The FDA has granted fast track designation to varsetatug masetecan for relapsed/refractory metastatic colorectal cancer.
The FDA has granted fast track designation to varsetatug masetecan (Varseta-M; CX-2051), an EpCAM-directed, masked, conditionally activated antibody-drug conjugate (ADC), for the treatment of patients with relapsed/refractory metastatic colorectal cancer (R/R mCRC).1
The designation follows phase 1 dose-expansion data from the ongoing CTMX-2051-101 trial (NCT06265688).² CytomX plans to initiate a potential Varseta-M monotherapy registrational study in this population in the first half of 2027.¹
Across the three prioritized expansion doses (7.2 mg/kg, 8.6 mg/kg, and 10 mg/kg every 3 weeks; n = 56 efficacy evaluable), the confirmed objective response rate (ORR) per RECIST v1.1 criteria was 6% (n = 1/17) at 7.2 mg/kg, 20% (n = 4/20) at 8.6 mg/kg, and 32% (n = 6/19) at 10 mg/kg.² The median progression-free survival (PFS) was 5.5 months (95% CI, 2.5-not evaluable [NE]) at 7.2 mg/kg, 6.8 months (95% CI, 2.8-NE) at 8.6 mg/kg, and 7.1 months (95% CI, 3.9-NE) at 10 mg/kg. The disease control rates (DCRs) were 88% (n = 15/17), 90% (n = 18/20), and 84% (n = 16/19) across the respective doses, for an overall DCR of 88% (n = 49/56) across the expansion range.²
“Varseta-M was intentionally designed for patients with colorectal cancer based on the high expression of EpCAM in this cancer type. Receiving fast track designation is an important milestone for the program and reflects its potential to address a highly unmet medical need in patients with R/R mCRC where we continue to work towards a planned first registrational trial in the first half of 2027,” Sean McCarthy, DPhil, chairman and chief executive officer of CytomX Therapeutics, stated in a news release.1
Varseta-M is built on CytomX's Probody platform, which masks the antibody until it reaches the tumor microenvironment, where tumor-associated proteases cleave the mask and locally activate the conjugate.² The agent is directed against EpCAM and is armed with a topoisomerase-1 inhibitor payload. EpCAM is highly and uniformly expressed across CRC but has historically been considered undruggable because of expression on normal tissue; the conditional-activation design is intended to open a therapeutic window around that target.
CTMX-2051-101 is an ongoing, multicenter, first-in-human phase 1 study that began dose escalation in April 2024 across seven dose levels ranging from 2.4 mg/kg to 12 mg/kg.2,3 Expansion cohorts were subsequently opened at 7.2 mg/kg, 8.6 mg/kg, and 10 mg/kg administered once every 3 weeks, and starting in October 2025, the 8.6-mg/kg and 10-mg/kg doses were prioritized for a dose-optimization cohort using adjusted ideal body weight dosing and revised adverse-event management guidelines.
As of the January 16, 2026, data cutoff, 93 patients with late-line metastatic CRC had been enrolled overall, including 60 across the expansion dose range and 20 in dose optimization.² Enrolled patients had received a median of 3 prior lines of therapy in the metastatic setting; 96% had prior irinotecan exposure, 76% had liver metastases, and 71% harbored KRAS mutations.
The primary end points are safety and tolerability, as well as determining the recommended phase 2 dose.3 Secondary end points included ORR, DOR, PFS, time to treatment failure, DCR, duration of disease control, and overall survival.
Of 93 patients evaluable for safety, most treatment-related adverse effects (TRAEs) were grade 1 or 2, and the profile was generally consistent with earlier dose-escalation findings.2 Among the 80 patients treated across the 7.2-mg/kg to 10-mg/kg expansion and optimization doses, the most common TRAEs were diarrhea (n = 68; n = 19 grade 3), nausea (n = 44; n = 4 grade 3), vomiting (n = 29; n = 3 grade 3), fatigue (n = 32; n = 2 grade 3), hypokalemia (n = 21; n = 13 grade 3 or higher), and anemia (n = 13; n = 6 grade 3). In the 20 patients who received an updated prophylactic regimen of an antimotility agent plus budesonide in the dose-optimization cohorts, the grade 3 diarrhea rate was 10%.
No interstitial lung disease, febrile neutropenia, or pancreatitis was reported. One treatment-related grade 5 acute kidney injury, previously disclosed on August 13, 2025, occurred in a patient with a solitary kidney treated at 7.2 mg/kg; no additional grade 5 TRAEs had been reported as of the January 16, 2026, cutoff.
