A phase 2 trial of cetuximab for patients with locally advanced/metastatic chordoma.

11527 Background: Unresectable/metastatic chordoma is a rare notochordal malignancy with no approved systemic treatments. EGFR is widely expressed on chordomas. Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that inhibits EGFR signaling. In vivo testing of cetuximab has demonstrated growth inhibition and regression of chordoma. An investigator-initiated, single center, phase II study (NCT05041127) was developed to evaluate the efficacy of cetuximab for patients (pts) with advanced/metastatic chordoma. Methods: Eligible pts were ≥18 years of age, had adequate organ function, and had an ECOG performance status (PS) of ≤2. Any prior line of therapy was allowed except EGFR inhibitors. A minimum of 10 pts and maximum of 29 pts were to be enrolled onto the trial based on Simon's two-stage optimal design (H 0 RR 5% vs H 1 RR 20%; one-sided α=0.05; power=80%). Pts received cetuximab 500 mg/m 2 IV Q2 weeks until disease progression or unacceptable toxicity. The primary end point was response rate (RR) according to RECIST 1.1. Secondary objectives included safety/tolerability and survival metrics. Efficacy was assessed in the modified intention-to-treat (mITT) population (≥1 dose; ≥1 post-baseline scan). Exploratory objectives included analysis of the EGFR pathway at 2 time points from research-related biopsies. Pt reported outcomes (PROs) were assessed with MDASI (general and spine) questionnaires at several time points on study. Results: From May 2022 to Dec 2025, 29 pts enrolled. 4 were excluded from the efficacy analysis (2 withdrawal, 1 cetuximab allergy, 1 has not completed the 1 st imaging assessment). Median age was 58 years (range 21-76), 15 (58%) were men, and 24 (92%) had ECOG PS of 0 or 1. The most common primary site was skull base (46%). Tumor was classified as locally recurrent in 8 pts (31%) and metastatic in 18 pts (69%). One median line of prior systemic therapy was noted (range, 0-6). At a median follow up of 28.7 months, 12 pts (48%) had radiographic cytoreduction (any tumor reduction [ATR]), but only 2 pts (8%) had a partial response (PR). Neither PR was associated with an EGFR gene alteration. Stable disease (SD) was noted in 23 pts (92%). Preliminary median PFS and median OS was 9.9 months (95% CI, 6.3 to 13.4) and 38.8 months (95% CI, 18.6 to NR), respectively. Significantly longer PFS was observed in SD-ATR (log-rank p=0.038), with median of 14.2 months in SD-ATR versus 9.6 months in SD without tumor reduction. 7/26 pts (27%) experienced a grade 3 cetuximab-related adverse event (AE), the most common being rash in 4 pts (15%). No grade 5 AE related to cetuximab was reported. Dose reduction occurred in 2 pts (8%). 4 pts (15%) discontinued the study due to toxicity. 4 pts remain on study. Conclusions: Although the primary end point has not been reached, 2 PRs are noted, and pts with SD-ATR have a longer PFS. Translational and PRO analysis are ongoing to better define biological predictors of cetuximab activity in chordoma. Clinical trial information: NCT05041127 .