LBA4002 Background: In pts with HER2-negative advanced gastric/GEJ cancer and PD-L1 low/absent expression, platinum/fluoropyrimidine doublets are a standard first-line therapy. In this patient population, the outcomes are unsatisfactory and second-line therapy is given in only 40% of clinical trial patients. Switch consolidation maintenance may prolong the benefit of the initial strategy and delay clinical deterioration. Despite ramucirumab failing to prolong both progression-free survival (PFS) and overall survival (OS) in the first-line setting, paclitaxel plus ramucirumab is a standard second-line therapy and warrants investigation as a post-induction strategy. Methods: Pts with HER2-negative advanced gastric/GEJ cancer without disease progression after 3 months of initial oxaliplatin-based chemotherapy, stratified by site of origin (GEJ vs gastric), prior gastrectomy and peritoneal disease, were randomized 1:1 to ramucirumab 8 mg/Kg on days 1,15 plus paclitaxel 80 mg/sqm on days 1,8,15 every 28 days (arm A) vs CAPOX/FOLFOX at the same doses used in the last induction cycle, for additional 3 mos followed by fluoropyrimidine monotherapy maintenance (arm B). The primary endpoint was PFS, OS was a key secondary endpoint; quality of life, safety, and biomarkers were evaluated. A sample size of 280 pts achieved a 90% power to detect as significant at a 5% level (2-sided log-rank test) a median PFS increase from 4 to 6 mos (target HR=0.67). HRs were estimated by Cox models adjusting for stratification factors. Restricted Mean Survival Time (RMST) analysis was conducted in case of violation of proportional hazards assumption. Results: From Jan 2017 to Oct 2023, 280 patients were randomly assigned (144 arm A/136 arm B). Baseline characteristics were: male sex 67/61%, median age 64/66 years, PS 0 74/65%, GEJ 26/26%, prior gastrectomy 28/23%, peritoneal metastases 53/42%. At a median follow-up of 43.7 months (IQR 22.0-57.9), median PFS was 6.6 vs. 3.5 mos in Arm A vs. B (HR=0.63, 95%CI 0.49-0.81; P<0.001). 24-mos RMST analysis showed a statistically significant 2.4-mos average increment (p=0.002). Median OS was 12.6 vs. 10.4 mos in Arm A vs. B (HR=0.75, 95%CI 0.58-0.97; P=0.030). The frequency of grade ≥3 adverse events was 40.4% vs. 20.7% in arms A vs. B, respectively, mainly neutropenia 25.5/9.6%; febrile neutropenia 2.1/0%; hypertension 6.4/0%; venous thromboembolism 2.1/0%; peripheral neuropathy 5.7/6.7%. No treatment-related deaths were reported. Conclusions: Switch maintenance with paclitaxel plus ramucirumab after 3 months of oxaliplatin-based doublets may be a new strategy in patients with HER2-negative metastatic gastric/GEJ cancer who are non-eligible for initial immune checkpoint inhibitor-based regimens according to specific guidelines and regulatory approvals. Clinical trial information: NCT02934464 .

358 Background: In resectable GAC/GEJAC, MSI status is associated with better survival and potential lack of benefit from chemotherapy. Given the high responsiveness of MSI tumors to immunotherapy, neoadjuvant or definitive dual CTLA-4/PD(L)-1 inhibition may allow omission of chemotherapy or surgery. Methods: INFINITY is a multicentre, single-arm, multi-cohort phase II trial (NCT04817826) investigating the activity and safety of tremelimumab+durvalumab as neoadjuvant (Cohort 1) or definitive (Cohort 2) treatment for MSI, mismatch repair deficient (dMMR) and EBV-negative resectable GAC/GEJAC. In Cohort 1, patients (pts) received a 12-week treatment with single high dose tremelimumab 300 mg and durvalumab 1500 mg q4 weeks (T300/D) for 3 cycles followed by surgery. The primary endpoint was pCR rate (ypT0N0) with negative ctDNA after T300/D. Secondary endpoints: disease-free survival, overall survival, quality of life. Exploratory: correlation of pCR with clinical variables, PDL-1 CPS assessed by IHC 22C3, tumor mutational burden (TMB) by Foundation One, liquid biopsies and other biomarkers. Cohort 2 investigates non operative management after same treatment regimen. Results: Overall, 18 pts with MSI/dMMR resectable cT2-4 any N GAC/GEJAC were recruited in Cohort 1. One withdrew consent and 2 achieved a complete clinical-pathological response at radiology and endoscopy (ongoing) and refused surgery. Among 15 evaluable patients, 1 had disease progression and 14 underwent resection. pCR rate was 60% (9/15) and major-complete pathological response (<10% viable cells) was 80%. All pts with pCR had negative ctDNA status pre-surgery. pCR rate was 1/6 (17%) in T4 vs 8/9 (89%) in T2-3 tumors (p=0.011), whereas no correlation was found with baseline N status. PDL-1 CPS was not associated with outcomes and TMB had a non-significant trend of correlation with pCR (median TMB 26 in non-pCR vs 40 in pCR group, p=0.2). Grade≥3 immune-related AEs occurred in 3 pts of safety population (n=18): colitis, pneumonitis, liver toxicity, all resolved with high dose steroids and did not impair surgery. Two pts died after surgery for other reasons than disease or AEs, whereas no disease relapses were observed in remaining pts. QoL and additional translational analyses on RNA-seq, digital spatial profiling and ctDNA monitoring will be presented. Conclusions: Pre-operative T300/D for 3 months was safe and provided promising proof of efficacy in MSI, dMMR GAC/GEJAC pts. These results open the way to investigate NOM in pts with clinical, pathological and molecular (ctDNA minimal residual disease) complete response after T300/D. Enrollment in Cohort 2 has started after IDMC evaluation and protocol. amendment to include only pts with cT2-3 tumors confirmed at staging laparoscopy. Clinical trial information: NCT04817826 .

Background: Colorectal cancer (CRC) is one of the most common cancers; w20% of patients have metastases at diagnosis, and 50%-60% subsequently develop metachronous metastases. Bone involvement, despite being rare, is usually associated with higher disease burden, worse prognosis, impaired quality of life, and significant health -related cost. In the last few years, following the positive results of the TRIBE and TRIBE2 trials, the association of FOLFOXIRI plus bevacizumab has become the new standard of care for metastatic CRC. Despite being highly efficacious in all subgroups, little is known about the activity of this regimen in patients with bone metastases. Patients and methods: We carried out a pooled analysis of TRIBE and TRIBE2 studies focusing on patients with skeletal deposits.Results: Our analyses on the whole population showed that patients with baseline bone involvement reported shorter overall survival [OS; 14.0 versus 26.2 months; hazard ratio (HR) 2.04, 95% confidence interval (CI) 1.46-2.87; P < 0.001] and progression-free survival (PFS; 6.2 versus 11.1 months; HR 1.96, 95% CI 1.42-2.69; P < 0.001) compared with those without bone metastases; no significant interaction with the treatment was reported for PFS (P = 0.094) and OS (P = 0.38). Bone metastases had a negative prognostic implication in the multivariate analysis (HR 2.24, 95% CI 1.54-3.26; P < 0.001). Furthermore, patients with bone lesions at first radiological progression (including those with baseline bone metastases) had a shorter OS compared with those who progressed in other sites (10.4 versus 13.2 months; HR 1.48, 95% CI 1.15-1.91; P = 0.002). A trend toward inferior OS (7.5 versus 11 months, HR 1.50, 95% CI 0.92-2.45; P = 0.10) appeared in patients with basal skeletal deposits compared with those with bone involvement at first radiological progression. Conclusions: Our study confirmed the negative prognostic impact of bone metastases in CRC. Furthermore, we demonstrated for the first time that the survival advantage of triplet chemotherapy plus bevacizumab is maintained even in this prognostically unfavorable subgroup.

Pancreatic Ductal Adenocarcinoma (PDAC) harboring germlineBRCA1-2 pathogenic variants (gBRCA1-2pv) is emerging as a distinct entity, benefitting from specific treatments (platinum agents, PARP-inhibitors). Information on second-line therapy (2LT) outcome in this setting is lacking.

Regorafenib (R) is a key agent for metastatic colorectal cancer (mCRC) treatment but no validated factors predicting longer survival are available. REALITY was a retrospective multicentric trial in Italian refractory mCRC patients (pts) reaching OS≥ 6 months (m) with R. We aimed to assess the association between clinical parameters and outcome in the study population to define a panel identifying long term survivors among R candidates. Primary and secondary endpoints were OS and PFS, respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier method; survival curves comparison: log-rank test). 100 R-treated mCRC pts from Jan 2014 to Dec 2015 with OS≥6 m were enrolled. Median OS was 11.5 m (95%CI 9,60-12,96). OS was longer in moderately differentiated (G2) mCRC (12,4 versus [vs] 7,4 vs 9,1 m G1 vs G3; p=0,0026) and for LDH levels ≤217 U/l (12,1 vs 8,7 m, p=0,0470). OS was improved with 160 mg starting dose at cycle 2 (12,4 vs 10,9 m 120 mg vs 9,1 m 80 mg, p=0,0325) and 4 (17,7 vs 12,1 m 120 mg vs 14,5 m 80 mg, p=0,0288), and in absence of adverse events (AE) over the first 4 cycles (22,5 vs 10,2 m, p=0,0018), cycle 1 (14,7 vs 10,7 m, p=0,0410) and 2 (15,6 vs 10,9 m, p=0,0474). OS was longer in absence of dose/schedule changes overall during the first 4 cycles (17,7 vs 10 m, p=0,0012), cycle 3 (14,7 vs 9,7 m, p=0,0031), and 4 (15,4 vs 10,9 m, p=0,0351), for single site PD (12,9 vs 10,7 m, p=0,0349), non-liver single site PD (15,6 vs 8,1 m, p=0,0066), no liver PD (13,6 vs 10 m, p=0,0043). Median PFS was 4.2 m (95%CI 3,43-43,03). PFS was longer in G2 mCRC (4,5 m vs 2,2 G1 vs 3,3 G3, p<0,0001), in absence of AE over the first 4 cycles (6,53 vs 3,9 m, p=0,0047), cycle 1 (6,1 vs 3,8 m, p=0,0056) and 2 (6,1 vs 3,9 m, p=0,0244) and of dose/schedule changes globally during the first 4 cycles (11,3 vs 3,4 m, p=0,0020), cycle 2 (4,5 vs 3,7 m, p=0,0298), 3 (6,5 vs 3,3 m, p=0,0008) and 4 (6,5 vs 4,2 m, p=0,0080). PFS was improved for single site PD (4,5 vs 3,7 m, p=0,0138), non-liver single site PD (6,5 vs 3 m, p=0,0090), no lung (4,8 vs 3,9 m, p=0,0338) and no liver PD (6,3 vs 3,3 m, p<0,0001). In our study G2 mCRC, low LDH, single site PD, absence of AE, treatment changes and of liver/lung PD were associated with better outcome in pre-treated long term mCRC survivors receiving R.

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1-2% of gastrointestinal tumours. We evaluated the clinico-pathological characteristics, outcomes and prognostic factors of patients who underwent surgery for SBA. Methods: We retrospectively analysed the features and outcome parameters of 54 SBA patients from 6 italian institutions between 2005 and 2017. Results: The primary tumour was in the duodenum, jejunum and ileum in 30 (55.6%), 18 (33.3%) and 6 (11.1%) patients, respectively. Among the 54 patients studied, adjuvant chemotherapy were performed in 35.2 % of patients with stage II and in 27.8 % of patients with stage III. Relapse rates were higher for chemonaive patients compared to treated patients (50% vs 23.5%). Median overall (OS) and progression-free survival (PFS) were 26.98 and 19.78 months, respectively. Duodenal adenocarcinoma (p = 0.022), lymph node metastases (p = 0.00269), long-term treatment with metformin (p = 0.0095), no adjuvant treatment (p = 0.0006) and PLR >0,1766 (p = 0,0137) were associated with poor overall survival outcomes. The factors associated with PFS were patients with older age (>75 years) (p = 0.04) and T4 according to TNM system (p = 0.02). Conclusions: The lack of well-defined guidelines for treatment of SBA justifies the heterogeneity of therapeutic choices resulting in negative impact on patient outcomes. Thus, there is an urgent need for prognostic and predictive biomarkers to guide therapy decisions for these patients. Our results suggest that the site, lymph node metastases, metformin and PLR >0,1766 could be novel prognostic markers for SBA patients who undergo curative surgery. However, prospective studies are necessary to confirm the role of these factors and identify new potential biomarkers of treatment efficacy, that could improve the selection of the right treatment for the right patient. Legal entity responsible for the study: Modena University Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.