Abstract B033: Petosemtamab (MCLA-158) monotherapy or with chemotherapy in metastatic colorectal cancer: Preliminary antitumor activity and safety data from a phase 2 trial

Abstract Background: EGFR is a known oncogenic driver in colorectal cancer (CRC). The leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is expressed in CRC stem-like cells and drives tumor initiation, growth and metastasis. Petosemtamab, a human, common light chain, IgG1 bispecific ADCC-enhanced antibody, targets tumor cells by degrading EGFR in LGR5+ stem-like cancer cells, blocking EGFR signaling and triggering Fc-mediated immune response. Here we report preliminary data from expansion cohorts of the phase 2 trial (NCT03526835) of petosemtamabin combination with standard of care FOLFOX or FOLFIRI in 1L, 2L metastatic CRC (mCRC) and petosemtamab monotherapy in 3L+ mCRC. Methods: Patients (pts) with left- and right-sided, KRAS, NRAS, and BRAF wildtype microsatellite stable mCRC received petosemtamab 1500 mg Q2W, in combination with FOLFOX or FOLFIRI or as monotherapy, until disease progression or unacceptable toxicity. Pts treated in 1L or 2L had no prior anti-EGFR therapy, with 2L having 1 prior chemotherapy regimen in the metastatic setting. 3L+ mCRC had at least 2 prior regimens in the metastatic setting, including a prior anti-EGFR therapy. Tumor imaging conducted Q8W. Primary endpoint is investigator-assessed overall response rate (RECIST v1.1); secondary endpoints include duration of response and safety. Results: As of April 28, 2025, 36 pts were treated. Median age was 56 yrs (range 30-80), 58% male, 75% white, ECOG PS 0/1 in 39%/61% of pts. 7 pts were treated in 1L (6 FOLFOX and 1 FOLFIRI), with 6 ongoing. 3 pts were efficacy evaluable, median follow up 2.6 months, with 1 unconfirmed complete response and 2 partial responses (PR; 1 unconfirmed). 10 pts were treated in 2L (1 FOLFOX and 9 FOLFIRI), with 8 ongoing. 8 were efficacy evaluable, median follow up 3.4 months, with 4 PRs (2 unconfirmed), 3 stable diseases (SD; all ongoing) and 1 clinical deterioration prior to first scan. All unconfirmed responders are ongoing without disease progression. Most frequent treatment-emergent adverse events (TEAEs) regardless of causality in FOLFOX combination (all Grades [G]/G3) were dermatitis acneiform (71%/0%), constipation (43%/0%), fatigue (43%/0%), and peripheral neuropathy (43%/0%). No fatal treatment-related TEAEs observed. Most frequent TEAEs regardless of causality in FOLFIRI combination (all G/G3) were diarrhea (70%/0%), mucosal inflammation (50%/10%), and fatigue (40%/0%). 19 pts were treated in 3L+ (monotherapy), with 12 pts ongoing. 14 were efficacy evaluable, median follow up 2.5 months, with 1 unconfirmed PR ongoing without disease progression, 6 SDs (all ongoing), 6 progressive diseases and 1 death unrelated to treatment prior to first scan. Most frequent TEAEs regardless of causality (all G/G3) were rash (58%/0%), and nausea (26%/0%). No fatal treatment-related TEAEs observed. Conclusions: Petosemtamab demonstrates promising efficacy and manageable safety across 1L, 2L and 3L+ mCRC. Updated data will be provided; biomarker analysis is ongoing. Citation Format: Moh'd Khushman, Ruth Vera, Thibault Mazard, DiSean Kendall, Maria Elena. Elez, Francesc Salva, Elisa Fontana, Gregory P. Botta, Marcos Melián, Leon Pappas, Ludovic Evesque, Anastasia Murat, Chris Yan, Marina Magin, Gianluca Laus, Fabian Zohren, Josep Tabernero. Petosemtamab (MCLA-158) monotherapy or with chemotherapy in metastatic colorectal cancer: Preliminary antitumor activity and safety data from a phase 2 trial [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B033.