Background: Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice. Materials and Methods: In 2012–2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes. Results: The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) (p = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T (p = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) (p = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) (p = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies. Conclusions: The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Background: There is no clear information on the proportion of patients who need therapy for immune-related thyroid dysfunction (irTD) or who need to delay, omit, or discontinue immunotherapy. Furthermore, it is not well known whether irTD correlates with better outcomes or not. Patients and Methods: We conducted a retrospective study in patients with metastatic non-small cell lung cancer (NSCLC) treated with anti-PD1 or anti-PD-L1. Results: Our study enrolled 75 patients, 25.3% of them developed immune-related thyroid dysfunction. Three patients delayed a course of immunotherapy due to irTD, 2 patients omitted a course and 1 patient permanently discontinued. In patients with irTD compared with those without irTD the ORR was 42.1% vs. 7.1% (p<0.001), DCR was 78.9% vs. 32.1% (p<0.001); mPFS was 15.7 vs. 3.6 months (p<0.001) and mOS was 18.6 months vs. 5.1 months (p<0.001). Conclusion: Immune-related thyroid dysfunction has a mild impact on the immunotherapy treatment program. The occurrence of irTD correlates with more favorable response and survival.

(1) Background: The clinical implications of COVID-19 outbreaks following SARS-CoV-2 vaccination in immunocompromised recipients are a worldwide concern. Cancer patients on active treatment remain at an increased risk of developing breakthrough infections because of waning immunity and the emergence of SARS-CoV-2 variants. There is a paucity of data on the effects of COVID-19 outbreaks on long-term survival outcomes in this population. (2) Methods: We enrolled 230 cancer patients who were on active treatment for advanced disease and had received booster dosing of an mRNA-BNT162b2 vaccine as part of the Vax-On-Third trial between September 2021 and October 2021. Four weeks after the third immunization, IgG antibodies against the spike receptor domain of SARS-CoV-2 were tested in all patients. We prospectively evaluated the incidence of breakthrough infections and disease outcomes. The coprimary endpoints were the effects of antibody titers on the development of breakthrough infections and the impact of COVID-19 outbreaks on cancer treatment failure. (3) Results: At a median follow-up of 16.3 months (95% CI 14.5–17.0), 85 (37%) patients developed SARS-CoV-2 infection. Hospitalization was required in 11 patients (12.9%) and only 2 (2.3%) deaths related to COVID-19 outbreaks were observed. Median antibody titers were significantly lower in breakthrough cases than in non-cases (291 BAU/mL (95% CI 210–505) vs. 2798 BAU/mL (95% CI 2323–3613), p < 0.001). A serological titer cut-off below 803 BAU/mL was predictive of breakthrough infection. In multivariate testing, antibody titers and cytotoxic chemotherapy were independently associated with an increased risk of outbreaks. Time-to-treatment failure after booster dosing was significantly shorter in patients who contracted SARS-CoV-2 infection (3.1 months (95% CI 2.3–3.6) vs. 16.2 months (95% CI 14.3–17.0), p < 0.001) and had an antibody level below the cut-off (3.6 months (95% CI 3.0–4.5) vs. 14.6 months (95% CI 11.9–16.3), p < 0.001). A multivariate Cox regression model confirmed that both covariates independently had a worsening effect on time-to-treatment failure. (4) Conclusions: These data support the role of vaccine boosters in preventing the incidence and severity of COVID-19 outbreaks. Enhanced humoral immunity after the third vaccination significantly correlates with protection against breakthrough infections. Strategies aimed at restraining SARS-CoV-2 transmission in advanced cancer patients undergoing active treatment should be prioritized to mitigate the impact on disease outcomes.

Background: Anti-SARS-CoV-2 mRNA vaccines can deeply affect cell-mediated immune responses in immunocompromised recipients, including cancer patients receiving active treatments. The clinical implications of changes in peripheral blood lymphocyte subsets following the third dose of mRNA-BNT162b2 vaccination (tozinameran) in patients on immune checkpoint blockade are not fully understood. We conducted a prospective analysis of the Vax-On-Third-Profile study to evaluate the impact of circulating lymphocyte dynamics on disease outcomes in this subgroup of patients. Methods: Recipients of booster dosing who had received before vaccination at least one course of an anti-PD-1/PD-L1 treatment for an advanced solid tumor were eligible. Immunophenotyping of peripheral blood was performed before the third dose of tozinameran (timepoint-1) and four weeks later (timepoint-2) to quantify the absolute counts of lymphocyte subpopulations, including CD3⁺CD4⁺ T cells, CD3⁺CD8⁺ T cells, B cells, and NK cells. Logistic regression was used to analyze the relationship between lymphocyte subsets and durable clinical benefit (DCB). The log-rank test and Cox regression model were applied to evaluate the relationship between lymphocyte subpopulations and both vaccine-related time-to-treatment failure (V-TTF) and overall survival (OS). Results: We included a total of 56 patients with metastatic disease who were given a third dose of tozinameran between 23 September and 7 October 2021 (median age: 66 years; male: 71%). Most recipients had a diagnosis of lung cancer and were being treated with pembrolizumab or nivolumab. Compared to baseline, the third immunization resulted in an incremental change in the median counts of all lymphocyte subpopulations, which was statistically significant only for NK cells (p < 0.001). A significant correlation was found between NK cell counts and DCB at timepoint-2 (p < 0.001). Multivariate logistic regression analysis of DCB confirmed the predictive significance of high-level NK cell counts (p = 0.020). In multivariate Cox regression analysis, high-level NK cell counts independently predicted longer V-TTF [HR 0.34 (95% CI 0.14–0.80), p = 0.014] and OS [HR 0.36 (95% CI 0.15–0.89), p = 0.027]. Conclusions: Our data suggest expansion of NK cell counts as the most noteworthy change in circulating lymphocytes after the third dose of tozinameran in cancer patients receiving PD-1/PD-L1-targeted agents. This change correlated with enhanced therapeutic efficacy, improving the rate of disease control, and prolonging survival outcomes. Similar findings have not been previously reported, implying that they have proof-of-concept value and warrant further confirmation.

Background: There is ongoing discussion around the optimal course of treatment for metastatic colorectal cancer (mCRC) following the second line. Trifluridine/tipiracil (T) and regorafenib (R) have been the mainstay of therapy in this situation, as they both increased overall survival (OS) in comparison to a placebo. Despite the paucity of evidence, therapy rechallenge is also recognized as an option for practical use. In the third-line scenario of mCRC, we planned to investigate the survival outcomes using (T) and (R), both with and without prior rechallenge treatment. Materials and methods: Between 2012 and 2023, we examined the medical records of 1156 patients with refractory mCRC who were enrolled in the multicenter retrospective ReTrITA study. We then separated the patients into two cohorts based on the rechallenge therapy that was given before regorafenib and/or trifluridine/tipiracil at 17 Italian centres. Results: A total of 981 patients underwent T and/or R therapy, while 175 patients had therapy rechallenge before T and/or R. The median overall survival (mOS) for patients treated with T/R and R/T sequences in the rechallenge therapy cohort was 14.5 months and 17.6 months, respectively (p = 0.1955). A statistically significant survival benefit was observed in patients who received monotheraphy with R (mOS: 6 months) compared to the T group (mOS: 4.2 months) (p = 0.0332). In the same cohort, a median progression-free survival (mPFS) benefit was demonstrated in favour of the R/T group (11.3 months) vs. 9 months of the reverse sequence (p = 0.4004). In the no-rechallenge cohort, the mOS was statistically longer in the R/T sequence than in the T/R sequence (16.2 months vs. 12.3 months, respectively; p = 0.0014). In terms of the mPFS, we saw the same significant result for the adoption of R/T treatment (11.5 months vs. 8.4 months, respectively; p < 0.0001). The two monotherapy groups did not reveal any significant differences. Conclusions: This study suggests that rechallenge therapy may improve survival rates in the third-line treatment of mCRC, particularly if it is administered before sequential R/T treatment. This could allow for the extension of mCRC treatment choices until prospective studies are finished or randomised trials are performed.

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.