On June 26, 2024 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported positive 18-month follow-up data from the OPTIMIZE-1 Phase 2 study of the company’s lead asset mitazalimab in 1st line metastatic pancreatic cancer (Press release, Alligator Bioscience, JUN 26, 2024, View Source [SID1234644545]). The open-label, multi-center study assessed the safety and efficacy of mitazalimab (CD40 mAb agonist) in combination with standard of care chemotherapy mFOLFIRINOX, in previously untreated, chemotherapy naïve pancreatic cancer patients.
The data demonstrated a near doubling of the 18-month survival rate to 36.2% in patients treated with mitazalimab in combination with mFOLFIRINOX, compared to 18.6% reported with FOLFIRINOX[1] alone.

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The updated Median Overall Survival (mOS) was 14.9 months, up from 14.3 months at the time of first analysis, comparing favorably to the 11.1 months demonstrated by FOLFIRINOX[1] and more recently by NALIRIFOX[2].

Median follow-up duration for the updated analysis was 18.2 months, indicating the maturity of these outcomes. At the time of the analysis, a total of 17 (30%) patients were still alive, and of these 9 (16% overall) were still on treatment. The longest ongoing treatment duration was 24 months.

The follow-up data further demonstrate:

An additional late responding patient increased the confirmed Objective Response Rate (ORR; as per the Response Evaluation Criteria in Solid Tumors RECIST 1.1) to 42.1% from the 40.4% reported in the top-line readout, comparing favorably to the ORR of 31.6% reported in a similar patient population treated with FOLFIRINOX alone[1] and an ORR of 42% reported by NALIRIFOX[2]
An increase in the unconfirmed ORR to 54.4% was reported in 57 evaluable patients
The median Duration of Response (DoR) was 12.6 months, an unprecedented outcome in this aggressive disease and much longer compared to 5.9 months with FOLFIRINOX[1] and 7.3 months with NALIRIFOX[2]
Median Progression Free Survival (PFS) was 7.7 months, and a nearly 3-fold increase in the 12-month PFS rate was reported; 35.1% in OPTIMIZE-1 against 12.1% previously reported for FOLFIRINOX[1].
"These latest results from the OPTIMIZE-1 study of our lead asset provide a strong validation of the clear and sustained clinical benefit produced by mitazalimab when combined with mFOLFIRINOX in the treatment of first-line pancreatic cancer. In fact, mitazalimab increases your chance of being alive at the 18-month mark by 95 percent, compared to published FOLFIRINOX data," said Søren Bregenholt, CEO of Alligator Bioscience. "These highly promising outcomes warrant continued clinical development of mitazalimab in a confirmatory setting and we are committed to bringing mitazalimab to pancreatic cancer patients as fast as possible."
"These results clearly represent a remarkable outcome in pancreatic cancer, with the robust Duration of Response indicating highly consistent clinical benefit resulting in prolonged Overall Survival," said Prof. Jean-Luc van Laethem, Head of the Digestive Oncology Clinic in the Gastroenterology Department of Erasmus Hospital (ULB) Brussels and Principal Investigator of the OPTIMIZE-1 trial. "Particularly noteworthy is the high proportion of patients surviving at the 18-month landmark, which most patients in this disease unfortunately do not see. With such a strong immunotherapeutic contribution, mitazalimab combined with mFOLFIRINOX has the potential to become the new treatment standard in pancreatic cancer, and we are eagerly awaiting the initiation of a randomized confirmatory study."
Top-line results from the OPTIMIZE-1 study were published in the world-leading oncology journal The Lancet Oncology and will also be presented at the upcoming ESMO (Free ESMO Whitepaper) Gastrointestinal Cancers Congress 2024 being held in Munich, Germany from June 26-29.

Phase 3 on track to start in first half of 2025
Alligator is continuing its preparations for the global Phase 3 registration study to evaluate mitazalimab in pancreatic cancer and the company remains on track to initiate the study in 2025. This follows Alligator’s discussions with the US Food and Drug Administration (FDA) which established a clear development and approval pathway for mitazalimab in pancreatic cancer.

In 2023, mitazalimab was granted orphan drug designation in pancreatic cancer by both the FDA and the European Medicines Agency (EMA).

On June 26, 2024 AstraZeneca reported that Tagrisso (osimertinib) with the addition of pemetrexed and platinum-based chemotherapy has been approved in China for the 1st-line treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose tumours have exon 19 deletions or exon 21 (L858R) mutations (Press release, AstraZeneca (Australia), JUN 26, 2024, View Source [SID1234644537]).

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The approval by China’s National Medical Products Administration (NMPA) was based on the results from the FLAURA2 Phase III trial published in The New England Journal of Medicine, and results from a prespecified exploratory subgroup analysis of efficacy and safety in Chinese patients, which was presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Congress 2023.

In the overall trial population, Tagrisso with the addition of chemotherapy reduced the risk of disease progression or death by 38% by investigator assessment compared to Tagrisso monotherapy, which is the 1st-line global standard of care (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). Median progression-free survival (PFS) was 25.5 months for patients treated with Tagrisso plus chemotherapy, an 8.8-month improvement versus Tagrisso monotherapy (16.7 months).

PFS results by blinded independent central review (BICR) in the overall trial population were consistent with results by investigator assessment, showing 29.4 months median PFS with Tagrisso plus chemotherapy, a 9.5-month improvement over Tagrisso monotherapy (19.9 months) (HR 0.62; 95% CI 0.48-0.80; p=0.0002).

While the overall survival (OS) remained immature at the second interim analysis (41% maturity), an encouraging trend towards an OS benefit was observed with Tagrisso plus chemotherapy versus Tagrisso alone (HR 0.75; 95% CI 0.57-0.97). The trial continues to assess OS as a key secondary endpoint.

Efficacy results from the China cohort of FLAURA2 were broadly consistent with the overall trial. By investigator assessment, Tagrisso with the addition of chemotherapy reduced the risk of disease progression or death by 44% compared to Tagrisso monotherapy (HR 0.56; 95% CI 0.34-0.92). Median PFS was 27.4 months for patients treated with Tagrisso plus chemotherapy, a 5.1-month improvement versus Tagrisso monotherapy (22.3 months).

PFS results in the China cohort by BICR were consistent with the results by investigator assessment, showing 33.2 months median PFS with Tagrisso plus chemotherapy, an 11.2-month improvement over Tagrisso monotherapy (22.0 months) (HR 0.58; 95% CI 0.34-1.01).

A trend towards an OS benefit was also observed in the China cohort for Tagrisso plus chemotherapy versus Tagrisso alone (HR 0.97; 95% CI 0.45-2.06).

Each year in China, there are over one million people diagnosed with lung cancer, accounting for more than a third of the world’s lung cancer patients.1,2 Among those with NSCLC, the most common form of lung cancer, approximately 40% of patients in China have tumours with an EGFR mutation.3 Additionally, the majority of patients with NSCLC are diagnosed with advanced disease.4

Professor Ying Cheng, MD, Director of Jilin Lung Cancer Diagnosis and Treatment Centre, and principal investigator in China said: "The approval of osimertinib with the addition of chemotherapy in China is critical for the treatment of the largest population of patients with EGFR-mutated lung cancer worldwide. These patients will now have a choice of two highly effective osimertinib-based options for 1st-line treatment, allowing physicians to tailor their approach to their patients. This is especially important for those with a poorer prognosis, such as cancer that has spread to the brain or those who have L858R mutations."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "Tagrisso with the addition of chemotherapy in FLAURA2 has not only shown unprecedented progression-free survival in the overall trial population, but also among Chinese patients, reducing the risk of disease progression by nearly half. This approval reinforces Tagrisso as a backbone therapy in EGFR-mutated lung cancer and acknowledges its important role, as monotherapy or with chemotherapy, in addressing the high prevalence of this disease in Asian countries and China, specifically."

The safety profile of Tagrisso with the addition of chemotherapy was generally manageable and consistent with the established profiles of the individual medicines. Adverse event (AE) rates were higher in the Tagrisso plus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Discontinuation rates of Tagrisso due to AEs were 11% for Tagrisso plus chemotherapy and 6% for monotherapy.

Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage EGFRm NSCLC. In addition to this new approval in China, Tagrisso with the addition of chemotherapy is also approved in the US and several other countries for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.5 Lung cancer is broadly split into NSCLC and small cell lung cancer.6 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.5-8

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.9-11 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.12

FLAURA2
FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once-daily oral tablets with the addition of chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks.

The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve patient outcomes in early-stage disease in the ADAURA Phase III trial , locally advanced stages in the LAURA Phase III trial and late-stage disease in the FLAURA Phase III trial and FLAURA2 Phase III trial.

As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial with results expected later this year and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial.

The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.

On June 25, 2024 TwoStep Therapeutics, a biotechnology company developing new targeted therapeutics for solid tumors, reported its official launch following a successful $6.5 million seed round led by NFX, with participation from other investors including 2048 Ventures, Alexandria Venture Investments, Cooley’s affiliated fund GC&H Investments, and the family office of the founder of Arcadia Investment Partners (Press release, TwoStep Therapeutics, JUN 25, 2024, View Source [SID1234644544]). Proceeds from the financing will be used to advance TwoStep’s therapeutic pipeline of solid tumor-targeting therapies, with an initial focus on targeted cytotoxic drug delivery and immunotherapy.

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Solid tumors, which account for approximately 90% of all cancers, have been historically challenging to treat due to a scarcity of extracellular targets that meet the criteria for effective treatment delivery. While tumor-targeted therapies have begun to transform the treatment paradigm for hematological malignancies, their viability in solid tumors has been limited to small subsets of patients with high levels of specific tumor markers. This presents a critical unmet need – and vast therapeutic opportunity – to develop a tumor-targeted approach that can viably treat the majority of solid tumors.

"For the majority of solid tumors lacking well-defined targets, there are few precise treatment options and limited development of new modalities, which is a painful reality for many people with cancer," said Caitlyn Miller, PhD, CEO and co-founder of TwoStep Therapeutics. "Our initial focusat TwoStep is to couple our tumor-targeting technology with clinically-validated payloads, which has the potential to extend the benefits of paradigm-shifting therapies to a greater number of patients."

"NFX Bio backs scientist-founders creating ‘defensible magic’ for massive markets. Imagine one system that can target most solid tumors and deliver the exact treatment needed. It could mean many lives saved with one core technology platform," said Omri Amirav-Drory, PhD, General Partner at NFX. "Caitlyn is a perfect example for a ‘scientist-founder’ and is surrounded with amazing scientific founders from Stanford including Jennifer Cochran, Ronald Levy, and Carolyn Bertozzi."

TwoStep’s unique PIP agent enables targeted delivery to virtually any solid tumor by binding multiple tumor-associated integrins. Additionally, by binding with strong affinity to integrin conformations that are highly expressed on solid tumor tissue, exposure to healthy tissue is minimized. The modular design of this tumor-targeting agent makes for a modality-agnostic technology with tunable pharmacokinetics, compatible with a diversity of therapeutic payloads.

"In its compact form, PIP is a synthetic, ultra-stable peptide that has been engineered to localize and penetrate tumors – ideal properties for broad targeted therapy applications," said Jennifer Cochran, PhD, co-founder of TwoStep Therapeutics and Professor of Bioengineering at Stanford University, whose laboratory first developed the PIP molecule.

Development of TwoStep’s solid tumor-focused platform was driven by the combined expertise of its founding team in chemical biology, antibody-drug conjugates (ADCs), and immuno-oncology. The founders established in vivo proof of concept of its multi-targeted agent using various therapeutic payloads and fusion proteins in the academic labs of its co-founders, and later within the Stanford Innovative Medicines Accelerator (IMA). It is the first company to emerge from the IMA entrepreneur-in-residence program.

Caitlyn Miller, PhD, founded TwoStep Therapeutics in collaboration with world-renowned academic entrepreneurs affiliated with Stanford University, including Carolyn Bertozzi, PhD, Professor of Chemistry, Investigator at Howard Hughes Medical Institute and Nobel Laureate, Jennifer Cochran, PhD, Senior Associate Vice Provost for Research and Professor of Bioengineering, and Ronald Levy, MD, Professor of Medicine, Oncology. As CEO Dr. Miller is joined by Chief Business Officer Michael Ostrach and drug development and scientific advisor Robert Coffman, PhD, both veterans of Dynavax.

On June 25, 2024 Charles River Laboratories International, Inc. (NYSE: CRL) and the Gates Institute at the University of Colorado Anschutz Medical Campus reported a lentiviral vector contract development and manufacturing organization (CDMO) agreement (Press release, Charles River Laboratories, JUN 25, 2024, View Source [SID1234644543]). Gates Institute will leverage Charles River’s premier cell and gene therapy CDMO expertise to develop Good Manufacturing Practice (GMP)-grade lentiviral vectors (LVVs) for use in novel chimeric antigen receptor (CAR) T-cell therapies for hematological cancers.

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The Gates Institute mission at the University of Colorado Anschutz Medical Campus is to develop and deliver advanced therapies in cell and gene therapy. The Institute brings together researchers, clinicians, and a GMP biomanufacturing facility for first-in-human clinical trials. Through this strategic collaboration, Gates Institute will have access to Charles River’s established manufacturing platforms and dedicated viral vector CDMO center of excellence, utilizing a range of services including process development evaluation of Gates Institute’s LVV backbone, phase-appropriate research grade and High –Quality (HQ) plasmid DNA production, and GMP LVV manufacturing. Materials produced within the collaboration will support an upcoming Investigational New Drug (IND) application for Phase I clinical trials.

Plasmid DNA and Viral Vector Manufacturing Services

With over 20 years of plasmid DNA and viral vector CDMO expertise and validated platform processes including eXpDNA and Lentivation with a proven track record, Charles River has standardized protocols and high-yield, optimized methods to accelerate speed to clinical and commercial manufacturing by reducing process development time and costs while ensuring premium quality production.

In recent years, Charles River has significantly broadened its cell and gene therapy portfolio with several acquisition integrations and expansions to simplify complex supply chains and meet the growing demand for plasmid DNA, viral vector, and cell therapy services. Combined with the company’s legacy testing capabilities, Charles River offers a premier "concept to cure" advanced therapies solution.

To learn more about LVV design, manufacturing, and regulation, join Charles River for a roundtable webinar to examine key trends, address manufacturing challenges, and overcome quality control and regulatory hurdles: https://bit.ly/3Ttijzz

Approved Quotes

"The cell therapy ecosystem that Gates Institute has created is exciting and we look forward to helping them advance the development of CAR-T therapies for hematological cancers. Our complementary strengths and concept to cure capabilities are well positioned to help move the science forward into the clinic and beyond for oncology patients." – Kerstin Dolph, Corporate Senior Vice President, Biologics Solutions, Charles River
"We value this new partnership with Charles River, an industry leader in biopharmaceutical services. In the near term, this collaboration will accelerate the Gates Institute CAR-T programs with their plasmid and lentiviral vector production. Looking ahead to our long-term collaboration, we remain committed to advancing patient impact more broadly." – Terry Fry, MD, Executive Director, Gates Institute

On June 25, 2024 CDR-Life Inc. reported an expansion of its pipeline of novel T cell engagers (TCE) with the addition of CDR813 and CDR505 (Press release, CDR-Life, JUN 25, 2024, View Source [SID1234644542]).

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CDR813 is a highly potent and selective TCE candidate targeting tumors expressing PRAME (preferentially expressed antigen in melanoma) in HLA-A*02:01 patients. PRAME is a clinically validated pan-cancer target expressed in a broad set of tumors including non-small cell lung cancer (NSCLC), endometrial cancer, melanoma and ovarian cancer, but not in normal tissue. A bi-valent and bi-specific antibody-based TCE, CDR813 targets a PRAME peptide presented on tumor cells by the HLA-A*02 complex and the CD3 receptor on T-cells with unparalleled potency and specificity.

CDR505 is a TCE targeting KK-LC-1, a novel HLA-A*01 target relevant in common cancer populations not yet addressed by other T cell receptor (TCR) therapeutics. While most TCE programs target the HLA-A02 haplotype, CDR505 targets KK-LC-1/HLA-A*01, expanding the potential of TCEs to benefit a large patient population with high unmet need. Preclinical data on CDR505 was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2024.

"With our continued investment in building a broad pipeline of unique, potent and highly cancer-targeted therapies, we are expanding the promise of our differentiated T cell engager platform to treat a range of solid tumors," said Christian Leisner, Ph.D., Chief Executive Officer at CDR-Life. "Importantly, the CDR813 and CDR505 programs are geared toward populations with significant unmet medical need, increasing our reach to benefit more patients."