Breakthrough Clinical Results
Lisata Therapeutics announced encouraging preliminary data from the Phase 1/2a CENDIFOX trial evaluating certepetide in combination with FOLFIRINOX for pancreatic, colon, and appendiceal cancers. The data, from the pancreatic ductal adenocarcinoma (PDAC) cohort, showed the combination was safe and feasible, with promising R0 resection rates, pathologic partial response, and early survival data. The results also demonstrated enhanced immune cell infiltration, suggesting certepetide can transform tumors from 'immune-cold' to 'immune-hot'.
Key Highlights
- Certepetide in combination with FOLFIRINOX shows promising results in resectable and borderline resectable PDAC patients.
- The combination therapy was safe and feasible, with no serious adverse events attributed to certepetide.
- Improved R0 resection rate and pathologic partial response observed in patients treated with the combination.
- Enhanced immune cell infiltration and increased expression of immune markers suggest a potential for improved response to immunotherapies.
Incidence and Prevalence
Global Pancreatic Cancer Incidence and Prevalence
Pancreatic cancer represents a significant global health burden, currently ranking as the sixth leading cause of cancer-related death worldwide. In 2022, there were an estimated 510,922 new cases and 467,409 deaths globally, highlighting the deadly nature of this disease.
The global incidence of pancreatic cancer continues to show an alarming upward trend. Projections indicate a 95.4% increase in new cases by 2050, potentially reaching a staggering 998,663 new cases worldwide. This dramatic rise makes pancreatic cancer an increasingly urgent public health concern.
Geographic variations in pancreatic cancer incidence are substantial. The highest incidence rates are observed in North America and Western Europe, while lower rates are found in Asian and African populations. The age-standardized incidence rates range from 7.2 per 100,000 in high-incidence regions to 2.8 per 100,000 in low-incidence areas.
In the United States, pancreatic cancer is now the third leading cause of cancer deaths and is projected to become the second leading cause by 2030. The overall incidence from 2001 to 2015 was 5.2 per 100,000 people per year. The 5-year survival rate remains extremely low at just 10.8% in the US and 10% worldwide, showing only modest improvement over the past decade.
Racial disparities in pancreatic cancer incidence are significant. For decades, the incidence rate among Blacks has been 30% to 70% higher than other racial groups in the United States. While rates among Black males and females have remained unchanged in recent years, they continue to be higher compared to other racial/ethnic groups.
Gender differences are also evident, with overall incidence rates during 2000-13 being higher among males than females (male-to-female incidence rate ratio = 1.28). However, an interesting pattern emerges in younger age groups, where rates among females were higher at younger ages.
Age-specific trends show concerning patterns, particularly the rapid increase in pancreatic cancer among young adults. Incidence rates increased more dramatically in females aged 18-26 (Annual Average Percent Change, 9.37%) compared to males (4.43%). Among various demographic groups and cancer types, young females had the highest AAPCs for pancreatic cancer.
In Taiwan, the incidence of pancreatic cancer increased from 4.62 per 100,000 in 2002 to 6.04 per 100,000 in 2013, reflecting the global upward trend.
Histologically, nearly 85% of pancreatic cancer is adenocarcinoma, which carries a particularly poor prognosis. In Taiwan, patients with adenocarcinoma showed a dismal 5-year survival of 5.2%, while other subtypes like endocrinomas, neuroendocrine tumors, and lymphoma displayed better outcomes with 5-year survival ranging from 41.8% to 59.1%.
The rising global burden of pancreatic cancer may be partially attributed to increasing prevalence of risk factors including diabetes, obesity, and smoking. Additionally, worldwide increases in early-onset pancreatic cancer may be partly driven by increases in excess body weight.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Pancreatic Cancer Treatment
Immunotherapy Approaches
Recent advances in immunotherapy show promise for pancreatic cancer treatment. A 2024 phase 1b/2 study evaluated mitazalimab, a human CD40 agonistic IgG1 antibody, combined with modified FOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma. This combination demonstrated manageable safety and an impressive 40% objective response rate, warranting further investigation in phase 3 trials.
Another immunotherapy approach targets inflammatory pathways through IL1β blockade using canakinumab combined with PD1 blockade (spartalizumab) and chemotherapy. This combination induced modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs, though these changes didn't uniformly alter the tumor microenvironment.
Novel Molecular Targets
Several molecular pathways have emerged as promising targets:
- RIP1 kinase: GSK3145095 shows excellent activity in blocking RIP1 kinase-dependent cellular responses and promotes a tumor suppressive T cell phenotype
- Purinergic signaling: Targeting P2X7 receptor, P2Y receptors, and ecto-nucleotidases CD39 and CD73 presents new therapeutic approaches
- Anaplastic lymphoma kinase (ALK): NVP-TAE684 suppresses proliferation, increases G2/M arrest and apoptosis, and synergistically enhances gemcitabine-induced cell death
- Riluzole: Inhibits pancreatic cancer growth by targeting the Wnt-β-catenin/TCF-LEF pathway and disrupting mitochondrial homeostasis
- PD-L1: Plays a role in regulating response to ATR inhibition, with PD-L1 inhibition enhancing DNA damage and increasing VE-821 sensitivity
Anti-metastatic Strategies
The combination of juglone and sodium selenite has shown cytotoxic and dose-dependent suppressive effects on invasion and metastasis in pancreatic cancer cells, presenting a promising approach to inhibit metastasis.
Novel Delivery Systems
Exosomes are emerging as effective drug delivery systems due to their biocompatibility, targeting specificity, and low immunogenicity. Exosomes derived from human bone marrow mesenchymal stem cells for targeted delivery of gemcitabine significantly augmented apoptosis in pancreatic cancer cells.
Epigenetic Regulation
N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) are closely related to poor prognosis and immunotherapeutic effect in PDAC. A risk prognosis model based on 4 m6A-related lncRNAs can predict overall survival, with phenformin showing higher sensitivity in high-risk groups and pyrimethamine in low-risk groups.
Targeting Cell Death Pathways
Both apoptosis and autophagy play critical roles in chemoresistance. Small-molecule anticancer agents target apoptosis through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off protective autophagic effects, showing synergistic effects with chemotherapy.
Tumor Microenvironment Modulation
In pancreatic cancers with high-risk genomes, cancer cell-neutrophil signaling provokes neutrophil-derived transmembrane TNF-TNFR2 interactions that dictate inflammatory polarization in cancer-associated fibroblasts and T-cell dysfunction. Targeting this signaling may sensitize pancreatic cancer to chemo±immunotherapy.
Recent Studies
Recent Pancreatic Cancer Studies: Interventions and Outcomes
CheckMate 032 (2023)
This study investigated the safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without cobimetinib in advanced/metastatic solid tumors, including pancreatic cancer. The cobimetinib-containing triplet therapy showed three confirmed partial responses (ORR 10% per BICR) while no responses were observed in the other arms. Median PFS was 1.4, 1.4, and 3.0 months for monotherapy, nivolumab plus ipilimumab, and triplet arms, respectively, with median OS of 5.1, 4.0, and 6.2 months. Most treatment-related adverse events were grade 2 or less, with manageable safety overall.
Sintilimab with mFFX (2023)
This phase II study evaluated sintilimab (PD-1 inhibitor) with modified FOLFIRINOX (mFFX) for metastatic/recurrent pancreatic ductal adenocarcinoma. While median overall survivals were similar (10.9 months for combination vs 10.8 months for mFFX alone), the objective response rate was significantly higher in the sintilimab + mFFX group (50.0% vs 23.9%, P < 0.05). Median progression-free survival was comparable (5.9 vs 5.7 months). Grade ≥ 3 treatment-emergent adverse events occurred in 84.9% of combination patients vs 74.1% with mFFX alone, and grade ≥ 3 immune-related adverse events in 5.7% vs 0. The regimen demonstrated feasibility with an acceptable safety profile.
SWOG Cancer Research Network (2022)
This randomized phase II clinical trial evaluated veliparib and mFOLFIRI versus FOLFIRI (control) for metastatic pancreatic cancer. The study showed no improvement with the combination, with median overall survival of 5.4 vs 6.5 months (HR, 1.23; P = 0.28) and median progression-free survival of 2.1 vs 2.9 months (HR, 1.39; P = 0.09). Grade 3/4 toxicities were more common with veliparib (69% vs 58%, P = 0.23). The study was halted after interim futility analysis.
OPTIMIZE-1 (2024)
This single-arm, multicentre, phase 1b/2 study tested mitazalimab (a human CD40 agonistic IgG1 antibody) with modified FOLFIRINOX in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma. The study enrolled 70 adults across 14 university hospitals in Belgium, France, and Spain between 2021 and 2023.
Masitinib Study (2016)
This study compared masitinib (tyrosine-kinase inhibitor) combined with gemcitabine against single-agent gemcitabine. While median OS was similar between treatment arms (7.7 and 7.1 months, HR = 0.89), a significant treatment effect was observed in the 'ACOX1' subgroup (median OS 11.7 months, HR = 0.23) and 'pain' subgroup (median OS 8.0 months, HR = 0.62). Despite increased toxicity with the combination, side-effects remained manageable.