Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.

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.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) amplification/overexpression (HER2-pos) is detected in 5% of RAS/BRAF wild-type metastatic colorectal cancers (mCRCs). Its prognostic/predictive role in terms of benefit from anti-EGFR/bevacizumab (bev) is debated. Similarly, the role of activating HER2 mutations (mut) is unclear. METHODS: We collected individual data of 1,604 patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) RAS/BRAF wild-type untreated mCRC with HER2 amplification/expression status available enrolled in eight randomized clinical trials (RCT; TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM, and CALGB/SWOG80405). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed with respect to HER2 amplification/expression and HER2 mutational status and according to biologics (anti-EGFR/bev). RESULTS: Patients with HER2-pos were 81 (5%). HER2-pos patients experienced shorter PFS (median PFS [mPFS]: 9.8 v 12.2 months, hazard ratio [HR], 1.31, P = .02) and OS (median OS [mOS]: 28.0 v 34.9 months, HR, 1.37, P = .01), also after adjustment for covariates ( P _adj PFS = .02, P _adj OS = .048). ORR was similar between HER2-pos and HER2-negative (HER2-neg) tumors (75% v 72%, odds ratio [OR], 1.21, P = .47). We found no interaction between HER2 amplification/expression status and biologics' effect in terms of PFS ( P _int = .76), OS ( P _int = .76), and ORR ( P _int = .64). In left-sided HER2-pos tumors, outcomes were similar with chemotherapy plus bev/anti-EGFRs in terms of PFS (9.8 v 9.3 months, HR, 0.73, P = .29), OS (29.8 v 28.0 months, HR, 1.29, P = .40), and ORR (59% v 79%, OR, 0.39, P = .10). HER2 -mutant tumors (2% of patients with HER2-neg tumors) showed shorter OS than HER2 wild-type ones (mOS: 23.7 v 34.4 months, HR, 1.56, P = .04) with no differential effect of biologics ( P _int ORR = .81; P _int PFS = .95; P _int OS = .92). CONCLUSION: To our knowledge, this is the largest analysis of HER2 status in patients with untreated mCRC enrolled in RCT. Waiting for targeted approaches, HER2-pos and mut do not predict benefit from bev/anti-EGFRs and should be regarded as negative prognostic factors in pMMR/MSS RAS/BRAF wild-type mCRC.

Background: Conventional Right Colectomy with D2 lymphadenectomy (RC-D2) currently represent the most common surgical treatment of right-sided colon cancer (RCC). However, whether it should be still considered a standard of care, or replaced by a routine more extended D3 lymphadenectomy remains unclear. In the present study, we aim to critically review the patterns of relapse and the survival outcomes obtained from our 11-year experience of RC-D2. Methods: Clinical data of 489 patients who underwent RC-D2 for RCC at two centres, from January 2009 to January 2020, were retrospectively reviewed. Patients with synchronous distant metastases and/or widespread nodal involvement at diagnosis were excluded. Post-operative clinical–pathological characteristics and survival outcomes were evaluated including the pattern of disease relapse. Results: We enrolled a total of 400 patients with information follow-up. Postoperative morbidity was 14%. The median follow-up was 62 months. Cancer recurrence was observed in 55 patients (13.8%). Among them, 40 patients (72.7%) developed systemic metastases, and lymph-node involvement was found in 7 cases (12.8%). None developed isolated central lymph-node metastasis (CLM), in the D3 site. The estimated 3- and 5-year relapse-free survival were 86.1% and 84.4%, respectively. The estimated 3- and 5-year cancer-specific OS were 94.5% and 92.2%, respectively. Conclusions: The absence of isolated CLM, as well as the cancer-specific OS reported in our series, support the routine use of RC-D2 for RCC. However, D3 lymphadenectomy may be recommended in selected patients, such as those with pre-operatively known CLM, or with lymph-node metastases close to the origin of the ileocolic vessels.