Explore the vast range of titles available.

Background The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointestinal cancers, the presence of circulating tumor DNA (ctDNA) after surgery is associated with a high risk of relapse, and the lack of ctDNA clearance after post-operative treatment is strongly associated with early relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after preoperative chemotherapy and surgery for non-cross resistant regimens in the post-operative setting. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of at least one prior trastuzumab-based regimen. The DESTINY-Gastric01 and 02 trials showed remarkable activity and efficacy of T-DXd, thus supporting the investigation of this agent in early-stage disease to increase the chance of achieving disease eradication. Finally, the DESTINY-Gastric03 trial showed the safety profile and feasibility, with preliminary promising activity results of the combination of T-DXd with a fluoropyrimidine. Trial design TRINITY is an ongoing multicentre, randomized, open-label, interventional phase II study which will enroll approximately 46 patients with HER2-positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of minimal residual disease detected by the Signatera™ assay in a liquid biopsy collected between 2 and 6 weeks after surgery. The trial is designed with an observational phase enrolling patients with HER2-positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1–14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1–5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies. The primary objective is ctDNA clearance at 1 year after randomization. Considering alpha- and beta-errors of 0.10 and 0.20 and hypothesizing a ctDNA clearance of 10% and 35% in the control and experimental arm, respectively, 23 patients per arm are required to prove the superiority of the experimental strategy. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints. Enrollment is active and ongoing. Trial registration TRINITY is registered at ClinicalTrials.gov (NCT06253650).

Background The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval. Methods Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model. Results A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7–6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3–4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p  = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p  = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p  = 0.003) and multivariable (HR 0.57, p  = 0.02) analysis. Conclusions The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab.

In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

IntroductionEarly palliative care (PC) in the clinical pathway of advanced cancer patients improves symptom control, quality of life and has a positive impact on overall quality of care. At present, standardised criteria for appropriate referral for early PC in oncology care are lacking. The aim of this project is to develop a set of standardised referral criteria and procedures to implement appropriate early PC for advanced cancer patients (the palliative care referral system, PCRS) and test its impact on user perception of quality of care received, on patient quality of life and on the use of healthcare resources.SettingSelected oncology clinics and PC outpatient clinic.Methods and analysisA scoping literature review and an expert consultation through a nominal group technique will be used to revise existing referral tools and to develop a new one, the PCRS. 25 patients will be enrolled in a pilot study to assess feasibility of the implementation of PCRS; 10 interviews with patients and healthcare professionals will be carried out to evaluate applicability.A pretest–post-test quasiexperimental study involving 150 patients before implementation of the PCRS and 150 patients after implementation will be carried out.Patient satisfaction with care received, quality of life and use of resources, and caregiver satisfaction with care will also be assessed to explore the impact of the intervention.Ethics and disseminationEthical approval for the study has been granted by the Institutional Review board of the Fondazione IRCCS Istituto Nazionale Tumori; approval reference INT201/19.Results will be disseminated through open access publications and through scientific communication presented at national and international conferences.Trial registration numberNCT04936568.

BackgroundImmune checkpoint inhibitors (ICIs) are the new standard of care in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Since tumor response dynamic parameters already shown a strong association with survival outcomes in patients with mCRC treated with first-line therapy, we investigated the association of early tumor shrinkage (ETS) and depth of response (DoR) in patients with MSI-H/dMMR mCRC treated with ICIs.MethodsThis is a retrospective, multicenter, cohort study in patients with dMMR and/or MSI-high mCRC treated with ICIs (anti-PD-1/PD-L1 with or without anti-CTLA-4 agents) with measurable disease and at least one post-baseline radiological disease reassessment. The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. A maximally selected statistics method in a Cox regression model for progression-free survival (PFS) was used to determine the optimal cut-offs for ETS and DoR.ResultsWe included a total of 169 patients: 116 (68.6%) were treated with anti-PD-1 monotherapy, whereas 53 (31.4%) with anti-PD-1 plus anti-CTLA-4 agents. Patients with primary progressive disease (N=37, 21.9%), experienced an extremely poor overall survival (OS) and were evaluated separately. In patients with clinical benefit, we observed a significant association between ETS and DoR with both OS and PFS, and we identified a relative reduction of at least 1% as the optimal cut-off for ETS and a relative reduction of at least 50% as the optimal cut-off for DoR.ConclusionsETS and DoR are important prognostic factors in patients with MSI-high mCRC treated with ICIs that might be useful to design treatment intensification/deintensification strategies. A prospective validation of both is warranted.

Background: O-6-methylguanine-DNA methyltransferase is responsible for the direct repair of O6-methylguanine lesions induced by alkylating agents, including temozolomide. O-6-methylguanine-DNA methyltransferase promoter hypermethylation is a well-established biomarker for temozolomide response in glioblastoma patients, also correlated with therapeutic response in colorectal cancer. Objectives: The ARETHUSA clinical trial aims to stratify colorectal cancer patients based on their mismatch repair status. Mismatch repair-deficient patients are eligible for treatment with immune checkpoint inhibitors (anti-PDL-1), whereas mismatch repair-proficient samples are screened for O-6-methylguanine-DNA methyltransferase promoter methylation to identify those suitable for temozolomide treatment. Methods: In this context, a subset of ARETHUSA metastatic colorectal cancer samples was used to compare two different techniques for assessing O-6-methylguanine-DNA methyltransferase hypermethylation: Methyl-BEAMing, a highly sensitive digital PCR approach that combines emulsion PCR and flow cytometry, and droplet digital PCR, a more automated procedure that enables the rapid, operator-independent analysis of a large number of samples. Results: Our study clearly demonstrates that the results obtained using Methyl-BEAMing and droplet digital PCR are comparable, with both techniques showing similar accuracy, sensitivity, and reproducibility. Conclusions: Digital droplet PCR proved to be an efficient method for detecting gene promoter methylation. However, the Methyl-BEAMing method has proved more sensitive for detecting low quantities of DNA.

Immunotherapy has changed the therapeutic scenario of metastatic renal cell carcinoma (mRCC), however the evaluation of disease response to immune-checkpoint inhibitors is still an open challenge. Response evaluation criteria in solid tumors (RECIST) 1.1 criteria are the cornerstone of response assessment to anti-neoplastic treatments, but the use of anti-programmed death receptor 1 (PD1) and other immunotherapeutic agents has shown atypical patterns of response such as pseudoprogression. Therefore, immune-modified criteria have been developed in order to more accurately categorize the disease response, even though their use in the everyday clinical practice is still limited. In this review we summarize the available evidence on this topic, with particular focus on the application of immune-modified criteria in the setting of mRCC.

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.

Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy. ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m2 on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete. Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0–57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9–7·8) in the switch maintenance group and 3·5 months (2·8–4·2) in the control group (HR 0·61, 95% CI 0·48–0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7–9·9) in the switch maintenance group and 6·1 months (5·0–7·2) in the control group (p=0·0010). The most frequent grade 3–4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred. Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents. Partly funded by Eli Lilly.

IntroductionIn patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in comparison with CEA and RECIST-defined sum of target lesions.MethodsIn this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel. For each patient, the gene with the highest VAF in ctDNA was selected.ResultsThe final cohort included 135 patients. The median VAF was 12.6% (IQR: 2.0–45.2%). Higher VAF was observed in patients with liver metastases and with synchronous metastases presentation. Patients with high VAF had poorer median OS compared to those with low VAF (21.8 vs 36.5 months; HR: 1.82, 95%CI: 1.20–2.76; p = 0.005). VAF outperformed baseline CEA and target lesion diameter in the prognostic stratification and remained significantly correlated with OS (p = 0.003) in a multivariate model. VAF was not significantly correlated with dimensional response and PFS.ConclusionCtDNA measured by VAF is prognostic in patients with RAS wild-type mCRC. Response and PFS after an anti-EGFR-based first-line strategy are independent from initial tumour burden.