417 Background: Interleukin-1 Receptor Associated Kinase -4 (IRAK4) drives pro-survival NF-kB signaling in various gastrointestinal cancers. In preclinical animal models, the oral IRAK4 inhibitor, emavusertib (CA-4948), augments the efficacy of cytotoxic chemotherapy by suppressing cell intrinsic survival mechanisms and prolongs survival when combined with cytotoxic chemotherapy as well as reduces desmoplasia in preclinical models. Methods: This is a single-institution, Phase I, dose escalation/expansion clinical trial of emavusertib in combination with FOLFOX and PD-1 inhibitor (nivolumab or pembrolizumab) and anti-Her2 therapy (trastuzumab if Her2 positive) as first-line therapy for metastatic or unresectable esophageal, gastroesophageal junction, or gastric cancers (adenocarcinoma or squamous cell carcinoma) (NCT05187182). The primary objectives of this study are to determine the safety, dose-limiting toxicities, and Recommended phase 2 dose (RP2D) of emavusertib in combination with FOLFOX/ PD-1 inhibitor +/- trastuzumab. Emavusertib is given orally at escalating doses of DL0 (150mg BID) and DL1 (200mg BID) with FOLFOX/ PD-1 inhibitor +/- trastuzumab on a 14-day cycle. Dose escalation is according to the BOIN design to determine the MTD of emavusertib with the combination. Toxicities are graded according to CTCAE v5.0. Response is evaluated according to RECIST v1.1 criteria. Results: We have treated 7 patients in dose escalation (DL0 N=3, DL1 N=4) with no DLTs at either dose level. One patient in DL1 was replaced due to non-compliance with study therapy. DL1 (emavusertib 200mg BID) was determined to be the expansion dose. Four patients have been treated at DL1 in dose expansion cohort A (Her2 negative), and 2 patients have been treated at DL1 in dose expansion cohort B (Her2 positive). There have been no SAEs related to emavusertib at either dose level. Of the 3 patients treated at DL0 (escalation), there was 1 CR, 1 PR, and 1 SD ( the CR patient progressed after 25 months on study) . Of all patients treated at DL1 who have reached their first scan on study (escalation and expansion), there are 2 PRs and 4 SDs. For all patients, the median duration on study is 4.9 months (range 0.5-25 months). Nine patients continue to receive study therapy. Conclusions: At this early stage of the study, emavusertib in combination with FOLFOX/ PD-1 inhibitor +/- trastuzumab as first-line therapy for metastatic or unresectable gastroesophageal cancers has a manageable toxicity profile and shows encouraging preliminary results. Enrollment in dose expansion arms at emavusertib 200mg BID (Her2 positive and negative) is ongoing. Clinical trial information: NCT05187182 .
Grierson et al. (2026) studied this question.