On September 17, 2024 Merus N.V. (Nasdaq: MRUS) (Merus, the Company, we, or our), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported the acceptance of an abstract on petosemtamab, a Biclonics targeting EGFR and LGR5, in previously treated (2L+) patients with recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC) for presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Congress 2024 taking place in Singapore December 6-8, 2024 (Press release, Merus, SEP 17, 2024, View Source [SID1234646706]).

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Rapid oral presentation:
Title: Petosemtamab (MCLA-158) monotherapy in previously treated (2L+) recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 trial
Abstract #: 411MO
Session Title: Mini Oral session: Head and Neck cancers
Session Date and Time: December 7, 2024; 3:25-3:30 p.m. SGT
Location Hall: 404

The abstract will be available on the ESMO (Free ESMO Whitepaper) Asia Congress website on Sunday, Dec. 1, 2024 at 11:05 a.m. ET. The full presentation will be available on the Merus website at the start of each session.

Merus provided an interim clinical update on petosemtamab monotherapy in 2L+ HNSCC at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, demonstrating a 37% response rate among 43 evaluable patients. The presentation at ESMO (Free ESMO Whitepaper) Asia will include updated efficacy, durability and safety data from that initial 2L+ HNSCC cohort along with interim data from the dose optimization cohort evaluating petosemtamab monotherapy 1500 or 1100 mg dose levels in 2L+ HNSCC.

Merus has confirmed through feedback with the U.S. Food and Drug Administration (FDA) that petosemtamab 1500 mg every two weeks is appropriate for further development in HNSCC as monotherapy, and in combination with pembrolizumab.

Merus is currently enrolling LiGeR-HN2, a phase 3 trial evaluating the efficacy and safety of petosemtamab compared to investigator’s choice of single agent chemotherapy or cetuximab in previously treated (2/3L) patients with r/m HNSCC and plans to initiate LiGeR-HN1, a phase 3 trial evaluating petosemtamab in combination with pembrolizumab in frontline (1L) HNSCC by year end 2024.

About Petosemtamab
Petosemtamab, or MCLA-158, is a bispecific Biclonics low-fucose human full-length IgG1 antibody targeting the epidermal growth factor receptor (EGFR) and the leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5). Petosemtamab is designed to exhibit three independent mechanisms of action including inhibition of EGFR-dependent signaling, LGR5 binding leading to EGFR internalization and degradation in cancer cells, and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity.

About LiGeR-HN2
LiGeR-HN2, a phase 3 trial, will evaluate the safety and efficacy of petosemtamab compared to investigator’s choice of methotrexate, docetaxel, or cetuximab in 2/3L r/m HNSCC patients. The trial is open to adult patients that have progressed on or after anti-PD-1 therapy and platinum-containing therapy. The primary endpoints are overall response rate as assessed by BICR based on RECIST v1.1 and overall survival. Secondary endpoints are duration of response and progression free survival. Merus plans to enroll approximately 500 patients in the trial.

On September 17, 2024 Merck reported that the HERTHENA-Lung02 phase 3 trial evaluating patritumab deruxtecan in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who received prior EGFR tyrosine kinase inhibitor (TKI) treatment met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement versus platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy (Press release, Merck & Co, SEP 17, 2024, View Source [SID1234646705]). Overall survival (OS) data were immature at the time of the analysis and the trial will continue to further assess OS, a secondary endpoint.

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Patritumab deruxtecan is a specifically engineered potential first-in-class HER3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and Merck (NYSE: MRK), known as MSD outside of the United States and Canada.

NSCLC accounts for approximately 85% of all lung cancers worldwide with up to 70% of NSCLC cases diagnosed at an advanced stage and EGFR-activating mutations occur in 14% to 38% of all NSCLC tumors worldwide.1,2,3 Following initial treatment for metastatic EGFR-mutated NSCLC with an EGFR TKI, many patients experience disease progression and currently available therapies in the second-line setting are limited, highlighting the need for new approaches to improve outcomes.3,4

Data from the HERTHENA-Lung02 trial will be presented at an upcoming medical meeting and shared with global regulatory authorities.

"These results from HERTHENA-Lung02 demonstrate the potential of patritumab deruxtecan to become an important treatment option for certain patients with EGFR-mutated non-small cell lung cancer with prior tyrosine kinase inhibitor treatment," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "We plan to share these findings with regulatory authorities to discuss next steps."

"We are encouraged by these results demonstrating a statistically significant progression-free survival improvement compared to platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer who received prior tyrosine kinase inhibitor treatment," said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck. "Together with Daiichi Sankyo, we are committed to helping patients with previously treated EGFR-mutated non-small cell lung cancer, where there is a high unmet need."

The safety profile seen in HERTHENA-Lung02 was consistent with that observed for patritumab deruxtecan in previous lung cancer clinical trials with no new safety signals identified. The majority of interstitial lung disease (ILD) events were low grade (grade 1 and 2). There were two grade 5 ILD events observed.

About HERTHENA-Lung02

HERTHENA-Lung02 is a global, multicenter, open-label, phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan (5.6 mg/kg every three weeks) versus four cycles of pemetrexed and platinum chemotherapy in patients with metastatic or locally advanced NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) after failure of third-generation (e.g., osimertinib, lazertinib, aumolertinib, alflutinib) EGFR TKI therapy. Patients in the comparator arm without disease progression after four cycles of pemetrexed and platinum chemotherapy are able to continue treatment with maintenance pemetrexed with no restriction on the number of cycles.

The primary endpoint of HERTHENA-Lung02 was PFS as assessed by blinded independent central review (BICR). Secondary endpoints included OS, objective response rate, duration of response, clinical benefit rate, time to response, disease control rate, and safety. Patients enrolled in the study underwent brain imaging to allow for assessment of intracranial endpoints, including intracranial PFS as assessed by BICR.

HERTHENA-Lung02 enrolled 586 patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov.

About EGFR-Mutated Non-Small Cell Lung Cancer

Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.5 Lung cancer is the most common cancer and the leading cause of cancer-related deaths worldwide.5 Approximately 85% of lung cancer is classified as NSCLC with EGFR-activating mutations occurring in 14 to 38% of all NSCLC tumors worldwide.1,3 NSCLC is diagnosed at an advanced stage in up to 70% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy.2,6

Following initial treatment for metastatic EGFR-mutated NSCLC with an EGFR TKI, many patients experience disease progression and currently available therapies in the second-line setting are limited, highlighting the need for new approaches to improve outcomes.3,4

About HER3

HER3 is a member of the HER family of receptor tyrosine kinases.7 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment.8 HER3 is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival.9,10 There is currently no HER3 directed therapy approved for the treatment of any cancer.

About Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other therapies in a global development program, which includes HERTHENA-Lung02, a phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan versus pemetrexed plus platinum chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression on or after treatment with a third-generation EGFR TKI; HERTHENA-Lung01, a phase 2 trial in metastatic or locally advanced NSCLC with an activating EGFR mutation previously treated with at least one EGFR TKI and one platinum-based chemotherapy-containing regimen; HERTHENA-PanTumor01, a phase 2 trial in 10 locally advanced or metastatic solid tumor types, including melanoma, gastric and head and neck cancer, among other types of cancer, previously treated with at least one prior systemic therapy; a phase 1 trial in combination with osimertinib in EGFR-mutated locally advanced or metastatic NSCLC; and a phase 1 trial in previously treated patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing metastatic breast cancer also has been completed.

On September 17, 2024 Takeda reported detailed final overall survival (OS) results from CONTACT-02, a phase 3 pivotal study led by Exelixis, evaluating cabozantinib (CABOMETYX) in combination with atezolizumab, an immune checkpoint inhibitor, compared with a second novel hormonal therapy (NHT) in patients with metastatic castration-resistant prostate cancer (mCRPC) and measurable extra-pelvic soft tissue disease who have progressed on one prior NHT (Press release, Takeda, SEP 17, 2024, View Source [SID1234646704]). These data were presented by Neeraj Agarwal, M.D. of the Huntsman Cancer Institute at the University of Utah, USA on September 15 at the 2024 European Society for Medical Oncology Congress (ESMO 2024) during the Proffered Paper Session: GU Tumors, Prostate.

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The dual primary endpoints for CONTACT-02 were progression-free survival (PFS) and OS. At a median follow-up of 24.0 months, the final analysis of OS showed a numerical but not statistically significant improvement favoring cabozantinib in combination with atezolizumab (hazard ratio: 0.89; 95% confidence interval: 0.72-1.10; P=0.296). An improvement in OS was observed in multiple clinical subgroups, notably in patients with bone or liver metastases, with the latter category representing a population whose disease may be evolving away from androgen receptor signaling.

As previously announced, CONTACT-02 met the other dual primary endpoint, demonstrating a statistically significant benefit in PFS in the predefined PFS ITT population (i.e., the first 400 randomized patients). Detailed results were presented by Neeraj Agarwal, M.D. at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2024 Genitourinary Cancers Symposium in January 2024.

The CONTACT-02 Trial
CONTACT-02 is a phase III, randomized, open-label, controlled trial of cabozantinib plus atezolizumab versus a second new hormone therapy in patients with metastatic castration-resistant prostate cancer. Exelixis is leading the CONTACT-02 trial, which is co-funded by Roche. Both Ipsen, Exelixis’ partner and Takeda have committed to participation in the trial and are funding it under the terms of their respective collaboration agreements with Exelixis.

Cabometyx(Cabozantinib)
Cabometyx is a drug created and developed by Exelixis. It has been approved in the United States for the treatment of advanced renal cell carcinoma and for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib. It has also been approved in the European Union and in other countries and regions. In Japan, Cabometyx was approved by the Ministry of Health, Labour and Welfare in March 2020 for the treatment of unresectable or metastatic renal cell carcinoma, and was launched in May of the same year under the brand names of Cabometyx Tablets 20 mg and 60 mg. In November 2020, Takeda received approval for a partial change to the manufacturing and marketing approval for Cabometyx, specifically for the treatment of unresectable hepatocellular carcinoma that has worsened after chemotherapy. In August 2021, the company received a further approval for a partial change to the manufacturing and marketing approval for Cabometyx as a combination therapy with nivolumab for the treatment of unresectable or metastatic renal cell carcinoma.

On September 17, 2024 Rakovina Therapeutics Inc. (TSX-V: RKV), a biopharmaceutical company committed to advancing new cancer therapies based on novel DNA-damage response technologies, and Variational AI, developer of the Enki generative artificial intelligence (AI) platform for drug discovery, reported a research collaboration aimed at leveraging each company’s expertise to identify and develop novel small-molecule therapies against DNA-damage response (DDR) targets for the treatment of cancer (Press release, Rakovina Therapeutics, SEP 17, 2024, View Source;utm_medium=rss&utm_campaign=rakovina-therapeutics-and-variational-ai-announce-drug-discovery-collaboration [SID1234646703]).

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Under the terms of the agreement, Rakovina Therapeutics has been granted an exclusive right to compounds generated by the Enki platform against the selected target product profiles and an option to license validated drug candidates for further development. Variational AI will employ the Enki platform to identify novel inhibitors of specific DDR kinase targets selected by Rakovina Therapeutics. Rakovina Therapeutics will synthesize and evaluate the viability of these drug candidates as potential cancer therapies in its laboratories at the University of British Columbia.

According to Rakovina Therapeutics Executive Chairman Jeffrey Bacha, "This collaboration is an ideal addition to our already established Deep Docking AI partnership as it expands Rakovina Therapeutics’ pipeline beyond our current focus of developing next-generation PARP inhibitors."

"Leveraging Variational AI’s expertise in kinases where it overlaps with our DDR interest will significantly increase partnering opportunities as ‘big pharma’ maintains a close interest in novel therapies against these targets," added Bacha.

Rakovina Therapeutics will pay a low upfront fee to initiate work against each selected target and a "TPP Fee" upon exercise of its option to acquire rights to drug candidates meeting a pre-specified target-product profile (TPP) and additional payments upon achievement of specified development milestones. Additional financial terms were not disclosed.

According to Variational AI CEO Handol Kim, "We are thrilled to be partnering with Rakovina Therapeutics in their quest for lifesaving cancer drugs. Variational AI is at the forefront of Artificial Intelligence drug discovery, and we look towards a successful and lasting partnership. Our unique Enki platform is the first commercially accessible foundation model for small molecules and represents an ideal drug discovery solution for Rakovina Therapeutics for these initial targets and beyond."

Bacha said, "Variational AI will deliver a short list of potential drug candidates within four to six weeks of target selection. We anticipate determining the validity of these novel drug candidates against our target-product profile within 12 to 18 months upon receipt of each Variational AI deliverable."

"We are excited about the potential of this collaboration. The Enki AI platform, already used by leading pharmaceutical companies, brings a powerful addition to our AI-driven drug discovery toolkit as we expand our research focus to additional DDR targets," Bacha added.

On September 17, 2024 Novartis reported that the US Food and Drug Administration (FDA) has approved Kisqali (ribociclib) in combination with an aromatase inhibitor (AI) for the adjuvant treatment of people with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) stage II and III early breast cancer (EBC) at high risk of recurrence, including those with node-negative (N0) disease (Press release, Novartis, SEP 17, 2024, View Source [SID1234646702]).

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The approval is based on results from the pivotal Phase III NATALEE trial, which showed a significant and clinically meaningful 25.1% (HR=0.749; 95% CI: 0.628, 0.892; P=0.0006) reduction in risk of disease recurrence in a broad population of patients with HR+/HER2- stage II and III EBC treated with adjuvant Kisqali plus endocrine therapy (ET) compared to ET alone, including those with high-risk N0 disease3-6. The invasive disease-free survival (iDFS) benefit was consistently observed across all patient subgroups3-6.

"The FDA approval of Kisqali for this early breast cancer population, including those with N0 disease, is a pivotal moment in improving our approach to care," said Dennis J. Slamon, M.D., Director of Clinical/Translational Research, UCLA Jonsson Comprehensive Cancer Center and Chairman of the Board of Translational Research In Oncology (TRIO) and NATALEE trial lead investigator. "Today’s approval allows us to offer treatment with a CDK4/6 inhibitor to a significantly broader group of people as a powerful tool that, combined with endocrine therapy, can help further minimize their risk of cancer returning."

In EBC, Kisqali is taken with or without food as a once-daily oral dose of 400 mg (two 200 mg tablets) for three weeks, followed by one week off treatment, in combination with four weeks of any AI1. Patients should take Kisqali for three years. The NATALEE trial showed the safety profile of Kisqali at the 400 mg dose was well tolerated, with discontinuations mainly driven by asymptomatic laboratory findings3. Adverse events (AEs) of special interest in the Kisqali + ET arm of the NATALEE trial include (all Grades, and Grades 3/4, respectively): neutropenia (62.5%, 44.3%), liver-related AEs (26.4%, 8.6%), QT interval prolongation (5.3%, 1.0%), and interstitial lung disease/pneumonitis (1.5%, 0.0%)4.

An updated analysis from the NATALEE trial recently presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 reinforces the data analyzed by the FDA. Results showed a deepening benefit beyond the three-year treatment period and reduced the risk of recurrence by 28.5% (HR=0.715; CI 95% 0.609–0.840; P<0.0001), compared to ET alone, in patients with stage II and III HR+/HER2- EBC7. Novartis will continue evaluating NATALEE patients for longer-term outcomes, including overall survival.

Raising the bar for EBC survivors
Approximately 90% of breast cancer cases in the US are diagnosed early (stages I-III) and treated promptly with curative intent – sometimes with adjuvant ET21,22. In spite of this, people with stage II and III HR+/HER2- EBC remain at risk of cancer coming back – in most cases, as incurable metastatic disease8,9. Recurrence remains a lifelong concern, though most tumors return within the first years, even in cases with no lymph node involvement8,23. Despite ET, 10% of people with high-risk N0 disease may face recurrence within the first three years after diagnosis24.

"With this approval, we are redefining treatment options for a broader population of people impacted by breast cancer and facing the persistent risk of recurrence," said Victor Bultó, President, US, Novartis. "We continue to transform cancer care with Kisqali, building on its established profile in the metastatic setting and now helping a wide range of people as they strive to stay cancer-free following an early-stage diagnosis."

"Breast cancer treatment can take a toll on your physical and mental health, and you may worry about the risk of your cancer coming back. This risk is different for everyone, depending on many factors, but should not be underestimated," said Valarie Worthy, Co-Founder & Vice President of Community Outreach and Engagement, Touch, The Black Breast Cancer Alliance. "The FDA approval of Kisqali for more people with breast cancer is welcome news and empowers people diagnosed with early breast cancer with a new option to help manage and control their risk of cancer coming back."

Novartis prioritizes patient access by offering the Novartis Patient Support program. This resource assists eligible patients in navigating treatment initiation, providing educational materials, clarifying insurance coverage, and identifying potential financial assistance options. For additional information, patients and healthcare professionals can call 1-800-282-7630.

About NATALEE
NATALEE is a global Phase III multi-center, randomized, open-label trial to evaluate the efficacy and safety of Kisqali (ribociclib) with ET as an investigational adjuvant treatment versus ET alone in patients with stage II and III HR+/HER2- EBC, being conducted in collaboration with TRIO25. The adjuvant ET in both treatment arms was a non-steroidal AI (NSAI; anastrozole or letrozole) and goserelin if applicable25. The primary endpoint of NATALEE is iDFS as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria25. A total of 5,101 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial25.

About Kisqali (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Beyond today’s FDA approval of Kisqali for EBC patients in the US, regulatory reviews for Kisqali as an EBC treatment are ongoing worldwide, including in the EU and China.

Kisqali has been approved as a treatment for metastatic breast cancer (MBC) patients in 99 countries worldwide, including by the US FDA and the European Commission1,26. In the US, Kisqali is indicated for the treatment of adults with HR+/HER2- advanced or MBC in combination with an AI as initial ET or fulvestrant as initial ET or following disease progression on ET in post-menopausal women or in men1. In the EU, Kisqali is approved for the treatment of women with HR+/HER2- advanced or MBC in combination with either an AI or fulvestrant as initial ET or following disease progression. In pre- or peri-menopausal women, the ET should be combined with a luteinizing hormone-releasing hormone agonist26.

In MBC, Kisqali has consistently demonstrated statistically significant overall survival benefit across three Phase III trials10-20. The NCCN Guidelines for breast cancer recommend ribociclib (Kisqali) as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of people living with HR+/HER2- when combined with an AI, making Kisqali the preferred first-line treatment of choice for US prescribers in HR+/HER2- MBC27. Additionally, Kisqali has the highest rating of any CDK4/6 inhibitor on the ESMO (Free ESMO Whitepaper) Magnitude of Clinical Benefit Scale, achieving a score of five out of five for first-line pre-menopausal patients with HR+/HER2- advanced breast cancer28. Further, Kisqali in combination with either letrozole or fulvestrant has uniquely, among other CDK4/6 inhibitors, received a score of four out of five for post-menopausal patients with HR+/HER2- advanced breast cancer treated in the first line29.

Kisqali was developed by Novartis under a research collaboration with Astex Pharmaceuticals.

Please see full Prescribing Information for Kisqali, available at www.Kisqali.com