On June 12, 2024 The 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, held in Chicago from May 31 to June 4, reported a spotlight on MRG004A, a novel antibody-drug conjugate (ADC) designed to treat advanced solid tumors with high tissue factor (TF) expression. TF, whose levels are significantly elevated in various cancers, particularly in pancreatic cancer, is strongly linked to poor prognosis and metastasis (Press release, Memorial Sloan-Kettering Cancer Center, JUN 12, 2024, View Source [SID1234644296]). As a result, TF has emerged as a pivotal target for new therapeutic strategies aimed at enhancing the treatment outcomes of patients with solid tumors. At the conference, a highly anticipated oral presentation focused on the "Phase I/II First-in-Human Study to Evaluate the Efficacy and Safety of TF-ADC MRG004A in Patients with Solid Tumors." The study was featured in a 15-minute keynote session, standing out as one of only two ADC studies presented in the ASCO (Free ASCO Whitepaper) Main Session. This recognition underscores the significance of the research and ASCO (Free ASCO Whitepaper)’s high regard for the clinical study. To provide further insights, YIXUEJIE invited the study’s lead investigator, Prof. Wungki Park from Memorial Sloan Kettering Cancer Center (MSK), to offer a detailed explanation of this groundbreaking research.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Background

TF overexpression is associated with thrombosis, metastasis and poor prognosis in solid tumors, including cervical and pancreatic cancer. MRG004A is a novel anti-TF monoclonal antibody conjugated (ADC) to MMAE payload (drug-to-antibody ratio: 3.8), utilizing Glycoconnect site-specific conjugation technology. Herein, this research presents the preliminary safety and efficacy data from phase I/II MRG004A-001.

Methods

This is an interim report (Data cutoff: Dec 15, 2023) of first-in-human, dose-escalation and expansion study ongoing in the USA and China. Pts with ECOG 0-1 with unresectable/metastatic solid tumor with measurable disease per RECIST v1.1 that progressed on prior systemic therapy, received MRG004A monotherapy Q3W intravenously. The primary objectives were to assess the safety, activity, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Baseline tissue was evaluated for the association of TF expression with objective response rate (ORR) and disease control rate (DCR).

Results

Sixty-three pts were enrolled with 43 in dose-escalation phase (8 dose levels [0.3-2.6mg/kg]) and 20 in dose-expansion phase (15 at 2.0mg/kg and 5 at 2.4mg/kg). Median age 58 (38-75). ECOG0: 8 (13%) pts. Female: 37 (59%) pts. Median 3 prior lines of therapy: 3 (1-10). MTD was not reached. Sixteen baseline samples were evaluated for overall % membrane positivity by immunohistochemistry. Nineteen were pancreatic cancer (PC) and 68% (13/19) had TF ≥50% and 2 or 3 (+). Five received dose <2 mg/kg Q3W. Significant anti-tumor activity of MRG004A was observed in pts with PC. Among 12 evaluable pts with PC in the 2.0mg/kg cohort, who have received median 3 lines of prior therapy, there were 4 PR and 6 SD. ORR was 33.3% (4/12) and DCR was 83.3% (10/12). Among them, 5 pts with PC of TF expression ≥50% and 3+ intensity and ≤2 prior lines of therapy received MRG004A at 2mg/kg. 4 of 5 TF-overexpressed PC achieved PR and 1 SD. Also, MRG004A showed efficacy in other cancers. In 4 pts with heavily-treated triple-negative breast cancer (TNBC), ORR and DCR were 25% (1/4) and 50% (2/4), respectively. In 2 pts with cervical cancer with four prior therapy lines, 1 PR and 1 SD. Common treatment-related adverse events (TRAE) of any grade include conjunctivitis (27%), anemia (17%), and hypoalbuminemia (13%) and 7.9% (5/63) pts had serious adverse events. One pt with TNBC treated at 1.8mg/kg experienced G3 Steven Johnson Syndrome, a dose-limiting toxicity (DLT), but resolved. No other DLT was observed and dose expansion and matured outcome evaluation is ongoing.

Conclusions

MRG004A demonstrated a manageable toxicity and a striking antitumor activity across multiple tumor types with high TF expression in heavily pretreated setting, including pancreatic cancers. These encouraging findings warrant further evaluation of MRG004A, particularly in the context of TF-overexpressed solid tumors.

Expert Commentary
MRG004A: Pioneering TF-Targeted Therapy for Pancreatic Cancer

Highlighting the significance of TF as an emerging treatment target in pancreatic cancer, and the success stories of ADC drugs targeting this marker, Prof. Park remarked, "TF’s high expression in pancreatic cancer presents a precise target for ADC drugs. MRG004A, a novel ADC targeting TF, precisely recognizes and acts on TF-expressing cancer cells, effectively suppressing their growth and spread. The FDA-approved Tivdak (tisotumab vedotin-eftv), the first TF-targeted ADC, has achieved notable efficacy in cervical cancer treatment, offering robust evidence for TF targeting in pancreatic cancer therapies."

Prof. Park shed light on MRG004A’s promising potential, "Phase I and II clinical trials for TF high-expressing tumors are progressing in China and the US, evaluating MRG004A’s safety, efficacy, and other attributes. In pancreatic cancer patients, MRG004A displayed remarkable results, with four of 12 patients treated with 2.0 mg/kg achieving remission. Notably, one patient resistant to both FOLFIRINOX and PD-1 therapy responded well to MRG004A. A 100% disease control rate (DCR) was achieved in patients with baseline TF expression ≥50% and limited prior therapies. This underscores MRG004A’s significant therapeutic potential and broad applicability. We eagerly await the study’s completion, paving the way for new treatment options for patients."

MRG004A: High Efficacy, Low Toxicity, and Broad Prospects

Commenting on the current state of pancreatic cancer treatment and the potential of MRG004A, Prof. Park stated, "Researchers in pancreatic cancer treatment must persist in developing innovative therapies and identifying more effective targets to forge new drugs and refine strategies. The need is dire for more efficacious options for patients, often diagnosed at later stages with limited survival rates. Standard chemo combinations, though widely used, have modest results. MRG004A, however, shows remarkable promise for those resistant to second-line therapies, offering fresh hope for extended survival and enhanced quality of life."

Highlighting MRG004A’s unique advantages, Prof. Park stated, "TF high level probably matters for PDAC. MRG004A’s efficacy transcends target expression levels, even exhibiting efficacy in low expression states, owing to its exceptional specificity and stability. Clinical trials reveal no serious toxic side effects, a marked reduction in bleeding events, and significant improvement in other side effect profiles. Its safety record surpasses previous drugs. Given its proven efficacy, safety, Orphan Drug Destination (ODD) and Fast Track Designation (FTD), MRG004A promises to be a key treatment option for pancreatic cancer. The research team aims to further explore its application in a broader range of diseases."

MRG004A Pioneers New Pancreatic Cancer Treatment Frontiers, Highlighting Potential in Combination Therapy and TF Research

Commenting on the pancreatic cancer treatment approach, Prof. Park highlighted, "Despite being in early development, MRG004A holds promise in combination therapies. Experts are exploring synergies with existing chemotherapeutics, targeted therapies, and immunotherapeutics to boost efficacy and patient survival. This multi-pronged approach will broaden treatment options for pancreatic cancer patients and inspire new approaches for other challenging diseases. To expedite patient access, industry experts are committed to securing timely approvals at critical trial stages."

Envisioning the future of pancreatic cancer research, Prof. Park emphasized TF’s role as a key therapeutic target. Its high expression in pancreatic cancer presents precision therapy opportunities, leading to the development of MRG004A, an ADC drug targeting TF. Preliminary studies have validated its high specificity and stability. The research team will continue to investigate TF’s mechanism in pancreatic cancer and explore effective combinations with therapies like immune checkpoint inhibitors, aiming to design tailored regimens based on tumor microenvironments. Additionally, they will focus on other therapeutic targets to broaden patient treatment options and improve prognosis.

On June 12, 2024 Accuray Incorporated (NASDAQ: ARAY) reported that the registration dossier for the Accuray Precision Treatment Planning System (TPS) has been approved by the Chinese National Medical Products Administration (NMPA) (Press release, Accuray, JUN 12, 2024, View Source [SID1234644295]). The Accuray Precision TPS is now available for use with the CNNC-Accuray joint venture Tomo C radiation therapy system and in combination, will provide medical care teams with a new option for delivering extremely precise and accurate radiotherapy treatments, ultimately expanding access to care for more cancer patients in China.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We couldn’t be more pleased about the approval of the Accuray Precision Treatment Planning System and the potential it represents, in combination with the Tomo C System, for cancer patients in China, a country which accounted for approximately 25 percent of new cancer cases diagnosed worldwide in 20201. With this approval our China joint venture can begin shipping the Tomo C System to their end customers, an important step forward in helping to address an unmet need for precision radiation therapy," said Suzanne Winter, president and CEO of Accuray.

Continued Ms. Winter, "Customers in China who use our organization’s CyberKnife, Radixact and TomoTherapy Systems are familiar with the Accuray Precision Treatment Planning System, a powerful, full-featured system that enables clinicians to efficiently generate high quality radiation therapy treatment plans. The availability of the treatment planning solution for the Tomo C System, a domestic made radiation therapy delivery device, will expand our portfolio in China and enhance our access in the regional Type B market."

The Accuray Precision TPS was developed to facilitate the creation and adaptation of precise treatment plans in less time. The planning solution enables clinicians to routinely incorporate modifications to treatment planning into the course of treatment to account for changes in tumor size, shape and location – as well as subtle changes in the location of organs and other healthy tissue – thereby increasing treatment precision.

The Tomo C platform features helical imaging and radiation delivery. With fully-integrated treatment planning, centralized data management and ultra-precise treatment delivery using patented beam-shaping technology, the system enables greater control of the radiation dose so it conforms precisely to the tumor and helps minimize dose to healthy tissue. The system is designed to enable medical care teams to optimize outcomes for standard radiation therapy indications including breast, prostate, lung, and head and neck cancers, in addition to complex treatments such as total marrow irradiation.

On June 12, 2024 Immorta Bio Inc, a science-based Life Extension company reported positive preclinical findings utilizing its senescent cell-killing immunotherapeutic product SenoVax in a model of non-small cell lung cancer (Press release, Immorta Bio, JUN 12, 2024, View Source [SID1234644294]). The results, which are reported in a filed patent, demonstrate successful induction of immunity to senescent cells surrounding lung cancer cells, and reproducible regression of established tumors. The SenoVax immunotherapy was administered in absence of other cancer killing therapeutics.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"It has been published that tumors surround themselves with senescent cells, with negative correlations between the amount of senescent cells and patient survival1. Furthermore, increased resistance to cancer therapies such as chemotherapy2, radiation therapy3, and immunotherapy4 is associated with accumulation of senescent cells," said Dr. Thomas Ichim, President and CSO of Immorta Bio. "The fact that we are able to induce regression of tumors by simply killing the senescent cells that surround them, without other interventions, points to the potency of our approach."

The Company is currently in the late phase of preclinical development and plans to file an Investigational New Drug (IND) application with the FDA shortly to initiate treatment of advanced lung cancer patients.

"Immorta Bio is a Scientific Longevity Company. In that regard we are developing two longevity therapeutics platforms: Cellular Rejuvenation and Senolytic Immunotherapy (SenoVax)," said Dr. Boris Reznik, Chairman and CEO of Immorta Bio. "The results disclosed today are part of our second technology platform, which augments the immune system’s natural tendency to ‘clean up’ dysfunctional and senescent cells. Application of SenoVax to cancer treatment not only can potentially produce some effective oncology drug, but also is proving its potency in Senolytic life extension applications."

On June 13, 2024 Zumutor Biologics Inc. "Zumutor", a Boston-based clinical stage Oncology Company developing first-in-class monoclonal antibody molecules targeting innate immunological pathways, reported that the first patient was dosed in its Phase 1 clinical trial, with ZM008 (Press release, Zumutor Biologics, JUN 12, 2024, View Source [SID1234644293]). The dose escalation trial is evaluating ZM008 in patients with advanced solid tumors, as a single agent and in combination with pembrolizumab.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

ZM008 is a novel fully human IgG1 monoclonal antibody against LLT1 (CLEC2D), which disrupts the interaction of LLT1-CD161 between NK cells and tumor cells. ZM008-mediated NK cell activation and subsequent T cell activation will modify the immune infiltrate in the tumor microenvironment driving eventual antitumor effects. The mode of action of ZM008 is to convert the ‘cold’ or less immune responsive cancers (TME) into ‘hot’ or highly immune responsive tumors. This approach could provide significant benefits to patients resistant to available immunotherapy treatments.

"While immunotherapy has made a significant and positive impact on patient outcomes, there remains a significant unmet need. ZM008 is a first-in-class antibody that could help patients, both as a single agent as well as in combination with anti-PD-1 directed therapy. We are pleased to participate in the study and are optimistic that early clinical activity may be observed in this heavily pre-treated patient population based on clinical evaluation and translational data," commented Dr. Ildefonso Ismael Rodriguez, MD, Principal Investigator at NEXT Oncology.

Understanding the Trial Design

The ZM008-001 trial is an open-label, first-in-human, multicenter, Phase 1 dose escalation trial of ZM008 administered alone or combined with Pembrolizumab. The trial will assess the safety, pharmacokinetics, establish the maximum tolerated dose, pharmacodynamic biomarkers, and initial antitumour activity of ZM008. The study will recommend the Phase 2 dose.

In stage 1A, increasing doses of ZM008 will be administered to patients with solid tumors, without standard therapeutic options. This will be followed by stage 1B, where ZM008 will be given in combination with the anti PD1 drug, Pembrolizumab. Multiple solid cancer indications will be enrolled: non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), prostate cancer, colorectal cancer (CRC), high-grade serous ovarian cancer (HGSOC), and others. Clinical responses and detailed translational studies will be performed, to evaluate the activation of the immune system, safety and patient benefits, after ZM008 monotherapy and combination therapy.

Knowing the Criteria

The ZM008-001 clinical trial is for adults, aged 18 or older, with advanced metastatic solid tumors. Patient must have adequate hematologic, renal and hepatic functions. Patients with a history of auto-immune reactions and toxicities with previous anti-cancer therapies (irAEs) are not eligible. ZM008 will be administered intravenously once every three weeks. This trial requires multiple visits to NEXT Oncology sites for lab tests, safety evaluations, and other follow-up appointments each month.

"Advancing our first novel drug ZM008 into clinical development is an important inflection point for Zumutor and underscores the power of our Antibody discovery engine, INABLR, supporting the immuno-oncology pipeline," said Maloy Ghosh, PhD, Chief Scientific Officer at Zumutor Biologics. "We are excited to enroll patients in this first-in-human Phase 1 study, focused on advanced solid tumor patients. Activation of immune pathways, by targeting this novel mechanism with ZM008, will be a viable option for patients to fight advanced solid cancers."

"We are looking forward to see safety and efficacy data from the ZM008-001 clinical trial," said Kavitha Iyer Rodrigues, Founder/CEO of Zumutor. "There is such a tremendous unmet need for patients suffering from multiple solid cancers. We are eager to see this novel monoclonal antibody advance through clinical trials and hope it will one day be available for these patients in need."

"ZM008 is a very exciting molecule. The preclinical work, including the ex-vivo studies, have shown remarkable activity both as a single agent and in combination with pembrolizumab. We are hoping this will translate to beneficial activity in patients and are thankful to the trial sites for joining us in developing ZM008," said Dr. Debasish Roychowdhury, MD, Medical Oncologist.

Additional information on this clinical trial will be updated on www.clinicaltrials.gov (NCT06451497).

For questions or to enroll in this study, the patient’s treating physician can contact Jordan Georg. Phone: 210-580-9521

On June 12, 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, cardiovascular and metabolic, autoimmune, ophthalmology and other major diseases, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation to its TOPO1i anti-CLDN18.2 ADC (R&D code: IBI343), for the treatment of advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC) that has relapsed and/or is refractory to one prior line of therapy (Press release, Innovent Biologics, JUN 12, 2024, View Source [SID1234644292]). Previously, IBI343 has already received FDA approval of its IND application for the treatment of PDAC.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

At the ASCO (Free ASCO Whitepaper) 2024 Annual Meeting, Innovent reported the preliminary Phase 1 results of IBI343 in advanced PDAC patients who have received at least one prior line of treatment. In the 6 mg/kg dose group, among the 10 evaluable PDAC patients with CLDN18.2 1/2/3+≥60%, the overall response rate (ORR) was 40% (link).

Dr. Hui Zhou, Senior Vice President of Innovent, said, "Pancreatic cancer is highly malignant and difficult to diagnose early. At present, the treatment of advanced pancreatic cancer is still based on systemic chemotherapy. The clinical options for the second-line treatment are particularly limited, with response rate of only 6%-16%, and median survival period of only about 3-6 months. There are urgent clinical needs to be met. As the world’s first CLDN18.2 ADC to obtain FTD certification in this difficult-to-treat cancer, IBI343 single-agent therapy shows encouraging efficacy and tolerable safety in the late-line treatment of patients with advanced pancreatic cancer. We will continue to confirm its efficacy and safety in this disease in subsequent clinical trials, and also explore IBI343 in combination therapy and other solid tumors including gastric cancer."

Fast Track Designation (FTD) is a rapid review process designed to facilitate the clinical development of a drug that may treat serious conditions and fulfill an unmet medical need. According to regulations, drug candidates that obtain FTD qualifications will have more opportunities to communicate with the FDA during subsequent drug development and review processes, which will help speed up the clinical development and approval of the drug.

About Pancreatic Ductal Adenocarcinoma

Pancreatic cancer is one of the most malignant tumors of the digestive system, with a 5-year survival rate of about 10% [i]. In recent years, the incidence of pancreatic cancer has increased, but the early diagnosis rate is still low, seriously endangering human life and health. At present, the treatment of advanced pancreatic cancer is still based on systemic chemotherapy. Currently, the first-line treatment options mostly use fluorouracil (5-FU) or gemcitabine-based chemotherapy. In the second-line treatment, clinical options are very limited, mainly alternatives to the first-line regimen, and the median survival period is only about 3 to 4 months[ii], [iii]. Claudin, a member of the tight junction molecule family, is a key structural and functional component of epithelial tight junctions. Among them, CLDN18.2 is normally buried in the gastric mucosa, but the development of malignancy leads to disruption of tight junctions and exposure of CLDN18.2 epitopes on the membrane of tumor cells[iv]. CLDN18.2 is present in 50% to 70% of pancreatic cancer patients, making it a highly scrutinized target[v].

About IBI343 (Claudin18.2 ADC)

IBI343 is a recombinant human anti-Claudin 18.2 monoclonal antibody-drug conjugate (ADC) developed by Innovent Biologics. IBI343 binds to the Claudin 18.2-expressing tumor cells, which causes the Claudin 18.2-dependent ADC internalization to occur. Following lysosomal processing of the ADC, the active drug (TOP1i) is liberated, which results in DNA damage and eventually apoptosis of the tumor cells. The free drug can also diffuse through the plasma membrane and effectively eliminate neighboring cells, leading to a "bystander killing effect". As an innovative TOPO1i ADC, IBI343 has demonstrated tolerable safety and encouraging efficacy signals in Phase 1 clinical studies. The therapeutic potential of IBI343 is currently being explored in tumor types such as gastric cancer and pancreatic cancer.

In May 2024, The National Medical Products Administration (NMPA) of China granted breakthrough therapy designation (BTD) to IBI343 for use as a single agent in patients with claudin 18.2–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who experienced disease progression following 2 prior lines of systemic treatment. The multi-center Phase 3 trial of IBI343 for this indication is in preparation.