Re-treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies offers a promising approach to extend the continuum of care of patients with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) with no mutations of resistance in their circulating tumor DNA (ctDNA) at the time of treatment re-exposure. PARERE (NCT04787341) is an open-label, multicenter, randomized phase II trial investigating the optimal sequencing of panitumumab and regorafenib in chemorefractory RAS and BRAF wt mCRC patients, who previously derived benefit from first-line anti-EGFR-containing regimens, then received at least one intervening anti-EGFR-free line of treatment, and were prospectively selected for the absence of RAS and BRAF mutations in their ctDNA. Eligible patients were randomly assigned 1 : 1 to receive anti-EGFR re-treatment with panitumumab followed by regorafenib after progression (arm A) versus the reverse sequence (arm B). The primary endpoint was overall survival (OS). Between December 2020 and December 2024, 428 patients underwent molecular screening, and 213 with RAS/BRAF ctDNA wt were randomized (arm A/B = 106/107). At a median follow-up of 31.9 months, no difference in terms of OS was observed between treatment arms, with a median OS of 11.7 and 11.6 months in arms B and A, respectively (hazard ratio 1.13, 85% confidence interval 0.90-1.41, P = 0.441). However, re-treatment with panitumumab was associated with higher objective response rate (ORR; first ORR: 16% versus 2%, P = 0.003; second ORR: 18% versus 0%, P = 0.013) and disease control rate (DCR; first DCR: 61% versus 36%, P < 0.001; second DCR: 62% versus 38%, P = 0.003), and longer progression-free survival (PFS; first PFS: 4.2 versus 2.4 months, P = 0.103; second PFS: 3.9 versus 2.7 months, P = 0.019) than regorafenib, regardless of the sequence of the study treatments. Anti-EGFR re-treatment should be regarded as an option in the continuum of care of chemorefractory mCRC patients with RAS and BRAF wt tumors, with no alterations of acquired resistance in their ctDNA.

Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated. Methods: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles. Results: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7–34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95–1.89); p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3–18.1) and 12.7 (95%CI: 8.8–17.5) months, respectively (HR= 1.31 (95%CI: 0.89–1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02–2.03); p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99–2.17); p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively (p = 0.0001). Conclusion: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed.

Background. FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF-mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated BRAF-mutant CRC. Methods. We monitored patients in randomized, controlled studies who had advanced CRC and were undergoing second-line chemotherapy in addition to utilizing Bevacizumab, Ramucirumab or Aflibercept treatments. These data were pooled together with the data and results of BRAF-mutant patients enrolled in two phase III trials (TRIBE and TRIBE-2 study), who had been treated with second-line treatment both with or without Bevacizumab. Overall survival (OS), in relation to BRAF mutational status, was the primary focus. Results. Pooled analysis included 129 patients. Anti-angiogenics were found to have a significant advantage over the placebo in terms of OS (HR 0.50, 95%CI 0.29–0.85) (p = 0.01). Conclusions. Our pooled analysis confirms the efficacy of anti-angiogenics in pre-treated BRAF-mutant CRC, establishing the combination of chemotherapy plus Bevacizumab or Ramucirumab or Aflibercept as a valid treatment option.

Liver metastases (LMs) are related to poor efficacy of immune checkpoint inhibitor (ICI)-containing therapies. In the AtezoTRIBE trial, Immunoscore-Immune-Checkpoint (immunoscore-IC) was a predictor of benefit from atezolizumab in mismatch repair-proficient (pMMR) metastatic colorectal cancer (mCRC). In pMMR patients enrolled in the AtezoTRIBE study, we investigated the association of LMs with immune-related biomarkers and treatment outcomes, and the predictive role of immunoscore-IC in the LMs group. Out of 202 pMMR patients, 151 (75%) had LMs. No differences in immune-related features were observed according to the presence or not of LMs, except for a lower prevalence of tumour-infiltrating lymphocytes-high tumours in the LMs group (33% versus 52%, P = 0.03). Worse outcomes were observed among patients with LMs [progression-free survival (PFS), P = 0.002; overall survival (OS), P = 0.011], also in multivariable models. The effect of adding atezolizumab to FOLFOXIRI/bevacizumab was independent from LMs in terms of PFS (P_int = 0.990) and OS (P_int = 0.800). Among patients with pMMR mCRC and LMs, those with immunoscore-IC-high but not those with immunoscore-IC-low tumours achieved benefit from atezolizumab, though in the absence of a statistically significant interaction effect (P_int for PFS and OS = 0.166 and 0.473, respectively). LMs are associated with poor prognosis in pMMR mCRC and do not predict resistance to the addition of atezolizumab to FOLFOXIRI/bevacizumab. Immunoscore-IC seems to retain its predictive impact also among patients with LMs.

We report 5-year results of the phase III randomized TRIPLETE study. Eligible patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) received first-line modified fluorouracil, leucovorin, oxaliplatin (mFOLFOX)/panitumumab (control group, n = 217) versus modified fluorouracil, leucovorin, oxaliplatin, irinotecan (mFOLFOXIRI)/panitumumab (experimental group, n = 218). We present overall survival (OS) and updated outcomes in the intention-to-treat population. The median follow-up was 60.2 months (IQR, 49.3-70.0). The median OS was 41.1 and 33.3 months for experimental and control groups, respectively (hazard ratio [HR], 0.79 [95% CI, 0.63 to 0.99]; P = .049). OS outcomes favored the experimental group regardless of clinical features. No differences in objective response rate (primary end point; 75%/78%, odds ratio, 0.84 [95% CI, 0.54 to 1.31]; P = .442), early tumor shrinkage rate ( P = .954), depth of response ( P = .573), no residual tumor resection rate ( P = .329), and progression-free survival (HR, 0.95 [95% CI, 0.78 to 1.16]; P = .606) were confirmed. Among patients alive at the time of disease progression, the median postprogression survival was 24.6 and 17.7 months for experimental and control groups, respectively (HR, 0.79 [95% CI, 0.62 to 1.01]; P = .062). Similar proportions of patients in both groups received subsequent lines of therapy (control/experimental: second line 73%/71%, third line 51%/49%, fourth line 31%/32%), as well as nonpalliative locoregional treatments (control/experimental: 16%/16%). Upfront mFOLFOXIRI/panitumumab significantly improves OS compared with mFOLFOX/panitumumab in patients with RAS/BRAF wild-type mCRC.

Colorectal cancer (CRC) is a common tumor, and its incidence increases with age. Elderly CRC patients constitute a daily challenge for oncologists when deciding if they are worthy of active treatments and of which kind, as data from the literature are incomplete or even lacking in specific subsets. To fill this gap, we conducted a narrative review that included not only studies dedicated to the elderly but also extracted elderly groups from major clinical trials. Results in terms of harm and benefit were dissected according to frailty categories (fit, vulnerable, unfit). As it emerged, the management of elderly CRC patients should be based not on age alone, but rather on their frailty level, as assessed by Comprehensive Geriatric Assessment (CGA), which should be implemented in trials and clinical practice. Elderly patients should be treated similarly to young patients in the first and subsequent lines, without precluding the use of innovative drugs. Vulnerable elderly individuals should receive personalized schedules that focus more on symptoms and quality of life; for frail patients, supportive care alone is often a valid option.