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Two Phase 3 Trials of Datopotamab Deruxtecan Plus Durvalumab Initiated in Patients Across Two Breast Cancer Subtypes

On December 18, 2023 Daiichi Sankyo reported that the first patient has been dosed in two global, randomized phase 3 trials evaluating the efficacy and safety of Daiichi Sankyo (TSE: 4568) and AstraZeneca’s (LSE/STO/Nasdaq: AZN) datopotamab deruxtecan (Dato-DXd) in combination with durvalumab, AstraZeneca’s anti-PD-L1 therapy, in two types of breast cancer (Press release, Daiichi Sankyo, DEC 18, 2023, View Source [SID1234638665]).

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Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca.

TROPION-Breast04 is evaluating neoadjuvant datopotamab deruxtecan plus durvalumab followed by adjuvant durvalumab with or without chemotherapy in patients with stage II-III triple negative breast cancer (TNBC) or hormone receptor (HR) low, HER2 low or negative breast cancer. TROPION-Breast05 is evaluating datopotamab deruxtecan alone and in combination with durvalumab in patients with locally recurrent inoperable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10).

Approximately 300,000 people worldwide are diagnosed annually with TNBC, accounting for approximately 15% of all breast cancer diagnoses.1,2 TNBC is characterized by its aggressive nature and high likelihood of recurrence and progression regardless of stage.3 Standard treatment for patients with early-stage disease (stage II-III) is typically chemotherapy alone or in combination with immunotherapy prior to tumor resection.5 For patients with metastatic disease, standard first-line treatment can include chemotherapy alone or in combination with immunotherapy.2,3,4

In addition to patients with TNBC, TROPION-Breast04 will enroll patients with HR low, HER2 low or negative breast cancer whose tumors express low levels of hormone receptors (estrogen and/or progesterone receptor levels 1% to < 10%). Patients with HR low, HER2 low or negative disease have historically been excluded from TNBC research as their tumors are not triple negative. However, these patients tend to have worse outcomes relative to those with hormone receptor-strongly positive tumors (estrogen and/or progesterone receptor levels ≥ 10%) on standard endocrine therapies.5

"While the addition of immune checkpoint inhibitors to chemotherapy has led to survival improvements for patients with triple negative breast cancer, the overall prognosis for these patients remains poor," said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. "These two phase 3 trials will evaluate whether combining datopotamab deruxtecan, a TROP2 directed antibody drug conjugate, with durvalumab may offer a more effective option for patients across different settings of breast cancer."

"In an early phase trial, the datopotamab deruxtecan and durvalumab combination has shown robust and durable tumor responses and a manageable safety profile in patients with previously untreated advanced triple negative breast cancer," said Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. "The initiation of the TROPION-Breast04 and TROPION-Breast05 phase 3 trials underscores our confidence in this promising combination and our commitment to researching its potential across multiple settings of triple negative breast cancer and in HR low disease."

Daiichi Sankyo and AstraZeneca have two additional ongoing phase 3 trials evaluating datopotamab deruxtecan in TNBC. TROPION-Breast02 is evaluating datopotamab deruxtecan versus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-1/PD-L1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without durvalumab versus investigator’s choice of therapy in patients with stage I to III TNBC with residual disease after neoadjuvant therapy.

About TROPION-Breast04
TROPION-Breast04 is a global, randomized, open-label, double-arm, phase 3 trial evaluating the efficacy and safety of neoadjuvant datopotamab deruxtecan plus durvalumab followed by adjuvant durvalumab with or without chemotherapy compared to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in patients with previously untreated stage II or III TNBC or HR low, HER2 low or negative breast cancer.

The primary endpoints of TROPION-Breast04 are pathological complete response and event-free survival. The key secondary endpoint is overall survival (OS) and additional secondary endpoints include distant disease-free survival, pharmacokinetics, immunogenicity, safety and tolerability.

TROPION-Breast04 will enroll approximately 1,700 patients with previously untreated TNBC or HR low, HER2 low or negative breast cancer at study sites in Asia, Europe, North America, Oceania and South America. For more information, visit ClinicalTrials.gov.

About TROPION-Breast05
TROPION-Breast05 is a global, randomized, open-label, three-arm phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan alone and in combination with durvalumab versus investigator’s choice of chemotherapy plus pembrolizumab in participants with locally recurrent inoperable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10). Patients must have completed treatment for stage I to III breast cancer, if indicated, and ≥ 6 months have elapsed between completion of treatment with curative intent and the first documented recurrence.

The primary endpoint of TROPION-Breast05 is progression-free survival (PFS) as assessed by blinded independent central review. The key secondary endpoint is OS and additional secondary endpoints include PFS as assessed by investigator, objective response rate, duration of response, pharmacokinetics, immunogenicity, safety and tolerability.

TROPION-Breast05 will enroll 625 patients with TNBC at study sites across Asia, Europe, North America and Oceania. For more information, visit ClinicalTrials.gov.

About Triple Negative Breast Cancer
Breast cancer is the most common cancer in the world and leading cause of cancer-related death.1 More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.1

While some breast cancers test positively for estrogen receptors, progesterone receptors or an overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three.2 Approximately 15% of breast cancer tumors or 300,000 cases annually are considered triple negative.1,2 Standard treatment for patients with early stage disease (stage II-III) is typically chemotherapy alone or in combination with immunotherapy prior to tumor resection.6 For patients with metastatic disease, standard first-line treatment can include chemotherapy alone or in combination with immunotherapy.2,3,4 The median OS of patients living with metastatic TNBC is 12 to 18 months, with only about 12% of patients living five years following diagnosis.7,8

TNBC is characterized by its aggressive nature and high likelihood of progression and recurrence regardless of stage.4 There is a great need for innovative therapeutic options across disease stages and treatment settings.

TROP2 is a protein broadly expressed in several solid tumors, including TNBC.9 TROP2 is associated with increased tumor progression and poor survival in patients with breast cancer.10

About Hormone Receptor Low, HER2 Low or Negative Breast Cancer
HR low, HER2 low or negative breast cancers test positively for hormone receptors but at low levels (estrogen and/or progesterone receptor levels 1% to < 10%) and low or negatively for HER2 (immunohistochemistry [IHC] scores of 0 or 1+ or IHC 2+/ISH-).11,12 HR low breast cancer occurs in approximately 2 to 3% of patients with HR positive disease and continues to represent a clinical challenge as limited data are available regarding optimal treatment for these patients.12

HR expression is a key prognostic and predictive biomarker in breast cancer. While HR positive tumors (estrogen and/or progesterone receptor levels 1% to ≥ 10%) are likely to derive clinical benefit from standard endocrine therapies, HR low tumors do not.12 Patients with HR low tumors have also historically been excluded from TNBC research given their tumors are not triple negative. However, early research suggests HR low tumors may be more similar to TNBC than HR positive tumors, supporting the inclusion of these patients in TNBC clinical trials.

Blueprint Medicines to Present at 42nd Annual J.P. Morgan Healthcare Conference

On December 18, 2023 Blueprint Medicines Corporation (Nasdaq: BPMC) reported that Kate Haviland, Chief Executive Officer, will present a corporate overview and 2024 outlook at the 42nd Annual J.P. Morgan Healthcare Conference on Monday, January 8, 2024, at 10:30 a.m. PT (1:30 p.m. ET) (Press release, Blueprint Medicines, DEC 18, 2023, View Source [SID1234638664]).

A live webcast of the presentation will be available by visiting the Investors & Media section of Blueprint Medicines’ website at View Source A replay of the webcast will be archived on Blueprint Medicines’ website for 30 days following the presentation.

Nectin Therapeutics Adds Combination Therapy Arm and Expands Sites in Phase 1 Clinical Trial of Its First-in-Class Anti-PVR Immune-Oncology Agent

On December 18, 2023 Nectin Therapeutics Ltd., (Nectin), a biotechnology company developing novel targeted immunotherapies that address resistance to approved immune oncology treatments, reported that it has progressed its Phase 1 clinical trial of NTX1088 to include a combination therapy arm with the immune-oncology drug KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, and expanded the clinical trial to five global sites (Press release, Nectin Therapeutics, DEC 18, 2023, View Source [SID1234638663]).

The clinical trial sites include City of Hope in California, Sheba Medical Center and Hadassah Medical Center in Israel, along with MD Anderson Cancer Center in Houston, Texas and Ochsner MD Anderson Cancer Center in Louisiana. Notably, the NTX1088 clinical trial is the first to enroll patients at the new Ochsner MD Anderson Cancer Center partnership that was established to ensure that Ochsner cancer patients have access to the most advanced care, including to clinical trials of innovative therapies.

"As a leader in cancer care, Ochsner MD Anderson Cancer Center is committed to providing world-class care to the southeastern Louisiana community," said Dr. Marc Matrana, Director, Precision Cancer Therapies and Research Program at Ochsner. "Part of that commitment is ensuring that our patients have access to clinical trials of innovative new cancer therapies. We are impressed by the promising preclinical data and the novel mechanism of action of PVR blockade, and we are delighted to join with Nectin Therapeutics to support the Phase 1 trial of NTX1088."

NTX1088 is Nectin’s first-in-class lead candidate – a highly potent monoclonal antibody directed against PVR (CD155), a transmembrane protein expressed on cancer cells and associated with resistance to PD1 and PDL1 immune checkpoint inhibitors. PVR blockade by NTX1088 is the first and only therapeutic approach aimed at restoring the antitumor immune activity of DNAM1 (CD226). DNAM1 is a cell surface glycoprotein, central to the function of T-cells and NK cells, which are degraded by PVR on tumor cells. Restoring the expression and activation of DNAM1 by blocking PVR results in increased antitumor activity from T-cells and NK cells. Additionally, PVR blockade by NTX1088 further stimulates an antitumor immune response by preventing the suppressing signaling of several immune checkpoint receptors, including TIGIT and CD96. NTX1088 is currently being clinically evaluated as a monotherapy and in combination with KEYTRUDA in patients with advanced solid tumors.

"We are encouraged by the rapid progress of our NTX1088 clinical program," said Dr. Keren Paz, Chief Development Officer of Nectin Therapeutics. "Our collaboration with Merck, and the rapid expansion of our clinical trial sites significantly increase cancer patients’ access to the trial. We value the commitment of our new partners to the mission of developing life-saving therapies and look forward to advancing innovative medicines to improve the lives of cancer patients."

The NTX1088 Phase 1 trial is being conducted with support from The Cancer Focus Fund, a unique investment fund established in collaboration with The University of Texas MD Anderson Cancer Center. The fund provides investment support to advance promising cancer therapies along with the clinical trial expertise and infrastructure of MD Anderson Cancer Center sites.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About NTX1088
NTX1088 is a first-in-class monoclonal antibody directed against a key immune checkpoint, PVR (CD155), currently in a Phase I clinical trial. NTX1088 blocks the interaction between PVR and DNAM1 (CD226), a transmembrane molecule involved in the activation of anti-cancer T-cells and NK cells. By preventing internalization and degradation of DNAM1, NTX1088 leads to restoration of DNAM1 expression on the surface of immune cells, resulting in robust antitumor activity. NTX1088 also blocks PVR interactions with its other ligands, such as TIGIT and CD96, preventing their immune inhibitory signaling. NTX1088 demonstrated superior antitumor activity compared to approved and investigational immune checkpoint inhibitors in preclinical models and had a favorable safety profile in non-human primates. NTX1088 is currently being clinically evaluated as a monotherapy and in combination with KEYTRUDA (pembrolizumab) in patients with advanced solid tumors.

Avstera Therapeutics Announces FDA Clearance of IND Application for AVS100, a Novel Highly Selective HDAC6 Inhibitor Targeting Solid Tumors

On December 18, 2023 Avstera Therapeutics Corp, an oncology-focused biotech dedicated to addressing the large disease burden and significant unmet need of cancer patients, reported the U.S. FDA clearance of its Investigational New Drug application (IND) for AVS100, a novel highly selective oral HDAC6 inhibitor intended to treat locally advanced or metastatic solid tumors in a Phase I clinical study (Press release, Avstera Therapeutics, DEC 18, 2023, View Source [SID1234638662]).

"The FDA clearance of our IND for AVS100 marks an amazing step for our company towards the fulfillment of our mission. We are excited to advance this promising new therapy into the clinic to address the disease burden for the benefit of patients, and our transition to a viable clinical stage biotech. AVS100 has demonstrated significant preclinical efficacy, remarkable safety, and durability in numerous in-vivo studies." said Karthik Musunuri, CEO & Co-Founder, Director of Avstera Therapeutics.

AVS100 is a highly selective, orally bioavailable, isoxazole-3-hydroxamate based HDAC6 inhibitor. AVS100 demonstrated unique ability in its class preclinically in suppressing the polarization of macrophages toward pro-tumoral phenotypic pathways. This immunomodulatory function is both pivotal and of keen interest as tumor associated macrophages can constitute up to 50% or more of solid tumor cell mass. AVS100 is AMES negative and demonstrated a strong safety profile in animals, including GLP toxicology studies in dogs and rats with no major adverse events.

"FDA clearance of our IND for AVS100 represents a significant milestone for Avstera’s mission in providing state of the art oncological agents to tackle solid tumors. I am proud of our team’s efficiency as drug developers in advancing to FIH trials in a just over a year since our seed round." said Ajay Raju, Co-Founder & Director of Avstera Therapeutics.

"New findings demonstrating a critical role of tumor-associated macrophages in resistance to immunotherapy suggest that targeting this cell population could both effectively reverse and/or avoid resistance to existing ICB. Therefore, an emerging interest is in developing new immunotherapies targeting this immune population, including selective HDAC6 inhibitors, which have been proven effective modulators of immunosuppressive macrophages. Undoubtedly, the IND approval of AVS100 selective HDAC6 inhibitor will open new opportunities to potentially enhance response rates for patients." said Alejandro Villagra, PhD, Georgetown University Associate Professor and Co-Inventor of AVS100 who also serves on Avstera’s Scientific Advisory Board (SAB).

More About the Phase I Clinical Study

The Phase Ia/b clinical trial for AVS100 is targeting locally advanced or metastatic solid tumors. This trial is an open label, dose-escalation and confirmation study to characterize the safety, tolerability, pharmacokinetics, and MTD of AVS100 when administered as a monotherapy and in combination with pembrolizumab. The primary endpoints are to evaluate the incidence of adverse events including DLTs in monotherapy and in combination, while secondarily assessing the PK, Objective Response Rate (ORR) using RECIST v1.1, and Progression Free Survival (PFS). Avstera will also assess multiple exploratory biomarkers, including conducting multi-omics analyses on patient samples.

Avstera intends to initiate the Phase Ia/b clinical trial in the first half of 2024. The principal investigator of the study is Apostolia M Tsimberidou, MD, PhD, FASCO, FAAAS, Professor of Medicine at MD Anderson Cancer Center, Houston, TX.

Telix Submits Biologics License Application (BLA) for TLX250-CDx (Zircaix™) for Imaging of Kidney Cancer

On December 18, 2023 Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) reported that it has submitted its Biologics License Application (BLA) to the United States (U.S.) Food and Drug Administration (FDA) for its investigational positron emission tomography (PET) imaging agent TLX250-CDx (Zircaix,[1] 89Zr-DFO-girentuximab) in clear cell renal cell carcinoma (ccRCC) (Press release, Telix Pharmaceuticals, DEC 18, 2023, View Source [SID1234638661]).

Under the Breakthrough Therapy designation, TLX250-CDx has been granted a rolling review process, which enables a progressive submission and review of required modules in a timetable pre-agreed with the FDA. With the BLA submission, Telix has also requested Priority Review, which if granted would support an expedited review time.

Dr. Christian Behrenbruch, Managing Director and Telix Group CEO said, "This is a major milestone and achievement for Telix, which paves the way for a commercial availability for patients in the U.S. in 2024, subject to regulatory review and approval."

James Stonecypher, Chief Development Officer at Telix added, "If approved by the FDA, TLX250-CDx will be the first targeted radiopharmaceutical imaging agent for kidney cancer to be commercially available to patients in the U.S.. The collaborative approach shown by the FDA under the Breakthrough Therapy designation has been highly valuable as we work to bring this novel, non-invasive, first-in-class 89-zirconium-labeled monoclonal antibody (mAb) based imaging agent to market."

Associate Professor Brian Shuch, MD, Director of the Kidney Cancer Program and the Alvin & Carrie Meinhardt Endowed Chair in Kidney Cancer Research at UCLA Institute of Urologic Oncology said, "The ZIRCON study demonstrated the superior sensitivity and specificity of this advanced diagnostic imaging agent, which, if approved, will be the first and only agent available to target carbonic anhydrase IX, a highly relevant target in kidney cancer. This delivers on a major unmet need to provide confidence in the diagnosis of ccRCC, the most aggressive and common form of kidney cancer."

This submission is based on Telix’s successful global Phase III ZIRCON study (Zirconium in Renal Cancer Oncology, ClinicalTrials.gov ID: NCT03849118), which reported positive results in November 2022, meeting all co-primary and secondary endpoints.[2]

Telix has opened an expanded access program in the U.S. and a named patient program in Europe to allow access to TLX250-CDx outside of a clinical trial to patients for whom there are no comparable or satisfactory alternate options.