Breakthrough Clinical Results
Adagene announced updated Phase 1b/2 data for its anti-CTLA-4 antibody, Muzastotug (ADG126), in combination with pembrolizumab, in patients with microsatellite stable colorectal cancer (MSS CRC) without liver metastases. The 20 mg/kg Q6W dose showed a 29% confirmed overall response rate (ORR) with low toxicity (<20% Grade 3 adverse events). All six responders in the 20 mg/kg cohorts remain on treatment, demonstrating durable responses. The 10 mg/kg cohorts showed a median overall survival (OS) of 19.4 months. These results suggest a potential benefit of ADG126 in combination with pembrolizumab for MSS CRC.
Key Highlights
- 29% confirmed ORR in 20 mg/kg cohorts of Muzastotug (ADG126) + pembrolizumab in MSS CRC patients without liver metastases.
- Low toxicity profile (<20% Grade 3 adverse events) observed with the 20 mg/kg Q6W dose.
- Durable responses observed, with all six responders in the 20 mg/kg cohorts remaining on treatment.
- Median OS of 19.4 months in the 10 mg/kg cohorts.
Incidence and Prevalence
Global Colorectal Cancer Incidence and Prevalence
Global Incidence Patterns
Colorectal cancer is recognized as one of the most deadliest malignancies worldwide and there is an alarming uptrend in the incidence of early onset colorectal cancer (EOCRC) across the globe.
According to the International Agency for Research on Cancer (IARC) data for 1998-2002, the highest colorectal cancer incidence rates were observed in registries from: - North America - Oceania - Europe, including Eastern European countries
These high rates are likely the result of increases in risk factors associated with "Westernization," such as obesity and physical inactivity.
In contrast, the lowest colorectal cancer incidence rates were observed from registries in: - Asia - Africa - South America
In Iran, colorectal cancer is noted as one of the most common incident cancers and a common cause of cancer death.
For immigrants, particularly those born in Asia and Africa, lower rates of all site cancer incidence compared to Italian natives were observed. The lowest incidence rate ratio (IRR) for colorectal cancer was observed in: - Males from South-Central America (IRR 0.19, 95%CI 0.09-0.44) - Females from Asia (IRR 0.32, 95%CI 0.18-0.70)
Regional Variations
Asian countries have a wide range of colorectal cancer mortality-to-incidence ratio (MIR), from a minimum of 0.24 to a maximum of 0.86.
In 2012, for males, lung, prostate, and colorectal cancer in combination represented almost 30% of the cancer burden in countries that have attained very high levels of human development in the Eastern Mediterranean region.
Colon cancer is one of the cancer types showing the smallest relative variation in incidence between occupational categories.
Mortality Trends
Colorectal cancer mortality rates have declined in many longstanding as well as newly economically developed countries but continue to increase in some low-resource countries of South America and Eastern Europe.
There is limited data available on the incidence and genetic characteristics of EOCRC from resource-poor countries, particularly Africa.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Colorectal Cancer
Based on recent publications, several key mechanisms of action (MoA) are emerging for colorectal cancer treatment:
Signaling Pathway Interventions
- PF-04449913 demonstrates anti-tumor effects by blocking the ERK/p65 signaling pathway and repressing MMP9 expression, reducing colorectal cancer cell viability in a dose-dependent manner
- B7-H4 siRNA inhibits colorectal cancer proliferation, invasion, and migration by targeting the CXCL12/CXCR4 and JAK2/STAT3 signaling pathways
- Transforming Growth Factor-β (TGF-β) signaling plays a dual role: tumor suppressor in early stages and promoter of tumor progression in later stages
- Wnt regulatory genes DKK1 and Wnt5a contribute to colonic carcinogenesis and are often silenced by promoter hypermethylation
- Glucose-regulated protein 78 (GRP78) influences tumor growth through the HIF-1α/VEGF/VEGFR2 pathway
Anti-inflammatory Approaches
- Selective cyclooxygenase-2 inhibitors (rofecoxib, celecoxib) reduce risk of colorectal neoplasia
- Nonselective nonsteroidal anti-inflammatory drugs demonstrate protective effects against colorectal neoplasia
- MABp1, an antibody targeting interleukin 1α, shows antitumor activity and relief of symptoms in advanced colorectal cancer, with 33% of MABp1-treated patients achieving clinical benefits versus 19% with placebo
Targeted Therapies
- EGFR-targeted therapies including cetuximab and panitumumab are FDA approved for metastatic colorectal cancer
- Other monoclonal antibody agents under investigation include matuzumab, MDX-447, nimutozumab, and mAb806
- EGFR tyrosine kinase inhibitors being evaluated include erlotinib, gefitinib, EKB-569, lapatinib, PKI-166, and canertinib
- Anti-VEGF antibody therapy in combination with chemotherapy improves patient survival
Metabolic Regulation
- Oxymatrine exhibits anti-metastatic activity by inhibiting PKM2-mediated aerobic glycolysis
- It suppresses production of ATP, pyruvate, and lactate while inhibiting glucose transporter 1 (GLUT1)
- Oxymatrine significantly inhibits liver metastasis of CRC cells in mice
Genetic and Epigenetic Mechanisms
- Long noncoding RNAs (lncRNAs) play roles in biological processes in CRC and may serve as prognostic and diagnostic biomarkers
- Noncoding RNAs (ncRNAs) including microRNAs, long noncoding RNAs, and circular RNAs modulate TGF-β signaling
- Vitamin D intake is strongly negatively associated with DKK1 methylation, suggesting vitamin D may alter CRC risk by mediating extracellular Wnt inhibition
Novel Therapeutic Approaches
- Probiotics can enhance the antitumor effect of 5-fluorouracil (5-FU) chemotherapy
- Thymol creates oxidative stress through ROS production, DNA damage, and mitochondrial damage
- Thymol upregulates expression of PARP-1, p-JNK, cytochrome-C and caspase-3 proteins, triggering mitoptotic cell death
These emerging mechanisms represent promising avenues for developing more effective colorectal cancer treatments, with particular emphasis on targeting specific molecular pathways and combining therapies to enhance efficacy.
Recent Studies
Recent Colorectal Cancer Studies: Interventions, Safety and Efficacy
Taurolidine vs. Povidone-iodine Study
- Intervention: 0.5% taurolidine/2,500 IU heparin (TRD) versus 0.25% povidone-iodine (control) intraperitoneally
- Sample: 120 patients with resectable colorectal, gastric or pancreatic cancers
- Safety: No difference in perioperative complications between groups
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Efficacy outcomes:
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Cytokine values (IL-1beta, IL-6, IL-10) significantly lower after TRD lavage
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No statistically significant differences in overall mortality, cancer-related death, local recurrence, distant metastasis, or time to relapse
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Median follow-up: 50.0 months
Napabucasin Study
- Intervention: Napabucasin 480 mg versus placebo, both orally every 12h with best supportive care
- Sample: 282 patients with advanced colorectal cancer (ECOG 0-1) who failed standard therapies
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Safety:
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Higher rates of treatment-related adverse events in napabucasin group
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Diarrhea (79% vs 19%, with grade 3+ in 15% vs 1%)
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Nausea (51% vs 24%)
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Anorexia (38% vs 16%)
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Fatigue (grade 3+: 10% vs 6%)
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Dehydration (grade 3+: 4% vs 1%)
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Efficacy outcomes:
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No significant difference in overall survival in unselected population (4.4 vs 4.8 months)
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In pSTAT3-positive patients (22% of population), napabucasin showed improved overall survival (5.1 vs 3.0 months; HR 0.41, p=0.0025)
Columbamine Study
- Intervention: Columbamine treatment in human colon cancer cell lines
- Safety: Noted as having "only minor side effects"
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Efficacy outcomes:
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Significantly inhibited proliferation, migration, and invasion of colon cancer cells
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Dramatically promoted apoptosis rate of colon cancer cells
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Suppressed development of colon cancer to tumor
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Mechanism: Repressed Wnt/β-catenin signaling pathway in a dose-dependent manner
Peer Support Study
- Intervention: Peer support interventions for colorectal cancer screening in ethnic minorities
- Sample: Meta-analysis of 13 studies comprising 8,090 participants
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Efficacy outcomes:
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Increased colorectal cancer screening implementation
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Raised awareness and intention to undergo screening compared to fecal occult blood test outreach, print, and usual care
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Best results in Asian Americans and with peer counseling intervention
Systematic Review of 242 Trials (1967-2007)
- Interventions: Fluorouracil-based regimens, irinotecan, oxaliplatin, bevacizumab, and cetuximab
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Outcomes:
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Most decreased risk of death with irinotecan plus bevacizumab (HR 0.60)
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Significant disease progression benefits with various combinations
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Absolute survival benefit: 8 months with irinotecan plus bevacizumab; 4.7 months with oxaliplatin plus bevacizumab or irinotecan plus oxaliplatin
Multi-centre 2×2 Factorial Randomized Controlled Trial
- Interventions: Primary vs. secondary care follow-up for colon cancer patients; with/without Oncokompas(2.0) eHealth application
- Primary outcome: Quality of life
- Secondary outcomes: Physical and psychosocial outcomes, recurrence detection, patient satisfaction
Drug used in other indications
Based on the provided context, there is no information available about Muzastotug (ADG126) and Pembrolizumab being trialed for indications other than Colorectal Cancer.
The context does not contain any specific information about: - Muzastotug or ADG126 in any clinical trials - Any combination therapy involving Muzastotug (ADG126) and Pembrolizumab - Intervention models for trials involving these specific drugs - Other indications being studied for this drug combination
The only mention of Pembrolizumab in the context is related to its use as "an anti-PD-1 immune checkpoint inhibitor" in relation to colorectal cancer with mismatch repair deficiency, but no information is provided about its combination with Muzastotug or trials in other indications.