Background Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy. Methods In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan–Meier method and Cox hazards regression models were used for survival analyses. Results A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36–2.03, P < 0.001) and worse OS (HR, 2.01; 95% CI, 1.57–2.57; P < 0.001) compared to patients with low PIV. PIV outperformed the other IIBs in the GBR model and in the multivariable models. Conclusion PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy.

The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients’ outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in patients with high microsatellite instability, RAS/BRAF wild-type colorectal cancer. mCRC patients harboring such alterations show a poor prognosis with standard treatments that could be reversed by adopting novel therapeutic strategies. Moving forward to a positive selection of mCRC patients suitable for targeted therapy in the era of personalized medicine, actionable gene fusions, although rare, represent a peculiar opportunity to disrupt a tumor alteration to achieve therapeutic goal. Here we summarize the current knowledge on potentially actionable gene fusions in colorectal cancer available from retrospective experiences and promising preliminary results of new basket trials.

Background Few real‐world series on the efficacy and safety of anti‐programmed cell death protein‐1(PD‐1)/programmed death ligand‐1(PD‐L1)–based therapy are available in molecularly unselected patients with poor performance status (PS) and specific types of advanced cancers, because such populations are typically excluded from clinical trials due to poor life expectancy and risk of toxicity. Materials and Methods This multicenter retrospective case series included patients with microsatellite instability (MSI)‐high metastatic cancers with Eastern Cooperative Oncology Group (ECOG) PS of 2 or 3 not related to comorbidities receiving anti‐PD‐1 with or without anti‐CTLA‐4 therapy after failure of at least one prior treatment line. Results We included 27 patients with six diverse tumor types: colorectal (n = 18), gastric (n = 5), biliary tract, pancreatic, small bowel, and endometrial cancers (n = 1 each). Baseline ECOG PS was 2 (74%) or 3 (26%). Overall response rate was 33%, with six partial and three complete responses. Median time to response was 3.1, months and median duration of response was 16.9 months. Median progression‐free survival was 3.4 months (95% CI: 2.3 to not evaluable), and 18‐month overall survival was 50.8% (95% confidence interval, 32.7–78.8). Baseline variables were not associated with survival outcomes. ECOG PS 1 was reached by 52% of patients in a median time of 6 weeks, and ECOG PS 0 was reached by 30% of patients in a median time of 10 weeks. Conclusion In a high proportion of patients with MSI‐high cancers and poor performance status related to end‐stage disease, salvage immunotherapy can induce potentially long‐lasting “Lazarus responses”. Immunotherapy decisions near the end‐of‐life should be carefully integrated with predictive biomarkers and with palliative care measures in the real‐world setting. Implications for Practice In this retrospective cohort study of 27 pretreated patients with microsatellite instability (MSI)‐high cancers and Eastern Cooperative Oncology Group performance status of 2 or 3 not related to comorbidities, PD‐1/PD‐L1‐based therapy induced a RECIST response in 33% of patients, with a median duration of 16.9 months, and an improvement of performance status in 52% of patients. MSI‐high status can be used in clinical practice as a tumor‐agnostic predictive biomarker to select critically ill patients with end‐stage cancers for salvage immunotherapy.

Background Epstein‐Barr virus (EBV)‐positive gastric cancers (GCs) have been recently identified as a molecular subgroup showing excellent outcomes after surgery for early‐stage disease and responsiveness to immune checkpoint inhibitors (ICIs) for metastatic stage. No data are available on the prevalence, clinical characteristics, and prognosis of this subgroup of GCs in the metastatic setting. Materials and Methods In this cohort study, we assessed the impact of EBV status in patients with metastatic GC treated with chemotherapy at two Italian institutions. Results Among the 175 cases analyzed, only 7 (4%) were EBV positive and all showed long‐lasting and even complete responses to first‐line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV‐negative patients (3‐year overall survival: 80% vs. 20.1%; hazard ratio: 0.12). Conclusion If confirmed in larger data sets, our results may give a strong rationale for investigating the addition of ICIs to chemotherapy, in order to maximize the chance of achieving durable and complete responses in this uncommon subtype of GC. Implications for Practice To date, no data are available on the prevalence and clinical characteristics of patients with Epstein‐Barr virus (EBV)‐positive metastatic gastric cancer (GC), a specific subtype of GC showing excellent outcomes after radical surgery in early‐stage disease and responsiveness to immune checkpoint inhibitors (ICIs). This cohort study showed that patients with EBV‐positive GC who did not receive ICIs had exceptional, long‐lasting, and even complete responses to first‐line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV‐negative patients. If confirmed in larger series, these results may give a strong rationale for investigating the combination of chemotherapy and ICIs to achieve durable and potentially complete response in this uncommon subtype of GC.

Human epidermal growth factor receptor 2 (HER2) positive cancers account for 15–20% of all breast tumors. Several drugs have been approved in the metastatic setting, including monoclonal antibodies, tyrosine kinase inhibitors (TKI) and, more recently, antibody-drug conjugates. Neratinib is a pan-HER, irreversible TKI with potent preclinical activity against trastuzumab-resistant breast cancer models. Based on Phase I and II clinical trials, the combination of neratinib plus capecitabine was compared to lapatinib and capecitabine, an established regimen for trastuzumab-resistant disease, in the randomized, Phase III NALA trial. In this trial, neratinib yielded increased progression-free survival, response duration and a benefit in time to intervention for CNS progression. However, there was no overall survival benefit, no increase in overall response rate and no improvement in QoL. The most frequent adverse event in the neratinib arm was diarrhea, which was manageable with prophylactic treatment with loperamide. Conclusion: Neratinib is a valuable addition to the therapeutic armamentarium to treat metastatic, HER2-positive breast cancer. The current positioning of the combination of neratinib and capecitabine based on the results of the NALA trial needs to consider the rapidly evolving scenario due to the recent introduction of new drugs, like the pure-HER2 TKI tucatinib and the antibody drug-conjugate trastuzumab-deruxtecan.