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2025 Background: Brain metastases (BM) from primary colorectal cancer (prCRC) are rare (1-3%); few is known about CRC BM predictive factors, prognosticators and molecular pathways. High rate of HER2 amplification ( HER2+) in CRC with BM was previously described, being HER2+ overall rare in CRC (

5 Background: Advanced squamous cell anal cancer (aSCAC) is a rare and aggressive disease, accounting for poor prognosis and high morbidity. No targeted therapies are currently available and, after the first line, no standard treatments are approved. Immune checkpoint inhibitors (ICI) showed signs of activity in previous phase I/II trials, but predictive and prognostic biomarkers are lacking. Anti-EGFR have been tested given the rarity of KRAS mutations in aSCAC, with encouraging results. Earlier preclinical evidence suggests possible synergism between cetuximab (cet) and ICI. Methods: In the phase II randomized trial CARACAS (NCT03944252), we tested avelumab (ave) alone (Arm A) or with cet (Arm B) in pretreated aSCAC; overall response rate (ORR) was the primary endpoint. With one-sided a error set at 0.05 and power of 80%, at least 4 responses out of 27 patients (pts) per arm had to be observed to declare the study positive. On pre-treatment tumor tissue samples, we assessed HPV status, PD-L1 expression, microsatellite status, tumor mutational burden (TMB) and performed next generation sequencing (NGS) via FoundationOne CDx. Primary objective was to describe the clinical outcomes of ICI in SCAC in the CARACAS trial population according to molecular analyses. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular characteristics to individuate new prognostic biomarkers in SCAC. Cox regression was used to investigate the effect of the main variables analysed on survival. Translational analyses were performed on the 100% of the study population since all the pts received ICI. Results: In the clinical trial, the Arm B reached the primary endpoint (ORR 17%, 95% CI 5·6-34·7). High TMB (≥10 mutations per megabase) was related with longer OS (HR=0.09; 95% CI 0.01-0.68; p=0.019), showing the same trend in PFS (HR=0.44; 95%CI=0.15-1.27; p=0.129). As well, tumors with high expression of PD-L1 (>40 measured with combined positive score, CPS) showed significantly longer OS (HR=2.19; 95% CI=0.92-5.19; p=0.075) and PFS (HR=2.35; 95%CI=1.09-5.1; p=0.03). High TILs (>1.2) did not affect significantly OS (HR=0.77; 95% CI=0.42-1.4; p=0.39) nor PFS (HR=1.19; 95%CI=0.57-2.48; p=0.645). When combined together and with high TILs, high TMB and PD-L1identified pts with significantly better prognosis in OS (HR=0.43; 95% CI=0.21-0.87; p=0.019) and PFS (HR=0.48; 95%CI=0.23-1.00; p=0.051). Remarkable responses were also observed in pts with high PD-L1 expression and TMB. Conclusions: TranslaCARACAS study documented prognostic role of high TMB and PD-L1 in mSCAC treated with ICI with or without anti-EGFR. Stratifying per high TMB, PD-L1 and TILs, a subgroup of pts with particularly favorable prognosis and deep responses were detected. Further investigation in larger cohorts is warranted to confirm our findings.

The melastatin-like transient-receptor-potential-7 protein (TRPM7), harbouring a cation channel and a serine/threonine kinase, has been implicated in thymopoiesis and cytokine expression. Here we show, by analysing TRPM7 kinase-dead mutant (Trpm7 R/R) mice, that the enzymatic activity of the receptor is not essential for thymopoiesis, but is required for CD103 transcription and gut-homing of intra-epithelial lymphocytes. Defective T cell gut colonization reduces MHCII expression in intestinal epithelial cells. Mechanistically, TRPM7 kinase activity controls TGF-β-induced CD103 expression and pro-inflammatory T helper 17, but not regulatory T, cell differentiation by modulating SMAD2. Notably, we find that the TRPM7 kinase activity promotes gut colonization by alloreactive T cells in acute graft-versus-host disease. Thus, our results unravel a function of TRPM7 kinase in T cell activity and suggest a therapeutic potential of kinase inhibitors in averting acute graft-versus-host disease., Gut-homing and colonization of T cells are important for maintaining local immune homoeostasis and protective immunity. Here the authors show that the kinase activity of TRPM7 regulates Th17 differentiation and T cell alloreactivity in the gut by modulating SMAD2 activation and CD103 expression in T cells

4051 Background: Advanced squamous cell anal carcinoma (advSCAC) is a rare disease with poor prognosis. No standard therapies beyond first line are currently available, yet a promising activity was documented for the anti-EGFR cetuximab (CET) and for anti-PD-1 agents in previous retrospective case series and phase I-II studies, respectively. In experimental models combination of EGFR and PD-L1 blockade was synergistic as PD-L1 blockade led to NK cells activation enhancing cetuximab ADCC. In this trial we aimed to evaluate safety and activity of the anti-PD-L1 avelumab (AVE) alone or in combination with CET in pretreated advSCAC. Methods: This was an open-label, prospective, multicenter randomized phase 2 trial (NCT03944252). Patients (pts) with advSCAC progressed after at least 1 line of treatment were randomized 1:1 to receive either AVE 10 mg/kg (arm A) or AVE + CET 500 mg/sqm (arm B) as bi-weekly regimens. A Simon’s two-stage Mini-Max design was used. The null hypothesis of a true response rate 5% was tested against the one-sided alternative of a true response rate 20% in each arm. Setting type I error at 0.05 and power at 80%, 30 pts per arm had to be randomized. No formal comparison between the two arms was planned. Primary endpoint was overall response rate (ORR); secondary endpoints were Progression-Free Survival (PFS), Overall Survival (OS) and safety. Results: Sixty pts were enrolled, 30 in each arm. All baseline characteristics were well balanced between the two arms. Median age was 63 years; M/F was 19/41; 12 out of 30 pts in each arm had distant metastases; 7 in arm A and 10 in arm B received > 1 previous lines of treatment. At a median follow up of 8.7 months, 3 out of 30 pts in each arm obtained PR (ORR 10%); SD was observed in 12 pts in arm A (40%) and 14 in arm B (47%). Disease control rate was thus 50% in arm A and 57% in arm B. Duration of disease control was 6.1 (95%CI 3.7–11.0) and 6.1 (95%CI 4.1–9.6) months in arm A and B, respectively. Median PFS was 2.1 (95%CI 1.8–4.0) in arm A and 3.9 months (95%CI 2.1–5.6) in arm B. Grade 3-4 adverse events were 13.3% in arm A and 33.3% in arm B: anemia 10% vs 13.3%, fatigue 0 vs 6.7%, skin toxicity 0 vs 6.7%. Treatment interruption due to AE occurred in 3 pts, 1 in arm A and 2 in arm B. Translational analyses will be performed on tissue and blood samples for exploratory purpose. Conclusions: The CARACAS trial was the first clinical study to test dual EGFR and PD-L1 blockade in advSCAC. Both AVE monotherapy and AVE-CET showed promising activity with manageable safety profile. Clinical trial information: NCT03944252 .