Clinical and mutational profile of AT-rich interaction domain 1A-mutated cancers.

Aim: AT-rich interaction domain 1A (ARID1A) encodes a key component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that participates in gene expression. ARID1A alterations are quite common among cancer patients, although their role remains debated. The aim of this article was to study ARID1A-mutated cancer patients. Methods: Molecular and clinical data of cancer patients evaluated at Phase 1 Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS were collected. Molecular analyses were performed using FoundationOne® CDx (Foundation Medicine Inc., Cambridge, MA, United States). Cancer patients with at least one molecular alteration in ARID1A gene were identified as ARID1A+. Results: Among the 270 patients undergoing molecular analysis, we found 25 (9%) with at least one pathogenic alteration in ARID1A. The vast majority of these patients were female (84%). The median age at diagnosis was 59; most of the cancers (15, 60%) were gynecological (especially endometrioid endometrial cancers and clear cell ovarian cancers), diagnosed at an early stage. Frameshift alterations in ARID1A were the most common (19/31, 61%) alterations. The median number of mutations in ARID1A+ population was higher compared to ARID1A- population (6 vs. 4), as well as tumor mutational burden (TMB) [20 mutations/megabase (mut/Mb) vs. 1.26 mut/Mb]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), catenin beta 1 (CTNNB1), and lysine methyltransferase 2D (MLL2) mutations were enriched in ARID1A+ population. In this cohort, ARID1A did not display any relation with response to platinum chemotherapy. Cancers with double alterations in ARID1A (ARID1A2+) were all gynecological cancers (83% endometrioid endometrial cancers). Conclusions: This analysis provides clinical and molecular details about the phenotypes of ARID1A+ cancers, in particular the subgroup of gynecologic cancers. The high frequency of concurrent mutations in the phosphoinositide 3-kinase (PI3K) pathway among endometrioid endometrial cancers may support the proposal of a new treatment strategy based on the combination of ataxia telangiectasia and Rad3-related (ATR) inhibitor and PIK3CA inhibitor.

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study.

INTRODUCTION: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms. METHODS: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2). RESULTS: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007). CONCLUSIONS: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results.

Effects of Plant Biostimulation Time Span and Soil Electrical Conductivity on Greenhouse Tomato 'Miniplum' Yield and Quality in Diverse Crop Seasons.

Biostimulants help plants cope with environmental stresses and improve vegetable yield and quality. This study was conducted to determine the protein hydrolysate (PH) effect of three different durations (weekly applications: three, six, or nine times plus an untreated control) in factorial combination with four soil electrical conductivities (EC: 1.5, 3.0, 4.5, or 6.0 mS·cm-1) on yield, fruit quality, and elemental composition of tomato 'miniplum' grown in a greenhouse. Fruit yield was best affected, during the summer, by six and nine biostimulant applications at EC 3.0 mS·cm-1, and in the same season, the six treatments led to the highest fruit number with no difference compared to nine applications; during the winter, the three and six treatments improved the mentioned variables at each EC level. Fruits' dry residue and Brixo were positively affected by biostimulation both in summer and winter. In summer, the 6.0 mS·cm-1 EC led to the highest dry residue and Brixo values, though the latter did not show any significant difference compared to 4.5 mS·cm-1; in winter, the best results corresponded to 4.5 and 6.0 mS·cm-1. A higher beneficial effect of PH on fruit antioxidant status, i.e., lycopene, polyphenols, ascorbic acid levels, and lipophilic (LAA) and hydrophilic (HAA) activity, was recorded in winter compared with summer. Positive correlations between polyphenols and LAA, as well as ascorbic acid content and HAA were found for all EC and PH treatments. Most of the mineral elements tested demonstrated concentration stability, whereas the highest EC decreased P, Mg, Cu, and Se accumulation. The opposite effect was shown by PH application on Se and Mn levels, with P tending to increase. The concentrations of Fe, Zn, and Cu were the lowest under the longest duration of PH supply. These results further confirm the essential role of plant biostimulation in enhancing tomato yield and quality, with a particular focus on the treatment duration.

Overview of Trop-2 in Cancer: From Pre-Clinical Studies to Future Directions in Clinical Settings.

Trophoblast cell surface antigen-2 (Trop-2) is a glycoprotein that was first described as a membrane marker of trophoblast cells and was associated with regenerative abilities. Trop-2 overexpression was also described in several tumour types. Nevertheless, the therapeutic potential of Trop-2 was widely recognized and clinical studies with drug-antibody conjugates have been initiated in various cancer types. Recently, these efforts have been rewarded with the approval of sacituzumab govitecan from both the Food and Drug Administration (FDA) and European Medicines Agency (EMA), for metastatic triple-negative breast cancer patients. In our work, we briefly summarize the various characteristics of cancer cells overexpressing Trop-2, the pre-clinical activities of specific inhibitors, and the role of anti-Trop-2 therapy in current clinical practice. We also review the ongoing clinical trials to provide a snapshot of the future developments of these therapies.

Efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis.

BACKGROUND: Several regimens have been introduced in clinical practice in the last twenty years to treat chemotherapy-induced nausea and vomiting (CINV). However, direct comparative data remain insufficient, as many new regimes lack head-to-head comparisons. In this study, through an indirect comparison, we overcome this limit by providing the most up-to-date estimate of the efficacy and safety of all combinations used for HEC-induced nausea and vomiting. PATIENTS AND METHODS: We retrieved randomized controlled trials (RCTs) published in Pubmed, Embase, and Cochrane Library until June, 30th 2022. We included phase II-III RCTs, including adults with any cancer receiving HEC, and compared different antiemetic regimes to prevent CINV. The primary outcome was the overall complete response (defined as the absence of vomiting and of the use of rescue drugs from 0 to 120 hrs since chemotherapy); secondary outcomes were acute (absence of vomiting and use of rescue medicine 0-24 hrs after chemotherapy) and delayed (24-120 hrs) response and adverse events. RESULTS: A total of 53 RCTs enrolling 22 228 patients were included. We classified the different antiemetic regimes into 21 different groups. Overall, 3- or 4-drug regimens containing a combination of dexamethasone, 5HT3 antagonists, mirtazapine or olanzapine with or without NK antagonists, yielded the highest probability to be the most effective regimen in terms of complete response. Regimens containing a combination of dexamethasone and 5-HT3 antagonist have the lowest probability of being the most effective regimen in terms of complete, acute, and delayed response. CONCLUSION: In our network meta-analysis, 4-drug regimens with olanzapine displayed the highest probability of efficacy in terms of complete response. A 3-drug regimen with olanzapine represents a valid option in a limited resource context.

Molecular Profile and Matched Targeted Therapy for Advanced Breast Cancer Patients.

(1) Background: Precision oncology is opening new treatment opportunities for patients suffering from solid tumors. In the last two decades, the advent of CDK4/6 inhibitors, immunotherapy, and antibody-drug conjugates (ADC) improved survival outcomes for advanced or metastatic breast cancers (BC). Nevertheless, some patients progress to approved therapies and still maintain good clinical conditions. (2) Methods: With the aim to estimate the accrual rate to experimental precision oncology treatments, we collected molecular and clinical characteristics of BC patients evaluated at Phase 1 Unit of Fondazione Policlinico Gemelli. Clinical data were retrieved from hospital records. Molecular analysis was performed using Next-Generation Sequencing (NGS) FoundationOne CDx on tissue or blood. (3) Results: Among the 38 BC patients referred to our unit, 35 completed the genomic analysis. All patients were female with advanced (mean number of metastatic sites: 3, range 1-6) BC. Median age at our evaluation was 52 (IQR, 48-59). ECOG PS was good in 97% of the study population, although heavily pre-treated (median number of systemic treatments: 5, IQR 3-7). Half of referred patients were HR+/HER2- BC, with 39% triple negative breast cancer (TNBC). NGS testing was performed on relapsed disease among most (71%) participants, in particular lymph nodes and soft tissue. Liquid biopsy was requested in 23% of cases. The median time from sample collection to NGS testing was 1 month and from diagnosis 54 months. The median value of mutations, VUS, and TMB were 6, 11, and 5, respectively. TP53, PIK3CA, BRCA2, ESR1, and RAD21 were the genes with the highest number of molecular alterations. In 5 patients (14%), the molecular analysis was helpful to assign targeted therapy in the context of clinical trials with a median progression-free survival of 5 months. (4) Conclusions: HR+/HER2- and TNBC were the most frequent subtypes referred for NGS testing. Tissue biopsy of relapsed disease was feasible in 71% of cases. The molecular analysis offered a new treatment opportunity in 14% of patients. The real benefit of these treatments remains to be evaluated in larger cohorts.

Fluoropyrimidine­induced cardiotoxicity in colorectal cancer patients: a prospective observational trial (CHECKPOINT).

Fluoropyrimidines (FP) are the backbone chemotherapy in colorectal cancer (CRC) treatment; however, their use is associated with cardiotoxicity, which is underreported. In the present study, it was aimed to prospectively determine the incidence rates and related risk factors of FP­induced cardiotoxicity (FIC) in CRC patients and at identifying predictive biomarkers. A total of 129 consecutive previously untreated CRC patients underwent active cardiological monitoring, including 5­items simplified questionnaire on symptoms, electrocardiogram (ECG) and plasma sample collection during FP chemotherapy. FIC was defined as the presence of ECG alterations and/or the arising of at least one symptom of chest pain, dyspnoea, palpitations or syncope. The primary objective was the evaluation of FIC incidence. Secondary objectives were the correlation of FIC with well­known cardiological risk factors and the identification of circulating biomarkers (serum levels of troponin I, pro hormone BNP; miRNA analysis) as predictors of FIC. A total of 20 out of 129 (15.5%) patients experienced FIC. The most common symptoms were dyspnoea (60%) and chest pain (40%), while only 15% of patients presented ECG alterations, including one acute myocardial infarction. Retreatment with FP was attempted in 90% of patients with a favourable outcome. Despite 48% of patients having cardiological comorbidities, an increased FIC was not observed in this subgroup. Only the subgroup of females with the habit of alcohol consumption showed an increased risk of FIC. None of the circulating biomarkers evaluated demonstrated a clinical utility as FIC predictors. FIC can be an unexpected, life­threatening adverse event that can limit the subsequent treatment choices in patients with CRC. In this prospective study, well­known cardiological comorbidities were not related to higher FIC risk and circulating biomarkers predictive of toxicity could not be found. With careful monitoring, mainly based on symptoms, almost all patients completed the FP treatment.

Comparing efficacy and safety of upfront treatment strategies for anaplastic lymphoma kinase-positive non-small cell lung cancer: a network meta-analysis.

Aim: This article is based on our previous research, which was presented as a post at the Congress Aiom 2022 Congress and published in Tumori Journal as Conference Abstract (Tumori J. 2022;108:1-194. doi: 10.1177/03008916221114500). In this paper, a comprehensive presentation of all the achieved results is provided. Several tyrosine kinase inhibitors (TKIs) have been investigated to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, direct comparisons between these TKIs are lacking, with many only being compared to crizotinib. To address this gap, a network meta-analysis was conducted to compare the efficacy and safety of various first-line systemic therapies for ALK-positive NSCLC. Methods: A thorough search of PubMed, Embase, and Cochrane Library was performed to identify randomized controlled trials (RCTs) published between January 01, 2000 and April 01, 2022, and included trials that investigated upfront treatments for this molecular subgroup and reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher (grade ≥ 3 AEs). Results: The analysis included 9 RCTs with 2,443 patients receiving eight different treatments: alectinib (at two different dosages), brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Second and third-generation TKIs significantly prolonged PFS compared to crizotinib, with lorlatinib having the highest probability of yielding the most favorable PFS, followed by alectinib (300 mg or 600 mg). However, only alectinib has been shown to significantly prolong OS compared to crizotinib to date. Lorlatinib appears superior in reducing the risk of central nervous system (CNS) progression, followed by alectinib 600 mg. Ceritinib had the highest rate of AEs, followed by lorlatinib and brigatinib. Conclusions: Based on the network meta-analysis, alectinib and lorlatinib emerged as the most promising upfront treatment options. These treatments provide prolonged disease control while maintaining an acceptable safety profile.

New first-line immunotherapy-based combinations for metastatic renal cell carcinoma: A systematic review and network meta-analysis.

Several first-line immune-checkpoints inhibitors (ICI) based combinations have been studied in metastatic renal cell carcinoma (mRCC) without any direct comparison between the regimens. The objective of this systematic review and network meta-analysis was to provide the most updated evidence about the preferred first line ICI-based regimen for mRCC. We searched various databases, including PubMed, Web of Science and Scopus and the major conference proceedings (ASCO, ESMO). Eligible studies were randomized trial, published before June 2021 that evaluated first-line, ICI-based combinations compared with the standard of care in mRCC. Screening was performed independently by two investigators. A Cochrane risk-of-bias tool was used to assess trial quality. Relative effects of competing treatments were assessed by Bayesian network meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate, complete response and adverse events. Six trials with 5478 patients comparing 7 treatments were identified. Network meta-analysis showed that lenvatinib plus pembrolizumab had the highest probability to be the best treatment in terms of OS (surface under the cumulative ranking (SUCRA) 80.7%) and PFS (SUCRA 99.6%), while in sarcomatoid patients, nivolumab plus cabozantinib had the highest rank in terms of survival outcomes (SUCRA 85.8% and SUCRA 77.3%, respectively). Although we established a ranking among new first-line mRCC treatment combinations, the absence of direct comparisons between the multiple treatment options represents a major hurdle in establishing optimal therapeutic sequences. Our results could represent a starting point for head-to-head trials between the most promising combinations.

Oncologic Drugs Approval in Europe for Solid Tumors: Overview of the Last 6 Years.

(1) Background: Drug development in oncology is changing rapidly. The aim of the present study was to provide an insight into the features of anti-tumor drugs approved in Europe; (2) Methods: We included all the indications for solid tumors issued by the European Medicines Agency (EMA) between 2015 and 2020. We extracted data from European Public Assessments Reports (EPAR), including drug name, mechanism of action, setting, features of pivotal clinical trials, primary end-points, quality of life (QoL); (3) Results: In the explored period, EMA issued 132 new indications (81 indications' extensions) for 62 oncology drugs. In about half of indications (47%), the approval was biomarker-based. Immune check point inhibitors (ICIs) and signal transduction inhibitors were the two most representative drug categories (62%). Most of the indications were for the advanced setting (91%) and front-line therapy (66%). The most common tumor types were non-small cell lung cancer (24%), breast (16%), and melanoma (10%). Two thirds of the indications (73%) were approved based on phase III trials. Overall survival (OS) represented the primary end-point only in 39% of indications, mainly limited to advanced setting (98%) and ICI trials (80%). Almost all (94%) cell cycle and DNA repair mechanism inhibitors were approved based on progression free survival (PFS) data. In pivotal trials with signal transduction inhibitors, objective response rate (ORR) was the prevalent (45%) primary end-point. QoL was never considered as primary end-point; (4) Conclusions: In this analysis, we intended to offer an updated picture of the recent drug development in oncology. Most of the efforts led to broadening indications of pre-existing molecules, with signal transduction inhibitor and ICIs contending the leadership. Twenty-seven percent of the indication were approved without a phase III trial. The majority of drugs entered the market without evidence of OS or QoL benefit but based on surrogate outcomes.

Bevacizumab-induced hypertension as a predictor of clinical outcome in metastatic colorectal cancer: An individual patient data-based pooled analysis of two randomized studies and a systematic review of the literature.

BACKGROUND: Retrospective series suggest that bevacizumab-induced hypertension (HTN) is a prognostic and potentially predictive biomarker of efficacy of the antiangiogenic drug in the upfront treatment of metastatic colorectal cancer (mCRC) patients. The immortal-time bias and the effect of pre-existing HTN might affect these findings. We conducted a pooled, post hoc analysis of 2 prospective randomized trials of chemotherapy plus bevacizumab in mCRC, and performed a systematic review of the available literature focusing on how the immortal-time bias was taken into account and how pre-existing HTN potentially requiring the use of antihypertensive drugs was managed. METHODS: The pooled-analysis included patients enrolled in the phase III TRIBE and TRIBE-2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively. Association between HTN and survival outcomes was assessed by incorporating a time-dependent Cox regression model to consider the time-dependency of the probability of HTN onset during the treatment. The systematic review was conducted according to PRISMA guidelines. RESULTS: The systematic review retrieved 14 eligible and highly heterogeneous studies. A positive prognostic impact of bevacizumab-induced HTN was reported in the 58% of the analyses reporting Progression Free Survival (PFS) and in the 54% of the analyses reporting Overall Survival (OS) data. Immortal-time bias was incorporated in 4 studies (28%). In TRIBE and TRIBE-2 study populations (N = 1175), patients experiencing ≥ G2 HTN during first-line bevacizumab administration showed longer PFS (median: 14.7 versus 10.3 months, p < 0.001) and OS (median: 31.7 versus 24.2 months, p < 0.001). The association with OS retained statistical significance after correction for time-dependency (p = 0.003) and was confirmed in the multivariable model including HTN as a time-dependent variable (p = 0.02). Moreover, in patients with pre-existing HTN, no difference in terms of PFS and OS was observed compared with the subgroup of patients who never experienced ≥G2 HTN (HR 1.01, p = 0.86 and HR 1.02, p = 0.78 respectively. CONCLUSIONS: Bevacizumab-induced HTN during the first-line treatment of mCRC is an independent prognostic factor, also adopting a time-dependency correction. Toxicity should be interpreted as a time-dependent variable when exploring its association with clinical outcome.

Clinical insights and prognostic factors from an advanced biliary tract cancer case series: a real-world analysis.

Advanced biliary tract cancer (aBTC) comprises a heterogeneous group of rare malignancies with dismal prognosis. Given the scarcity of prospective evidence, the aim of this study was to derive clinically useful insights and prognostic factors from a large, real-world series of aBTC. Clinicopathologic variables and treatment outcomes were retrospectively collected involving 940 patients diagnosed with aBTC between 2001 and 2017, and treated with first-line chemotherapy (CT1) at 14 Italian medical oncology institutions. Median overall survival (OS) was 10.3 months (CI95% 9.5-11.1). CT1 with gemcitabine-Platinum salts doublets achieved OS of 11.7 months vs 7.5 with gemcitabine alone (HR 0.67, p < 0.001). However, a clear temporal trend towards improved OS could not be demonstrated. Radical surgery of recurrent disease achieved a relapse-free survival of 5.9 months. A substantial minority (44.5%) of patients were able to receive a second-line chemotherapy, which achieved a response rate of 7.6%, and disease control in 30% of patients with no significant differences between combination regimens and monotherapies. In a large retrospective series of real-world aBTC, outcomes of standard CT1 closely resembled those of the registrational trials. A limited set of easily retrievable independent prognostic factors was defined. Further research is needed on second-line regimens.

A multicenter study of skin toxicity management in patients with left-sided, RAS/BRAF wild-type metastatic colorectal cancer treated with first-line anti-EGFR-based doublet regimen: is there room for improvement?

BACKGROUND: Skin toxicity in patients affected by metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors is well known. However, ad hoc ESMO guidelines have only recently been published. AIM AND METHODS: To describe the management (pre-emptive or reactive) of anti-EGFR-related cutaneous adverse events (AEs), in a real-life clinical context, in a selected population of patients with left-sided, metastatic RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR monoclonal antibody (i.e., panitumumab or cetuximab) as first-line regimen at 22 Institutions. The measured clinical outcomes were treatment-related adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 515 patients included in the analysis, 173 (33.6%) received a pre-emptive and 342 (66.4%) a reactive treatment. The median follow-up period for the overall population was 30.0 months. A significantly lower incidence of any grade acneiform rash was found in the pre-emptive compared to the reactive cohort both in the overall population (78.6% vs 94.4%, p < 0.001) and in patients treated with panitumumab (76.1% vs 93.7%, p < 0.001) or cetuximab (83.3% vs 95.4%, p = 0.004), respectively. A lower incidence of any grade (41.6% vs 50.9%, p = 0.047) but a higher incidence of G3-G4 (9.2% vs 4.7%, p = 0.042) paronychia/nail disorders were found in the pre-emptive compared to the reactive cohort. Nevertheless, a lower rate of patients within the reactive compared to the pre-emptive cohort was referred to dermatological counseling (21.4% vs 15.3%, respectively, p = 0.001). A higher rate of anti-EGFR therapy modification was needed in the pre-emptive compared to the reactive cohort (35.9% vs 41.6%, respectively, p < 0.001). The pre-emptive approach did not reduce the efficacy of antineoplastic therapy compared to the reactive in terms of ORR (69.2% vs 72.8%), median PFS (12.3 vs 13.0 months), and median OS (28.8 vs 33.5 months). CONCLUSION: Although recommended by international guidelines, the pre-emptive approach of anti-EGFR-related skin toxicity in mCRC patients still appears less adopted in daily clinical practice, compared to the reactive one. A wider reception and application of this indication is desirable to improve patients' quality of life without compromising the continuity and efficacy of antineoplastic therapy.

Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study.

BACKGROUND: Few data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR). RESULTS: At the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9-35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3-17.7, 86 events), 13.0 (95%CI = 11.4-14.5, 56 events), 14.0 (95%CI = 8.1-20.0, 8 events), and 10.1 months (95%CI = 9.0-11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5-47.7, 43 events), 36.1 (95%CI = 31.6-40.7, 36 events), 39.5 (95%CI = 28.2-50.8, 4 events), and 25.1 months (95%CI = 22.6-27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44-0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51-0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38-0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51-0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts. CONCLUSION: Among the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a "real-life" setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.

Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials.

Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.

Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study.

INTRODUCTION: Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution. METHODS: Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1). RESULTS: Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). DISCUSSION: We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.

Clinicians' Attitude to Doublet Plus Anti-EGFR Versus Triplet Plus Bevacizumab as First-line Treatment in Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Patients: A Multicenter, "Real-Life", Case-Control Study.

BACKGROUND: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. RESULTS: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041). CONCLUSION: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.

A prognostic model in patients with advanced biliary tract cancer receiving first-line chemotherapy.

BACKGROUND: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. METHODS: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. RESULTS: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p <0.01). The prognostic score could generate a highly significant stratification (all between-group p values ≤0.001) into groups of favorable (comprising 51.5% of the sample), intermediate (39.2%), and poor prognosis (9.3%): median OS was 12.7 (CI95% 11.0-14.4), 7.1 (CI95% 5.8-8.4), and 3.2 months (CI95% 1.7-4.7), respectively. This OS gradient was replicated in the validation set (129 patients), with median OS of 12.7 (CI95% 11.0-14.3), 7.5 (CI95% 6.1-8.9), and 1.4 months (CI95% 0.1-2.7), respectively (all between-group p values ≤0.05). CONCLUSION: A prognostic score, derived from a limited set of easily-retrievable variables, efficiently stratified a large population of unselected aBTC patients undergoing CT1. This tool could be useful to clinicians, to ascertain the potential benefit from CT1 at the start of treatment.

Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data.

INTRODUCTION: There have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice. METHODS: We performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs. RESULTS: One hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials. CONCLUSION: The present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice.