CX-2051 Demonstrates Preliminary Activity in Heavily Pretreated Advanced Colorectal Cancer

Colorectal Cancer |
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CX-2051, an investigational EpCAM-targeting Probody antibody-drug conjugate (ADC), demonstrated encouraging early clinical activity and a favorable safety profile in heavily pretreated patients with advanced colorectal cancer (CRC), according to interim findings from the ongoing phase 1 CTMX-2051-101 study (NCT06265688).1

Findings announced by CytomX Therapeutics showed that as of the April 7, 2025, data cutoff, efficacy-evaluable patients (n = 18) achieved a confirmed objective response rate (ORR) of 28% across three prioritized dose levels of 7.2 mg/kg, 8.6 mg/kg, and 10 mg/kg administered once every three weeks. The disease control rate (DCR) was 94% across these 3 doses. Notably, among 7 patients treated at the highest expansion dose of 10 mg/kg, the confirmed ORR was 43%.

The median progression-free survival (PFS) across patients treated at the prioritized dose levels was 5.8 months, and 10 of 18 patients remained on treatment at data cutoff.

Additionally, no dose-limiting toxicities (DLTs) were reported, and the initial safety profile was considered manageable with most treatment-related adverse effects (TRAEs) observed at grade 1 or 2. No grade 4 or 5 TRAEs were reported.

“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 shows potential for markedly improved outcomes for [patients with] CRC,” Sean McCarthy, DPhil, chief executive officer and chairman of CytomX, stated in a news release.

CTMX-2051-101 Study Design and Eligibility Criteria

The ongoing, multicenter, phase 1, first-in-human study is evaluating the safety, tolerability, and preliminary efficacy of CX-2051 in patients with advanced solid tumors, including CRC. The study was initiated in April 2024 and is following a dose-escalation design. Patients need to be at least 18 years of age with metastatic or locally advanced, unresectable solid tumors that have progressed after standard therapy, and they must have an ECOG performance status of 0 or 1 and measurable disease per RECIST 1.1 criteria.2 Investigators are excluding patients with active central nervous system involvement and those previously treated with an ADC featuring a topoisomerase 1 payload.

As of data cutoff, 25 patients with metastatic CRC had been treated across five dose levels ranging from 2.4 mg/kg to 10 mg/kg once every 3 weeks.1 The 2.4-mg/kg and 4.8-mg/kg cohorts were single-patient dose-escalation groups and were not expected to yield therapeutic activity. Among the 23 patients treated at the 3 highest dose levels, 18 were deemed efficacy-evaluable after completing at least 1 post-baseline tumor assessment.

Safety and establishing the recommended phase 2 dose (RP2D) are the trial’s primary end points. Secondary end points include ORR, duration of response, PFS, DCR, duration of disease control, and overall survival.

Patients with advanced CRC enrolled in this trial were heavily pretreated with a median of 4 prior lines of systemic therapy. All patients had previously received irinotecan. At baseline, 64% had liver metastases, 64% harbored KRAS mutations, and 96% had microsatellite-stable disease. Importantly, EpCAM expression was not used as a biomarker for patient selection, allowing for the assessment of CX-2051 activity in an unselected population.

Safety Analysis

The most common any-grade TRAEs included diarrhea (n = 18), nausea (n = 11), vomiting (n = 8), fatigue (n = 8), anemia (n = 5), and hypokalemia (n = 3).

Grade 3 TRAEs included diarrhea (n = 5), anemia (n = 3), neutrophil count decrease (n = 2), fatigue (n = 1), nausea (n = 1), hypokalemia (n = 1), and neutropenia (n = 1). Serious TRAEs occurred in 5 patients, consisting of 1 grade 2 effect and 4 grade 3 effects. No cases of pancreatitis, interstitial lung disease, or febrile neutropenia were observed at the time of data cutoff.

The ongoing evaluation of CX-2051 in dose-expansion cohorts aims to further characterize safety, efficacy, and inform the RP2D in patients with advanced CRC.

Dose expansions have been initiated at the 7.2-mg/kg, 8.6-mg/kg, and 10-mg/kg dose levels. Each expansion cohort is expected to enroll approximately 20 patients. Additional data are expected to read out in the first quarter of 2026.

“CX-2051 is showing impressive, durable antitumor activity in late-line metastatic CRC, an area of high unmet need and a very difficult tumor to treat. Furthermore, CX-2051 has been generally well tolerated, highlighting the power of CytomX PROBODY masking technology,” McCarthy added in the news release.1 “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. We are excited to rapidly advance CX-2051 for the benefit of [patients with] CRC and to explore the full potential of this novel ADC.”

References

1. CytomX announces positive interim data from phase 1 dose escalation study of EpCAM antibody drug conjugate (CX-2051) candidate in patients with advanced colorectal cancer (CRC). News Release. Cytomx Therapeutics. May 12, 2025. Accessed May 12, 2025. https://ir.cytomx.com/news-releases/news-release-details/cytomx-announces-positive-interim-data-phase-1-dose-escalation
2. First in human study of CX-2051 in advanced solid tumors. ClinicalTrials.gov. Updated January 20, 2025. Accessed May 12, 2025. https://clinicaltrials.gov/study/NCT06265688