both dose levels.
"The objective of molecularly targeted therapeutics in cancer is to significantly enhance efficacy while simultaneously maintaining or improving safety over established treatments. The emerging Phase 1 profile of TORL-1-23 suggests that this ADC may achieve that goal for patients with platinum-resistant ovarian cancer, a serious unmet medical need," said Scientific Co-founder Dennis Slamon, MD, PhD, Professor of Medicine, and Chief of the Division of Hematology/Oncology at UCLA’s David Geffen School of Medicine.

Phase 1 evaluation of TORL-1-23 in NSCLC and other CLDN6+ cancers is ongoing. A multi-dose Phase 2 study that is designed to support accelerated registration in CLDN6+ PROC is being initiated.

Presentation Details

Title: Phase 1, Two-Part, Multicenter First-In-Human (FIH) Study of TORL-1-23, A Novel Claudin 6 (CLDN6) Targeting Antibody Drug Conjugate (ADC) In Patient with Advanced Solid Tumors
Lead Author: Gottfried Konecny, M.D., UCLA Medical Center
Presentation Number: 721MO
Presentation Session: Mini Oral Session 2: Gynaecological cancers
Presentation Session Date and Time: September 15, 2024, at 15:50 CEST

About Claudin 6

Claudin 6 (CLDN6) is overexpressed in multiple cancers with limited to no detectable expression observed in normal tissues, thus an ideal target for antibody-drug conjugate development. CLDN6 is a tumor-specific transmembrane protein of tight junctions important for cell-to-cell connectivity. Overexpression of CLDN6 is implicated in the initiation, progression, and metastasis of certain cancers, including ovarian, non-small cell lung, endometrial, testicular and others. High expression correlates with shortened survival outcomes for patients with ovarian cancer.

About TORL-1-23

TORL-1-23 is a first and potentially best-in-class clinical-stage antibody-drug conjugate (ADC) for the treatment of Claudin 6 positive (CLDN6+) solid tumors. Select centers are enrolling patients in the Part 2 expansion of Phase 1 study TORL123-001 (TRIO-049), assessing the safety, pharmacokinetics, biomarkers, and antitumor activity of TORL-1-23. Further details including current study sites can be found at View Source

On September 15, 2024 AstraZeneca reported positive results from the NIAGARA Phase III trial showed AstraZeneca’s Imfinzi (durvalumab) in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival (EFS) and the key secondary endpoint of overall survival (OS) versus neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer (MIBC) (Press release, AstraZeneca, SEP 15, 2024, View Source [SID1234646625]). Patients were treated with Imfinzi in combination with neoadjuvant chemotherapy before radical cystectomy (surgery to remove the bladder) followed by Imfinzi as adjuvant monotherapy.

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These results will be presented today during a Presidential Symposium at the 2024 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Barcelona, Spain (abstract #LBA5) and simultaneously published in The New England Journal of Medicine.

In a planned interim analysis, patients treated with the Imfinzi perioperative regimen showed a 32% reduction in the risk of disease progression, recurrence, not undergoing surgery, or death versus the comparator arm (based on EFS hazard ratio [HR] of 0.68; 95% confidence interval [CI] 0.56-0.82; p<0.0001). Estimated median EFS was not yet reached for the Imfinzi arm versus 46.1 months for the comparator arm. An estimated 67.8% of patients treated with the Imfinzi regimen were event free at two years compared to 59.8% in the comparator arm.

Results from the key secondary endpoint of OS showed the Imfinzi perioperative regimen reduced the risk of death by 25% versus neoadjuvant chemotherapy with radical cystectomy (based on OS HR of 0.75; 95% CI 0.59-0.93; p=0.0106). Median survival was not yet reached for either arm. An estimated 82.2% of patients treated with the Imfinzi regimen were alive at two years compared to 75.2% in the comparator arm.

Professor Thomas Powles, MD, Director of Barts Cancer Centre (QMUL), London, UK, and principal investigator in the NIAGARA trial, said: "Neoadjuvant chemotherapy with bladder removal has been the mainstay of treatment for patients with muscle-invasive bladder cancer for nearly twenty years; however, half of patients still go on to suffer a devastating recurrence. Adding durvalumab before and after surgery significantly reduced the chance of recurrence and extended survival, a significant advance with the potential to transform the standard of care for these patients who desperately need better outcomes."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "The NIAGARA data showed compelling improvements in both event-free survival and overall survival, with more than 80 per cent of patients treated with the Imfinzi perioperative regimen alive at two years. This is the first immunotherapy regimen to significantly extend overall survival in muscle-invasive bladder cancer, and it further validates our strategy to move cancer treatment as early as possible to maximise benefit for patients."

On September 15, 2024 Daiichi Sankyo reported initial results from dose escalation in the firstin-human phase 1 trial of DS-9606 suggest early promising clinical activity in patients with advanced solid tumors known to express Claudin-6 (CLDN6) (Press release, Daiichi Sankyo, SEP 15, 2024, View Source [SID1234646622]). These data were presented today during a Proffered Paper session (610O) at the 2024 European Society for Medical Oncology (#ESMO24).

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DS-9606 is an investigational CLDN6 directed, modified pyrrolobenzodiazepine (PBD) antibody drug conjugate (ADC) from Daiichi Sankyo’s (TSE: 4568) second antibody drug conjugate (ADC) platform.

CLDN6 is expressed in several tumor types including endometrial, ovarian and gastric cancers, germ cell tumors (GCT) and non-small cell lung cancer (NSCLC), and can be associated with poor prognosis, making CLDN6 a promising therapeutic target. 1-6

Preliminary safety and efficacy results of DS-9606 were reported from the dose escalation part of the phase 1 trial in 53 heavily pretreated patients, including 19 with ovarian, 11 with GCT, seven with gastric/esophageal, seven with NSCLC, five with pancreatic, two with breast and two with endometrial cancer. Patients received a median of four prior therapies (range, 1- 9).

The safety and tolerability of DS-9606 were evaluated at increasing dose levels from 0.016 mg/kg to 0.225 mg/kg with no dose-limiting toxicities observed and no treatment withdrawals due to treatmentrelated adverse events. The most common treatment emergent adverse events (TEAEs) of any grade in ≥7.5% of patients were nausea (18.9%), fatigue (18.9%), anemia (17.0%), abdominal pain (15.1%), constipation (13.2%), vomiting (13.2%), diarrhea (11.3%), pyrexia (9.4%), weight loss (9.4%), decreased appetite (9.4%), arthralgia (9.4%), cough (9.4%), sinusitis (7.5%), dyspnea (7.5%) and pleural effusion (7.5%). Grade 3 or higher TEAEs occurred in 30.2% of patients (n=16) and included anemia (3.8%), abdominal pain (3.8%), pleural effusion (3.8%), constipation (1.9%), vomiting (1.9%) and diarrhea (1.9%). When grouped, skin-associated events (17%) were also identified as common TEAEs with the majority being grade 1 except for one grade 2 (skin hyperpigmentation) and one grade 3 (rash) event, which resulted in a dose reduction for each patient.

Preliminary efficacy results were observed in doses greater than or equal to 0.072 mg/kg (except 0.190 mg/kg due to immature data) and included four confirmed objective responses including two responses observed in patients with GCT and one response each in patients with gastric/esophageal cancer and NSCLC. Of seven evaluable patients with GCT, the two patients with confirmed objective response remained on treatment for more than six months and five had a greater than or equal to 90% reduction in alpha-fetoprotein and human chorionic gonadotropin tumor markers. Twenty one of the 53 patients are still receiving treatment with DS-9606 as of data cutoff of June 14, 2024.

"These initial results of DS-9606 are encouraging, particularly those observed in germ cell tumors which are known to express CLDN6 and where the majority of patients experienced a reduction in tumor markers," said Manish R. Patel, MD, Director of Drug Development, Florida Cancer Specialists and Sarah Cannon Research Institute. "Enrollment continues into the study in order to determine the recommended dose for expansion and better understand how advanced solid tumors may respond to DS-9606."

"While these results provide preliminary proof-of-concept for DS-9606, further clinical evaluation is warranted across different tumor types that are known to express CLDN6," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "We continue to apply our science and technology expertise to DS-9606, which has been developed from our second antibody drug conjugate platform in order to create potentially new and innovative treatments for certain patients with cancer."

About the Phase 1 Trial
The multicenter, open-label, first-in-human phase 1 trial is evaluating the safety, tolerability and efficacy of DS-9606 in adult patients with advanced solid tumors that are known to express CLDN6.

The dose escalation part of the study is assessing the safety and tolerability of increasing doses of DS-9606 to determine the maximum tolerated dose and/or the recommended dose for expansion. Dose expansion will follow to further evaluate the safety and tolerability as well as efficacy of DS-9606 at the recommended dose in patients with advanced solid tumors in cohorts that will be determined based on data obtained in dose escalation.

The study will evaluate safety and efficacy endpoints, including objective response rate, duration of response and progression-free survival per investigator assessment. Pharmacokinetic and immunogenicity endpoints will also be evaluated.

The phase 1 trial is currently enrolling patients in Europe and North America. For more information, please visit ClinicalTrials.gov.

About Claudin-6 (CLDN6)
Claudin-6 (CLDN6), a member of the claudin family, is a gene that encodes a protein that plays an important role in cell production and differentiation.7,8 CLDN6 is expressed in several tumor types including endometrial, ovarian and gastric cancers, GCT and NSCLC, and can be associated with poor prognosis, making CLDN6 a promising therapeutic target.1-6

About DS-9606
DS-9606 is an investigational CLDN6 directed, modified PBD ADC. Designed using Daiichi Sankyo’s second ADC technology platform, DS-9606 consists of a humanized CLDN6 monoclonal antibody, developed in collaboration with Tokyo University of Pharmacy and Life Sciences, attached to a modified PBD payload. DS-9606 is being evaluated in a phase 1 clinical trial in several advanced solid tumors that are known to express CLDN6.

About the ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two
distinct ADC technology platforms discovered in-house by Daiichi Sankyo.

The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified PBD payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

On September 15, 2024 Veracyte, Inc., a leading cancer diagnostics company, reported that new data from a phase 3 trial of the multi-center, randomized STAMPEDE clinical trial show that its Decipher Prostate Genomic Classifier is prognostic for clinical outcomes and predicts benefit from docetaxel in patients with metastatic prostate cancer (Press release, Veracyte, SEP 15, 2024, View Source [SID1234646618]). The findings were presented today (Presentation #15960) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2024 Congress in Barcelona. These findings support Veracyte’s plan to expand use of the Decipher Prostate test – currently widely used to guide care for localized prostate cancer – to patients with metastatic disease.

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Prostate cancer accounts for a fifth (approximately 375,000) of all male cancer-related deaths globally and the number is expected to double over the next two decades.1 In the United States, it is the second-leading cause of cancer deaths among men, with more than 35,000 men expected to die of the disease in 2025.2 Most prostate cancer deaths occur in patients who first presented with advanced or metastatic disease.

"For patients with metastatic prostate cancer, adding the chemotherapy docetaxel to standard-of-care androgen deprivation therapy (ADT) can increase survival. However, patient response varies and today physicians have limited tools for identifying who will likely benefit from the drug and who won’t," said Gerhardt Attard, M.D., Ph.D., Professor and John Black Charitable Foundation Endowed Chair in Urological Cancer Research at University College London and STAMPEDE trial co-investigator. "Our findings are important because they show that the Decipher Prostate test can help clinicians better distinguish patients with metastatic prostate cancer who receive the greatest benefit from docetaxel from those who don’t and may therefore avoid unnecessary toxicity."

In the new study, researchers analyzed data for 1,523 patients with advanced or metastatic prostate cancer who were followed in the STAMPEDE trial for a median of 14 years. They found that higher Decipher Prostate test scores were associated with an increased risk of death in both groups. Additionally, among the 832 patients with metastatic disease, only those with higher Decipher Prostate scores received a significant survival benefit from the addition of docetaxel to ADT. These patients had a 36% reduction in risk of death (HR 0.64, 95% CI, 0.48-0.86) with the addition of docetaxel as compared to those with lower Decipher scores who did not significantly benefit (HR 0.96, 0.71-1.30; interaction p=0.039).

Notably, docetaxel was beneficial in patients with higher Decipher Prostate scores regardless of whether they had high- or low-volume prostate cancer. This is important because current clinical practice favors use of docetaxel in patients with high- but not low-volume disease.

"The Decipher Prostate test’s ability to help guide treatment for patients with localized prostate cancer is already proven in dozens of peer-reviewed publications and is the only molecular test to achieve ‘Level 1B’ evidence status in the most recent NCCN Guidelines* for prostate cancer," said Elai Davicioni, Ph.D., Veracyte’s medical director for Urology. "These new phase 3 data from the STAMPEDE trial now further prove the performance and utility of our test in patients with metastatic prostate cancer. We believe our test can have a tremendous positive impact on care for these patients."

Veracyte expects to begin offering the Decipher Prostate test to patients with metastatic prostate cancer in early 2025, after its anticipated reimbursement by Medicare. MolDX, a program that establishes Medicare coverage for advanced molecular diagnostic tests, recently issued a local coverage determination for molecular testing in patients with metastatic prostate cancer, providing what Veracyte believes is a pathway to coverage for its test.

"We are excited about the new Decipher Prostate data presented at ESMO (Free ESMO Whitepaper) and the opportunity to advance cancer care for even more patients," said Marc Stapley, Veracyte’s chief executive officer. "These important advances clearly demonstrate the power of our Veracyte Diagnostics Platform, which delivers high-performing cancer tests and a powerful evidence-generation engine. Ultimately, this novel approach helps drive widespread test reimbursement and adoption, along with new insights to support our pipeline. This includes expanding the use of Decipher Prostate now to patients across the prostate cancer continuum, from those who are low risk and can benefit from active surveillance, to those who are metastatic and can benefit from chemotherapy."

About Decipher Prostate

The Decipher Prostate Genomic Classifier is a 22-gene test, developed using RNA whole-transcriptome analysis and machine learning, that helps inform treatment decisions for patients with prostate cancer. The test is performed on biopsy or surgically resected samples and provides an accurate risk of developing metastasis with standard treatment. Armed with this information, physicians can better personalize their patients’ care and may recommend less-intensive options for those at lower risk or earlier, more-intensive treatment for those at higher risk of metastasis. The Decipher Prostate test has been validated in more than 80 published studies involving more than 100,000 patients. More information about the Decipher Prostate test can be found here.

On September 15, 2024 Replimune Group, a clinical stage biotechnology company pioneering the development of novel oncolytic immunotherapies, reported that data from the primary analysis of the IGNYTE clinical trial of RP1 combined with nivolumab were presented by Caroline Robert, M.D., Ph.D. of Gustave Roussy as a late breaking abstract during an oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona (Press release, Replimune, SEP 15, 2024, View Source [SID1234646617]).

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"We are excited to share the full IGNYTE primary analysis data which clearly shows clinically meaningful and durable systemic anti-tumor activity across the enrolled population, with responses in both injected and non-injected tumors, including visceral lesions," said Kostas Xynos, MD, PhD, MBA, Chief Medical Officer of Replimune. "These positive data will form the basis of our upcoming BLA submission for RP1 in anti-PD1 failed melanoma in the 2H 2024, which is an important step forward as we continue to progress RP1 plus nivolumab as a potential new option in a setting with only limited treatments currently available."

The anti-PD1 failed melanoma cohort from the IGNYTE clinical trial included 140 patients who received RP1 plus nivolumab after confirmed progression while being treated for at least 8 weeks with anti-PD1 based therapy (+/- anti-CTLA-4). The primary analysis by blinded independent central review was triggered once all patients had been followed for at least 12 months. Because of requirements that patients must have confirmed progressive disease on an immediate anti-PD1-based therapy, which is the current first line standard of care, most of the patients enrolled had 1 (45.7%) or 2 (18.6%) lines of prior therapies.

Results from the IGNYTE clinical trial presented at ESMO (Free ESMO Whitepaper) show:

The overall response rate (ORR) was 33.6% by modified RECIST (mRECIST) 1.1 criteria, the primary endpoint as defined in the protocol, and 32.9% by RECIST 1.1 criteria, an additional sensitivity analysis requested by the FDA.
The complete response rate by mRECIST was 15%.
In patients who had prior anti-PD1 and anti-CTLA-4, the ORR was 27.7% and for those who had primary resistance to anti-PD1, the ORR was 35.9% by mRECIST.
Median duration of response from response initiation was 21.6 months and media duration of response from treatment initiation was 27.6 months. At the time of the analysis, 85% of responses were ongoing more than a year from starting treatment.
While median overall survival has not been reached, one-, two- and three-year survival rates were 75.3%, 63.3% and 54.8% respectively.
RP1 combined with nivolumab continues to be well-tolerated. Treatment-related adverse events associated with RP1 in combination with nivolumab were predominantly Grade 1-2 constitutional type events (> 5% of patients), including fatigue, chills, pyrexia, nausea, influenza-like illness, injection-site pain, diarrhea, vomiting, headache, pruritis, asthenia, arthralgia, myalgia, decreased appetite, and rash, with a low incidence (12.8% of patients) of Grade 3-4 events, which were predominantly Grade 3. Grade 4 events were one each of lipase increased, cytokine release syndrome, myocarditis, hepatic cytolysis and splenic rupture. There were no Grade 5 events.

The presentation is available on the Company website under Events and Presentations.

About RP1
RP1 (vusolimogene oderparepvec) is Replimune’s lead product candidate and is based on a proprietary strain of herpes simplex virus engineered and genetically armed with a fusogenic protein (GALV-GP R-) and GM-CSF, intended to maximize tumor killing potency, the immunogenicity of tumor cell death, and the activation of a systemic anti-tumor immune response.