On April 29, 2025 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the publication of a manuscript in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which supports the rational molecular design of zidesamtinib, its novel and selective ROS1 inhibitor (Press release, Nuvalent, APR 29, 2025, https://investors.nuvalent.com/2025-04-29-Nuvalent-Announces-Publication-in-Molecular-Cancer-Therapeutics-Reinforcing-Rational-Molecular-Design-of-Zidesamtinib-as-a-Novel-ROS1-Selective-Inhibitor [SID1234652317]). Zidesamtinib is currently being evaluated in the ongoing ARROS-1 Phase 1/2 trial for patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors, which is designed with registrational intent for tyrosine kinase inhibitor (TKI) pre-treated and TKI-naïve patients with advanced ROS1-positive NSCLC.

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The publication, entitled "Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations," is published online and can be accessed here: View Source

"Zidesamtinib was specifically designed with the goal of addressing the combined medical needs of treating tumors that have developed resistance, treating brain metastases and avoiding off-target adverse events. Structural studies play a critical role in the development and optimization of novel therapeutics, particularly when aiming to solve for multiple, and at times competing, challenges. To date, structural studies for ROS1-positive cancers have been hindered by a lack of ROS1 G2032R crystal structures, despite G2032R being the most commonly occurring ROS1 resistance mutation," said first author Anupong Tangpeerachaikul, Ph.D., Director, Biology at Nuvalent. "With this publication in Molecular Cancer Therapeutics, we are pleased to have shared what is, to our knowledge, the first structure of ROS1 G2032R, or any ROS1 mutation, offering a framework for understanding ROS1 TKI activity against these important drivers of disease progression. This structure further illustrates the intentional design of zidesamtinib and adds to the growing body of preclinical data supporting its ROS1-selective and TRK-sparing design."

The manuscript explores the activity of zidesamtinib and other approved or investigational ROS1 TKIs at clinically relevant concentrations against ROS1 resistance mutations, including the most commonly occurring resistance mutation, ROS1 G2032R, in preclinical mutagenesis screens and an intracranial ROS1 G2032R xenograft model. Findings presented in the manuscript show that, at clinically relevant concentrations, zidesamtinib suppressed on-target resistance in ENU mutagenesis screens simulating first-line and later-line treatment and inhibited ROS1 G2032R brain tumors more effectively than the other ROS1 TKIs evaluated. This favorable preclinical activity suggests the potential for zidesamtinib to delay tumor progression, both peripherally and intracranially.

In addition, the manuscript details the first crystal structure of ROS1 G2032R in complex with zidesamtinib, which further supports zidesamtinib’s molecular design and provides structural insights into how the ROS1 G2032R mutation affects TKI binding. Zidesamtinib was designed with the goal of being active against ROS1 and ROS1 resistance mutations while avoiding the inhibition of the structurally related tropomyosin receptor kinase (TRK) family in the central nervous system (CNS), which has been associated with neurological adverse events that can be dose limiting. The crystal structure elucidates zidesamtinib’s preclinical affinity for ROS1 G2032R and selectivity for ROS1 over TRK.

The company expects to report pivotal clinical data for TKI pre-treated patients with advanced ROS1-positive NSCLC from the ARROS-1 Phase 1/2 trial in the first half of 2025 in support of an anticipated New Drug Application submission by mid-year 2025, with an initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC.

About Zidesamtinib
Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.

On April 29, 2025 Innate Pharma SA (Euronext Paris: IPH; Nasdaq: IPHA) ("Innate" or the "Company") reported new preclinical data for IPH4502, its novel and differentiated topoisomerase I inhibitor Antibody Drug Conjugate (ADC) targeting Nectin-4 (Press release, Innate Pharma, APR 29, 2025, View Source [SID1234652337]). The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025.

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Nectin-4 targeting is validated by enfortumab vedotin (EV), an ADC with a monomethyl auristatin E (MMAE) payload, approved for urothelial carcinoma (UC), an indication with high Nectin-4 expression. However, EV discontinuation due to toxicity, disease relapse, or treatment ineligibility, along with its limited efficacy in tumors with lower Nectin-4 expression, underscores the need for a differentiated Nectin-4 ADC with improved therapeutic window and improved mechanisms of action.

IPH4502 demonstrated anti-tumor activity in EV-resistant patient-derived xenograft (PDX) model with upregulation of multi-drug resistance protein 1 (MDR1), supporting its potential to overcome resistance mechanisms in EV-refractory disease.

Beyond UC, IPH4502 also exhibited anti-tumor activity in preclinical models of triple-negative breast cancer, head and neck squamous cell carcinoma, and esophageal cancer, suggesting broader potential clinical applicability.

In addition, in preclinical tumor models with low Nectin-4 expression, IPH4502 showed superior anti-tumor activity compared to a clinical-stage Nectin-4-exatecan ADC supported by higher internalization, cytotoxicity, and bystander killing effect.

"We are highly encouraged by these preclinical data, which suggest that IPH4502 has the potential to translate into improved clinical benefit in indications with unmet medical need. These findings also reinforce the rationale for our ongoing Phase 1 trial. We look forward to sharing initial clinical data in 2026 as the program advances," said Sonia Quaratino, Chief Medical Officer of Innate Pharma.

IPH4502 is currently investigated in a Phase 1 trial in advanced solid tumors known to express Nectin-4 (NCT06781983).

The poster is available on Innate Pharma’s website.

About IPH4502

IPH4502 is a differentiated topoisomerase I inhibitor Antibody Drug Conjugate (ADC) conjugated to exatecan targeting Nectin-4, a cell adhesion molecule that is overexpressed in several types of solid tumors, such as urothelial carcinoma, breast cancer, non-small cell lung cancer or gastro-intestinal tract cancer.

IPH4502 is currently investigated in a Phase 1 trial in advanced solid tumors. The Phase 1 trial will assess the safety, tolerability, and preliminary efficacy of IPH4502 in different solid tumors known to express Nectin-4, including but not limited to urothelial carcinoma, non-small cell lung, breast, ovarian, gastric, esophageal, and colorectal cancers. The study plans to enroll approximately 105 patients.

In preclinical models, IPH4502 demonstrates strong bystander killing effect, and efficient internalization, enabling a potent anti-tumor activity in models with various Nectin-4 expression levels. Additionally, IPH4502 shows efficacy in models resistant to MMAE-ADC. These results support its potential for development beyond UC and in cancer patients treated with MMAE-based ADCs.

On April 29, 2025 AstraZeneca reported that it is discontinuing the CAPItello-280 Phase III trial evaluating the efficacy and safety of Truqap (capivasertib) in combination with docetaxel and androgen-deprivation therapy (ADT) compared to docetaxel and ADT with placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) (Press release, AstraZeneca, APR 29, 2025, View Source [SID1234652260]).

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This decision is based on the recommendation of the Independent Data Monitoring Committee (IDMC) following their review of data from a pre-specified interim analysis, which concluded that the Truqap combination was unlikely to meet the dual primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) versus the comparator arm upon trial completion. The safety profile for Truqap was consistent with previous trials.

The Company will work with investigators to ensure the necessary follow up with patients. Data from the trial will inform ongoing research.

Notes

Prostate cancer
Prostate cancer is the second most prevalent cancer in men and the fifth leading cause of male cancer death globally, with an incidence of more than 1.4 million and over 397,000 deaths in 2022.1

Metastatic prostate cancer is associated with a significant mortality rate, with only one third of patients surviving five years after diagnosis.2 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.3

Metastatic castration-resistant prostate cancer
Approximately 10-20% of men with advanced prostate cancer will develop castration-resistant prostate cancer within five years.4 In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.3 At least 84% of these men will have metastases at the time of CRPC diagnosis and, of those patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.4 Approximately half of patients with mCRPC may receive only one line of active treatment, and those that go on to receive further treatment often have diminishing benefit of subsequent therapies.5-6

Despite the advances in mCRPC treatment with taxane and new hormonal agent treatments, there is high unmet need in this population.4,7,8

CAPItello-280
CAPItello-280 is a Phase III, double-blind, randomised trial evaluating the efficacy and safety of Truqap in combination with docetaxel and ADT compared to docetaxel and ADT in combination with placebo in patients with mCRPC.

The global trial enrolled 1,033 adult patients with histologically confirmed prostate adenocarcinoma with evidence of mCRPC with progression of disease despite ADT. The dual primary endpoints of the CAPItello-280 trial are rPFS as assessed by investigator and OS in the overall trial population. Key secondary endpoints include OS and rPFS as assessed by investigator in patients with mCRPC and PTEN-deficient tumours, OS and rPFS as assessed by investigator in patients with mCRPC and PTEN-proficient tumours, time to pain progression (TTPP) in the overall trial population and time to first symptomatic skeletal-related event (SSRE) in the overall trial population.

Truqap
Truqap is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg 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.

Truqap in combination with Faslodex (fulvestrant) is approved in the US, EU, Japan, China and several other countries for the treatment of adult patients with HR-positive (or estrogen receptor-positive), HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen based on the results from the CAPItello-291 trial. Truqap is also approved in Australia for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine based regimen based on these trial results.

Truqap is being evaluated in ongoing Phase III trials for the treatment of breast and prostate cancers.

Truqap 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).

On April 29, 2025 Quanterix Corporation (NASDAQ: QTRX), a company fueling scientific discovery through ultra-sensitive biomarker detection, and Akoya Biosciences (NASDAQ: AKYA), The Spatial Biology Company, reported an amendment to the terms of their previously announced merger agreement (Press release, Akoya Biosciences, APR 29, 2025, View Source [SID1234652300]).

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Under the amended terms, Quanterix will issue approximately 7.76 million shares of its common stock and pay $20 million in cash to Akoya shareholders. Each Akoya share will receive $0.38 per share in cash and 0.1461 shares of Quanterix common stock.

With the amended exchange ratio, Quanterix will issue over 9 million fewer shares than under the original deal terms. Quanterix shareholders will own approximately 84% of the combined company and Akoya shareholders will own approximately 16%.

Masoud Toloue, PhD, Chief Executive Officer of Quanterix, said, "The strategic merits of the transaction remain strong even as the market has been focused on academic funding and tariff concerns. In light of recent volatility, we re-engaged with Akoya to revise the terms of the agreement. The combined company will provide a significant value creation opportunity for shareholders."

Brian McKelligon, Chief Executive Officer of Akoya, said, "We remain excited to combine with Quanterix and believe this partnership offers compelling value for Akoya shareholders. We look forward to closing the transaction and leveraging our collective scale to drive synergies across our organizations and customers, expediting our path to profitability."

Additional Details about the Transaction

The revised transaction terms and amended merger agreement have been approved by the Quanterix Board and the Akoya Board, respectively.

Shareholders of Akoya who hold more than 50% of Akoya’s common stock have agreed to vote in favor of the merger on the amended terms.

As a result of the amended merger agreement, Quanterix will no longer hold its previously announced special meeting of shareholders.

The transaction is expected to close during the second quarter of 2025, subject to the approval of Akoya shareholders and satisfaction of other customary closing conditions.

An updated investor presentation is being furnished by Quanterix to the Securities and Exchange Commission and also is available at View Source, highlighting the benefits of the combination.

Advisors

Goldman Sachs & Co. LLC is serving as financial advisor to Quanterix with Covington & Burling LLP and Sidley Austin LLP serving as legal counsel. Perella Weinberg Partners LP is serving as financial advisor to Akoya and DLA Piper LLP is serving as legal counsel.

On April 29, 2025 Pasithea Therapeutics Corp. (NASDAQ: KTTA) ("Pasithea" or the "Company"), a clinical-stage biotechnology company developing PAS-004, a next-generation macrocyclic MEK inhibitor, for the treatment of neurofibromatosis type 1 (NF1) and other MAPK pathway driven cancer indications, reported the Company has completed enrollment and initial dosing of three subjects in Cohort 6 with 30 mg capsules of PAS-004 (Press release, Pasithea Therapeutics, APR 29, 2025, View Source [SID1234652321]).

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"We are pleased to have recruited, enrolled and commenced dosing of the initial three subjects in Cohort 6 more rapidly than anticipated and we currently expect to complete enrollment of all patients in the trial by the end of 2025," said Dr. Tiago Reis Marques, Chief Executive Officer of Pasithea.

The ongoing Phase 1 clinical trial is a multi-center, open-label, dose escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of PAS-004 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 or RAF mutation or patients who have failed BRAF/MEK inhibition (NCT06299839).