On April 28, 2025 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that clinical data on neratinib were presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 (Press release, Puma Biotechnology, APR 28, 2025, View Source [SID1234652287]). The AACR (Free AACR Whitepaper) Annual Meeting is currently taking place at the McCormick Place in Chicago, Illinois. The poster is entitled, "CT071: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495)." Andrew A. Davis, Assistant Professor at Washington University School of Medicine, presented the poster during Session PO.CT01.01 – First-in-Human Phase I Clinical Trials 1.

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NCI 10495 is sponsored by the National Cancer Institute, part of National Institutes of Health, and conducted in the NCI funded Experimental Therapeutics Clinical Trials Network (ETCTN). This open label, multi-center, Phase I clinical trial (NCT05372614) enrolled 20 patients in three cohorts treated with three increasing dose levels, or a 3+3 trial design, to evaluate the safety and tolerability of trastuzumab deruxtecan (T-DXd or ENHERTU) in combination with neratinib (NERLYNX). Eligible patients had advanced solid tumors with HER2 immunohistochemistry 3+ (IHC3+), HER2 amplification identified by in situ hybridization or next-generation sequencing, or an activating HER2 mutation. Prior treatment with trastuzumab deruxtecan was not allowed. The dose of trastuzumab deruxtecan was fixed at 5.4 mg/kg. The three dose levels (DLs) for neratinib all started at 120 mg daily for the first week. DL1 remained at 120 mg daily throughout the course of treatment, DL2 escalated to 160 mg daily in week 2 and 200 mg by week 3, and DL3 escalated to 160 mg in week 2 and 240 mg by week 3. The primary endpoints were the determination of the dose-limiting toxicities (DLTs) during the first two cycles of treatment (42 days) and the determination of the recommended Phase II dose of the combination of trastuzumab deruxtecan and neratinib.

Twenty patients received study treatment (DL1 N=7, DL2 N=4, and DL3 N=9). The most common treatment-emergent adverse events of any grade included nausea (N=15, 75%), diarrhea (N=15, 75%), fatigue (N=13, 65%), and hypokalemia (N=11, 55%). Grade 3 treatment-emergent adverse events that occurred in more than 2 patients included anemia (N=6, 30%), diarrhea (N=4, 20%), and hypokalemia (N=3, 15%). The only Grade 4 treatment-related adverse event was neutropenia that occurred in 1 patient (5%). One DLT (acute kidney injury) was observed at DL1, 0 DLTs were observed in DL2, and 1 DLT was observed (fatigue leading to early drug discontinuation) at DL3. Three patients developed Grade 1 pneumonitis or interstitial lung disease (ILD), 2 at DL1 and 1 at DL3. The proportion of reported treatment-emergent adverse events was lower at higher dose levels.

Of 15 response-evaluable patients by RECIST v1.1, 4 patients had a partial response (PR), including patients with gastroesophageal (N=2, one HER2 IHC 3+ and one HER2 mutated), pancreatic (N=1, IHC 3+), and ovarian (N=1, IHC 3+; unconfirmed response) cancers. Notably, 3 of 5 patients with advanced pancreatic cancer were observed to have tumor regression (1 PR for 13+ cycles, 2 with stable disease consisting of one patient with -29.4% tumor regression for 9 cycles and one patient with -13.3% tumor regression for 8 cycles).

Dose level 3, which consisted of trastuzumab deruxtecan at 5.4 mg/kg and neratinib at 120 mg in week 1, 160 mg week 2, and 240 mg week 3 onward, was selected as the recommended Phase II dose. Part 2 of this study, which consists of a pharmacodynamic evaluation of trastuzumab deruxtecan (5.4 mg/kg) and neratinib (RPD2) in 12 patients, opened to enrollment in March 2025. Patients with any advanced solid tumor and HER2 amplification/overexpression or a HER2 mutation will be enrolled.

"Neratinib and trastuzumab deruxtecan showed impressive combination activity in preclinical models of HER2-mutated breast cancers, which prompted evaluation of the combination in this first-in-human clinical trial. I am pleased to report that the combination not only had a manageable safety profile, but we also observed early signs of efficacy across a variety of HER2-altered tumors," said Dr. Davis.

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, added, "We are pleased with the tolerability and potentially promising signals of efficacy of neratinib in combination with trastuzumab deruxtecan, especially in hard-to-treat tumors including pancreatic cancer. We look forward to continued evaluation of this combination in the Phase II portion of this study."

NCI 10495 is also supported by Puma Biotechnology and Daiichi Sankyo, Inc. through Cooperative Research and Development Agreements with NCI.

Trastuzumab deruxtecan is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

On April 28, 2025 Adicet Bio, Inc. (Nasdaq: ACET), a clinical stage biotechnology company discovering and developing allogeneic gamma delta T cell therapies for autoimmune diseases and cancer, reported the acceptance of an abstract for an oral presentation at the upcoming American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting taking place May 13-17, 2025, in New Orleans, LA (Press release, Adicet Bio, APR 28, 2025, View Source [SID1234652286]).

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Details of the oral presentation are as follows:

Title: ADI-270, an Armored Allogeneic Anti-CD70 CAR γδ T Cell Therapy, Demonstrates Robust CAR-Directed and -Independent Anti-Tumor Activity Against Hematologic and Solid Tumor Models Compared to Conventional CAR αβ T Cells
Session Name: Engineered Immune Effector Cells for Solid Tumors
Presenting Author: Melinda Au
Date and Time: May 17, 2025; 11:45 a.m. – 12:00 p.m. CT

On April 28, 2025 Clasp Therapeutics, a biotechnology company bringing unparalleled precision to immuno-oncology using next-generation T-cell engagers (TCEs), reported dosing of the initial patient in the GUARDIAN-101 phase 1 trial of CLSP-1025, the first tumor-specific TCE to enter clinical development. CLSP-1025 exclusively targets cancer cells expressing the p53R175H mutation, a mutation associated with a wide range of solid tumors, including colorectal, pancreatic, lung, gastric, esophageal, gynecological, and prostate cancers (Press release, Clasp Therapeutics, APR 28, 2025, View Source [SID1234652285]).

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Unlike first-generation TCEs that target proteins present on both tumor and normal cells, Clasp’s TCEs target tumor-specific peptides derived from cancer driver mutations, ensuring absolute specificity and minimizing risk of toxicity to healthy tissues. Truncal mutations like p53R175H occur early in tumorigenesis and are present in every tumor cell, making them ideal targets for immune system attack. Moreover, these pHLAre molecules (precise HLA redirecting engagers) are designed to mimic the natural T cell receptor interface between a cancer cell and T cell, maximizing anti-cancer activity.

"Treating the first patient in the GUARDIAN-101 trial marks a pivotal milestone in Clasp’s mission to transform patient outcomes through precision immunotherapy," said Dr. Lauren Harshman, M.D., SVP of Clinical Development at Clasp Therapeutics. "Advancing CLSP-1025 into the clinic is an important step in validating the potential of our pHLAre platform to overcome the limitations of current T-cell engagers and offer a breakthrough treatment option for patients."

At the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting this week, Clasp also presented nonclinical data supporting the clinical development of CLSP-1025, including data supporting the therapeutic candidate’s selectivity, activity, pharmacokinetics and safety profile.

About GUARDIAN-101 and CLSP-1025

Clasp’s Phase 1 GUARDIAN-101 dose escalation study evaluates the safety and initial anti-tumor activity of CLSP-1025. CLSP-1025 is a bispecific antibody-like molecule that directs a patient’s T cells to the tumor, generating a precise immune response to selectively and potently eliminate cancer cells. CLSP-1025 is designed to target the p53R175H peptide in the context of HLA-A*02:01. Enrolled patients must be HLA-A*02:01 positive and have an advanced solid tumor that harbors the p53R175H mutation. This Phase 1 study will identify the dose of CLSP-1025 for use in future studies. Visit clinicaltrials.gov (NCT06778863) for more details.

On April 28, 2025 Kairos Pharma, Ltd. (NYSE American: KAPA), a clinical stage biopharmaceutical company, reported it will be presenting at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2025 Annual Meeting to be held May 30-June 3, 2025 at McCormick Place, Chicago, Ill (Press release, Kairos Pharma, APR 28, 2025, View Source [SID1234652284]).

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The poster is titled, "Effect of KROS 101, a small molecule GITR ligand agonist, on T effector cells, T reg cells and intratumoral CD8 T cell cytotoxicity," and will be presented on June 2.

John Yu, M.D., Kairos CEO commented, "We look forward to the opportunity to continue to share data regarding our platform assets at one of the most prestigious oncology meetings in the world. We believe that KROS 101 has the potential to help optimize cancer treatment and we look forward to discussing our findings with the medical and scientific communities."

On April 28, 2025 Schrödinger, Inc. (Nasdaq: SDGR) reported preclinical data on SGR-3515, its investigational Wee1/Myt1 co-inhibitor today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 (Press release, Schrodinger, APR 28, 2025, View Source [SID1234652283]). The data demonstrated that SGR-3515 has improved anti-tumor activity in preclinical models compared to known Wee1 and Myt1 monotherapy inhibitors. The poster also described how the dosing schedule of SGR-3515 can be optimized to preserve efficacy and minimize target-related side effects. New data was also presented on the development of a computational method that predicts the response to Wee1-based drug combinations, including in novel cancer settings such as head and neck cancers. Schrödinger expects to report initial data from the ongoing Phase 1 clinical trial of SGR-3515 in patients with advanced solid tumors in the second half of 2025.

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Additionally, Schrödinger presented its first preclinical data for SGR-4174, its SOS1 inhibitor that disrupts the interaction between SOS1 and KRAS, the most frequently mutated oncogene in human cancers. SGR-4171 demonstrated high selectivity for SOS1 over SOS2 as well as over other kinases. The data also demonstrated that SGR-4174 has strong tumor growth inhibition as a monotherapy as well as in combination with MEK or KRAS inhibitors, while maintaining a favorable safety profile. SOS1 development opportunities include cancers such as lung adenocarcinoma or RASopathies such as Neurofibromatosis Type 1.

"The preclinical data for SGR-3515 and SGR-4174 further demonstrate that molecules discovered and developed by Schrödinger have favorably differentiated molecular profiles compared to existing development-stage molecules," said Karen Akinsanya, Ph.D, president of R&D therapeutics at Schrödinger. "The preclinical profiles of these development candidates reinforce the power of our computationally-driven approach to designing molecules that meet challenging target product profiles and have the potential for meaningful benefit to patients."

SGR-3515 Data at AACR (Free AACR Whitepaper)

The poster (Abstract #3025), "Optimization of therapeutic index of SGR-3515, a first-in-class Wee1/Myt1 inhibitor through intermittent dosing for monotherapy and combination with chemotherapy in xenograft tumor models," includes preclinical data demonstrating that SGR-3515 monotherapy has superior anti-tumor activity compared to the Wee1 inhibitor ZN-c3 and the Myt1 inhibitor RP-6306 in multiple tumor models as well as synergistic efficacy when used in combination with chemotherapy. The poster also shares for the first time preclinical data demonstrating that the potential efficacy and tolerability of SGR-3515 can be optimized with three to five days of dosing, depending on the tumor type, in a two-week dosing cycle across multiple tumor settings. The optimized dosing schedule preserves efficacy while allowing for complete recovery from reversible on-target myelosuppression in preclinical tumor models.

A second poster (Abstract #3660), "Machine learning-based combination prediction for Wee1 inhibitor," presents data showing that a machine learning model, built on the integration of two large cell line combination screening studies of the Wee1 inhibitor AZD1775, successfully identified known and novel synergistic Wee1 drug combinations such as with tyrosine kinase inhibitors in ovarian and breast cancers, and with chemotherapy in head and neck or cancers. The data suggests potential for machine learning based approaches to make predictions with a high degree of confidence and gain novel insights beyond the data they are trained on.

SGR-4174 Data at AACR (Free AACR Whitepaper)

The poster (Abstract #4376), "Preclinical characterization of SGR-4174, a potent and selective SOS1 inhibitor for the treatment of pan KRAS mutant cancers in combination with KRAS pathway inhibitors," includes preclinical data demonstrating the superior binding, selectivity, and drug-like properties of SGR-4147 compared to MRTX0902 as assessed via comprehensive in vitro potency, ADME, and safety assays. The preclinical data for SGR-4174 also show robust suppression of the RAS signaling pathway and potent cell killing activity across multiple cancer types harboring diverse KRAS mutations as well as EGFR and SOS1 mutations. SGR-4174 monotherapy achieved dose-dependent target engagement and tumor growth inhibition and induced tumor shrinkage when used in combination with MEK or KRAS inhibitors in preclinical models of pancreatic and non-small cell lung cancer.