On December 8, 2022 Astrazeneca reported Detailed results from the CAPItello-291 Phase III trial showed AstraZeneca’s capivasertib in combination with Faslodex (fulvestrant) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus placebo plus Faslodex in patients with hormone receptor (HR)-positive, HER2-low or negative, locally advanced or metastatic breast cancer, following recurrence or progression on, or after, endocrine therapy (with or without a CDK4/6 inhibitor) (Press release, AstraZeneca, DEC 8, 2022, View Source [SID1234624932]). Results will be presented today in an oral presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS).

Results showed capivasertib in combination with Faslodex demonstrated a 40% reduction in the risk of disease progression or death versus placebo plus Faslodex in the overall trial population (based on a hazard ratio [HR] of 0.60, 95% confidence interval [CI] 0.51-0.71; p=<0.001; median 7.2 versus 3.6 months).1 In the AKT pathway biomarker-altered population, capivasertib plus Faslodex reduced the risk of disease progression or death by 50% versus placebo plus Faslodex (HR of 0.50, 95% CI 0.38-0.65; p=<0.001; median 7.3 versus 3.1 months).1 Alterations within the AKT pathway (PI3K/AKT/PTEN) occur frequently in breast cancer, affecting up to 50% of patients with advanced HR-positive breast cancer.2-4

Nicholas Turner, MD, PhD, Professor of Molecular Oncology at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, London, UK, and principal investigator in the CAPItello-291 Phase III trial, said: "These data demonstrate the practice-changing potential of capivasertib as a new treatment option for patients with advanced HR-positive breast cancer. Critically, this potentially first-in-class treatment has shown it delays disease progression for those who have progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Capivasertib brings important progress to an area with persistent treatment gaps as the first therapy of its kind shown to be effective in a Phase III trial in patients with advanced HR-positive, HER2-low or negative breast cancer. We believe these results which showed benefit in all-comers and biomarker positive populations can reshape HR-positive breast cancer treatment, and that capivasertib can become an important new option for patients."

Summary of results: CAPItello-2911

Capivasertib plus Faslodexn=355
Placebo plus Faslodex
n=353
Median PFS in overall population (months)

7.2
3.6
HR (95% CI)

0.60 (0.51-0.71)
p-value

p=<0.001
Median PFS in the biomarker-altered population (months)

7.3
3.1
HR (95% CI)

0.50 (0.38-0.65)
p-value

p=<0.001
ORR in overall population

22.9%
12.2%
ORR in biomarker-altered population

28.8%
9.7%
HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; ORR, objective response rate

Confirmed objective response rate (ORR) was 22.9% for the capivasertib plus Faslodex arm versus 12.2% for the placebo plus Faslodex arm in the overall trial population, and 28.8% versus 9.7%, respectively, in the biomarker-altered population.1 Although the overall survival (OS) data were immature at the time of the analysis, early data are encouraging.1 The trial will continue to assess OS as a key secondary endpoint.

The safety profile of capivasertib plus Faslodex was similar to that observed in previous trials evaluating this combination.1 In the overall trial population, the most frequent any grade adverse events (AEs) with capivasertib plus Faslodex occurring in 20% or more of patients were diarrhoea (72.4%), nausea (34.6%), rash (group term including rash, rash macular, maculo-papular rash, rash papular and rash pruritic; 38%) fatigue (20.8%) and vomiting (20.6%).1 The most frequent Grade 3 or higher AEs occurring in 5% or more of patients were diarrhoea (9.3%) and rash (12.1%).1

Notes

HR-positive breast cancer
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.5 More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.5

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with approximately 70% of breast cancer tumours considered HR-positive and HER2-low or negative.6

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER),7 andendocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with cyclin-dependent kinase (CDK) 4/6 inhibitors.8,9 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.9 Once this occurs, treatment options are limited9 – with chemotherapy being the current standard of care10 – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.6

Optimising endocrine therapy and overcoming resistance for patients with ER-driven disease at all stages of treatment as well as identifying new therapies for those who no longer have ER-driven disease are active areas of focus for breast cancer research.

CAPItello-291
CAPItello-291 is a Phase III, double-blind, randomised trial that is part of a larger clinical programme focused on capivasertib, an investigational AKT (serine/threonine kinase) inhibitor. CAPItello-291 is evaluating the efficacy of capivasertib in combination with Faslodex versus placebo plus Faslodex for the treatment of locally advanced (inoperable) or metastatic HR-positive, HER2-low or negative breast cancer.

The global trial enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The trial has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumours have qualifying alterations in the AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumours had these alterations.

Capivasertib
Capivasertib is an investigational oral treatment currently in Phase III trials for the treatment of multiple subtypes of breast cancer, prostate cancer and a Phase II trial for haematologic malignancies. A potent, selective adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3), capivasertib is being evaluated as a monotherapy and in combination with existing therapies in tumours harbouring alterations in the AKT pathway (PI3K/AKT/PTEN), and in tumours reliant on signalling via this pathway for survival. Capivasertib 400 mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

The capivasertib clinical research programme is investigating the safety and efficacy of capivasertib when used alone and in combination with established treatment regimens.

Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

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On December 8, 2022 Arvinas presented its clinical trial results for ARV-471 Veritac trial (Presentation, Arvinas, DEC 8, 2022, View Source [SID1234624931]).

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On December 8, 2022 Instil Bio, Inc. ("Instil" or the "Company") (NASDAQ: TIL), a clinical-stage biopharmaceutical company focused on developing next-generation tumor infiltrating lymphocyte, or TIL, therapies for the treatment of patients with cancer, reported a reprioritization of its clinical programs to focus on development of its CoStAR-TIL product candidates (Press release, Instil Bio, DEC 8, 2022, View Source [SID1234624929]).

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"From the beginning of Instil, we have been committed to advancing TIL therapy by enhancing the native activity of TILs with innovative strategies designed to improve product efficacy and safety," said Bronson Crouch, CEO of Instil Bio. "Although it was a difficult decision to discontinue the development of ITIL-168, this decision provides us the opportunity to accelerate the development of CoStAR and other novel technologies to enhance TIL therapies for patients. We are excited to resume dosing patients in the Phase 1 ITIL-306 study and anticipate providing initial data readouts next year."

Strategic Update

Instil has prioritized development of its proprietary, genetically-engineered CoStAR-TIL programs, which are designed to boost the efficacy of T cells by providing potent synthetic costimulatory signals within the tumor microenvironment (TME). Instil’s lead CoStAR-TIL program, ITIL-306, is in a Phase 1 dose escalation trial in non-small cell lung cancer ("NSCLC"), ovarian cancer, and renal cell carcinoma, with the first patient dosed earlier this year. The Company expects to report data from the dose escalation cohorts of the Phase 1 ITIL-306 study in 2023.

Instil is undertaking a reduction in its U.S. workforce of approximately 60% to re-align its operating model from a registration-focused company to a development-stage company.

ITIL-168 Program Update

Instil is discontinuing its ITIL-168 clinical programs, the DELTA-1 trial in advanced melanoma and the DELTA-2 trial in NSCLC, cervical cancer, and head and neck squamous cell carcinoma. After an analysis of the potential scenarios to restart and complete a registration-enabling cohort in advanced melanoma in the DELTA-1 trial, the Company has decided to prioritize the CoStAR-TIL platform.

On December 8, 2022 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of targeted radiotherapies, reported that it has entered into a research collaboration with Columbia University to study Actimab-A, its clinical-stage CD33 targeting radiotherapeutic, with engineered hematopoietic stem cells (eHSCs) modified by CRISPR/Cas9 gene editing technology to knock out CD33 expression (Press release, Actinium Pharmaceuticals, DEC 8, 2022, View Source [SID1234624928]). Dr. Siddhartha Mukherjee, MD, DPhil, Assistant Professor of Medicine at Columbia University Medical Center in the Department of Medicine and Division of Hematology/Oncology and his research group developed the technology. Technology from Dr. Mukherjee’s lab has been licensed and is currently being developed by Vor Biopharma, Inc., including trem-cel (formerly VOR33). Vor is currently using Mylotarg, a CD33 targeting antibody drug conjugate (ADC), in its clinical trial to target residual CD33 positive leukemia cells post-transplant.

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Dr. Siddharth Mukherjee, MD, DPhil, stated, "I am very excited to be collaborating with Actinium to study Actimab-A targeted radiotherapy with our eHSCs to prevent relapse and improve post-transplant outcomes. Actimab-A is highly differentiated from other CD33 targeting agents including the ADC Mylotarg, which demonstrates resistance with repeated use. Actimab-A due to its radiation modality is agnostic to cytogenetics and molecular mutations and the Actinium-225 warhead can produce double strand DNA breaks for which there is no known resistance or repair mechanism. With AML cells being highly sensitive to radiation, we believe Actimab-A has great potential given the potency of the Actinium-225 isotope warhead, its validated CD33 targeting ability and its strong clinical data to date. My team and I look forward to progressing this collaboration with Actinium to generate first ever data with a targeted radiotherapy following engineered HSC transplant to advance to this novel combination to the clinic."

Dr. Avinash Desai, Actinium’s Chief Medical Officer, added, "We are honored to be working with Dr. Mukherjee and his team at Columbia University in this exciting collaboration. This is another attractive setting for Actimab-A that builds on our leading-edge, combination focused development efforts that includes chemotherapy, targeted agents and immune checkpoint inhibitors. We are eager to show that Actimab-A will produce better post-eHSC transplant outcomes than other modalities including ADCs like Mylotarg given the specificity and potency of the Actinium-225 warhead. Recently, Actimab-A, in combination with the chemotherapy CLAG-M, produced deep remissions by wiping out residual leukemia cells resulting in high rates of MRD negativity rate in very difficult to treat relapsed or refractory AML patients, including patients with TP53 mutations and those receiving multiple lines of prior therapy including Venetoclax. These results give us confidence that Actimab-A will effectively eliminate any residual leukemia cells in this post-transplant setting where the leukemia burden is expected to be much lower. In addition to improved leukemia cell killing, Actimab-A’s highly targeted nature has been shown to be well tolerated with minimal extramedullary toxicities. We look forward the oral presentation at ASH (Free ASH Whitepaper) and to advancing this collaboration and furthering Actimab-A’s utility in treating patients with AML."

Under this collaboration, Actimab-A will be administered following transplantation of the eHSCs with the goal of eliminating any CD33 positive residual AML cells. eHSCs are intended to engraft and reconstitute patients’ blood and immune systems with cells that do not express cancer-specific targets such as CD33. This would then allow a patient to receive CD33 targeting therapy post-transplant to eradicate any residual CD33 positive leukemia cells and prevent relapse while sparing newly formed blood cells that do not express CD33. Actimab-A has been studied in over 150 AML patients in six clinical trials. It has the most clinical experience of any Actinium-225 based drug candidate in development. Actinium-225 is an alpha-particle emitting radioisotope that has the most potent cell killing ability of any medical grade isotope but has a short pathlength that limits potential off-target effects. Recently, Actimab-A demonstrated high rates MRD negativity following CLAG-M therapy in relapsed or refractory AML patients with adverse risk features including over 50% with a TP53 mutation and over 50% who received prior treatment with Venetoclax. This resulted in a 53% 1-year overall survival and 32% 2-year overall survival in a patient group that has an expected overall survival of less than 3 months.

On December 8, 2022 Sensei Biotherapeutics, Inc. (Nasdaq: SNSE), an immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients, reported that a streamlining and realignment of resources to support its key indications and programs, including its lead antibody, SNS-101, a conditionally active antibody targeting the immune checkpoint VISTA, as well as its other TMAb (Tumor Microenvironment Activated biologics) platform programs (Press release, Sensei Biotherapeutics, DEC 8, 2022, View Source [SID1234624927]).

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In connection with this announcement, the Company will close its research site in Boston and reduce its total workforce by approximately 40%. The Company expects that such reduction in operating expenses, including employee-related costs and reduced occupancy costs, will extend Sensei’s estimated cash runway into the second half of 2025.

The Company will maintain its Rockville, Maryland research facility, where antibody discovery and production in support of SNS-101 and other TMAb programs is conducted, while maintaining a smaller business office in the Boston area. Sensei plans to relocate any ongoing work at its Boston research site to its Rockville, Maryland site.

"Our Board of Directors and management team remain focused on ensuring that Sensei is well positioned to execute on our near-term clinical and preclinical milestones. As we continue to progress the development of SNS-101 towards an IND in the coming months, we have made the strategic decision to reduce our early-stage R&D expenses related to certain discovery stage targets to more closely align with our strategic and financial goals," said John Celebi, President and Chief Executive Officer of Sensei Biotherapeutics. "Today’s announcement follows a thoughtful decision-making process, where we ultimately determined that it is in the best interests of the Company to invest our resources where we believe they will have the greatest potential near-term impact. Decisions that impact our people are always extremely difficult, and I would like to express my gratitude to our departing employees for their hard work and service. We are committed to providing support for our impacted colleagues and to helping them identify other opportunities during this transition."

In conjunction with these announcements, Robert Pierce, M.D., Sensei’s Chief R&D Officer, will move to a consulting role as a Science Fellow, effective December 7, 2022, and Edward van der Horst, Ph.D., Sensei’s Senior Vice President, Biologics Discovery & Early Development, has been promoted to Chief Scientific Officer, effective December 7, 2022.

Dr. Edward van der Horst, Ph.D. has over 20 years of research and development experience with a strong focus on antibody drug development across diverse target classes in oncology. He has been instrumental in the discovery and development of several clinical-stage therapeutic antibodies, including a first-generation anti-VISTA antibody that is currently in clinical trials as well as the first clinical stage anti-HER3 antibody. During his time at Sensei, Dr. van der Horst has overseen the discovery and early development of SNS-101, Sensei’s conditionally active anti-VISTA antibody, as well as other TMAb platform drug programs. Prior to joining Sensei in 2019, Dr. van der Horst worked at Zenith Epigenetics Ltd., Igenica Biotherapeutics Inc., OncoMed Pharmaceuticals, Tularik, Inc. (now Amgen) and U3 Pharma GmbH (now Daiichi-Sankyo). Dr. van der Horst earned his Ph.D. in biochemistry from the Max-Planck Institute of Biochemistry and conducted his master’s thesis at Max-Planck Institute of Neurobiology. He graduated with an M.S. in chemistry from the Ludwig Maximilian University of Munich.

Sensei continues to advance SNS-101 through investigational new drug-enabling studies, and intends to submit an Investigational New Drug application (IND) in or prior to April 2023. The Company has reported differentiated preclinical data demonstrating anti-tumor effects, promising pharmacokinetic properties and a superior cytokine release profile compared with non-conditional anti-VISTA therapies. While it advances SNS-101 into the clinic in the near-term, Sensei will continue discovery work for its discovery-stage programs targeting VSIG-4 and ENTPDase1, also known as CD39.