A phase II open‐label study with atezolizumab (atezo) in combination with bevacizumab (bev) in patients (pts) with advanced chemotherapy-resistant colorectal cancer (CRC) and MSI‐like molecular signature: The MoTriColor Consortium CT3 study.
Authors: Elez Elena , Siena Salvatore , Sartore-Bianchi Andrea , Ciardiello Fortunato , Martinelli Erika , Tejpar Sabine , Steeghs Neeltje , Cervantes Andres , Salazar Ramon , Ros Montañá Javier , Wilmsen Bieke , Huijberts Sanne , Roselló-Keränen Susana , Santos Cristina , García-Galea Eduardo , de Schaetzen Gaetan , Moreno Aguado Victor , Bernards Rene , Dienstmann Rodrigo , Tabernero Josep 
Published: June 2024

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Background: The MoTriColor project aimed to test hypotheses generated in prospective clinical trials that stratified pts based on molecular genomic signatures matched to selected therapies. Up to 10% of microsatellite stable (MSS)/proficient mismatch repair (pMMR) metastatic CRC have microsatellite instable (MSI)-like genomic expression signature (GES) characterized by higher cytotoxic microenvironment infiltration and mutational burden. Preclinical data suggest that the addition of bev to atezo may improve antitumor effect in both MSI-H/deficient MMR (dMMR)- and MSS/pMMR- MSI-like tumors. The MoTriColor international phase II CT3 (NCT02982694) study was designed to assess this combination. Methods: Pts with mCRC on progression to >1 chemotherapy (CT) line whose tumors were classified as MSI-like by GES in primary tissue samples (Agendia microarray), either MSI-H/dMMR or MSS/pMMR by standard diagnostic assays, received atezo (1200 mg /21 days) plus bev (7.5 mg/kg/21 days) until progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR) in the MSI-like population, assuming minimum response rate of 25% and an overall efficacy of 45%. Results: Overall, 46 pts with MSI-like mCRC were enrolled (24 MSI-H/dMMR-MSI-like and 22 MSS/pMMR-MSI-like). The median age was 64 years, 52% were male, 59% had right-sided tumors, and 33% had liver metastases (mets). Most pts (76%) received >2 CT lines. ORR for the whole cohort was 38.7% (CI 95%: 24.4%-54.5%; P=0.053). In the sub-cohorts of MSI-H/dMMR-MSI-like and MSS/pMMR-MSI-like pts, ORR was 65.2% (P<0.001) and 9.5% (P=0.13), respectively. Median progression-free survival (mPFS) was 6.4 months (CI95% 4.1-21). Among MSI-H/dMMR-MSI-like and MSS/pMMR-MSI-like, mPFS was 23.0 and 4.0 months, respectively. Exploratory analysis was performed to evaluate the clinical impact of liver mets. Among pts with MSI-H/dMMR-MSI-like tumors, ORR was 33% in pts with liver mets and 76% without liver mets. Among pts with MSS/pMMR-MSI-like tumors, ORR was 0% in pts with liver mets and 15% without liver mets. Grade 3/4 adverse events related to atezo and bev were reported in 11% and 20% of the pts. There were 2 Grade 5 AEs (1 pulmonary distress and 1 colonic hemorrhage). Conclusions: The primary study endpoint was not met, but we found clinically meaningful ORR with atezo in combination with bev in pts with MSI-H/dMMR-MSI-like tumors. In MSS/pMMR-MSI-like tumors, anti-tumor activity was confined to pts without liver mets. These results open a new therapeutic option for mCRC pts with MSI-H/dMMR tumors. Clinical trial information: NCT02982694 .