At the 2023 American Society of Clinical Oncology (ASCO) annual meeting, Carlotta Antoniotti, MD, PhD, University of Pisa, shares updated data and overall survival results from the AtezoTRIBE study. This study found a benefit to progression-free survival with the addition of atezolizumab to FOLFOXIRI plus bevacizumab for metastatic colorectal cancer patients in the first-line setting. 

Transcript:

My name is Carlotta Antoniotti, and I am a medical oncologist at the University Hospital of Pisa. And here at ASCO 2023, I am the presenter of updated and the overall survival results of the AtezoTRIBE study.

Many metastatic colorectal cancers, about 95%, are proficient mismatch repair or microsatellite stable, and thus intrinsically resistant to first generation immune checkpoint inhibitors. The AtezoTRIBE study was a phase 2, randomized, comparative trial sponsored by the Italian GONO Foundation, and it was conceived to provide preliminary evidence of benefit from the addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab metastatic colorectal cancer patients by exploiting the immunomodulatory properties of both an active chemotherapy regimen, such as the triplet FOLFOXIRI, and the anti-androgenic agent, bevacizumab.

AtezoTRIBE is a phase 2, randomized, comparative trial that included previously untreated metastatic colorectal cancer patients, selected according to the conventional eligibility criteria adopted in all GONO studies investigating FOLFOXIRI as a first-line treatment, in terms of age, ECOG performance status, and previous adjuvant chemotherapy. And in the AtezoTRIBE study, there was no molecular selection according to RAS, BRAF, or mismatch repair status. 

Patients were randomized in a 1-to-2 ratio to receive upfront FOLFOXIRI plus bevacizumab in the control arm, or the same regimen plus atezolizumab in the experimental arm. Treatment induction was administered up to 8 cycles, and then followed by maintenance with 5 mg bevacizumab with or without atezolizumab according to the randomization arm, until disease progression, and after disease progression, the reintroduction of the same agents received upfront was recommended. The primary end point was the progression-free survival.

The study included 218 patients, and after a median follow up of about 20 months, when around 70% of PFS events were recorded, the primary analysis was conducted and related results were already published in Lancet Oncology. A brief reminder of what we already know about the previously published AtezoTRIBE study results, patient characteristics were well-balanced between the 2 arms. Most patients at an ECOG performance status of 0, synchronous metastasis, and are right-sided and/or RAS-mutated tumor. All features that define the optimal candidate to first-line FOLFOXIRI plus bevacizumab, as recognized by current ASCO and ESMO guidelines.

We already know that the study met the primary end point to show that in the [intention-to-treat] ITT population the addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab, significantly prolonged the progression-free survival with no difference in response rate and with no safety issues. A significant interaction was found between the treatment arm and the mismatch repair status with a relevant magnitude of benefit from the addition of atezolizumab in the small subgroup of patients with deficient mismatch repair tumors. But more interestingly, a modest benefit from the experimental strategy was reported also among patients with proficient mismatch repair tumors.

Based on this data, we're looking for a predictive marker of benefit from the experimental strategy in this subgroup. More promising data are those about the Immunoscore IC, which is a novel immune-regulated tumor biomarker measuring the degree of immune reaction into the tumor by assessing a CD8 and the PD-L1 cell density into the tumor by means of immunochemistry and digital pathology. A significant interaction was found in terms of PFS in the proficient mismatch repair population between treatment arm and Immunoscore IC. In other words, patients with Immunoscore IC-high tumors, around 32% in our study population achieved higher benefit from the addition of atezolizumab to FOLFOXIRI plus bevacizumab, as compared to those with Immunoscore IC-low tumors.

At ASCO 2023, I presented updated and overall survival results of study after a median follow-up of 37 months when 80% of PFS events, and 54% of overall survival events were recorded. In the ITT population, the addition of atezolizumab FOLFOXIRI plus bevacizumab is confirmed to prolong progression-free survival with a significant P-value. And for the first time in the ITT population, a trend for a better overall survival in favor of the experimental arm is reported. And looking at subgroup analysis in the ITT population, the magnitude of benefit from the addition of atezolizumab plus bevacizumab is homogeneous across all analyzed subgroups with the exception of a significant interaction between treatment arm and mismatch repair status, TMB and Immunoscore IC with these associations confirmed at the multi-variable analysis.

Only Immunoscore IC is related to an overall survival differential benefit with patients with Immunoscore IC-high tumors achieving higher benefit from the addition of atezolizumab as compared to those with Immunoscore IC-low tumors. More interesting are data in the proficient match repair population where a progression-free survival benefit is confirmed in favor of the experimental strategy, and also in the proficient mismatch repair population, a trend for a better over survival is reported in favor of the experimental arm. 

Looking at subgroup analysis in the proficient mismatch repair population, a significant interaction is reported between treatment arm and Immunoscore IC and TMB with the independent potential predictive impact of these two biomarkers confirmed at the multi-variable models.

So, in conclusion, we can say that after a median extended follow-up of 37 months, the addition of atezolizumab to first line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer patients is confirmed to provide significant progression-free survival increase, and a trend for a better overall survival is reported for the first time. And similar results are observed in the cohort of patients with proficient mismatch repair tumors, where the magnitude of progression-free survival and overall survival benefit is heterogeneous according to TMB and Immunoscore IC being higher among patients with Immunoscore IC-high and/or TMB high tumors. And more interestingly, the independent predictive impact of both Immunoscore IC and TMB is confirmed at the multi-variable model in the proficient mismatch repair population. 

Based on this data, a confirmatory phase 3 trial will be launched by GONO Foundation to investigate the added value of the additional atezolizumab to FOLFOXIRI plus bevacizumab as first line in patients with metastatic colorectal cancer selected for having a proficient mismatch repair and Immunoscore IC-high tumors. 

Source:

Antoniotti C, Rossini D, Pietrantonio F, et al. FOLFOXIRI plus bevacizumab and atezolizumab as upfront treatment of unresectable metastatic colorectal cancer (mCRC): Updated and overall survival results of the phase II randomized AtezoTRIBE study. Presented at ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 3500