The Dual Attack of Dacomitinib and Figitumumab
When Sarah was diagnosed with advanced salivary gland cancer, she faced limited treatment options. Traditional chemotherapy offered little hope and came with devastating side effects. But Sarah's oncologist had a different approach—a targeted therapy clinical trial that would attack her cancer based on its specific genetic features, not just its location in her body 1 . This personalized approach represents a revolutionary shift in cancer treatment, moving away from one-size-fits-all therapies toward precisely targeted strategies.
At the forefront of this revolution are innovative combinations like dacomitinib and figitumumab, two targeted drugs that recently underwent simultaneous testing in both patients and specialized "avatar" mouse models that carry human tumors 2 3 . This dual-pronged research approach offers unprecedented insights into how we can smarter design cancer treatments to maximize effectiveness while minimizing harm.
Targeted therapies attack cancer based on genetic features rather than location in the body.
Unlike traditional chemotherapy that attacks all rapidly dividing cells indiscriminately, targeted therapies are designed to interfere with specific molecules that drive cancer growth and progression. These drugs work more like precision missiles than blanket bombs, targeting cancer cells while largely sparing healthy tissues.
The scientific rationale for combining these two drugs stems from growing evidence that multiple pathways often work together to drive cancer growth. Blocking just one pathway may allow cancer to escape through another, much like closing one road but leaving alternate routes open 2 .
Oral medication taken daily that specifically targets the EGFR pathway.
Administered intravenously every three weeks, targeting IGF-1R pathway.
Simultaneously blocking both EGFR and IGF-1R creates a more comprehensive blockade.
Patient-derived xenograft (PDX) models, sometimes called "avatar mice," are created by transplanting pieces of human tumors directly into specially bred mice with compromised immune systems 4 . These models have become invaluable tools in cancer research because they closely mirror human biology and maintain the original tumor's complexity.
| Feature | Traditional Cell Lines | PDX Models |
|---|---|---|
| Tumor Environment | Lack human tumor microenvironment | Preserve tumor structure and stromal components |
| Genetic Stability | Often drift genetically over time | Maintain genetic features of original tumor |
| Heterogeneity | Become homogeneous | Retain tumor diversity and complexity |
| Predictive Value | Poorly predict clinical response | Better correlate with patient drug responses |
PDX models serve as living biobanks of human tumors and allow researchers to test drug efficacy in a system that closely resembles human patients 4 6 . When used in parallel with clinical trials, as in the dacomitinib-figitumumab study, they provide complementary insights that help explain why certain drugs work in some patients but not others.
The phase I clinical trial followed a standard 3+3 design commonly used in early-stage cancer research to safely determine appropriate drug doses 2 3 . This cautious approach prioritizes patient safety while gathering critical information about how the body processes these drugs and what side effects they might cause.
Patients Enrolled
NSCLC Patients
Colorectal Cancer
Methodology Steps
The clinical trial revealed both promising results and significant challenges. While some patients experienced meaningful responses, the combination therapy proved more toxic than anticipated, requiring substantial dose reductions of both drugs 2 3 .
| Cancer Type | Number of Patients | Response Rate | Notable Findings |
|---|---|---|---|
| Adenoid Cystic Carcinoma | Not specified | Objective responses observed | Promising activity noted |
| Ovarian Carcinoma | Not specified | Objective responses observed | Encouraging results |
| Salivary Gland Cancer | Not specified | Objective responses observed | Clinical activity demonstrated |
| All Comers | 71 treated | Not specified | Most common cancers: NSCLC (24.3%), colorectal (14.9%) |
The recommended doses for further study were significantly reduced—dacomitinib to 10 or 15 mg daily and figitumumab to 20 mg/kg every three weeks 2 3 . This reduction highlighted the challenge of combining targeted therapies, where overlapping toxicities can limit the doses that patients can tolerate.
While the clinical trial was underway, researchers conducted a parallel study using patient-derived xenograft models of adenoid cystic carcinoma (ACC) 2 . This innovative approach allowed them to ask questions that would be difficult or impossible to address in human patients alone.
Tumor tissue from ACC patients was transplanted into immunodeficient mice
Mice divided into four groups receiving placebo, dacomitinib alone, figitumumab alone, or combination
Regular measurements of tumor sizes and toxicity monitoring
Tumor tissues analyzed to understand biological effects of treatments
The PDX study yielded crucial insights that helped explain the clinical trial results. Most notably, figitumumab alone demonstrated significant antitumor activity in the adenoid cystic carcinoma models, while dacomitinib showed little effect 2 . This finding was particularly important because it suggested that figitumumab was the more active drug in this specific cancer type.
Further molecular analysis revealed that tumors sensitive to figitumumab showed downregulation of genes in the IGF-1R pathway 2 , confirming that the drug was effectively hitting its intended target and providing clues about which patients might benefit most from this treatment.
The PDX results helped contextualize the clinical findings by demonstrating that the activity of the combination therapy appeared to stem primarily from figitumumab, at least in adenoid cystic carcinoma, and that different cancer types have varying dependencies on specific pathways.
| Research Tool | Function in Research | Application in This Study |
|---|---|---|
| PDX Models | Maintain tumor heterogeneity and microenvironment; predict drug response | Tested efficacy of dacomitinib-figitumumab combination in ACC models |
| Immunodeficient Mice | Accept human tumor grafts without rejection | Served as hosts for growing patient-derived tumors |
| Molecular Profiling | Identify genetic alterations and pathway activities | Analyzed IGF-1R pathway gene expression in responsive tumors |
| Dose Escalation Design | Safely determine optimal drug dosing in humans | Established recommended phase II doses for the combination |
| Pharmacokinetic Assays | Measure drug absorption, distribution, metabolism, and excretion | Confirmed no significant drug-drug interaction between dacomitinib and figitumumab |
Identifying genetic alterations and pathway activities in tumors
Measuring how drugs are absorbed, distributed, and eliminated
Using PDX models to predict drug responses in humans
The simultaneous investigation of dacomitinib and figitumumab in both clinical trials and PDX models represents an innovative approach to cancer drug development. While the combination required significant dose reductions that limited its broader application, the research yielded several important insights that extend beyond these specific drugs.
Molecular analysis of responsive tumors provides potential biomarkers for patient selection 2 .
For patients like Sarah, these incremental advances represent hope. The continuous refinement of targeted therapies, improved patient selection methods, and smarter drug combinations are steadily changing the outlook for people with advanced cancers. While the journey from laboratory discoveries to effective treatments remains long and complex, integrated approaches that combine clinical trials with sophisticated models like PDX are helping to ensure that this journey becomes progressively faster and more successful.
As research continues, the lessons learned from the dacomitinib-figitumumab study will undoubtedly inform future efforts to develop precisely targeted, effective combination therapies that give cancer patients better options and better outcomes.