Breakthrough Clinical Results
Nona Biosciences announced that its collaborator, Pfizer, will present the Phase 1 clinical study design of MesoC2 (HBM9033/PF-08052666), a first-in-class mesothelin (MSLN)-targeting antibody-drug conjugate (ADC), at the 2025 ASCO Annual Meeting. MesoC2, developed using Nona's Harbour Mice® and integrated ADC platforms, is being evaluated in a Phase 1, open-label study in patients with advanced solid tumors, including mesothelioma, platinum-resistant ovarian cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, endometrial cancer, and colorectal cancer. The presentation will detail the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of MesoC2. This Phase 1 trial marks a significant milestone in the collaboration between Nona Biosciences and Pfizer.
Key Highlights
- Pfizer will present Phase 1 study design of MesoC2 at ASCO 2025.
- MesoC2 is a first-in-class MSLN-targeting ADC.
- The Phase 1 trial will assess safety, tolerability, and preliminary efficacy in patients with advanced solid tumors.
- MesoC2 showed potent antitumor efficacy in preclinical studies.
Incidence and Prevalence
Latest Global Estimates of Mesothelioma Incidence and Prevalence
According to current data, mesothelioma incidence varies markedly from one country to another. The highest annual crude incidence rates (about 30 cases per million) are observed in Australia, Belgium, and Great Britain.
When standardized to the world population, pleural mesothelioma incidence rates can vary dramatically:
- Approximately 700 and 200 cases per 100,000 people annually in two exposed villages in Turkey (with erionite exposure)
- About 10 cases per 100,000 people in a control Turkish village
- In Western Australia, the standardized incidence was 260 per million person-years
On a global scale, the World Health Organization (WHO) estimates that approximately 107,000 people worldwide die each year from mesothelioma, lung cancer, and asbestosis.
The global trend shows that mesothelioma is still increasing in most European countries and in Japan but has peaked in the United States and Sweden. This variation reflects different patterns of industrial asbestos use and regulatory approaches across regions.
A strong relationship exists between mesothelioma and asbestos exposure, with "hot areas" corresponding to sites of industries with high asbestos use (shipbuilding, asbestos-cement industry). The latency periods between first exposure to asbestos and development of mesothelioma are mostly longer than 40 years. The risk increases with duration of exposure, and there is an inverse relationship between intensity of asbestos exposure and length of the latency period.
While the epidemic of asbestos-related disease has plateaued or is expected to plateau in most of the developed world, little is known about the epidemic in developing countries. This is concerning because although worldwide consumption of asbestos has decreased, consumption is increasing in many developing countries, suggesting potential future increases in mesothelioma cases in these regions.
These statistics highlight the continuing global health challenge posed by mesothelioma and its strong connection to asbestos exposure, with significant variations in incidence based on historical industrial practices and environmental exposures.
Key Unmet Needs and Targeted Populations for Mesothelioma
Unmet Needs in Treatment Outcomes
Mesothelioma presents significant treatment challenges, being described as a "uniformly fatal disease" with median survival of only 8-14 months after diagnosis. Current treatment options are characterized by:
- "Poor outlook" with conventional treatments
- "Unsatisfactory" results with "new approaches needed"
- Single and bimodality therapies that "do not improve survival"
- "Current treatment options are scarce and clinical outcomes are rather disappointing"
Chemotherapy Limitations
The effectiveness of existing chemotherapy approaches remains inadequate:
- "Poor response to conventional tumor treatment" with "outcome often fatal"
- Historically, chemotherapy had "minimal impact on natural history" of mesothelioma
- Most drugs achieved "response rates below 20% and median survival of <1 year"
- The current benchmark (pemetrexed plus cisplatin) offers only "modest" improvements
Genetic and Molecular Research Gaps
Several crucial genetic and molecular research needs have been identified:
- Translation of genomic landscape into effective tumor suppressor gene (TSG)-specific therapies
- Understanding predictive biological features that influence response to immune-checkpoint inhibitors (ICIs)
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Research on specific genetic targets including:
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CDKN2A/2B loss which activates G2/M checkpoint and PI3K/AKT
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Previously unrecognized deletions of SUFU locus (10q24.32) in 21% of tumors
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Co-deletion of Interferon Type I genes and CDKN2A present in half of tumors
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Previously unrecognized deletions in RB1 in 26% of cases
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Defects in Hippo pathways present in 50% of tumors
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LATS2 deficiency linked with dysregulated immunoregulation
Emerging Therapeutic Areas Requiring Development
Several promising treatment approaches need further investigation:
- Immunotherapy approaches (checkpoint inhibitors expected to receive regulatory approval)
- Targeted therapies against specific growth factors and pathways
- Multimodality treatment strategies including surgery with hyperthermic intraperitoneal chemotherapy (HIPEC)
- Biomarker development ("biomarker research has lagged behind in mesothelioma")
- Limited data on combining immunotherapy and immuno-gene therapy with radiotherapy
Targeted Populations in Research
Research is increasingly focusing on specific patient populations:
- Elderly patients ("majority of mesotheliomas in the United States occur in the elderly")
- Patients with non-epithelial histology (sarcomatoid or mixed histology tumors)
- Patients with nodal involvement (identified as "significant negative prognostic factor")
- Patients with NF2 mutations (present in "60% of primary malignant mesothelioma")
- Patients with epithelioid malignant pleural mesothelioma
- Patients with specific genetic profiles (CDKN2A deficient, LATS2-mutant, SETD2 loss)
- Patients with microscopic disease who could benefit from adjuvant treatments
- Immunocompetent individuals who could respond to immunotherapy approaches
- Patients who have undergone surgical procedures such as pleurectomy
Study Design Parameters
Study Design Parameters and Endpoints in Key Mesothelioma Trials
Study Design Parameters
The key trials for mesothelioma included various study designs with specific parameters:
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The European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients.
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Trials were grouped into three categories according to published response rate (RR):
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Significant clinical activity (n = 259)
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Moderate clinical activity (n = 142)
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Insufficient clinical activity (n = 122)
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The DETERMINE study was a double-blind, placebo-controlled, phase 2b trial investigating tremelimumab (CTLA-4 monoclonal antibody) in mesothelioma patients with:
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571 patients with unresectable pleural or peritoneal malignant mesothelioma
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Patients who had progressed after one or two previous systemic treatments
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Randomization 2:1 to receive tremelimumab (10 mg/kg) or placebo
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Treatment administered intravenously every 4 weeks for 7 doses and every 12 weeks thereafter
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Patient eligibility: Age 18 years or older, Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease per modified RECIST
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Randomization stratified by European Organisation for Research and Treatment of Cancer status, line of therapy, and anatomic site
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The NIBIT-MESO-1 phase II study evaluated anti-PD-L1 durvalumab combined with anti-CTLA-4 tremelimumab compared to tremelimumab alone in mesothelioma patients.
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A phase Ib study evaluated trametinib and FAK inhibitor GSK2256098 in mesothelioma patients.
Endpoints
The key trials utilized various primary and secondary endpoints:
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Progression-free survival rates (PFSRs) at 3, 4, 5, and 6 months for different clinical activity groups:
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Significant CA: 72%, 67%, 51%, and 43%
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Moderate CA: 59%, 51%, 42%, and 35%
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Insufficient CA: 52%, 40%, 34%, and 28%
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Phase II trials used PFSR at fixed time points (3, 4, 5, or 6 months) as an alternative primary endpoint to response rate, especially with cytostatic agents or when response assessment is difficult.
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The DETERMINE study:
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Primary endpoint: Overall survival in the intention-to-treat population
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Safety was assessed in all patients who received at least one dose of study drug
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The phase Ib study of trametinib and FAK inhibitor GSK2256098:
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Primary endpoints: Maximum tolerated dose (MTD), Adverse events (AEs), Dose-limiting toxicities, Disease progression, Pharmacokinetics/pharmacodynamics
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Secondary endpoint: Progression-free survival (PFS)
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11.8 weeks median PFS in subjects with mesothelioma
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15.0 weeks in Merlin-negative tumors vs 7.3 weeks in Merlin-positive tumors
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The pembrolizumab study endpoints included:
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Overall response rate (18%)
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Disease control rate (56%)
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Median progression-free survival (4.8 months)
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Median overall survival (9.5 months)
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Immune-related adverse events (occurred in 27% of patients)
Drug used in other indications
Based on the provided context, there is no information available about MesoC2 (HBM9033/PF-08052666) clinical trials for mesothelioma or any other indications. The context does not contain any mentions of MesoC2, HBM9033, or PF-08052666.
The context only references other treatments for mesothelioma, including:
- Chemotherapy agents: pemetrexed, cisplatin, lomustine, carboplatin, vinorelbine, fluorouracil
- Immunotherapies: nivolumab, ipilimumab, tremelimumab with durvalumab, dostarlimab
- Targeted therapies: pazopanib, belinostat, bortezomib, ranpirnase, talazoparib, niraparib
- Mesothelin-directed therapies: amatuximab, anetumab ravtansine
- Other treatments: exemestane, irinotecan
There is also no information available about intervention models for MesoC2 trials.