Background: KRAS^G12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRAS^G12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. Methods: A multicentre retrospective analysis was conducted including KRAS^G12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/− bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment–effect interactions. KRAS^G12D-mutated patients were analysed as control. Results: One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRAS^G12D-mutated cohort (N = 153). Conclusions: First-line irinotecan-based regimens provided better survival results in KRAS^G12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

RAS mutations involving codon 61 are rare in metastatic colorectal cancer (mCRC), accounting for only 1–4%, but they have recently been identified with high frequency in the circulating tumor DNA (ctDNA) of patients with secondary resistance to anti-EGFRs. This retrospective monocentric study aimed to investigate the clinical phenotype and prognostic performance of codon 61 RAS-mutated mCRC. Fifty patients with codon 61 RAS-mutated mCRC treated at our institution between January 2013 and December 2021 were enrolled. Additional datasets of codon 61 RAS wild-type mCRCs (648 patients) were used as comparators. The endpoint for prognostic assessment was overall survival (OS). Metastatic involvement of the peritoneum or ovary was significantly more frequent in codon 61 RAS-mutated mCRC compared to codon 61 RAS wild-type (54 vs. 28.5%), non-codon 61 RAS-mutated (35.6%), BRAF V600E-mutated (25%), and RAS/BRAF wild-type (20.5%) cohorts. At a median follow up of 96.2 months, the median OS for codon 61 RAS-mutated patients was significantly shorter compared to RAS/BRAF wild-type (26.9 vs. 36.0 months, HR 0.56) patients, while no significant difference was observed compared to non-codon 61 RAS-mutated and BRAF V600E-mutated patients. We showed a negative prognostic impact and a statistically significant correlation between codon 61 RAS mutations and metastatic involvement of the peritoneum and ovary.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis, particularly in older patients (≥70 years), who represent an increasing proportion of cases. However, this population is underrepresented in clinical trials. This study aimed to evaluate the prognostic impact of the Geriatric 8 (G8) screening tool and the comprehensive geriatric assessment (CGA) in older patients with advanced PDAC. We conducted a retrospective observational study of patients aged ≥70 years with locally advanced or metastatic PDAC treated at Fondazione Policlinico Gemelli IRCCS between January 2018 and August 2023. Clinical, demographic, and treatment data were extracted through structured and unstructured data mining. All patients underwent G8 screening at the start of first-line therapy; if G8 was ≤14, patients could have received CGA. Primary endpoints were progression-free survival (PFS) and overall survival (OS), analyzed through Kaplan-Meier estimates and Cox regression models. Of 268 eligible older patients, 210 (78.4 %) received first-line chemotherapy. Most received gemcitabine plus nab-paclitaxel (58.1 %). Median PFS and OS were 6.5 (95 % CI: 5.7-7.3) and 9.9 months (95 % CI: 9.1-11.7), respectively. Baseline Geriatric 8 score was ≤14 in 149 out of 210 (70.9 %) patients and ≥ 15 in 61 out of 210 (29.1 %). A baseline G8 score ≥ 15 was significantly associated with higher PFS (7.9 vs. 5.3 months, HR 0.57, p = 0.001) and OS (16.6 vs. 7.8 months, HR 0.39, p < 0.001), both at univariate and multivariate analyses. Among the 149 patients with a baseline G8 ≤ 14, 97 (65.1 %) were referred for CGA, and 60 (40.3 % of the overall G8 ≤ 14 population) completed the assessment. No difference in mPFS (p = 0.28) nor in mOS (p = 0.25) emerged according to CGA assessment. However, the 12-month survival rate was higher in patients who underwent CGA (31.8 %) compared with those who did not (14.2 %). First-line chemotherapy provides particular clinical benefit to older adults with PDAC with higher G8 scores, though benefit was observed across the broader cohort. The G8 score was a strong independent prognostic tool for treatment response and survival.

There is limited evidence comparing second-line therapies following gemcitabine plus nab-paclitaxel (GemNab) in metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to compare the effectiveness and safety of 5-fluorouracil plus nanoliposomal irinotecan (5-FU + Nal-IRI) versus oxaliplatin-based regimens (FOLFOX/XELOX) in this setting. We retrospectively analyzed 445 patients with metastatic PDAC progressing after first-line GemNab, treated across 12 centers in Italy and Asia (2014-2024). Patients received either 5-FU + Nal-IRI (n = 180) or FOLFOX/XELOX (n = 265) as second-line therapy. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. Exact propensity score matching was carried out to reduce baseline imbalances. In the matched cohort, median OS was 7.2 months [95% confidence interval (CI) 5.8-8.4 months] for 5-FU + Nal-IRI and 5.8 months (95% CI 4.1-6.8 months) for FOLFOX/XELOX [hazard ratio (HR) 0.74, 95% CI 0.58-0.95, P = 0.015], and median PFS was 3.0 months (95% CI 2.5-3.6 months) versus 2.5 months (95% CI 2.2-2.9 months), respectively (HR 0.75, 95% CI 0.61-0.91, P = 0.0048). ORR was similar (9% versus 10%, P = 0.79). Grade 3-4 adverse events were more frequent with 5-FU + Nal-IRI (31.1% versus 9.4%), particularly anemia (13.9% versus 1.7%) and diarrhea (5.6% versus 1.2%). FOLFOX/XELOX was associated with higher rates of any-grade thrombocytopenia and peripheral neuropathy. 5-FU + Nal-IRI showed a modest yet statistically significant survival advantage compared with FOLFOX/XELOX in patients with metastatic PDAC previously treated with GemNab, despite being associated with a higher incidence of adverse events. None the less, the selection of second-line therapy should be guided by a balanced evaluation of both efficacy and toxicity profiles.