3573 Background: Emerging evidence suggests that WNT mutations and liver/peritoneal metastases in mCRC may have an immunosuppressive role that could affect ICI activity. Aim: To evaluate the impact of WNT alterations and liver/peritoneal metastasis among patients with mCRC treated with ICi. Methods: Patients from Vall d’Hebron Hospital, with mCRC treated with ICI from 2017-2022 were included. WNT alterations (APC, AXIN1/2, CTNNB1, FBXW7, EPHB2, RNF43 and SOX9) were evaluated using NGS (tissue). Clinical outcomes were calculated using survival Kaplan-Meier curves. Patients' characteristics were collected retrospectively. Results: Overall, 104 patients were included (66 MSI patients and 38 MSS patients). Among MSI patients, median age was 63 years (22-95), with 53% female, and 64% of patients received immunotherapy in 1st or 2nd line. Regarding tumor characteristics, 72% were right-sided and 82% harbored WNT alterations. 75% of patients presented with liver/peritoneal metastases. Patients with WNT mutations and peritoneal/liver metastases exhibit lower ORR (46% vs 57% p 0.5 and 45% vs 75%, p 0.03 respectively). Peritoneal/liver metastases were associated with lower PFS (HR 3.6 CI95% 1.27-10.24 p 0.02 respectively). Overall, tumors with WNT pathway alterations tend to have shorter PFS and OS. Liver metastases were associated with lower OS (NR vs 34 months HR 2.49 CI95% 1.01-6.17 p 0.05). Table summarizes outcomes. Among MSS patients, median age was 57 years (41-75), with 25% female and 92% of patients receiving immunotherapy > = 3rd line. Regarding tumor characteristics, 78% were left-sided and 90% harboured WNT alterations. 79%, of patients presented with liver or peritoneal metastases. WNT mutations were not associated with ORR, patients without liver/peritoneal metastases tend to have higher ORR (12.5% vs 3.3% p 0.335). Patients with WNT alterations had worse PFS (9.23 vs 1.87 months, p 0.12), and liver metastases were associated with lower PFS (6.98 vs 1.79 months HR 2.87 CI95% 1.17-7.09 p:0.02). Regarding OS, tumors harboring WNT alterations have shorter OS (8.4 vs 12 months p 0.63). The presence of liver or peritoneal metastases was associated with lower OS (NR vs 7.85 months HR 3.69 CI95% 1.09-12.55 p: 0.04). Conclusions: In our cohort, WNT pathway mutations, and liver metastases were associated with worse ORR, PFS, and OS regardless of MSI status. These findings need further validation in a prospective cohort. [Table: see text]

3560 Background: Currently, there are no well-established biomarkers available to select mCRC patients (pts) who will benefit most from antiangiogenic therapy. RAS mutant (mt) allele fraction in plasma (plMAF) is an independent prognostic factor in mCRC. Preliminary data from our group suggests the possible predictive role of plMAF in RAS mt pts treated with 1st line chemotherapy (ct) +/- bevacizumab (bev). Methods: Data prospectively/retrospectively collected from RASmt mCRC pts who received 1st line ct+/-bev treatment in our center, selecting the subset of pts with plMAF sample evaluable with digital PCR (BEAMing) at baseline. Pts were stratified as high (≥ 5.8%) or low ( < 5.8%) plMAF, based on a previously established prognostic cutoff (Elez et al, Mol Onc 2019). We investigated the associations between clinic-pathological variables, overall survival (OS), and progression-free survival (PFS) stratified by plMAF RAS levels using Cox regression models. OS and PFS were calculated by Kaplan-Meier method. Murine PDX were developed from mCRC pts including models from patients with KRASG12/G13 mutations to explore recapitulation of the clinical findings. Results: From October ‘17 to December ‘21, 102 basal plasma samples were analyzed by BEAMing. 47 pts (46%) were classified as high, 39 pts (38%) as low, and 16 (16%) as no-mt detected by BEAMing (non-shedding). OS was significant longer in low plMAF pts than in high plMAF pts (median OS 15.9 vs 37.1 months (mo); HR 0.43; p = 0.001). In high plMAF pts, a trend towards a better PFS was observed in those pts treated with ct+bev compared to ct alone (median 9.4 vs 6.1 mo; HR 0.6; p = 0.18). No differences were observed in low plMAF pts treated with ct +/- bev (median 14.5 vs 14.9 mo; HR 1.2; p = 0.58). Results were not modified when adjusted by the presence of liver metastases. The multivariate PFS model showed no association between RAS plMAF and clinicopathological variables, except for treatment benefit with ct+bev and better outcomes in pts with resectable liver metastases. Interestingly, human ctDNA in one murine PDX model from non-shedding pt was not detectable, whereas human ctDNA was present in another PDX model with a plMAF of 36.2%. Conclusions: This study suggests that plMAF could be a promising predictive biomarker of response to bev in 1st line RASmt mCRC, but more pts need to be analyzed to confirm this effect. Our results confirm the prognostic role of RASmt plMAF in mCRC. plMAF could partially depend on tumor cell shedding degree and characteristics on the tumor vasculature architecture, this is being investigated in ongoing imaging studies and PDX models. These models will also help to understand the biology behind tumor response to bev and its connection with ctDNA shedding.

e20604 Background: ALK rearrangements are present in 5% of NSCLC patients and its identification is of relevance as it confers sensitivity to ALK tyrosine kinase inhibitors (ALK-TKI). This study pretends to show treatment response and survival outcome in ALK+ patients treated in clinical trials at Vall Hebron Institute of Oncology (VHIO). Methods: This retrospective study includes 109 patients with ALK+ stage IV NSCLC, treated between 2010 and 2020 in the clinical trial setting. Objective response rate (ORR), progression free survival (PFS), overall survival from metastatic diagnosis (OS-d) and overall survival from targeted therapy start (OS-t) were assessed. A Multivariate Cox regression was applied to determine correlations between clinical features and OS-d. Results: Out of 109 patients with ECOG 0-1, 67% were women and 33% men. Median age at diagnosis was 53 yr, 64% were never-smokers, 30% former smokers, 5% current smokers. Histology was mainly adenocarcinoma (96%) and brain metastases were present in 58% cases at clinical trial treatment initiation. 13% of patients were treatment-naive, 42% were ALK-TKI naïve, 39% had previously received crizotinib, 21% had previously received second-generation ALK-TKIs. Most patients were treated in phase I clinical trials (54%), followed by phase II (22%), III (19%) and IV (5%). 7% were treated with crizotinib, 66% were treated with second-generation ALK-TKIs, 27% were treated with third-generation ALK-TKIs. Global ORR was 69% (83% in ALK-TKI naïve patients, 69% in patients previously treated with crizotinib and 56% in patients previously treated with a second-generation ALK-TKI) with no differences between patients with and without brain disease at study entry (68% vs. 70%). Median PFS was 16 months (m) (95% CI 11-24), 30m in ALK-TKI naïve patients (p = 0.06), 10m in patients previously treated with crizotinib (p = 0.04) and 10m in patients previously treated with second-generation ALK-TKIs (p < 0.001). No significant differences were seen between patients with and without brain metastasis at study entry (11 m vs. 16 m, p = 0.64). Global OS-d was 71m. Global OS-t was 60m. Multivariate Cox analysis showed smoking history [HR = 0.66 p = 0.358], presence of brain metastatic disease at clinical trial inclusion [HR = 0.87 p = 0.73] or gender [HR = 1.74 p = 0.231] did not affect OS-d. Having received, at least, a second generation ALK-TKI prolonged OS-d (p = 0.007) as well as having received third generation ALK-TKIs [HR 0.09, p < 0.001]. Conclusions: Clinical trials represent an opportunity of access to novel therapies and may provide an alternative for patients with no treatment options. This study, with 54% of patients treated in phase I clinical trials, has shown high ORR and prolonged PFS and OS for ALK + patients, regardless of brain disease extension. Sequential therapy with ALK inhibitors has also been proven important for OS.

12121 Background: Prognostic factors for oncologic pts after surgery or curative systemic treatment have been described, including ECOG performance status, tumor staging and malnutrition. However, there is no solid evidence on which combination of variables best predicts mortality after hospitalization of metastatic cancer pts under active systemic treatment. Methods: Prospective multicentric study of pts hospitalized between 2020 and 2022 at the Oncology wards of Vall d’Hebron, Sant Pau and Mar Hospitals [PLANTOLOGY database] in Barcelona, Spain. Clinical factors such as ECOG, comorbidities, tumor characteristics, and laboratory results were collected at admission. Mental status (depression and anxiety) and QOL were assessed through the HADS and EORTC-QLQ30 questionnaires, respectively. Nutritional assessment was performed using the chair and hand grip tests. All variables were analyzed in uni- and multivariable regressions including a machine learning LASSO model to assess predictive discriminators of 30-day mortality after discharge. Missing data was imputed using Multivariate Imputation by Chained Equations. A bootstrap with 1000 iterations was used to validate the model and c-index. Results: Among 1,663 pts, 932 had advanced disease and were under oncologic treatment during the 6 months previous to urgent admission, our target population for model development and validation. Median age was 64 years, 51% had an ECOG > 1, median Charlson comorbidity index was 8 and 34% were under treatment in a clinical trial. The most frequent tumor types were lung (25%), colorectal (14%) and breast (12%) cancer. The most relevant factors associated with higher mortality at 30-day after discharge in LASSO model were high Charlson index, low neutrophil count, high LDH, poor ECOG status and progressive disease at admission (all p-values p < 0.05). The c-index corrected after bootstrap validation was 0.75. After adding the nutritional assessment, mental health status and QoL (subset of 606 with complete data), the predictive power of the model increased to a c-index corrected after bootstrap validation of 0.81. Our final prognostic model called the PRognostic Oncologic Plantology score (PROP) obtained a sensitivity of 0.75 and a specificity of 0.80 with an overall accuracy of 0.80. Only 10% of “low” PROP score pts (72% of the population) died within 30 days of discharge, as compared to 58% of early mortality in “high” PROP score pts. Conclusions: Our model, including clinical and analytical factors, predicts with accuracy the 30-day mortality of oncologic pts after discharge which is significantly improved with the addition of nutritional assessment and standardized questionnaires of QoL and mental status. The PROP score calculator will be built to help physicians adjust medical interventions for hospitalized cancer pts.

4528 Background: Tyrosine kinase inhibitors (TKI) in monotherapy or TKI in combination with immunotherapeutic agents (IO) are standard of care fist-line treatment for advanced or metastatic renal cell carcinoma (RCC). Dose reduction due to toxicity is extremely frequently and represents an important clinical management issue, with frequent dose reduction, treatment suspension and change of schedule. We examined the outcomes of patient treated with TKI in monotherapy and in combination with immunotherapy (TKI-IO). Methods: We performed a retrospective analysis of clinical outcomes in patients with RCC treated with TKI (cohort 1) or TKI-IO (cohort 2) in Italian and Spanish institutions. A descriptive analysis was performed. Univariate logistic regression models were carried out to estimate the association between best response (CR or PR vs SD or PD) and type of TKI (monotherapy or combination therapy). Survival curves were estimated using the Kaplan-Meier method and were compared by the log-rank test. Cox proportional-hazard models were used to obtain hazard ratios (HRs) with 95%. Median follow-up was calculated using the reverse Kaplan-Meier method. Results: A total of 401 patients were divided in cohort 1 (329 patients) and cohort 2 (72 patients). Median Follow-up was 81.22 months in cohort 1 and 19.02 months in cohort 2. Most frequent toxicities that lead to dose reduction were mucositis (20.13%), Asthenia (16.88%) and Hand-foot syndrome (15.58%). Overall Response Rate was higher in patients that reduced dose, both in cohort 1 (48% vs 29%, p<0.01) and cohort 2 (81% vs 40%, p<0.01). In cohort 1 Progression Free Survival (PFS) was longer in patients with dose reduction (27.14 months vs 16.59 months) (HR 0.77 [0.6; 0.98]; p=0.04). Overall Survival (OS) was also improved (55 months vs 34.17) (HR 0.71 [0.53; 0.93]; p=0.01). In cohort 2, both PFS (39.13 months vs 41.3 months) (HR 0.63 [0.27; 1.48]; p=0.29) and OS (39.13 months vs 55.85 months) (HR 0.65 [0.26; 1.63]; p=0.29) did not statistically differ between patients that reduced dose and patients that did not reduce dose. Conclusions: TKI dose reduction due to toxicity seems to be related to improved outcomes, both in ORR and PFS/OS. ORR was statistically improved in both cohort 1 and cohort 2. PFS and OS in cohort 1 favoured patients that experienced dose reduction. PFS and OS in cohort 2 did not show a statistically significant difference, probably due to the short follow-up and small number of patients. However, outcomes seem to show a trend toward favouring patients that reduce dose.