Abstract 54P
Background
The standard 3rd-line treatment for metastatic colorectal cancer (CC) relies on the trifluridine/tipiracil (FTD-TPI) and bevacizumab combination. IL-1α is highly expressed by CC cells and is associated with a poor prognosis. FTD-TPI depletes tumor-associated macrophages and induces IL-1 release by dying macrophages and monocytic myeloid-derived suppressor cells. This supports testing the combination of TAS-102 plus XB2001 (an IL-1α monoclonal antibody).
Methods
In the phase 1/2 TASKIN study (NCT05201352), patients (pts) with chemorefractory metastatic CC after failure of oxaliplatin, irinotecan, and fluoropyrimidine were enrolled and received XB2001 from 250 mg to 1000 mg every 2 weeks plus FTD-TPI 35 mg/m2. A protocol amendment has allowed to add bevacizumab. We report the results of the phase I dose-escalation cohort. The primary endpoints were safety and tolerability.
Results
As of March 2024, 17 pts were enrolled, of whom 4 received bevacizumab (24%). No dose-limiting toxicity was observed. Grade ≥ 3 treatment-related adverse events (TRAE) occurred in 3 pts (17%). The most common TRAEs of any grade were nausea (47%), diarrhea (29%), thrombopenia (29%), anemia (23%), and neutropenia (23%). The only G3-4 TRAE was neutropenia (17%). For the PK profile of XB2001, the AUC proportionally increases with the dose level. Saturation of the target and stable plasmatic concentration were reached at 1000 mg. CT scan tumor shrinkage was observed in 10 (59%) pts. Partial Response (PR) by RECIST 1.1 was achieved in 3 pts, and 12 pts had stable disease (SD) for a Disease Control Rate (DCR) of 88% with a duration of up to 17 months. IL-6 serum level, a known surrogate marker for IL-1α activity, has decreased in 12 out of 16 pts. Better response and longer PFS were associated with a decrease in serum IL-6 level during therapy or with induction of an anti-NY-ESO1 immune response. Intratumoral CD8/PD-L1 infiltration at baseline was associated with a better outcome.
Conclusions
FTD-TPI plus XB2001 and bevacizumab demonstrated acceptable safety with promising efficacy in chemorefractory metastatic CC. The study continues as a randomized phase 2 study comparing FTD-TPI and bevacizumab with or without XB2001.
Clinical trial identification
NCT05201352.
Legal entity responsible for the study
Centre Georges-François Leclerc.
Funding
XBiotech.
Disclosure
F. Ghiringhelli: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Amgen, Merck Serono, MSD. All other authors have declared no conflicts of interest.