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.

Background: Unlike liver metastases, the role of surgery in colorectal cancer lung-limited metastases (CCLLM) is not yet established, and data are still poor. We performed a retrospective analysis to evaluate the impact of surgery on the management of CCLLM. Material and Method: We retrospectively analyzed patients who received surgery for CCLLM at our Institution from January 2010 to June 2019. The aim of the study was to evaluate the impact of clinical and pathological features on the survival (OS and DFS) of patients treated with surgery for CCLLM. Results: One hundred and fifty patients were included in the analysis. Seventy-six patients received preoperative chemotherapy (pCT) and 56 an adjuvant treatment (aCT), while 18 underwent up-front surgery without CT. In the whole population, median OS (mOS) and median DFS (mDFS) were 54.1 months (95%CI 44.0–82.1) and 24.0 months (95%CI 20.0–31.2), respectively. In multivariate analysis, number of metastases was the only factor correlated to DFS (p = 0.0006) and OS (p = 0.0018). Conclusion: Our study, although retrospective and of small size, shows that tumor burden (number of metastases) is the main prognostic factor in patients undergoing lung surgery for CCLLM. Moreover, our results suggest that surgery for lung metastases might prolong survival. These data strengthen the role of multidisciplinary management to allow patients with CCLLM to pursue local treatment whenever possible, even regardless of previous liver surgery or RAS mutated status.

Background: Regorafenib (R) and trifluridine/tipiracil (T) are approved treatments for metastatic colorectal cancer (mCRC) in refractory cases. However, the optimal sequencing of these agents is unknown. The ReTrITA study planned to assess the real-world efficacy of R and T, administered either sequentially or as monotherapy, in a large Italian multicentre population. Methods: This retrospective observational analysis comprised 1156 mCRC patients treated between 2012 and 2023 at 17 Italian cancer centres. Patients were divided into four groups: sequential T/R (n = 261), sequential R/T (n = 155), R monotherapy (n = 313), and T monotherapy (n = 427). The primary objectives were overall survival (OS) and progression-free survival (PFS), with secondary goals being disease control rate, objective response rate, and treatment-related toxicity. Results: The monotherapy cohorts showed no significant difference in OS (R: 5.0 months; T: 5.9 months; p = 0.8371) or PFS (R: 3.2 months; T: 3.3 months; p = 0.6531). Compared to T/R, the sequential R/T group had significantly better outcomes: median OS was 16.6 vs. 12.6 months (HR = 0.67; p = 0.0004), and median PFS was 11.5 vs. 8.5 months (HR = 0.60; p < 0.0001). The survival advantage of R/T was consistent across clinical subgroups. The toxicity profiles were comparable with known safety data, with a lower prevalence of neutropenia reported in the R/T sequence. Conclusions: ReTrITA confirms the efficacy of R and T as monotherapies and provides compelling real-world evidence that the R/T sequence improves survival in refractory mCRC. These findings support a regorafenib-first approach in patients who are eligible, and they emphasise the need for future research into combination strategies and comparisons with newer drugs such as fruquintinib.

Background: Regorafenib is a recognised treatment for refractory metastatic colorectal cancer (mCRC). The phase II ReDOS trial indicated that a stepwise dose escalation approach could enhance tolerability and persistence while maintaining efficacy. The ReTrITA study, a significant multicentre real-world cohort in Italy, served as the foundation for this sub-analysis concentrating solely on patients treated with regorafenib. Methods: This retrospective analysis encompassed 713 patients treated at 17 Italian centres from 2012 to 2023. Patients were categorised into two groups: ReDOS-like escalation (n = 313) and fixed dosing (no-ReDOS) (n = 400). The endpoints assessed were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and safety. Survival was assessed using Kaplan–Meier and Cox models, accompanied by exploratory subgroup analyses. Results: The median overall survival (OS) was comparable between the escalation and fixed dosing groups, recorded at 7.4 months and 6.7 months, respectively (HR 1.00, 95% CI 0.85–1.18, p = 0.93). Progression-free survival (PFS) demonstrated a significant improvement with escalation, recording 3.1 months compared to 3.9 months (HR 0.76, 95% CI 0.65–0.89, p = 0.0007). Subgroup analyses demonstrated a consistent progression-free survival (PFS) benefit in patients aged ≥70 years (HR 0.71, p = 0.015), with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 (HR 0.76, p = 0.022), RAS wild-type tumours (HR 0.69, p = 0.026), and rectal primaries (HR 0.72, p = 0.043). The disease control rate (DCR) and objective response rate (ORR) were comparable, at 23.2% versus 25.3% and 2.0% compared 2.6%, respectively. Although not statistically significant, the fixed dose group’s duration of response (DoR) was numerically longer (15.4 months) than that of the variable dosing group (8.9 months). A lower percentage of patients experienced grade 3/4 adverse events with escalation (35.4% compared to 39.5%, p = 0.0042). Conclusions: This sub-analysis of the ReTrITA cohort demonstrates that regorafenib dose escalation is achievable in real-world settings, resulting in notable improvements in progression-free survival and enhanced tolerability, while not adversely affecting overall survival. These results support and improve the findings of the ReDOS study, showing that dosage escalation is possible and helpful in a diverse, unselected group of people, which is what is performed in routine oncology treatment. The findings are consistent with both randomised and observational studies, endorsing individualised dosing as a practical strategy in refractory mCRC.