CytomX Therapeutics has announced promising interim data from its Phase 1 dose-escalation study of CX-2051, an EpCAM-targeting antibody-drug conjugate (ADC), showing significant anti-tumor activity in patients with advanced colorectal cancer (CRC).
The study demonstrated a 28% confirmed response rate across expansion doses, with particularly strong results at the highest dose level. These findings represent a potential breakthrough for patients with limited treatment options in late-line metastatic CRC.
Impressive Efficacy in Heavily Pretreated Population
The interim data, from the ongoing CTMX-2051-101 Phase 1 study with an April 7, 2025 cutoff date, showed that among 18 efficacy-evaluable patients treated at the expansion doses (7.2, 8.6, and 10 mg/kg Q3W), five achieved confirmed partial responses according to RECIST v1.1 criteria. This 28% response rate substantially exceeds the low to mid-single digit percentages typically seen with currently approved therapies in third-line or later CRC treatment.
At the highest dose level of 10 mg/kg, the response rate reached 43% (3 of 7 evaluable patients). The disease control rate was remarkably high at 94% across all three expansion dose groups, with 17 of 18 patients achieving stable disease or better.
"CX-2051 is showing impressive, durable anti-tumor activity in late line metastatic CRC, an area of high unmet need and a very difficult tumor to treat," said Sean McCarthy, D.Phil, chief executive officer and chairman of CytomX. "Furthermore, CX-2051 has been generally well tolerated, highlighting the power of CytomX PROBODY® masking technology."
The study enrolled patients with advanced disease who had received a median of four prior lines of therapy. All patients had previously been treated with irinotecan, 64% had liver metastases, 64% had KRAS mutations, and 96% were microsatellite stable—characteristics typically associated with more challenging treatment outcomes.
Promising Durability and Safety Profile
The durability of response appears promising, with a median progression-free survival of 5.8 months as of the data cutoff. Ten of the 18 patients remained on study treatment at the time of analysis.
CX-2051 demonstrated a manageable safety profile with no dose-limiting toxicities observed. Most treatment-related adverse events were Grade 1 or 2 in severity. The most common side effects included diarrhea (18 patients, 5 Grade 3), nausea (11 patients, 1 Grade 3), vomiting (8 patients, no Grade 3), and fatigue (8 patients, 1 Grade 3). No Grade 4 or 5 treatment-related adverse events were reported, and notably, no cases of pancreatitis, interstitial lung disease, or febrile neutropenia occurred.
Novel Approach to a Challenging Target
CX-2051 represents a significant technological advancement in targeting EpCAM (Epithelial Cell Adhesion Molecule), a protein highly expressed in many epithelial cancers but historically difficult to target due to its presence on normal tissues.
The drug utilizes CytomX's proprietary PROBODY® platform, which employs a masking technology designed to activate the therapeutic agent primarily within the tumor microenvironment, potentially reducing off-target effects in healthy tissues.
"EpCAM is a high potential and broadly expressed cancer target that has been challenging to drug historically due to expression on normal tissues. We believe we have broken important new ground with our data announced today, which show potential for markedly improved outcomes for CRC patients," McCarthy explained.
The investigational ADC is armed with a topoisomerase-1 inhibitor payload and was discovered in collaboration with ImmunoGen, now part of AbbVie.
Development Plans and Future Directions
Based on these encouraging results, CytomX has initiated dose expansions at 7.2, 8.6, and 10 mg/kg Q3W, with 20 patients expected to be enrolled at each dose level to inform the selection of a recommended Phase 2 dose.
The company has outlined several upcoming milestones for the CX-2051 program:
- Additional Phase 1 data update by Q1 2026
- Phase 2 study initiation planned for the first half of 2026
- Potential combination studies in earlier lines of CRC treatment in 2026
- Evaluation of non-CRC, EpCAM-expressing tumor indications for potential Phase 1b study initiation in 2026
"Importantly, we believe these results validate EpCAM as an oncology target and unlock a broad development opportunity for CX-2051 in CRC and potentially many other cancer types where EpCAM is expressed," added Dr. McCarthy. "We are excited to rapidly advance CX-2051 for the benefit of CRC patients and to explore the full potential of this novel ADC."
Broader Implications for Precision Oncology
The positive interim results for CX-2051 highlight the potential of innovative drug design approaches to address previously challenging targets in oncology. By successfully targeting EpCAM with a conditionally activated ADC, CytomX may have opened a new therapeutic avenue not only for colorectal cancer but potentially for multiple epithelial malignancies.
The company's PROBODY® platform represents part of a broader trend toward more precise targeting in cancer therapy, with the goal of maximizing efficacy while minimizing toxicity to normal tissues—a particularly important consideration for targets like EpCAM that are expressed in both cancerous and normal cells.
As the CX-2051 program advances toward Phase 2 development, it will be important to confirm these early signals of efficacy and safety in larger patient populations and potentially explore biomarkers that might identify those most likely to benefit from this novel approach.
