On September 17, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, cardiovascular and metabolic, ophthalmology and other major diseases, reported that clinical data of IBI363 (first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein) combined with bevacizumab in advanced colorectal cancer is presented at the 2024 ESMO (Free ESMO Whitepaper) Congress (Press release, Innovent Biologics, SEP 17, 2024, View Source [SID1234646711]). Currently, Innovent is conducting Phase 1/2 clinical trials in China, the United States, and Australia to evaluate the safety, tolerability and efficacy of IBI363 in subjects with advanced solid tumors.

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First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein IBI363 combined with bevacizumab in patients with advanced colorectal cancer: Results from Phase 1 study

This Phase 1 study was conducted to evaluate the safety, tolerability and preliminary efficacy of IBI363 combined with bevacizumab in subjects with advanced colorectal cancer.

A total of 35 subjects received treatment of IBI363 combined with bevacizumab, demonstrating promising anti-tumor efficacy with good tolerability and safety

As of the data cutoff date (Aug 30, 2024), a total of 35 subjects with advanced colorectal cancer received combination treatment at 3 different dose levels (0.6 mg/kg IBI363 combined with 5 mg/kg bevacizumab Q2W, 1 mg/kg IBI363 combined with 5 mg/kg bevacizumab Q2W, and 1.5 mg/kg IBI363 combined with 7.5 mg/kg bevacizumab Q3W). Among them, 91.4% of the subjects had advanced colorectal cancer with microsatellite stable (MSS) or proficient mismatch repair (pMMR), and the MSI/MMR status was unknown in 8.6% subjects. 91.4% of the subjects had previously received 2 or more lines of systemic anti-tumor treatment. 51.4% of the subjects had liver metastases. 25.7% of the subjects had received prior immunotherapy. 40% of the subjects had KRAS/NRAS exon 2/3/4 mutations.
The most common treatment related adverse events (TRAEs) were arthralgia, thyroid disorders, and rash. The total incidence of TRAEs ≥ grade 3 was 22.9%. Immune related adverse events (irAEs) ≥ grade 3 occurred in 5.7% of subjects. The safety profile of the combination regimen was similar to that of IBI363 monotherapy, and no new safety signals were identified.
Promising anti-tumor activity in subjects with MSS/pMMR colorectal cancer; durable responses with a trend towards long-term benefit

As of the cutoff date, 32 subjects were efficacy evaluable having underwent at least one post-baseline tumor assessment. The ORR was 21.9% (confirmed ORR was 15.6%), and DCR was 65.6%. The median DoR was 8.1 months (95% CI: 1.5~8.2). The median PFS follow-up time was 7.6 months (95% CI: 4.0~9.4), and the median PFS was 4.1 months (95% CI: 1.7~8.1). The median OS was not reached.
Promising efficacy signals in colorectal cancer with and without baseline liver metastases

Among the 17 subjects with baseline liver metastases who underwent at least one post-baseline tumor assessment, ORR was 11.8% and DCR was 58.8%.
Among the 15 subjects without baseline liver metastases who underwent at least one post-baseline tumor assessment, ORR was 33.3% and DCR was 73.3%.
Promising efficacy signals in both IO-treated and IO-naïve colorectal cancer

Among the 8 subjects who had received prior immunotherapy and underwent at least one post-baseline tumor assessment, ORR was 25.0% and DCR was 62.5%.
Among the 24 IO-naïve subjects who underwent at least one post-baseline tumor assessment, ORR was 20.8% and DCR was 66.7%.
Promising efficacy signals in colorectal cancer with and without KRAS/NRAS exon 2/3/4 mutations

Among the 14 subjects with RAS exon 2/3/4 mutations and who had undergone at least one post-baseline tumor assessment, ORR was 21.4% and DCR was 57.1%.
Among the 10 subjects without RAS exon 2/3/4 mutations who had undergone at least one post-baseline tumor assessment, ORR was 30.0% and DCR was 90.0%.
In addition, data from a Phase 1 clinical study of IBI363 monotherapy in a colorectal cancer cohort, presented at ASCO (Free ASCO Whitepaper) 2024, showed promising efficacy and good tolerability. Ongoing studies are now exploring IBI363 in other malignancies, including NSCLC, melanoma and other solid tumors, as well as in combination regimens for MSS/pMMR advanced colorectal cancer. Updates on relevant data and analysis will be shared at upcoming academic conferences and in journals.

Professor Tao Zhang, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, stated: "Colorectal cancer is the third most common cancer type globally and ranks fourth in cancer-related mortality[1]. Despite recent advancements in colorectal cancer treatment, challenges such as chemotherapy toxicity and resistance continue to affect patients and clinicians. While immunotherapy offers new hope for advanced colorectal cancer patients, it is currently only approved for those with MSI-H/dMMR tumors. Research indicates that immunotherapy has limited efficacy in non-MSI-H/dMMR advanced colorectal cancer[2]. As an important cytokine activating tumor-specific CD8+T cells, IL-2 is complementary to immune checkpoint inhibitors in MOA. The combination of PD-1 and IL-2 may reverse the exhaustion of tumor-specific CD8+ T cells thereby overcoming immune resistance. The PD-1/IL-2α-bias bispecific molecule IBI363, when combined with bevacizumab, has shown promising anti-tumor activity in patients with non-MSI-H/dMMR advanced colorectal cancer. This combination has shown clinical benefits in both ORR and PFS, and maintains a manageable safety profile. Additionally, the combination regimen has proven effective in colorectal cancer patients with or without liver metastasis, prior immunotherapy, and RAS exon 2/3/4 mutations. IBI363 combined with bevacizumab elicited encouraging objective response rates and disease control rates, with durable responses and a trend towards long-term benefits, without introducing new safety risks in a colorectal cancer population that has previously shown very little response to immunotherapy. Overall, current clinical data suggest that IBI363 combined with bevacizumab holds significant promise for colorectal cancer and deserves further exploration."

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "On top of the preliminary data reported at ASCO (Free ASCO Whitepaper), we are presenting more updated data at the ESMO (Free ESMO Whitepaper) Congress. In non-MSI-H/dMMR advanced colorectal cancer, the combination of IBI363 with bevacizumab has demonstrated strong anti-tumor effects, with durable responses and a trend towards long-term benefits. These promising results in a relatively ‘cold’ tumor suggest significant potential for IBI363 in this disease area. We are confident in the broad development prospects of IBI363 and look forward to seeing more mature data from higher doses and extended follow-up, which will help us advance to the next stage of clinical development."

About IBI363 (First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein)

IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein independently developed by Innovent Biologics. It functions by both blocking the PD-1/PD-L1 pathway and activating the IL-2 pathway. The IL-2 arm of IBI363 is designed to maintain its affinity for IL-2Rα while reducing binding to IL-2Rβ and IL-2Rγ, thereby minimizing toxicity. The PD-1 binding arm not only blocks PD-1 but also selectively delivers IL-2. This approach targets and activates tumor-specific T cells that express both PD-1 and IL-2α, leading to more precise and effective activation of this T cell subpopulation. IBI363 has demonstrated robust antitumor activity in various tumor-bearing pharmacological models, but also showed outstanding efficacy in PD-1 resistance and metastasis models. In response to urgent clinical needs, Innovent is conducting clinical studies in China, the United States and Australia to further explore the efficacy and safety of IBI363 in advanced tumors.

On September 17, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncologic, autoimmune, cardiovascular and metabolic, ophthalmologic and other major diseases, reported that clinical data of IBI354 (HER2 monoclonal antibody-camptothecin derivative conjugate) in advanced solid tumors was presented at the 2024 ESMO (Free ESMO Whitepaper) Congress (ClinicalTrials.gov, NCT05636215) (Press release, Innovent Biologics, SEP 17, 2024, View Source [SID1234646710]).

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The data presented is from a Phase 1/2 study aimed at evaluating the safety, tolerability, and preliminary efficacy of IBI354 in participants with advanced solid tumors. A total of 368 participants with advanced solid tumors were enrolled and received different doses of IBI354 monotherapy, including 178 with breast cancer, 92 with ovarian cancer, 38 with colorectal cancer, and 60 with other tumors. Among them, 42.7% of the participants had previously undergone five or more systemic treatment regimens.

IBI354 monotherapy demonstrated excellent safety profile.

The dosage was escalated to 18mg, with no DLT events observed.
The most common treatment-related adverse events (TRAEs) were nausea, decreased white blood cell count and anemia. The incidence of interstitial lung disease (ILD) was only 1.6%, all of which were grade 1.
Overall, 21.5% of patients experienced TRAEs ≥ grade 3, 2.4% experienced TRAEs leading to dose reduction and 1.6% experienced TRAEs leading to discontinuation, with no TRAEs leading to death.
IBI354 monotherapy showed promising efficacy signals in multiple tumor types.

In platinum-resistant ovarian cancer cohort (n=87, treated at 6~12mg/kg IBI354), the overall objective response rate (ORR) was 40.2% and the disease control rate (DCR) was 81.6%. In the 12mg/kg subgroup (n=40), the ORR reached 52.5% and the DCR was 90.0%. In participants with HER2 1+ (n=27), the ORR reached 55.6% and the DCR was 88.9%. As of the data cutoff date, the median follow-up time was 6.5 months, and both progression-free survival (PFS) and duration of response (DoR) had not yet matured.
In HER2-positive breast cancer cohort (n= 59, treated at 6~15mg/kg IBI354), the ORR and DCR were 67.8% and 88.1%, respectively.
In HER2-low breast cancer cohort (n=67, treated at 6~15mg/kg IBI354), the ORR and DCR were 41.8% and 82.1%, respectively. In the 12mg/kg subgroup (n=26), the ORR and DCR were 61.5% and 88.5%, respectively.
In HER2-positive gastrointestinal malignancies cohort (n=35, treated at 6~15mg/kg IBI354), the ORR and the DCR were 57.1% and 91.4%, respectively. 26 participants were diagnosed with colorectal cancer, of which 14 achieved an objective response (1 subject with HER2 IHC2+ FISH+ achieved a confirmed objective response), resulting in an ORR and DCR of 53.8% and 92.3%, respectively. As of press date, another participant with HER2 low expression (IHC2+ FISH-) colorectal cancer achieved a confirmed objective response.
Professor Qi Zhou, Chief Physician at the Gynecologic Oncology Center of Chongqing University Affiliated Cancer Hospital and the Principal Investigator of the gynecologic oncology cohort study, stated, "Approximately 70% of ovarian cancer patients experience relapse within 3 years following surgery and platinum-based adjuvant therapy, eventually developing platinum resistance after multiple recurrences[1]. These patients have limited effective treatment options. Current evidence indicates that non-platinum single-agent chemotherapy or the addition of anti-angiogenic therapy results in an ORR of just 4-13.2% and a median OS of merely 10.9-14 months[2]-[3][4][5][6]. As a fully-validated target, HER2-targeted therapy has proven effective in breast and gastric cancers. IBI354, an anti-HER2 monoclonal antibody-camptothecin derivative conjugate, has shown good anti-tumor activity in platinum-resistant ovarian cancer with HER2 expression of 1+. In our Phase 1 study, the ORR was 67.5%, DCR was 88.9%, and median rate is 39.0% at the 12mg/kg Q3W dose level, while maintaining a favorable safety profile. Extending the PFS and OS remains a critical clinical challenge in platinum-resistant recurrent ovarian cancer. The development of antibody-drug conjugates for the treatment of resistant recurrent cancers has become a hot spot, and promising results have been observed. The clinical efficacy of antibody-drug conjugates targeting HER2 low expression warrants further clinical research and exploration, which could benefit more patients with platinum-resistant ovarian cancer."

Doctor Daphne Day from the Medical Oncology Department at Monash Health in Melbourne, Australia, stated: "Breast cancer is the second most commonly diagnosed cancer globally, the most common cancer in women, and a cause of cancer-related deaths. HER2 amplification or overexpression has been proven to play a significant role in the occurrence and progression of breast cancer, underscoring the importance of HER2-directed therapy. IBI354, as an anti-HER2 monoclonal antibody-camptothecin derivative conjugate, has shown promising preliminary results, with meaningful objective response and disease control rates in HER2-positive and -low breast cancer. Additionally, IBI354 has demonstrated excellent clinical safety and tolerability. Existing clinical data suggest that IBI354 has substantial development potential in the breast cancer population."

Professor Lin Shen from Peking University Cancer Hospital, stated, "Colorectal cancer (CRC) has become the second most common malignant tumor in China, and its incidence and mortality rates are still rising annually[7]. The HER2-targeted therapy plays an important role in the later-line treatment of CRC. Preliminary results suggest that IBI354, an anti-HER2 monoclonal antibody-camptothecin derivative conjugate, has shown positive efficacy in HER2-positive gastrointestinal malignancies. Notably, IBI354 has also demonstrated antitumor effects in HER2-low CRC populations, where HER2-targeted therapies are relatively less effective. IBI354 has exhibited good clinical safety and tolerability in later-line CRC patients, supporting further exploration and development in this population."

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "With the rapid advancements in ADC drugs for oncology treatment, Innovent is strategically positioning itself in the ADC field. At this year’s ESMO (Free ESMO Whitepaper) conference, we are showcasing, for the first time, the safety and efficacy data of IBI354 across various advanced solid tumors, fully demonstrating Innovent’s platform capabilities in ADC drug development. We will continue to invest in research and development of ADC innovative molecules, with the aim of providing patients more and better treatment options."

About IBI354 (Anti-HER2 Antibody-Camptothecin Derivative Conjugate)

IBI354 is an innovative HER2-targeted antibody–drug conjugate developed using Innovent’s proprietary novel topoisomerase inhibitor NT3 platform. With a drug-to-antibody ratio (DAR) of 8, IBI354 delivers a high payload of effective drugs to tumors. The highly hydrophilic linker design contributes to its excellent biophysical and pharmacokinetic (PK) properties, while the hydrophobic payload enhances its bystander effect, targeting adjacent antigen-low or negative tumor cells. IBI354 exhibits extremely low exposure of free toxin in circulation and has an ideal safety profile based on pre-clinical and clinical studies. IBI354 has demonstrated remarkable anti-tumor activity in various tumor-bearing mice models, particularly in those resistant to HER2-targeted therapies and in metastatic tumors. Innovent Biologics is conducting clinical research in China, the United States, and Australia to assess the efficacy and safety of IBI354 for treating various advanced malignancies. Additionally, multiple new ADC molecules from Innovent’s NT3 platform are under clinical development and have shown promising safety and efficacy signals.

On September 17, 2024 Senhwa Biosciences, Inc. (TPEx: 6492), , a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, reported that an Investigational New Drug (IND) application for Pidnarulex has been submitted to the U.S. FDA by the NCI. Senhwa’ investigational drug, Pidnarulex (CX-5461), has been selected as an experimental drug in the NExT (NCI Experimental Therapeutics) cancer program, sponsored by the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), for a five-year period (Press release, Senhwa Biosciences, SEP 17, 2024, View Source [SID1234646709]). This drug will be used in a pharmacodynamic (PD) pilot study involving patients with advanced solid tumors.

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In addition to this monotherapy trial, NCI is considering to plan future clinical trials for Pidnarulex (CX-5461) in combination with other therapies, including immunotherapy, antibody-drug conjugates (ADC), and PARP inhibitors (Poly ADP-ribose Polymerase inhibitors, PARPi). Should these trials be realized, they will be led by the NCI, leveraging its medical team, scientific talent network, and regulatory resources—capabilities that most biotech companies would struggle to accomplish independently. This support from the NCI is hoped to significantly accelerate the development and expansion of indications for Pidnarulex (CX-5461), ultimately benefiting patients with an earlier market launch.

This clinical trial, for which the IND application has been submitted by NCI’s Division of Cancer Treatment and Diagnosis (DCTD), aims to explore the response of various biomarkers to Pidnarulex (CX-5461) in patients with or without homologous recombination deficiency (HRD).

Pidnarulex (CX-5461), developed by Senhwa, is a first-in-class small-molecule designed to stabilize G-quadruplex (G4) structures, which are frequently observed in promoters of oncogenes. By stalling replication fork progression, Pidnarulex induces DNA damage and promotes cancer cell death. Through this mechanism, Pidnarulex holds great potential as a therapeutic agent for various cancers.

In recent years, immunotherapy has become the fastest-growing category in the cancer drug market, while the development of antibody-drug conjugates (ADC) is undoubtedly an important trend in biopharmaceuticals. Major pharmaceutical companies, including Pfizer, AbbVie, AstraZeneca, and Merck, have invested billions of dollars in acquiring or licensing related technologies. According to a recent report from market research firm Evaluate, the ADC market is expected to reach $30 billion by 2028, while the global cancer immunotherapy market will surpass a staggering $224 billion by 2030. Given that only about 20% to 25% of patients are effectively treated with immunotherapy, combining immunotherapy with targeted drugs is becoming increasingly important in cancer treatment. Combination therapies can address multiple treatment pathways within the complex tumor microenvironment and may enhance the efficacy of immunotherapy, making it a hot research area for major pharmaceutical companies. Therefore, Senhwa is confident and optimistic about the NCI’s plans to advance clinical trials of Pidnarulex (CX-5461) in combination with immunotherapy and ADCs.

On September 17, 2024 Immutep reported new data from EFTISARC-NEO, a Phase II investigator-initiated trial of eftilagimod alpha (efti) in combination with radiotherapy plus KEYTRUDA (pembrolizumab) for patients with soft tissue sarcoma (STS), will be presented at the Connective Tissue Oncology Society (CTOS) 2024 Annual Meeting taking place 13-16 November 2024, in San Diego, California (Press release, Immutep, SEP 17, 2024, View Source [SID1234646707]).

Results from triple combination of efti, radiotherapy and KEYTRUDA (pembrolizumab) to be presented at the Connective Tissue Oncology Society 2024 Annual Meeting
EFTISARC-NEO is the first trial to evaluate efti in a neoadjuvant (prior to surgery) setting
Soft tissue sarcoma is a hard-to-treat orphan disease with poor prognosis & high unmet medical need

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Presentation Details
Title: Preliminary Results from a Phase 2 EFTISARC-NEO Trial of Neoadjuvant Soluble LAG-3 Protein Eftilagimod Alpha, Pembrolizumab, and Concurrent Radiotherapy in Patients with Resectable Soft Tissue Sarcoma
Presenter: Pawel Sobczuk, M.D., Ph.D., Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Date: Thursday, 14 November 2024
Format: Poster Presentation

EFTISARC-NEO is the first to evaluate efti in a neoadjuvant setting, which importantly provides access to tumour tissue before and after treatment to assess efti’s impact on the tumour microenvironment. Initial efficacy data from this novel triple combination reported in May 2024 showed very encouraging results in the first six patients with the majority having deep responses rarely seen in STS patients with standard therapeutic approaches.

STS is an orphan disease with high unmet medical need and a poor prognosis for patients. The incidence of STS varies in different regions across Europe, with ~23,400 cases annually according to the RARECARE project. In the United States, the number of new STS cases in 2024 is estimated to be ~13,590 with ~5,200 deaths, according to the American Cancer Society.

The open-label EFTISARC-NEO Phase II study will treat up to 40 patients and is being conducted by the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw. The trial is primarily funded with an approved grant from the Polish government awarded by the Polish Medical Research Agency program. For more information, visit clinicaltrials.gov (NCT06128863).

Immutep will announce the data to the ASX and make the poster presentation available on the Posters & Publications section of Immutep’s website, after the presentation at CTOS 2024.

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.