CX-904 Generates a Favorable Safety Profile in Phase 1 Trial of EGFR-Expressing Solid Tumors

Sean McCarthy, DPhil

The T-cell engager CX-904 had a favorable safety profile when administered as monotherapy in patients with advanced or metastatic solid tumors that are generally known to express EGFR, according to initial dose-escalation data from a phase 1a trial (NCT05387265).¹ These findings support the outpatient administration and monitoring of the agent in enrolled patients, according to a news release from CytomX Therapeutics.

At a data cutoff off April 16, 2024, investigators observed no instances of any-grade cytokine release syndrome (CRS) in the step-dosing cohorts and no instances of grade 2 or higher CRS in patients who received the agent at the highest dose of 6 mg. Furthermore, 8 patients experienced measurable tumor reduction.

CX-904 is a conditionally activated PROBODY T-cell engager designed to target EGFR on cancer cells and the CD3 receptor on T cells in the tumor microenvironment.

“We are delighted to share these initial results today for CX-904, a highly innovative masked T-cell engager that embodies our vision at CytomX of transforming lives with safer, more effective therapies,” Sean McCarthy, DPhil, chief executive officer and chairman of CytomX, stated in a news release.¹ “These data build on more than a decade of innovation at CytomX, and, we believe, open broad new possibilities for T-cell engagers across many targets and cancer types. For EGFR specifically, a target that is present on normal epithelial tissues, we are very encouraged to see CX-904 working as designed by eliciting meaningful tumor reductions in a very difficult-to-treat tumor type and with a favorable overall safety profile. We look forward to continuing to explore the potential of this exciting agent in multiple EGFR-positive cancers and to determining longer-term strategy with our global development partner, Amgen.”

As of the data cutoff, the phase 1 trial enrolled 35 patients with advanced or metastatic solid tumors, including colorectal, pancreatic, non–small cell, head and neck squamous cell, esophageal, and gastric cancers. Patients were required to have received prior standard therapy, and the enrolled population received a median of 4 prior lines of therapy.^1,2 Patients also needed to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate baseline laboratory values.²

Nineteen patients were enrolled into initial non–step-dosing cohorts, which had target doses of CX-904 ranging from 0.007 mg to 6 mg.¹ Sixteen patients were subsequently enrolled into step-dosing cohorts, with target doses of the agent ranging from 5 mg to 10 mg. Patients in the step-dosing cohorts also received tocilizumab (Actemra) prophylaxis.

The primary end point of the study evaluates the number of patients experiencing dose-limiting toxicities.2Secondary end points include overall response rate, duration of response, progression-free survival, disease-control rate, and overall survival.

Among all patients treated with CX-904, the most common treatment-related adverse effects (TRAEs) were rash (40%), arthralgia (37%), arthritis (14%), pruritis (14%), and vomiting (14%), most of which were low grade.1 The observed grade 3 TRAEs were arthralgia (n = 2), tenosynovitis (n = 1), rash (n = 1), and arthritis (n = 1).

Of the 6 efficacy-evaluable patients with advanced pancreatic cancer treated with CX-904, 33% achieved a confirmed partial response (PR) per RECIST v1.1 criteria, and all 6 patients achieved disease control, defined as objective response or stable disease (SD). One of the patients with a confirmed PR, who received the agent at a target dose of 6 mg, experienced an 83% tumor reduction. The second patient with a confirmed PR, who received the agent at a target dose of 5 mg, experienced a 51% tumor reduction and was still receiving study treatment at the data cutoff. A third patient with pancreatic cancer maintained SD and exhibited no evidence of tumor growth throughout 3.5 months of study treatment; this patient remained on treatment at the data cutoff.

Preliminary pharmacodynamic and pharmacokinetic data from the phase 1 trial were consistent with the PROBODY T-cell engager mechanism of action, including CD8-positive T-cell margination and tumor infiltration, as well as maintained masking in circulation.

The phase 1 trial continues its dose-escalation and -optimization efforts, and future patient enrollment will focus on identifying 1 or more recommended phase 2 doses. This trial is currently enrolling patients into a cohort with a CX-904 target dose of 15 mg. CytomX plans to release another phase 1a dose-escalation trial update by the end of 2024.

References

1. CytomX Therapeutics announces positive initial phase 1a dose escalation data for monotherapy CX-904 (EGFR/CD3 PROBODY T-cell engager). News release. CytomX Therapeutics, Inc. May 8, 2024. Accessed May 9, 2024. https://www.globenewswire.com/news-release/2024/05/08/2878255/37704/en/CytomX-Therapeutics-Announces-Positive-Initial-Phase-1a-Dose-Escalation-Data-for-Monotherapy-CX-904-EGFRxCD3-PROBODY-T-Cell-Engager.html
2. A trial to find safe and active doses for an investigational drug, CX-904, for patients with advanced solid tumors. ClinicalTrials.gov. Updated April 12, 2024. Accessed May 9, 2024. https://clinicaltrials.gov/study/NCT05387265