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Nerviano Medical Sciences Initiates Combination Phase 1 Trials of NMS-293 in Relapsed Small Cell Lung and BRCA Wild-Type Ovarian Cancers

On April 28, 2025 Nerviano Medical Sciences S.r.l. (NMS), a clinical-stage oncology company developing targeted therapies across DNA damage response and kinase pathways, reported the initiation of two Phase 1 clinical trials evaluating its unique non-trapping, highly specific and brain penetrant PARP1 inhibitor NMS-293 in combination therapies for relapsed small cell lung cancer (SCLC) and BRCA wild-type ovarian cancer (Press release, Nerviano Medical Sciences, APR 28, 2025, View Source [SID1234652238]). NMS-293 represents a third generation of PARP1 inhibitor using non-trapping as a way to combine with DNA-damaging therapies while preserving bone marrow safety. In this way, NMS-293 addresses tumors outside of BRCA or homologous recombination (HR) repair mutations which is unique. BRCA/HR mutation therapies represent only a small minority of tumors, mainly subsets of pancreatic, breast, prostate and ovarian cancers. Thus, therapies that leverage DNA damage response but are not limited to synthetic lethality of BRCA/HR mutations such as NMS-293 combinations with DNA damaging agents could address many tumor types in the future.

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PARPA-293-004: NMS-293 with Temozolomide in Relapsed SCLC

This open-label, single-arm Phase 1 trial will enroll approximately 10 patients with relapsed SCLC who have progressed after platinum-based chemotherapy, immunotherapy and other standards of care. The objectives include safety and preliminary anti-tumor activity. This regimen is similar to the ongoing Phase 2 -002 study in relapsed high-grade glioma. Boosting temozolomide activity in this relapsed setting of SCLC could lead to accelerated registration pathways and future early line combination study options with a variety of DNA-damage modalities.

ClinicalTrials.gov Identifier: NCT06931626

PARPA-293-003: NMS-293 with Topotecan in BRCA Wild-Type Ovarian Carcinoma
This open-label Phase 1 study will enroll approximately 24 patients with recurrent ovarian cancer who have received platinum-based treatments and other standards of care, including patients with platinum resistance. The objectives include safety, dose-finding and preliminary anti-tumor activity. Boosting topotecan activity in patients with relapsed ovarian cancer could lead to accelerated registration pathways as well as various DNA-damaging modality combination options for future early line studies.

ClinicalTrials.gov Identifier: NCT06930755

The rationale for initiating these trials is supported by both preclinical evidence and emerging clinical data from temozolomide combination studies which revealed an unprecedented combination safety profile coupled with preliminary antitumor efficacy in high grade gliomas (Mahnke, DDR Summit 2025 and Guerts et al, AACR (Free AACR Whitepaper)-NCI-EORTC 2023) including glioblastoma (unpublished). NMS-293 is a highly novel third generation PARP1 inhibitor distinguished by non-trapping as shown preclinically with high potency, selectivity and brain penetrance. Taken together, the profile improves on poor bone marrow features of first and second generation trapping PARP1 inhibitors (Yap et al AACR (Free AACR Whitepaper) 2024) and thus removes traditional barriers of combining a DNA damage repair inhibitor with a DNA damaging agent to address non-BRCA mutation tumors.

"These trials represent our focused, mechanism-driven approach to improving treatment outcomes in areas of high unmet medical need including relapsed small cell lung and BRCA wild type ovarian cancers," said Lisa Mahnke, MD, PhD, Chief Medical Officer of NMS. "NMS-293 has the potential to establish a new third generation of PARP1 inhibitor and which is not being developed as a classical PARP1 inhibitor due its unique chemotype. NMS-293 is a highly potent, highly selective, non-trapping PARP1, inhibitor which is highly brain penetrant and which can be developed across many tumor types including brain tumors like GBM or others with or without brain metastases in combination with a variety of DNA-damaging modalities such as chemotherapies or ADC payloads to reach many non-BRCA-mutation tumors in the future."

Mythic Therapeutics Presents Preclinical Data Demonstrating Potent Efficacy of MYTX-011 Across a Broad Range of Tumor Xenograft Models Harboring Clinically Relevant Mutations at the American Association for Cancer Research (AACR) Annual Meeting

On April 28, 2025 Mythic Therapeutics, a clinical-stage biotechnology company developing next-generation antibody-drug conjugate (ADC) therapies for the treatment of a wide range of cancers, reported preclinical data demonstrating the potential of MYTX-011 to treat multiple tumor types, regardless of mutation status or cMET expression level, in a poster session at the AACR (Free AACR Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Mythic Therapeutics, APR 28, 2025, View Source;utm_medium=rss&utm_campaign=mythic-therapeutics-presents-preclinical-data-demonstrating-potent-efficacy-of-mytx-011-across-a-broad-range-of-tumor-xenograft-models-harboring-clinically-relevant-mutations-at-the-american-associati [SID1234652237]).

"These findings highlight the broad therapeutic potential of MYTX-011 across a variety of cMET-expressing cancers and the opportunity to expand the treatable patient population to patients with EGFR, KRAS and MET mutations, which have shown reduced response rates in clinical studies of other anti-cMET ADCs in development," said Brian Fiske, Ph.D., chief scientific officer and co-founder of Mythic. "These preclinical data reinforce our confidence in the ongoing Phase 1 dose escalation trial of MYTX-011. Building on last year’s promising preliminary data, we remain highly optimistic and eagerly await additional readouts."

MYTX-011 is a novel cMET-targeted DAR 2 vcMMAE ADC with an antibody that has been engineered to have pH-dependent binding, which results in higher internalization and payload delivery to tumor cells with a range of cMET expression.

In the study, pH-dependent binding of MYTX-011 translated to potent efficacy in tumor xenografts regardless of mutation status, including models harboring MET exon 14 skipping, KRAS and EGFR mutations. Notably, MYTX-011 demonstrated anti-tumor activity in low or moderate cMET-expressing non-small cell lung cancer (NSCLC) KRAS G12C xenografts as well as tyrosine kinase inhibitor-resistant xenografts bearing EGFR T790M mutations. Additionally, live cell imaging studies demonstrated how FateControl technology drives increased uptake of MYTX-011 antibody in cMET-expressing tumor cells compared to a non-engineered parent antibody. In previous studies, a benchmark ADC was either inactive or had greatly reduced efficacy.

These findings support the continued clinical advancement of MYTX-011, which is currently being evaluated in the ongoing Phase 1 KisMET-01 trial in NSCLC.

The Company will present additional data from its Phase 1 KisMET-01 study at an upcoming major medical conference.

About MYTX-011

MYTX-011, an investigational cMET-targeting ADC, leverages Mythic’s innovative FateControl technology which is designed to allow ADCs to actively navigate inside of cells, potentially increasing delivery of anti-cancer agents to tumor cells with less impact on healthy cells. This breakthrough approach takes the next step beyond linker-payload technologies and is designed to improve ADC efficacy against a broad set of molecular targets and patient profiles. MYTX-011 is currently being evaluated in the Phase 1 KisMET-01 clinical trial, a first-in-human, open-label, multi-center, dose escalation and dose expansion study enrolling patients with locally advanced, recurrent or metastatic NSCLC (NCT05652868).

April 28, 2025: MaaT Pharma Presents Preclinical Data at AACR Annual Meeting Demonstrating Immune Activation and Anti-Tumor Activity of MaaT034

On April 28, 2025 MaaT Pharma (EURONEXT: MAAT – the "Company"), a clinical-stage biotechnology company and a leader in the development of Microbiome Ecosystem TherapiesTM (MET) dedicated to enhancing survival for patients with cancer through immune modulation, reported new preclinical data for MaaT034, the Company’s next generation product, showing compelling anti-tumor efficacy results in germ-free mice at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 in Chicago, Illinois, taking place from April 25 to 30, 2025 (Press release, MaaT Pharma, APR 28, 2025, View Source [SID1234652236]).

MaaT Pharma has built a versatile platform combining two complementary approaches. The first one leverages a GMP-compliant approach to produce standardized donor-derived therapies (MaaT013, MaaT033) using pooled donations, proven to restore a rich and diverse gut microbiome for patients with severe dysbiosis and currently in late-stage of clinical evaluation (Phases 2 and 3). In parallel, the Company is advancing a next-generation, AI-driven co-culture technology to develop a donor-independent synthetic microbiome ecosystem at large industrial scale targeting indication-specific diseases. MaaT034, the first-in-class co-cultured product, aims to optimize intestinal microbiome functions and to improve patient responses to immunotherapy in combination with Immune Checkpoint Inhibitors.

Below are the key results presented at AACR (Free AACR Whitepaper) for MaaT034:

Metagenomic analysis shows that MaaT034 reproduces the microbial functions of MaaT013 – the Company’s lead asset, currently evaluated in the randomized Phase 2 PICASSO trial in combination with immune checkpoint inhibitors (ICI), ipilimumab (Yervoy) and nivolumab (Opdivo) for unresectable or metastatic melanoma.
MaaT034 improves DC-mediated T cell activation and potentiates anti-tumor effects mediated by anti-PD-1 checkpoint blockade in vitro.
70% of MaaT034 microbial species engraft in mice, ensuring an enduring presence of beneficial bacteria in the gut environment.
MaaT034 increases the production of key microbial-derived metabolites such as short-chain fatty acids in germ-free mice. This translates into an improved gastrointestinal physiology as evidenced by gut mucosal restoration.
MaaT034 optimizes anti-PD1 mediated activity in tumor-bearing, germ-free mice. While anti-PD1 alone reduced tumor growth by 10%, the combination of anti-PD1 and MaaT034 resulted in a 83.7% tumor growth reduction (compared to a 24.2% reduction when using a single strain of Akkermansia muciniphila bacteria). These results demonstrate that improved tumor control is achieved with anti-PD1 in combination with MaaT034, as compared to PD-1 alone or in combination with a reference single bacterial strain.
"These positive data in tumor-bearing mice demonstrate the significant potential of MaaT034 as a microbiome ecosystem therapy candidate and provide a robust basis for the progression of this therapy into clinical development for solid tumors. We look forward to further evaluating the potential benefits of MaaT034 in the next phases of our research," said Gianfranco Pittari, MD PhD, Chief Medical Officer, MaaT Pharma.

Upcoming conferences participation

May 5-6, 2025 – Swiss Biotech Day, Basel
May 13, 2025 – Forum Midcaps Gilbert Dupont, Paris
June 12-15 – European Hematology Association (EHA) (Free EHA Whitepaper) Congress, Milan, IT
June 16-19, 2025 – Bio International Convention, Boston, MA – Company Presentation
June 18-19, 2025 – Portzamparc Conference Mid & Small Caps 2025, Paris
September 25, 2025 – KBC Healthcare Conference, Brussels
About MaaT034

MaaT034, currently in preclinical development, is a next-generation donor-independent full ecosystem synthetic microbiome therapy, dedicated to improving patient responses to immunotherapy in combination with Immune Checkpoint Inhibitors. Developed using the Company’s co-culturing proprietary MET-C platform, MaaT034 is optimized for large-scale production in oncology. Previous presented preclinical data showed that MaaT034 produced key metabolites, recognized as promoting gut barrier restoration and modulating immune responses, such as Short-Chain Fatty Acids (SCFA), secondary bile acids, and tryptophan derivatives. These data support the role of MaaT034 in gut barrier repair and in T cell reactivation either in combination with anti-PD1 or with anti-PD-L1. By enhancing gut barrier repair and modulating immune responses, MaaT034 is expected to complement the action of these immunotherapeutic agents, potentially improving their efficacy in treating solid tumors cancer.

Kura Oncology Announces First Patients Dosed in Phase 1 Combination Trial of Ziftomenib for the Treatment of Advanced GIST

On April 28, 2025 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported that the first patients have been dosed in KOMET-015, a Phase 1 clinical trial of ziftomenib, the Company’s potent and selective, oral investigational menin inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST) after imatinib failure (Press release, Kura Oncology, APR 28, 2025, View Source [SID1234652234]).

"Building on compelling clinical activity of ziftomenib in patients with NPM1-mutant and KMT2A-rearranged AML, we are committed to evaluating the full therapeutic potential of menin inhibitors for the treatment of cancer," said Mollie Leoni, M.D., Chief Medical Officer of Kura Oncology. "Approximately 4,000 to 6,000 new cases of GIST are diagnosed each year in the U.S., and advanced GIST patients have limited treatment options. Our preclinical data demonstrate the combination of ziftomenib and imatinib provides robust and durable antitumor activity in both imatinib-sensitive (1L) and imatinib-resistant (2L/3L) GIST patient-derived xenograft models, and we look forward to seeing whether the combination offers potential to transform the treatment paradigm."

In preclinical studies, the data demonstrates the combination exerts antitumor activity via a synthetic lethal mechanism through which ziftomenib epigenetically targets a vulnerability of GIST tumors actively induced by even ineffective tyrosine kinase inhibitor (TKI) treatments. Sixty percent of patients develop resistance to imatinib, the frontline standard of care for GIST, within two years, and ziftomenib has the potential to delay the onset of or overcome that resistance in these patients.

"This study is an important step in developing new combination treatments to potentially improve outcomes for patients with advanced gastrointestinal stromal tumors, a disease indication for which new therapeutic options are needed," said Mrinal Gounder, M.D., Sarcoma Oncologist & Early Phase Drug Development Specialist at Memorial Sloan Kettering Cancer Center. "KOMET-015 builds upon the promising preclinical data observed with ziftomenib in combination with imatinib in GIST models and we look forward to evaluating the investigational drug candidate and its potential to transform the treatment landscape."

"Until now, most approaches to treating gastrointestinal stromal tumors rely on targeted KIT inhibition via tyrosine kinase inhibitors such as imatinib, however most patients eventually progress due to acquired secondary KIT mutations highlighting the need for new treatment options," said Shreyaskumar Patel, M.D., Center Medical Director, Sarcoma Center, at The University of Texas MD Anderson Cancer Center. "We are highly encouraged by the substantial preclinical data generated to date supporting the combination for ziftomenib in combination with KIT inhibitors in advanced GIST, and the dosing of the first patients marks an important milestone to address the meaningful unmet need for these patients."

The KOMET-015 Phase 1a/1b, open-label, dose-escalation trial is designed to evaluate the safety, tolerability, and preliminary antitumor activity of ziftomenib in combination with imatinib in adults with GIST who have documented disease progression while currently on or previously treated with imatinib. Upon completion of the dose-escalation portion of the trial, expansion cohorts are planned to further assess the safety, tolerability, and clinical activity of ziftomenib. The primary objectives include evaluation of safety and tolerability and determination of the recommended Phase 2 dose, and key secondary endpoints include clinical benefit, overall response rate (ORR), progression free survival (PFS), duration of response, and overall survival (OS).

Currently, there are no other clinical trials evaluating the combination of a menin inhibitor with standards of care for the treatment of GIST. For more information regarding the KOMET-015 trial, please visit www.clinicaltrials.gov (identifier: NCT06655246).

About GIST

Gastrointestinal stromal tumors (GIST) are the most common form of sarcoma, and are characterized as KIT-dependent solid tumors, with an estimated 4,000 to 6,000 new cases diagnosed in the U.S. each year. Despite the successful disease control achieved with imatinib in advanced GIST patients, most patients eventually progress due to acquired secondary KIT mutations. TKIs such as sunitinib target imatinib-resistant genotypes and are approved in later lines, but response rates and long-term outcomes are modest, so new therapeutic options are needed.

About Ziftomenib

Ziftomenib is a once daily, oral investigational menin inhibitor currently in development for the treatment of genetically defined AML and GIST patients with high unmet need. In April 2024, ziftomenib received Breakthrough Therapy Designation (BTD) from the FDA for the treatment of relapsed/refractory (R/R) NPM1-mutant (NPM1-m) AML based on data from Kura’s KOMET-001 clinical trial. Additional information about clinical trials for ziftomenib can be found at www.kuraoncology.com/clinical-trials/#ziftomenib.

IN8bio Unveils Promising New Data from Next Generation Gamma-Delta T Cell Engager (TCE) Platform at AACR 2025

On April 28, 2025 IN8bio, Inc. (Nasdaq: INAB), a clinical-stage biopharmaceutical company developing innovative gamma-delta (γδ) T cell therapies for cancer and autoimmune diseases, reported new preclinical data from its innovative γδ T cell engager (γδ-TCE) platform. The data will be presented at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 30, 2025 (Press release, In8bio, APR 28, 2025, View Source [SID1234652233]). The data showed that IN8bio’s new γδ-TCE platform demonstrated potent and consistent cancer-killing activity across targets in leukemia models, while avoiding the secretion of cytokines that drive the dangerous side effects seen with other TCE based immune therapies.

Unlike traditional TCEs that rely on CD3 to activate all T cells in the body – often triggering excessive inflammatory responses, potential T cell exhaustion and other serious side effects – IN8bio’s next-gen platform is designed to specifically activate only γδ T cells, a small but powerful subset of immune cells. These cells can naturally detect, phagocytose (eat) and kill tumors cells without needing to be "trained" to recognize specific targets. The platform’s lead molecules, INB-619 (targeting CD19) and INB-633 (targeting CD33), were able to eliminate cancer cells in preclinical studies with minimal release of inflammatory cytokines. This potentially offers a lower risk of cytokine release syndrome (CRS) or the neurotoxicity that can impact 60-75% of patients treated with conventional CD3 TCEs.

William Ho, CEO and co-founder of IN8bio, commented, "Our INB-600 TCE platform combines the natural tumor-fighting abilities of γδ T cells with bispecific engagers to generate a more precise and powerful way to mobilize the immune system against cancer cells. These early results in leukemia models are exciting, and we believe this technology can eventually be applied to other hard-to-treat cancers, and even certain autoimmune diseases."

Key highlights from the in vitro studies:

INB-619 and INB-633 both triggered strong and specific, linear dose-related killing of leukemia cells (ALL and AML) at low picomolar concentrations.
Both molecules activated and expanded two key γδ T cell subsets (Vδ1+ and Vδ2+), which is critical since most cancer patients have reduced numbers of these cells.
Both molecules promoted activation and degranulation, with dose-related increases in the expression of cellular markers indicating a transition to a powerful cancer-cell killing phenotype.
Importantly, they did so with minimal, if any, changes in dangerous cytokines, such as IL-6, IL-10, and IL-17a – markers that are often linked to cytokine release syndrome (CRS) and other treatment-related toxicities.
Because this new off-the-shelf platform can drive γδ T cell expansion without the need for genetic engineering, it has the potential to offer a more scalable and flexible approach to building next-generation immunotherapies.

IN8bio continues to expand its γδ T cell therapeutic pipeline beyond genetically engineered and drug-resistant cellular therapies and is exploring various disease indications and any opportunities for partnership with the INB-600 platform. This preclinical data reinforces the company’s differentiated strategy to build modular and scalable therapeutic approaches to leverage the power of γδ T cells to target malignancies with increased precision and reduced toxicity.

The AACR (Free AACR Whitepaper) 2025 poster is available on the investor section of the company’s website at View Source