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Colorectal cancer (CRC) surgery can be associated with suboptimal outcomes in older patients. The aim was to identify the correlation between frailty and surgical variables with the achievement of Textbook Outcome (TO), a composite measure of the ideal postoperative course, by older patients with CRC.All consecutive patients ≥70years who underwent elective CRC-surgery between January 2017 and November 2021 were analyzed from a prospective database. To obtain a TO, all the following must be achieved: 90-day survival, Clavien-Dindo (CD) 3, no reintervention, no readmission, no discharge to rehabilitation facility, no changes in the living situation and length of stay (LOS) ≤5days/≤14days for colon and rectal surgery respectively. Frailty and surgical variables were related to the achievement of TO.Four-hundred-twenty-one consecutive patients had surgery (97.7% minimally invasive), 24.9% for rectal cancer, median age 80 years (range 70-92), median LOS of 4 days (range 1-96). Overall, 288/421 patients (68.4%) achieved a TO. CD 3-4 complications rate was 6.4%, 90-day mortality rate was 2.9%. At univariate analysis, frailty and surgical variables (ileostomy creation, p = 0.045) were related to. However, multivariate analysis showed that only frailty measures such as flemish Triage Risk Screening Tool≥2 (OR 1.97, 95%CI: 1.23-3.16; p = 0.005); Charlson Index6 (OR 1.61, 95%CI: 1.03-2.51; p = 0.036) or Timed-Up-and-Go20 s (OR 2.06, 95%CI: 1.01-4.19; p = 0.048) independently predicted an increased risk of not achieving a TO.The association between frailty and comprehensive surgical outcomes offers objective data for guiding family counseling, managing expectations and discussing the possible loss of independence with patients and caregivers.

Background: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. Methods: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III–IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016–004403–31). Findings: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2–29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7–12·1) in the standard group and 9·6 months (7·2–17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65–0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3–4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). Interpretation: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted.

Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer.AtezoTRIBE was a multicentre, open-label, randomised, controlled, phase 2 study of patients (aged 18-70 years with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-2 and aged 71-75 years with an ECOG performance status of 0) with histologically confirmed, unresectable, previously untreated metastatic colorectal cancer and adequate organ function, who were recruited from 22 oncology centres in Italy. Patients were stratified according to centre, ECOG performance status, primary tumour site, and previous adjuvant therapy. A randomisation system incorporating a minimisation algorithm randomly assigned (1:2) patients via a masked web-based allocation procedure to two groups: the control group received first-line FOLFOXIRI (intravenous 165 mg/mBetween Nov 30, 2018, and Feb 26, 2020, 218 patients were randomly assigned and received treatment (73 in the control group and 145 in the atezolizumab group). At the data cutoff (Aug 1, 2021), median follow-up was 19·9 months (IQR 17·3-23·9). Median progression-free survival was 13·1 months (80% CI 12·5-13·8) in the atezolizumab group and 11·5 months (10·0-12·6) in the control group (hazard ratio [HR] 0·69 [80% CI 0·56-0·85]; p=0·012; adjusted HR 0·70 [80% CI 0·57-0·87]; log-rank test p=0·018). The most frequent all-cause grade 3-4 adverse events were neutropenia (59 [42%] of 142 patients in the atezolizumab group vs 26 [36%] of 72 patients in the control group), diarrhoea (21 [15%] vs nine [13%]), and febrile neutropenia (14 [10%] vs seven [10%]). Serious adverse events were reported in 39 (27%) patients in the atezolizumab group and in 19 (26%) patients in the control group. Two (1%) treatment-related deaths (due to acute myocardial infarction and bronchopulmonary haemorrhage) were reported in the atezolizumab group; none were reported in the control group.The addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer.GONO Foundation, ARCO Foundation, F Hoffmann-La Roche, and Roche.

Background: ctDNA analysis is emerging as an attractive non-invasive approach to characterize tumor biology, describe its evolution over time, and predict treatment benefit. Here, we assessed the prognostic and predictive role of baseline and dynamic ctDNA analysis in HR+/HER2- aBC patients (pts) treated with R+L. Methods: 287 postmenopausal pts were enrolled in the BioItaLEE trial (NCT03439046). Liquid biopsies were collected at baseline (D0; n=263), day 15 of cycle 1 (D15; n=238), day 1 of cycle 2 (C2D1; n=241) and at first imaging (FI, at approximately 12 weeks; n=206). ctDNA analysis was carried out using a 533-amplicon Custom AmpliSeq HD Panel, with amplicons covering the coding exons of 39 BC-related genes (limit of detection: 0.1%). Target mutations were defined as single-nucleotide variant (SNV) or Insertion/Deletion detected at D0. When multiple target mutations were detected, the one with the highest variant allele frequency (VAF) was considered. The association between pre-treatment and on-treatment ctDNA dynamics with progression-free survival (PFS) was assessed using Multivariate Cox models. VAF clearance was defined as 100% decrease in a target mutation. Results: Median follow-up was 26.9 months and median PFS was 23.39 (20.8-NE) months. At baseline, target mutations were detected in 113 pts (43.0%), whereas 150 pts were wild-type (wt). Mean (SD) pre-treatment VAF at D0 was 11.3% (14.4). The absence of a target mutation at D0 was associated with good prognosis (HR: 0.41, 95% CI: 0.27–0.61; p Citation Format: Giampaolo Bianchini, Luca Malorni, Grazia Arpino, Alberto Zambelli, Fabio Puglisi, Lucia Del Mastro, Marco Colleoni, Filippo Montemurro, Giulia Bianchi, Ida Paris, Giacomo Allegrini, Marina Elena Cazzaniga, Michele Orditura, Claudio Zamagni, Stefano Tamberi, Daniela Castelletti, Matteo Benelli, Maurizio Callari, Angela Santoro, Michelino De Laurentiis. Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-07.

Background: Extending adjuvant endocrine treatment (ET) with aromatase inhibitors (AI) to 7-10 years decreases the risk of relapse in hormone receptor-positive (HR+) breast cancer (BC). However, such benefit comes at the price of higher incidence of skeletal and cardiovascular (CV) events. Biomarkers predicting such toxicities might help clinicians in tailoring adjuvant ET to patient’s needs. We conducted a prospective study to assess whether SNPs in the gene encoding for the aromatase enzyme (CYP19A1) affect the risk of skeletal and CV events in HR+ early BC patients enrolled in the GIM4 trial. Methods: The GIM4 trial randomized HR+ BC postmenopausal patients who had been already treated with 2-3 years of adjuvant tamoxifen to either 3-2 years or 5 years of adjuvant letrozole. Four SNPs of CYP19A1 were evaluated: rs10046, rs4646, rs479292 and rs727479. SNPs were genotyped through PCR on DNA obtained from patients’ peripheral blood samples. Skeletal and CV events were assessed from randomization in the GIM4 trial to last follow-up, disease recurrence or death. Skeletal events were defined as the onset of osteoporosis or bone fractures. CV events were defined as the onset of thrombosis, embolism, stroke, myocardial infarction, hearth failure, or arrythmia. Univariate and multivariate logistic regressions were performed to evaluate the association between SNPs and skeletal and CV events. Bonferroni correction for multiplicity was used for univariate SNPs association tests, with a corrected alpha of 0.012. Only associations with an alpha level Citation Format: Benedetta Conte, Chiara Molinelli, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Anna Turletti, Claudia Bighin, Francesca Poggio, Giulia Buzzatti, Matteo Lambertini, Luca Boni, Lucia Del Mastro. Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-03.

Background: Information about the adherence to scientific societies guidelines in the ‘real-world’ therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). Patients and methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine þ capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel þ gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nabpaclitaxel þ gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing.

This open-label phase II clinical trial evaluated the antitumor activity and safety of trabectedin in patients with advanced ovarian (OC) or uterine carcinosarcomas (UC).Eligible patients were adults (≥18 years) with histologically proven recurrent OC/UC not amenable to surgery or radiotherapy who received up to two prior chemotherapy lines. Trabectedin 1.3 mg/mForty-five patients with either OC (n = 32) or UC (n = 13) from seven MITO centers across Italy were enrolled. The ORR was 11.9% (90% CI: 6-23) and included two patients with a complete response and three with a partial response. Eight patients (19.0%) had disease stabilization for a disease control rate of 31.0% (90% CI: 20-44). Median progression-free survival was 2.01 months (95% CI: 1.78-2.30) and median overall survival was 4.64 months (95% CI: 3.19-8.29). Neutrophil count decreases (n = 8, 18.2%) and transaminase increases (n = 6, 13.6%) were the most common grade 3-5 adverse events related with trabectedin. Two patients died due to trabectedin-related grade 5 hematological toxicity.Although trabectedin did not meet the prespecified activity criteria, it confers modest but clinically meaningful benefit to patients with advanced OC/UC as being as effective as any other available treatment for this indication. The toxicity profile appears in line with that previously reported for the drug.

Background:No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III β-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported.Methods:We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival.Results:Patients with TUBB3 protein levels >750 and Conclusions:The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.

358 Background: In resectable GAC/GEJAC, MSI status is associated with better survival and potential lack of benefit from chemotherapy. Given the high responsiveness of MSI tumors to immunotherapy, neoadjuvant or definitive dual CTLA-4/PD(L)-1 inhibition may allow omission of chemotherapy or surgery. Methods: INFINITY is a multicentre, single-arm, multi-cohort phase II trial (NCT04817826) investigating the activity and safety of tremelimumab+durvalumab as neoadjuvant (Cohort 1) or definitive (Cohort 2) treatment for MSI, mismatch repair deficient (dMMR) and EBV-negative resectable GAC/GEJAC. In Cohort 1, patients (pts) received a 12-week treatment with single high dose tremelimumab 300 mg and durvalumab 1500 mg q4 weeks (T300/D) for 3 cycles followed by surgery. The primary endpoint was pCR rate (ypT0N0) with negative ctDNA after T300/D. Secondary endpoints: disease-free survival, overall survival, quality of life. Exploratory: correlation of pCR with clinical variables, PDL-1 CPS assessed by IHC 22C3, tumor mutational burden (TMB) by Foundation One, liquid biopsies and other biomarkers. Cohort 2 investigates non operative management after same treatment regimen. Results: Overall, 18 pts with MSI/dMMR resectable cT2-4 any N GAC/GEJAC were recruited in Cohort 1. One withdrew consent and 2 achieved a complete clinical-pathological response at radiology and endoscopy (ongoing) and refused surgery. Among 15 evaluable patients, 1 had disease progression and 14 underwent resection. pCR rate was 60% (9/15) and major-complete pathological response (

Background Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. Subjects, Materials, and Methods The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. Results A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. Conclusion Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. Implications for Practice Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.

Around 8–12% of patients with advanced colon rectal cancer (CRC) present with BRAF alterations, in particular V600E mutation, which is associated with right-side, poorly differentiated and mucinous type tumors. The presence of BRAF mutation (BRAF-mt) has been identified as a hallmark of poor prognosis and treatment optimization in this patient subgroup is an important goal. Currently, the standard of care is an aggressive strategy involving triplet chemotherapy and anti-VEGF agents, but new therapeutic approaches are emerging. Very promising results have been obtained with targeted therapy combinations, such as anti-BRAF agents plus anti-EGFR agents. Furthermore, around 60% of BRAF-mt patients show a strong association with high microsatellite instability (MSI-H) and immune checkpoint inhibitors could represent the new standard of care for this subgroup. The focus of this review is to summarize current strategies for BRAF-mt CRC treatment and highlight new therapeutic options.

Summary Background The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2–3 years of letrozole in postmenopausal patients with breast cancer who have already received 2–3 years of tamoxifen. Methods This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I–III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2–3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635. Findings Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2–3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5–13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57–66) in the control group and 67% (62–71) in the extended group (hazard ratio 0·78, 95% CI 0·65–0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed. Interpretation In postmenopausal patients with breast cancer who received 2–3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2–3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2–3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer. Funding Novartis and the Italian Ministry of Health. Translation For the Italian translation of the abstract see Supplementary Materials section.

LBA5504 Background: Trabectedin demonstrated antitumor activity when administered as single agent in relapsed platinum sensitive ovarian cancer (OC), with an overall response rate (ORR) ranging from 26 to 43% and a median PFS of 5 months. In addition, trabectedin showed 39.4% RR, 4.5 months median progression free survival (PFS) and 18 months median overall survival (OS) in a single arm phase 2 trial in recurrent BRCA mutated and/or the BRCAness phenotype OC patients. Methods: In this open-label, phase III, randomized trial, we assigned recurrent OC patients harboring BRCA 1/2 mutations or with BRCAness phenotype (defined as patients who had received and responded to at least 2 previous platinum-based treatments) to receive trabectedin 1.3 mg/mq q 21d or physician’s choice chemotherapy (among carboplatin, gemcitabine, weekly paclitaxel, pegylated liposomal doxorubicine or topotecan). The primary endpoint was OS. Secondary endpoints were PFS, ORR and Duration of Response (DoR). The sample size was calculated based on the assumption that trabectedin would increase median OS from 10 to 15 months (two-sided log-rank test at the error alfa= 0.05 and a power of 80%). Medians and lifetables were computed using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards model was used to assess the effect of treatment. Results: Two hundred and forty-four patients were randomized and analyzed based on the intent-to-treat principle. At a median follow up of 40 months, the median PFS was 4.4 and 4.9 months (HR= 1.03 p=0.848) and median OS was 17.9 and 15.8 months (HR=1.15 p=0.304), in the control and experimental arm, respectively. ORR was 20.2% in the group of patients receiving standard chemotherapies and 15.4% in the group of patients treated with trabectedin. No superior effect was reported for Trabectedin in the pre-specified sub-group analysis according to BRCA mutational status, type of chemotherapy and platinum-free interval. No new signal of toxicity were reported for all the chemotherapies employed. Conclusions: Trabectedin as single agent does not improve survival outcomes when compared to standard chemotherapy in BRCA mut and BRCAness phenotype OC patients. Clinical trial information: NCT02993705.

LBA3513 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. pathologic complete remission (pCR) can be considered as surrogate endpoint of efficacy of treatment in terms of disease-free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multicentre study in patient with locally advanced rectal cancer who receive standard concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is the proportion of pCRs after at least 1 cycle of durvalumab; secondary endpoints are the proportion of clinical complete remissions (cCRs) after at least 1 cycle of durvalumab, the proportion of adverse and serious adverse events (NCI CTCAE v5.0). The sample size has been estimated by using the optimal Simon’s two-stage design assuming a null pCR proportion of 0.15 and an alternative pCR percentage of 0.30 (alpha = 0.05, power = 0.80). If more than 4 pCRs were observed in the first 19 enrolled patients, 36 additional patients were to be accrued for a total of 55 evaluable patients. The null hypothesis is rejected if ≥ 13 pCRs are observed in 55 patients. Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were evaluable for study objectives. Fifty-two of 55 treated patients received all 3 infusions of durvalumab. After treatment, a clinical response percentage of 81.8% was observed; 3 patients had progression of disease due to local and/or metastases before surgical intervention. Eighteen patients achieved complete pathological response (32.7%), confirmed by central revision. Near complete regression, moderate and minimal regression were observed in 14 (25.5%), 9 (16.4%) and 11 (20.0%) patients respectively. Regarding toxicity, 23 patients (41.8%) had adverse events (AEs) related to durvalumab treatment. Two patients (1.8%) discontinued durvalumab for toxicity. Grade 3 AEs occurred in 4 (7.3%) patients (diarrhea, skin toxicity, transaminase increase, lipase increase and pancolitis). No Grade 4 toxicity was observed. In 20 patients (36.4%) G1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypo-thyroidism), dermatologic toxicity (skin rash) and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). Conclusions: This study met its primary endpoint showing a promising activity of neoadjuvant chemo-radiotherapy plus durvalumab in terms of pCR rate and a safe toxicity profile. Clinical trial information: NCT04083365.

1012 Background: Independent early dynamic assessment (baseline [D0] and day 15 of first cycle [D15]) of both TKa and ctDNA was prognostic and predictive in pts with HR+, HER2− ABC treated with RIB+LET enrolled in the BioItaLEE trial (NCT03439046). Here we performed a combined analysis of these two biomarkers. Methods: 287 pts were enrolled in the study. Overall, early dynamics were assessable for both biomarkers in 241/287 pts (84.0%). Methods applied for ctDNA and TKa evaluation were previously reported. For ctDNA, samples were defined as wild type (WT) if no mutations were observed at D0 and D15, ctDNA positive (+) if with or negative (-) if without a primary target mutation at D15. Samples were TKa+ or TKa- if TKa levels were above or below the limit of detection at D15. According to ctDNA and TKa pts were classified as: WT/TKa-, WT/TKa+, ctDNA-/TKa-, ctDNA-/TKa+, ctDNA+/TKa- and ctDNA+/TKa+ and then divided into 3 main study groups (GRs) WT/TKa- (GR1, n = 126), WT/TKa+, ctDNA-/TKa-, ctDNA-/TKa+, ctDNA+/TKa- (GR2, n = 96) and ctDNA+/TKa+ (GR3, n = 19). The association between biomarkers and PFS (progression-free survival) was estimated using Kaplan-Meier analysis and multivariate Cox models with 95% confidence intervals (CIs) adjusted for clinical variables. Results: Median follow-up was 26.9 months. In multivariate Cox models both TKa dynamics and mutational tumor burden at D15 were independently predictive of PFS. Hazard ratios (HRs) were 0.37 (95% CI: 0.23-0.60; p < 0.0001) for WT vs ctDNA+ and 0.56 (95% CI: 0.32-1.00; p = 0.0506) for ctDNA- vs ctDNA+. For TKa, HR was 0.49 (95% CI: 0.30-0.80; p = 0.0040) in TKa- vs TKa+. Interestingly combining the two variables further improve prediction of outcome. HRs for TKa- vs TKa+ were 0.17 (95% CI: 0.09-0.32; p < 0.0001), 0.28 (95% CI: 0.13-0.59; p = 0.0009) and 0.44 (95% CI: 0.23-0.86; p = 0.0169) in WT, ctDNA- and ctDNA+ pts, respectively. Considering the 3 study GRs, median PFSs (95% CI) were not reached (27.89, NE), 19.58 (13.83, 23.39) and 6.65 (2.83, 12.16) months in GR1, GR2 and GR3, respectively, p < 0.001. At multivariate Cox models, HRs of GR1 and GR2 compared with GR3 were 0.17 (95% CI: 0.09-0.32; p < 0.0001) and 0.37 (95% CI: 0.20-0.67; p = 0.001) respectively. Conclusions: These findings suggest that combining the early dynamic assessment of both ctDNA and TKa may improve outcome prediction in pts treated with RIB+LET. Pts with ctDNA+/TKa+ are strongly enriched for non-responders. TKa and ctDNA capture different features of tumor biological activity and their combination warrants further evaluation in relation to other treatments, settings, and diseases. Clinical trial information: NCT03439046.

Simple Summary An evaluation process and adequate referrals are an important part of a distress screening program but insufficient consideration is given to referrals and uptake of available supportive services. Identifying the reasons for accepting or refusing help is needed to implement a screening-for-distress policy in a clinical cancer setting, as confirmed in the present study. It is vital to reach and motivate the highest possible number of patients to be referred to psycho-oncology services when needed. A multidisciplinary approach could help to raise awareness of the benefit of screening for distress, the implementation of which would improve uptake. Abstract Introduction: Little consideration is given to the referral and uptake of available supportive services after distress screening. However, identifying the reasons for accepting or refusing help is mandatory for implementing a screening policy. The present study explored the practical usefulness of and potential barriers to the application of distress management. Methods: 406 cancer patients were consecutively selected and asked to complete the Distress Thermometer (DT) and Problem Check List (PL). All patients with a DT score ≥6 were invited for a post-DT telephone interview with a trained psychologist. Results: The 112 patients who refused to take part were more often older, retired, at a more advanced stage of illness, and with no previous experience of psychological intervention with respect to those who accepted. Of the 78 patients with a score ≥6 who were referred to the Psycho-Oncology Service, 65.4% accepted the telephone interview. Twenty-two patients rejected the initial invitation immediately for various reasons including logistic difficulties, physical problems, and feeling embarrassed about opening up to a psychologist. Conclusions: Our study confirms that screening per sé is insufficient to deal with the problem of distress and that more emphasis should be placed on implementing referral and treatment.

Simple Summary The status of microsatellite instability (MSI-H) in gastric or gastroesophageal junction cancer (GC/GEJC) patients eligible for radical surgery proved to be prognostic for an improved survival outcome and predictive for poor/no benefit from the combination of adjuvant/peri-operative chemotherapy. MSI-H tumors display a high sensitivity to immunotherapy and exploratory studies showed that a pre-operative treatment with immune-checkpoint inhibitors may achieve elevated rates of pathological complete responses. The ongoing proof-of-concept INFINITY study is aimed at investigating the role of the combo-immunotherapy durvalumab plus tremelimumab as a neoadjuvant or potentially definitive treatment (avoiding surgery in case of complete clinical response) for MSI-H resectable GC/GEJC patients. Abstract 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.

BackgroundImmune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes.Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns.Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation.MethodsAtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee.DiscussionThe AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status.Trial registrationAtezoTRIBE is registered at Clinicaltrials.gov (NCT03721653), October 26th, 2018 and at EUDRACT (2017–000977-35), Februray 28th, 2017.

Background Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile. Methods The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m2 ) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics. Results Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin Cmax , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m2 (SD, 14.08 L/h/m2 ), and 1460 L/m2 (SD, 561 L/m2 ), respectively. Conclusion Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data.

Background: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired. Methods: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported. Results: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68–0.95, p = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72–1.12, p = 0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49–0.84, p = 0.0011) versus CT alone. Conclusion: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies.

Summary Background Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. Methods We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , number NCT01655693 . Findings Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2–34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1–10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1–11·8) in the control group (HR 1·00 [95% CI 0·78–1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. Interpretation Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. Funding Onxeo.

3607 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multi-centre study, conducted with support from AstraZeneca, in patient with locally advanced rectal cancer who receive concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is pCR rate after at least 1 cycle of durvalumab. The sample size has been estimated by using the optimal Simon’s two-stage design. If more than 4 complete responses are observed in the first 19 enrolled patients, 36 additional patients will be accrued for a total of 55 evaluable patients. Results: Between November 2019 and July 2020, 20 patients were accrued and 19 were evaluable for study objectives, concluding the first stage of the trial. Baseline characteristics of the first 19 evaluable patients enrolled are listed in the table. All patients received 3 infusions of durvalumab; 18 patients underwent surgery after a median of 13 weeks from CHT/RT end. Five complete pathological responses (ypT0N0) were observed, allowing to proceed to the second stage. About toxicity, four patients had Grade 3-4 adverse events (AE); the most frequent G3-4 AE related to the neoadjuvant therapy were anemia (n=1), diarrhea (n=2) and neuthropenia (n=2). No grade 3 and 4 adverse events related to Durvalumab treatment were observed. Eight patients had G1-2 AE related to durvalumab, the most common being asthenia (n=2) and nausea (n=2). Conclusions: At the end of study’s first stage the preoperative treatment with radiotherapy plus capecitabine followed by durvalumab showed a safe toxicity profile and promising activity in terms of pCR rate. The second part of the trial is ongoing, and the accrual is under completion (44 patients enrolled as of 10 February 2021). Clinical trial information: NCT04083365. [Table: see text]