On September 9, 2024 Cellworks Group Inc., a leader in Personalized Therapy Decision Support and Precision Drug Development, reported findings from a study using the Cellworks Platform to predict the benefits of adding chemotherapy to osimertinib treatment in patients with EGFR mutated non-small cell lung cancer (NSCLC) (Press release, Cellworks, SEP 9, 2024, View Source [SID1234646458]). Leveraging data from a real-world retrospective cohort, the biosimulation study confirmed that adding chemotherapy to osimertinib led to a higher predicted overall response rate (ORR). The study revealed that while all patients responded to the addition of chemotherapy, the magnitude of benefit varied among individuals and was intricately determined by underlying genomic abnormalities, enabling the identification of patients who would benefit from combination therapies, and others who would achieve similar outcomes without the addition of chemotherapy.

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Results from the study were showcased in a poster presentation (P1.06A.03) titled ‘Use of Biosimulation to Predict Concomitant Chemotherapy Benefit in NSCLC Patients with EGFR Mutations Being Treated with Osimertinib’ as part of the IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer in San Diego, California on September 8, 2024.

"Osimertinib has become a standard treatment option in patients with NSCLC harboring EGFR mutations," said Dr. Charu Aggarwal, MD, MPH, Professor of Medicine, University of Pennsylvania, Associate Director, PC3I and Director, Program in Precision Oncology Innovation, Penn Center for Cancer Care Innovation; and Principal Investigator for the study. "However, while targeted therapies are generally effective for these patients, response rates can vary significantly, and the potential advantage of incorporating chemotherapy in some patients remains unclear. This study demonstrates how utilizing Cellworks biosimulation can provide valuable insights by more accurately predicting the benefit of chemotherapy, as it allows for a deeper understanding of an individual patient’s therapy response based on biosimulation of their full mutation profile."

"This study opens new potential avenues for optimizing treatment strategies in NSCLC patients with EGFR mutations," said Dr. Michael Castro, Cellworks Chief Medical Officer. "By identifying additional biomarkers that influence chemotherapy response in NSCLC patients, we gain a deeper understanding of how each patient’s unique disease profile impacts therapy effectiveness. EGFR blockade can reverse chemotherapy resistance for some patients by downregulating apoptotic blockade and DNA repair caused by EGFR. Through the use of Cellworks personalized therapy biosimulation, we can pave the way for individualized decision making to determine which patients should be offered combination therapy upfront, thereby improving survival outcomes."

Study Design

Cellworks computational biosimulation was performed in this study to evaluate the additive value of chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. A real-world retrospective cohort of 116 frontline NSCLC patients treated with osimertinib were obtained from the nationwide (US based) de-identified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database (FH-FMI-CGDB). Biosimulated efficacy scores were generated for both osimertinib alone and in combination with carboplatin and pemetrexed. The study then analyzed chemotherapy-driven improvements in predicted clinical response, using the upper 95% confidence interval of the osimertinib ES as a threshold.

Study Results

The efficacy scores for osimertinib were significantly associated with clinical outcomes, confirming the predictive power of Cellworks computational biosimulation. Importantly, the biosimulated addition of chemotherapy to osimertinib led to a higher efficacy score for some patients, allowing for a more refined selection of patients, moving beyond the generalized conclusion that chemotherapy is beneficial in combination, which may apply to some, but not all, patients. The benefit of chemotherapy is unevenly distributed in the population, and biosimulation aids in the selection of which patients are most likely to get a benefit from combination compared to sequential treatment.

On September 9, 2024 Vir Biotechnology, Inc. (Nasdaq: VIR) reported that the exclusive worldwide license agreement with Sanofi announced on August 1, 2024, has closed following expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (Press release, Sanofi, SEP 9, 2024, View Source [SID1234646457]). The agreement provides Vir with an exclusive worldwide license to three clinical-stage masked T-cell engagers (TCEs) with potential applications in a range of cancers and exclusive use of the proprietary PRO-XTENTM masking platform for oncology and infectious disease. Key employees from Sanofi with extensive scientific and development expertise in TCEs, and in-depth experience using the PRO-XTEN platform, will join Vir. Further information about the TCEs and their respective development plans will be provided at Vir’s upcoming R&D Day in November.

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"The closing of this strategic agreement with Sanofi is a pivotal moment for Vir and a significant opportunity to help address patient unmet needs. We are excited to further advance the masked T-cell engagers in clinical development, bolstering our clinical pipeline and adding near-term value creation opportunities," said Marianne De Backer, M.Sc., Ph.D., MBA, Vir’s Chief Executive Officer. "Our proven expertise in antibody engineering and clinical development combined with the innovative PRO-XTEN masking platform offers a unique opportunity to discover and develop therapies in oncology and infectious disease."

The clinical-stage assets Vir is licensing under the agreement are:

SAR446309 is a dual-masked HER2-targeted TCE in phase 1 clinical study including participants with metastatic treatment resistant HER2+ tumors such as breast and colorectal cancers.
SAR446329 is a dual-masked PSMA-targeted TCE in phase 1 clinical study including participants with metastatic castration-resistant prostate cancer.
SAR446368 is a dual-masked EGFR targeted TCE with an active IND. A phase 1 clinical study, which is expected to begin enrollment in the first quarter of 2025, will include participants with EGFR-expressing tumors of various types.
About the PRO-XTENTM Masking Platform

The PRO-XTEN proprietary masking platform can be applied to TCEs, cytokines, and other molecules potentially broadening the therapeutic index (TI) for patients. This technology exploits the high protease activity of the tumor microenvironment (TME) to specifically activate (unmask) drug candidates in tumor tissues. The selective cleavage results in the active molecule being released preferentially in the TME, potentially increasing the TI by minimizing off-target activity and toxicity associated with the systemic immune activation seen with traditional TCEs. Vir has exclusively licensed the PRO-XTEN proprietary masking platform from Sanofi in the fields of oncology and infectious diseases.

On September 9, 2024 Compugen Ltd. (Nasdaq: CGEN) (TASE: CGEN) a clinical-stage cancer immunotherapy company and a pioneer in computational target discovery, reported that Dr. Roy Granit, Head of Computational Discovery at Compugen will present a poster on applying AI to gain insights into the novel immune checkpoint PVRIG through single-cell and spatial transcriptomics at the Single Cell Genomics 2024 conference taking place between September 16-18, 2024, Corinthia, Greece (Press release, Compugen, SEP 9, 2024, View Source [SID1234646456]).

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Additional biological insights characterizing the uniqueness of the novel immune checkpoint PVRIG discovered by Compugen, were generated using Compugen’s AI/ML-powered computational discovery platform, recently branded as UnigenTM. The data further support previous findings that PVRIG inhibition may be differentiated from other immune checkpoints and may have the potential to induce anti-tumor activity in indications previously refractory to immunotherapy.

Poster presentation details:
Poster title: Applying AI to Gain Insights into the Novel Immune Checkpoint PVRIG Through Single-Cell and Spatial Transcriptomics
Poster number: 40
Presenter: Roy Granit, Ph.D., Head of Computational Discovery, Compugen Ltd.
Date: Monday, September 16, 2024

The poster will be available on the publications section of Compugen’s website, www.cgen.com, following presentation.

About Unigen
Compugen has been at the forefront of decoding cancer biology, with its AI/ML powered predictive computational discovery platform, recently branded as Unigen. Unigen is Compugen’s code-to-cure, flexible-loop platform for the computational prediction of novel drug target discovery and development of cancer immunotherapy. Unigen combines Compugen’s deep scientific knowledge, AI/ML predictive algorithms and a cloud-based, technology-agnostic platform integrating a variety of biological data such as multi-omics, single-cell RNA sequencing and spatial omics data. The outcomes from Compugen’s preclinical and clinical trials enrich the proprietary knowledgebase to discover additional novel drug targets and further understand complex biology. To date, Unigen has yielded multiple novel immuno-oncology drug targets, potential first- or best-in-class clinical stage immuno-oncology programs, validating partnerships with multiple pharmaceutical companies and undisclosed programs in its early-stage pipeline.

On September 9, 2024 Boehringer Ingelheim reported positive results from a Phase Ib primary analysis of Cohort 1 of the Beamion LUNG-1 trial evaluating zongertinib (BI 1810631) in pre-treated patients with advanced non-small cell lung cancer (NSCLC) with activating HER2 mutations (Press release, Boehringer Ingelheim, SEP 9, 2024, View Source [SID1234646455]). Zongertinib demonstrated a meaningful objective response rate and was generally well tolerated in the Cohort 1 setting. The results were presented in a Presidential Symposium at the IASLC 2024 World Conference on Lung Cancer (WCLC) and are included in the official 2024 WCLC Press Program.

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As of May 2024, 132 patients have been treated with 120 mg / 240 mg of zongertinib once a day (n=75/n=57). With a confirmed objective response rate (ORR) of 66.7%, 97.5% CI (53.8–77.5), (p<0.0001) as assessed by blinded independent central review (BICR), the primary endpoint was met for Cohort 1 (120 mg; n=75). Tumor shrinkage of any magnitude was observed in 94% of all patients across doses, per investigator assessment. The trial design includes a dose expansion that was carried out to find the optimal dose of zongertinib for this patient population. Patients were randomized 1:1 to either the 120 mg (n=58) or the 240 mg (n=55) group. After an interim futility analysis, 120 mg was selected as the dose to be evaluated further in Cohort 1, and 17 additional patients were enrolled. In the part of the trial where patients were randomized 1:1, zongertinib showed a response rate of 72.4% in patients treated with 120 mg daily, and 78.2% in patients treated with 240 mg daily as well as disease control rates (DCRs) of 95% and 100% respectively.

Phase Ib, Cohort 1 data also show preliminary brain activity with zongertinib. 33% (120 mg; n=27) and 40% (240 mg; n=25) of patients with asymptomatic brain metastases achieved confirmed objective response, with a DCR of 74% and 92% respectively, as per RANO-BM (recommendations for standardized tumor response and progression assessment) by BICR. The central nervous system is a common site of metastasis in NSCLC and is associated with poor prognosis and quality of life.2 Brain metastases are present in up to 30% of patients with NSCLC with activating HER2 mutations at diagnosis.3

"These new data could represent positive news in the future treatment of non-small cell lung cancer patients with activating HER2 mutations," said the trial’s principal investigator, Dr. John Heymach, MD, PhD, The University of Texas MD Anderson Cancer Center. "While these mutations are rare, they are critical drivers in a subset of non-small cell lung cancer cases, and current treatment options are severely limited. Patients with this type of cancer typically face a poor prognosis, with approximately 50% responding to first-line treatment and only 20% responding to second-line therapy." 4,5,6,7

Zongertinib is an investigational oral HER2 tyrosine kinase inhibitor (TKI) in development for patients with advanced NSCLC with activating HER2 mutations. Zongertinib was designed to spare wild-type EGFR thereby mitigating associated toxicities. Beamion LUNG-2, a global Phase III trial evaluating zongertinib compared to standard of care as first-line treatment in patients with advanced NSCLC with activating HER2 mutations is currently enrolling.

Paola Casarosa, Board of Managing Directors, Head of Innovation Unit at Boehringer Ingelheim, said: "Zongertinib’s efficacy and tolerability profile has the potential to become part of the future treatment landscape for patients with HER2 mutated lung tumors. Zongertinib is a perfect example of our approach to science in the discovery and development of novel treatments. Boehringer is committed to providing breakthrough therapies for cancer patients, and we look forward to advancing the zongertinib clinical program."

Zongertinib was generally well tolerated for 120 mg and 240 mg, with no deaths attributed to treatment and a low incidence of adverse events leading to dose reductions (11%) and discontinuation (3%). No new safety signals or treatment-related interstitial lung diseases (ILD) were observed, and Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 17% (120 mg) and 19% (240 mg) of patients treated with zongertinib. The most common TRAEs were Grade 1 or 2 diarrhea (43% and 11% respectively), Grade 1 or 2 rash (19% and 8% respectively).

Data are still maturing and with two thirds of responding patients still on treatment at data cut-off, progression-free survival (PFS) and duration of response (DoR) data will be reported at an upcoming conference.

About non-small cell lung cancer (NSCLC)
Lung cancer claims more lives than any other cancer type and the incidence is set to increase to over 3 million cases worldwide by 2040.8 NSCLC is the most common type of lung cancer.9 The condition is often diagnosed at a late stage,10 and fewer than 3 in 10 patients are alive five years after diagnosis.11 People living with advanced NSCLC can experience a detrimental physical, psychological, and emotional impact on their daily lives. There remains a high unmet need for additional treatment options for people living with advanced NSCLC. Up to 4% of lung cancers are driven by HER2 mutations (or gene alterations).12 Mutations in HER2 can lead to overexpression and overactivation, which can in turn result in uncontrolled cell production, inhibition of cell death and promotion of tumor growth and spread.13

About zongertinib
Zongertinib (also known as BI 1810631) is an investigational oral HER2-specific tyrosine kinase inhibitor (TKI) that is being developed as a potential treatment for HER2 mutated non-small cell lung cancer (NSCLC). Zongertinib was granted FDA Fast Track Designation in 2023, then in 2024 it was granted Breakthrough Therapy Designation by the U.S. FDA and China CDE for the treatment of adult patients with advanced NSCLC whose tumors have activating HER2 mutations, and who have received a prior systemic therapy. HER2 is a member of the ErbB family of receptor tyrosine kinases (enzymes that act like chemical messengers).14 A recent study has shown pre-clinically that the investigational compound zongertinib has potential for further clinical study in HER2 dependent solid cancers as monotherapy and as concurrent treatment with ADC therapy or with KRAS-targeted drugs.14 Read more here.

About the Beamion clinical trial program
Beamion LUNG-1 (NCT04886804): An open-label, Phase I dose escalation trial, with dose confirmation and expansion, of zongertinib as monotherapy in people with advanced or metastatic solid tumors and NSCLC with activating HER2 mutations. The study has 2 parts. The first part is open to adults with different types of advanced cancer (solid tumors with changes in the HER2 gene) for whom previous treatment was not successful. The second part is open to people with non-small cell lung cancer with a specific mutation in the HER2 gene. Beamion LUNG-2 is a phase 3, open label, randomized, active-controlled study that will enroll 270 patients with unresectable, locally advanced or metastatic non-squamous NSCLC harboring HER2 tyrosine kinase domain mutations to evaluate zongertinib compared with standard of care.

On September 9, 2024 NeoImmuneTech, Inc. (NIT or "NeoImmuneTech"), a global leader in T cell-based immunotherapy, reported that it will present interim results of the Phase 1b clinical trial (NIT-112) combining a CAR-T therapy with NT-I7 (efineptakin alfa) during the ‘Mini oral session 1: Haematological malignancies’ at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) in Barcelona, Spain, from September 13 to 17 (Press release, NeoImmuneTech, SEP 9, 2024, https://www.prnewswire.com/news-releases/neoimmunetech-presents-promising-interim-results-of-car-t-combination-with-its-nt-i7-asset-at-esmo-2024-302241828.html [SID1234646454]). These initial results present a promising approach to enhancing the potential of CAR-T therapies while maintaining a stable safety profile.

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The NIT-112 clinical trial involves patients with Large B-cell Lymphoma (LBCL) who received CAR-T therapies such as Kymriah, Yescarta, or Breyanzi, followed by NT-I7 administration 21 days after CAR-T infusion. The trial aims to evaluate safety, tolerability, the recommended Phase 2 dose (RP2D), and the potential for NT-I7 to enhance CAR-T expansion, persistence and stemness.

Interim results show that at dose levels 4 and 5, which are considered mid-level doses (360, 480 µg/kg), NT-I7 demonstrated a stable safety profile. No cases of Cytokine Release Syndrome (CRS) or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which are known as high-risk side effects of CAR-T therapies, were observed subsequent to NT-I7 administration. Only mild, manageable side effects (Grade 1-2), such as injection site erythema and swelling were observed in 6 out of 11 patients (54.5%). Overall, a strong safety profile was observed.

NT-I7 administration resulted in significant amplification of CAR-T cells, prolonged persistence and an increase in T cell stemness, characterized by a higher frequency of T cells with a stem-cell memory (Tscm) phenotype (CD45RA+CCR7+CD95+). The overall response rate (ORR) from the interim results was 81.1% (9 out of 11 patients), with 7 achieving a complete response (CR) and 2 achieving a partial response (PR). Kymriah is known to have an ORR of 52% in LBCL patients.

Dr Luke Oh, President and Chief Executive Officer of NeoImmuneTech, Inc., said: "We are thrilled by the preliminary results of study NIT-112 showing NT-I7’s ability to amplify CAR-T cells. This successful amplification of CAR-T cells is expected to translate into improved patient outcomes. NIT plans to actively pursue technology transfer related to the combination of NT-I7 with CAR-T therapies and we look forward to accelerating our discussions with the organizations already conducting preclinical studies combining NT-I7 with our own CAR-T technologies."

Title: Phase 1b study of NT-I7 (efineptakin alfa), a long-acting IL-7, post-CD19-directed CAR T cell therapy in diffuse large B-cell lymphoma (DLBCL)
Presentation Number: 806MO
Speakers: Armin Ghobadi (St. Louis, United States of America)
Lecture Time: 15:05 – 15:10 (Fri, 2024. 09. 13)
Session Name: Mini oral session 1: Hematological malignancies (ID 31)
Room: Toledo Auditorium – Hall 3

About NT-I7 (efineptakin alfa) (rhIL-7-hyFc)
NT-I7 (efineptakin alfa) is the only clinical-stage long-acting human IL-7 and is being developed in oncologic and immunologic indications, where T cell amplification and increased functionality may provide clinical benefit. IL-7 is a fundamental cytokine for naïve and memory T cell development and sustaining immune response to chronic antigens (as in cancer) or foreign antigens (as in infectious diseases). NT-I7 exhibits favorable PK/PD and safety profiles, making it an ideal combination partner. NT-I7 is being studied in multiple clinical trials in solid tumors and as vaccine adjuvant. Studies are being planned for testing in hematologic malignancies, additional solid tumors and other immunology-focused indications.