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218 Background: Immune checkpoint inhibitors (ICI) showed high efficacy in both first and subsequent lines in metastatic colorectal cancer with mismatch repair deficiency (dMMR-mCRC); however, they still fail in a minority of patients (pts). In non-preplanned analyses from previous studies, RAS mutations ( RASm) have been related to limited activity of ICI monotherapy (ICIm) as compared to ICI doublets (ICId) in dMMR-mCRC. Emerging data suggest different immunological features in presence of RASm, resulting in lower immunogenicity. Methods: NERDY is a retrospective, monocentric study designed to investigate the effect of ICIm and ICId on dMMR-mCRC basing on RASm. Pts with dMMR-mCRC treated with ICIm/ICId at our Institute were included. Clinical-pathological features for each patient were collected. On primary tumor specimens, proinflammatory pathways and CMS subgroup will be assessed by Nanostring and RNA-Seq respectively. The study is exploratory and no formal hypothesis has been postulated. Both PFS and OS were calculated with Kaplan-Meier. Cox proportional hazard model was adopted in the interaction tests. Primary objective was to assess OS and PFS according to RAS in dMMR-mCRC pts treated with ICIm or ICId. Secondary objectives were to describe the inflammatory infiltrate and TMB in dMMR-mCRC according to RAS status. Results: From June 2015 to January 2022, a total of 126 consecutive dMMR-mCRC pts treated with ICI were included, 33 RASm/93 RASwt. RASm pts were more frequently males (p=0.015) and younger (median age 47 vs 65). An imbalance was observed in sidedness (more right-CRC in RASwt than in RASm as BRAF effect, p=0.001) and timing of ICI (administered in later lines in RASm, p=0.013). No differences in ECOG-PS, histotype, disease burden, stage at diagnosis, treatment with ICIm vs ICId and best response. At a median follow up of 53.5 months (95%CI 34.7-56.9), a trend toward longer PFS in pts treated with ICId over ICIm was found in the overall population (HR 0.62; 95%CI 0.36-1.05; p=0.055), being significantly longer in RASm-only pts (HR 0.41; 95%CI 0.13-1.28; p=0.047) but not in RASwt-only pts (HR 0.64; 95%CI 0.34-1.20; p=0.139). No difference was observed in OS between ICId and ICIm in the overall population (HR 0.64; 95%CI 0.36-1.16; p=0.121), in RASwt (HR 0.59; 95%CI 0.29-1.20; p=0.132) nor in RASm pts (HR 0.59; 95%CI 0.19-1.78; p=0.275). Interaction test for RAS and ICI treatment type was not significant for PFS (HR 0.63; 95%CI 0.21-1.94; p=0.423) nor for OS (HR=1.00; 95%CI 0.29-3.41; p=0.999). Conclusions: Preliminary clinical results of the NERDY study suggest enhanced activity of ICId compared to ICIm in pts with RASm dMMR-mCRC. Further data are expected from pending translational analyses and a pre-planned adjunctive cohort from two other Italian centers will be used for external validation.

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.

87 Background: Anti-PD-(L)1-based therapy yielded unprecedented efficacy in patients with MSI-high mCRC. A relevant proportion of subjects may achieve long-term disease control when receiving ICIs, particularly anti-PD-1 plus anti-CTLA-4 combo. However, some patients still experience treatment refractoriness or short-term clinical benefit. Methods: We analyzed data of 163 patients with MSI-high mCRC treated with anti-PD-1 +/- anti-CTLA-4 agents. The endpoint was progression-free survival (PFS); multivariable analyses were performed using a cure model (Othus et al, CCR 2012), which allows to test which factors, including ICI type, could identify patients achieving long-term disease control. To account for biases consistent with non-random ICI assignment, we estimated a propensity score (covariates: ECOG PS, age, sex, primary tumor location, its resection, adjuvant treatment, synchronous presentation of mets, mucinous histotype, RAS/BRAF status, n. prior treatment lines, previous chemo, n. metastatic sites, presence of peritoneal, lung, liver, bone, brain, nodal mets), and then in the cure model we applied an inverse-probability-of-treatment-weight (IPTW) based on propensity score. A beforehand variable selection was operated using a random survival forest (RSF) model (RSF covariates: all the propensity score covariates plus ICI line and ICI type, platelets count (PLT), NLR, LDH), where we introduced a weight system in order to adjust variable selection net of ICI type. Results: RFS selected 5 variables: ICI type, ECOG PS, NLR, PLT and N. prior lines, the combination of which allowed to estimate the cure probability: the higher the probability the greater the chance of achieving long-term disease control. The Table shows the odds ratio estimates, defining the chance of being “cured” according to the values of the selected variables. ICI type was significantly associated with long-term disease control: patients treated with anti CTLA-4-combo achieved the highest chance of being cured, 3.41 times greater than the chance of patients treated with anti PD-1 mono. The median cure probability was as higher as 70.1% (IQR: 51.9-81.0%) with CTLA-4-combo vs 34.8% (IQR: 18.4-51.9%) with anti-PD-1 mono; the probability within treatment groups was varying according to ECOG PS, NLR, PLT and n. prior lines. Conclusions: Based on 5 variables including the ICI treatment type, a nomogram was built in order to estimate the cure probability in patients with MSI-high mCRC and potentially assist clinicians in their clinical practice. [Table: see text]

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 .

e12005 Background: Neutropenia (N) is a common chemotherapy (CT) related adverse event and febrile N (FN) often requires hospitalization, being associated with morbidity and mortality. Primary prop...