3534 Background: Gut microbiome has emerged as a biomarker of clinical benefit to immune-checkpoint inhibitors (ICI) but no data are available in metastatic colorectal cancer (mCRC). The AtezoTRIBE study demonstrated that the addition of atezolizumab (atezo) to FOLFOXIRI plus bevacizumab (bev) prolongs progression-free survival (PFS), but this benefit is limited for patients with proficient mismatch repair (pMMR) tumors. Here, we aimed at investigating the potential predictive role of microbiome in identifying mCRC patients able to achieve benefit from ICI. Methods: AtezoTRIBE was a phase II trial in which 218 mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bev (arm A) or FOLFOXIRI/bev/atezo (arm B). Stools were prospectively collected. Metagenomic (MG) data from whole genome sequencing (WGS) at level of species genome bins (SGBs) were analysed by linear models corrected for clinical and tumor-related parameters and fold-ratios. We defined as responders (R) those patients who experienced a PFS ≥ 12 months. Results: Stool samples were collected at baseline for 171 (78%) patients (55 in arm A and 116 in arm B) but only 163 were available for MG. Patients with deficient MMR (dMMR) tumors (N = 10) showed significantly lower MG diversity than pMMR ones (N = 148) harboring oral bacteria and pathobionts whose intrinsic immunogenicity has not been demonstrated. Regarding pMMR mCRC patients, baseline microbiome composition was not significantly different according to the treatment arm. The microbiome diversity was not significantly different between R and not-R in both arms, but specific immunogenic SGBs (Lachnospiraceae family members) were over-represented in R treated in arm B. Veillonellaceae and pathobionts were associated with poor prognosis and/or differential benefit from the addition of atezo. Fusobacterium nucleatum was associated with a poor prognosis, also in arm B. Conclusions: This is the largest prospective analysis showing that SGBs may be useful as a biomarker of potential benefit or detrimental effect from atezo in pMMR mCRC patients. Our results prompt the design of microbiota-centered diagnostic tests to identify pMMR mCRC patients more likely to benefit from ICI-based therapeutic strategies. Clinical trial information: NCT03721653 .

e15164 Background: Refining the selection of pts with HER2-positive mCRC for dual HER2 blockade is a challenge for precision oncology. Alterations in receptor tyrosin-kinase (RTK)/MAPK pathway and HER2 gene copy number (GCN) are promising predictive biomarkers for primary resistance or sensitivity, respectively. Methods: We conducted a multicentric case-control study to evaluate the negative predictive impact of a panel of candidate genomic alterations of primary resistance (PRESSING-HER panel) in pts with HER2-positive, RAS wt mCRC treated with trastuzumab-based dual HER2 blockade. Comprehensive genomic profiling was performed on archival pre-treatment tumor samples and screening sources were: the TRIUMPH trial (Oncomine Comprehensive Assay), the Italian-Spanish observational cohort (Foundation One CDx) and the MSKCC cohort (MSK-IMPACT). The panel grouped resistance alterations with a solid biological rationale as on-target, i.e. HER2 pathogenic mutations or rearrangements or off-target, i.e. mutations/amplifications in RTK/MAPK genes. Primary resistance was defined by PFS < 4 months (mos), sensitivity was defined by PFS ≥4 mos. Hypothesizing a prevalence of PRESSING-HER alterations equal to 5% and 30% among controls and cases, respectively, 35 cases and 35 controls were needed to reject the null hypothesis of equally prevalent alterations, with α and β errors of 0.05 and 0.20. HER2 GCN was derived from NGS and the cut-off was calculated by ROC curve analyses using 4-month PFS rate as endpoint. Results: Sixty-eight pts were evaluable (33 resistant and 35 sensitive). In the overall population, PRESSING-HER alterations were found in 14 (20.6%) pts and included HER2 mutations in 7 (50%), HER2 rearrangements in 4 (29%), BRAF class 1 mutations in 2 (14%) and EGFR amplification in 1 (7%). PRESSING-HER alterations were significantly more frequent in pts with primary resistant (12/21, 57%) versus (vs) sensitive tumors (2/35, 6%; P= 0.004). HER2 GCN had a median value of 34.5 (IQR: 18.7-78.5) and an optimal cut-off of 33. In multivariable analyses including the main baseline clinical prognostic features, PRESSING-HER alterations were independently associated with inferior PFS (median PFS 2.0 vs 5.4 mos; adjusted HR 3.5, 95%CI 1.7-7.0; P< 0.001) and OS (median OS 3.7 vs 14.8 mos; adjusted HR 3.9, 95%CI 1.8-8.3; P< 0.001). HER2 GCN < 33 was associated with significantly inferior median PFS (2.6 vs 5.4 mos; adjusted HR 1.8, 95%CI 1.0-3.1; P= 0.038) and numerically inferior OS (median OS 9.1 vs 15.4 mos; adjusted HR 1.3, 95%CI 0.7-2.5; P= 0.356). The predictive accuracy of PRESSING-HER was 66% and it was increased to 77% when combined with HER2 GCN. Conclusions: The combined assessment of HER2 on/off-target alterations and HER2 GCN stratifies patient outcomes to HER2 dual blockade.

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BackgroundImmune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.MethodsWe conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a ‘burden score’ constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.ResultsAmong 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two’s effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, ‘aggregated’ burden scores were developed to distinguish ‘protective’ (endocrine and musculoskeletal) and ‘harmful’ (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.ConclusionsOur results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.

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