FOLFOXIRI più cetuximab nel trattamento di prima linea di pazienti affetti da carcinoma colorettale metastatico RAS e BRAF wild-type: risultati dello studio di fase II randomizzato MACBETH

La prognosi dei pazienti con malattia metastatica da tumore del colon-retto è indubbiamente migliorata nell'arco degli ultimi anni, grazie al maggior utilizzo di trattamenti locoregionali (chirurgia, radioterapia, radiofrequenze) integrati con terapie sistemiche sempre più efficaci. Complessivamente, nell’ambito della terapia del tumore del colon-retto metastatico, essendo le possibilità attuali numerosissime, risulta fondamentale l’individualizzazione della strategia terapeutica, basata fin da subito su una valutazione multidisciplinare, comprendente fattori clinici legati al paziente e alla sua malattia e fattori molecolari. Al momento, il passo cruciale in questo processo decisionale è rappresentato dalla scelta della “miglior intensità della chemioterapia”, basata sulle fluoropirimidine, sia orali che endovenose, l’oxaliplatino e l’irinotecan, oltre che del "miglior farmaco biologico" tra quelli disponibili: gli anticorpi monoclonali anti-EGFR, cetuximab e panitumumab, e l’anti-angiogenico bevacizumab. La combinazione di una doppietta di chemioterapici (FOLFOX o FOLFIRI) e un farmaco biologico viene ritenuta un’opzione standard per la maggior parte dei pazienti. Tuttavia, recentemente, i risultati dello studio TRIBE hanno reso disponibile, in casi clinicamente selezionati, una nuova opzione terapeutica più intensiva (FOLFOXIRI più bevacizumab), mentre nei pazienti unfit per trattamenti di combinazione è possibile optare per la monochemioterapia con fluoropirimidine in associazione, quando possibile, al bevacizumab. L’efficacia e il tollerabile profilo di tossicità del bevacizumab sono stati, quindi, ampiamente dimostrati in associazione a tutte le possibili combinazioni di chemioterapia di diversa intensità (dalla monoterapia alla tripletta), così come nella terapia di mantenimento. Meno robuste sono le evidenze a sostegno della possibilità di modulare l’intensità della chemioterapia in combinazione con gli anticorpi anti-EGFR. I dati disponibili riguardano, in particolar modo, la loro associazione con doppiette di chemioterapici (FOLFIRI e FOLFOX), mentre più di recente sono stati valutati in combinazione con regimi a tre farmaci, triplette, in studi precoci che ne hanno dimostrato un’attività promettente, con qualche dubbio sul profilo di tollerabilità legato in particolare all’elevata incidenza di eventi avversi gastroenterici. Cetuximab e panitumumab non possono essere somministrati a pazienti i cui tumori presentino mutazioni a carico di RAS e, anche i tumori BRAF mutati traggono minimo beneficio da questi farmaci. I pazienti con mCRC RAS e BRAF wild type sono, quindi, i migliori candidati a questo trattamento, sebbene sviluppino poi invariabilmente meccanismi di resistenza acquisita. Nel tentativo di spiegare i meccanismi alla base dello sviluppo di questo tipo di resistenza è stata formulata l’ipotesi per cui, in seguito al blocco della via di trasduzione del segnale mediata da EGFR, se ne potenzino di alternative, una tra tutte quella che coinvolge VEGF. Ciò costituisce il razionale biologico dell’esposizione sequenziale del paziente ad anticorpi anti-EGFR e anti-VEGF. Tutte le prove soprariportate suggeriscono, quindi, che una strategia innovativa e promettente nel trattamento di pazienti affetti da mCRC molecolarmente selezionati potrebbe essere l’esporre subito agli agenti più attivi (cioè la combinazione tripletta di FOLFOXIRI più cetuximab), con lo scopo di ottenere un rapido controllo della malattia e la massima riduzione volumetrica tumorale e, successivamente, utilizzare una terapia di mantenimento meno aggressiva per inibire la ricrescita tumorale. Lo studio randomizzato, non comparativo, di fase II MACBETH ha lo scopo di valutare l'attività e la sicurezza in prima linea di un regime modificato di FOLFOXIRI associato a cetuximab e, allo stesso tempo, del mantenimento con cetuximab o bevacizumab, in pazienti con mCRC non resecabile. Lo studio ha arruolato pazienti con età compresa tra 18 e 75 anni, non precedentemente trattati per la malattia metastatica, selezionati inizialmente in base allo stato wild-type di KRAS e, dopo un emendamento nell’ottobre 2013, allo stato wt sia di RAS che di BRAF. I pazienti venivano randomizzati a ricevere fino a 8 cicli di mFOLFOXIRI + cetuximab, seguito da cetuximab (braccio A) o bevacizumab (braccio B) fino alla progressione. L’endpoint primario dello studio era la Progression Free Rate a 10 mesi dalla randomizzazione (10months-PFR). Tra l’ottobre 2011 e il febbraio 2015, è stato eseguito lo screening di 323 pazienti provenienti da 21 centri italiani. Dei 143 pazienti randomizzati, i 116 risultati all RAS/BRAF wt sono stati inclusi nell’intention-to-treat population modificata (mITT) (braccio A/B n=59/57). Nell’intera mITT si è registrata un’età mediana di 60 anni e ottime condizioni cliniche dei pazienti (ECOG PS 0) nell’89% dei casi. La diagnosi dello stadio IV era avvenuta in modo sincrono a quella di CRC nell’84% dei casi, mentre quasi la metà dei pazienti aveva secondarismi limitati al fegato (45%). Ad un follow-up mediano di 25,5 mesi, la 10m-PFR è stata del 52% nel braccio A e del 41% nel braccio B (endpoint primario non raggiunto), con una PFS mediana di 11.2 e 9.3 mesi. Il tasso di risposte era del 76% (braccio A/B) nei 106 pazienti valutabili e del 70% (braccio A/B 68%/72%) nell’intera popolazione mITT; soltanto in 2 pazienti per ciascun braccio sperimentale la PD è stata la miglior risposta registrata alle rivalutazioni in corso di trattamento. Il tasso di resezione è stato del 38% complessivamente (braccio A/B 46%/30%) e del 65% (braccio A/B 71% /58%) nel sottogruppo con malattia soltanto epatica. Le principali tossicità di grado 3-4 durante la terapia di induzione sono state neutropenia (33%), a cui si associa solo un 3% di neutropenia febbrile, diarrea (19%), eruzione cutanea (18%) e stomatite (6%). In conclusione, nessuno dei due bracci ha raggiunto l’endpoint primario. Tuttavia, la terapia di induzione di 4 mesi con mFOLFOXIRI e cetuximab risulta fattibile in un contesto multicentrico e dotata di un’attività rilevante, che si esprime in elevati tassi di risposta e di conversione alla chirurgia. Questo elemento potrebbe influenzare positivamente i risultati in termini di OS, attualmente ancora immaturi

a retrospective study of trifluridine tipiracil in pretreated metastatic colorectal cancer patients in clinical practice

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TRIPLETE: A randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer

FOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer. Methods This is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m 2, oxaliplatin 85 mg/m 2, L-leucovorin 200 mg/m 2, 5-fluoruracil 2400 mg/m 2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria. Discussion The relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres. Clinical trial information NCT03231722

Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (ATEZOTRIBE): a multicentre, open-label, phase 2, randomised controlled trial

Background Immune checkpoint inhibitors have not shown clinical benefit to metastatic colorectal patients 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. Methods 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/m² irinotecan, 85 mg/m² oxaliplatin, 200 mg/m² leucovorin, and 3200 mg/m² fluorouracil as 48-h infusion) plus bevacizumab (5 mg/kg intravenously), and the experimental group received the same regimen plus atezolizumab (840 mg intravenously). Combination treatments were administered up to eight 14-day cycles followed by maintenance with fluorouracil and leucovorin plus bevacizumab with or without atezolizumab, according to randomisation group, until disease progression, unacceptable adverse events, or consent withdrawal. The primary endpoint was progression-free survival, analysed by intention-to-treat principle. Safety was assessed in patients who received at least one dose of the study treatment. The study recruitment is completed. Findings Between Nov 30, 2018, and Feb 26, 2020, 218 patients were randomly assigned and received treatment (73 in the control group and 145 in the experimental group). At data cut-off (Aug 1, 2021) median follow-up was 19.9 months (interquartile range [IQR] 17.3–23.9). Median progression-free survival was 13.1 months (80% CI 12.5–13.8) in the experimental group and 11.5 months (80% CI 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 experimental group versus 26 [36%] of 72 patients in the control group), diarrhoea (21 [15%] versus 9 [13%]), and febrile neutropenia (14 [10%] versus 7 [10%]). Serious adverse events were reported in 39 (27%) patients in the experimental 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 experimental group; none were reported in the control group. Interpretation 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. Trial registration: Clinicaltrials.gov Identifier: NCT03721653

Immune Profiling of Deficient Mismatch Repair Colorectal Cancer Tumor Microenvironment Reveals Different Levels of Immune System Activation

To understand the immune landscape of deficient mismatch repair colorectal cancer (dMMR CRC) tumor microenvironment, gene expression profiling was performed by the nCounter PanCancer Immune Profiling Panel. This study was conducted retrospectively on 89 dMMR-CRC samples. The expression of CD3, CD8, programmed death-1, and programmed death ligand-1 protein was evaluated on a subset of samples by immunohistochemistry, and lymphocyte density was calculated. A subset of deregulated genes was identified. Functional clustering analysis performed on these genes generated four main factors: antigen processing and presentation, with its major histocompatibility complex-II-related genes; genes correlated with the cytotoxic activity of immune system; T-cell chemotaxis/cell adhesion genes; and T-CD4+ regulator cell-related genes. A deregulation score (DS) was calculated for each sample. On the basis of their DS, tumors were then classified as COLD (DS ≤ -3) to select the samples with a strong down-regulation of the immune system and NOT COLD (DS ≥ -2). The COLD group of patients showed a worse prognosis in terms of survival considering all patients (P = 0.0172) and patients with metastatic disease (P = 0.0031). These results confirm that dMMR-CRCs do not constitute a homogeneous group as concerns the immune system activity of tumor microenvironment. In particular, the distinction between COLD and NOT COLD tumors may improve the management of these two subsets of patients

A retrospective study of trifluridine/tipiracil in pretreated metastatic colorectal cancer patients in clinical practice

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A novel local impedance algorithm to guide effective pulmonary vein isolation in atrial fibrillation patients: Preliminary experience across different ablation sites from the CHARISMA pilot study

Introduction Recently, a novel technology able to measure local impedance (LI) and tissue characteristics has been made available for clinical use. This analysis explores the relationships among LI and generator impedance (GI) parameters in atrial fibrillation (AF) patients. Characterization of LI among different ablation spots and procedural success were also evaluated. Methods and Results Consecutive patients undergoing AF ablation from the CHARISMA registry at five Italian centers were included. A novel radiofrequency (RF) ablation catheter with a dedicated algorithm (DIRECTSENSE (TM)) was used to measure LI and to guide ablation. The ablation endpoint was pulmonary vein (PV) isolation. We analyzed 2219 ablation spots created around PVs in 46 patients for AF ablation. The mean baseline tissue impedance was 105.8 +/- 14 omega for LI versus 91.8 +/- 10 omega for GI (p < .0001). Baseline impedance was homogenous across the PV sites and proved higher in high-voltage areas than in intermediate- and low-voltage areas and the blood pool (p < .001). Both LI and GI displayed a significant drop after RF delivery, and absolute LI drop values were significantly larger than GI drop values (14 +/- 8 vs. 3.7 +/- 5 omega,p < .0001). Every 5-point increment in LI drop was associated with successful ablation (odds ratio = 3.05, 95% confidence interval: 2.3-4.1,p < .0001). Conversely, GI drops were not significantly different comparing successful versus unsuccessful sites (3.7 +/- 5 vs. 2.8 +/- 4 omega,p = .1099). No steam pops or major complications occurred during or after the procedures. By the end of the procedures, all PVs had been successfully isolated in all patients. Conclusions The magnitude of the LI drop was more closely associated with effective lesion formation than the GI drop

Lack of Benefit From Anti-EGFR Treatment in RAS and BRAF Wild-type Metastatic Colorectal Cancer With Mucinous Histology or Mucinous Component

Background: Adenocarcinoma with mucinous histology or mucinous component are histologic subtypes of metastatic colorectal cancers (mCRCs) with limited benefit from cytotoxic agents. Their sensitivity to anti-epithelial growth factor receptors (EGFRs) is not clear. Patients and Methods: The activity and efficacy of anti-EGFRs was retrospectively evaluated among patients with RAS and BRAF wild-type mCRC with or without mucinous histology or mucinous component. Subgroup analyses according to primary tumor location were conducted. Results: Overall, the study population included 22 mucinous or with mucinous component tumors (11 right- and 11 left-sided tumors) and 83 not mucinous tumors. One patient experienced partial response among mucinous tumors, whereas in the not mucinous group, 42 patients experienced partial response, with an overall response rate of 4% and 51%, respectively (P =.003). The median progression-free survival was 2.8 versus 6.7 months (hazard ratio, 0.28; 95% confidence interval, 0.13-0.59; P <.001), and the median overall survival was 6.5 and 16.7 months (hazard ratio, 0.58; 95% confidence interval, 0.33-1.00; P =.022), for the mucinous and not mucinous groups, respectively. Similar results were observed in subgroup analysis according to primary tumor location. Conclusion: Anti-EGFRs may not provide clinically meaningful benefit in mCRCs with mucinous histology or mucinous component compared with those without mucinous component, irrespective of sidedness. Adenocarcinoma with mucinous histology or mucinous component are histologic subtypes of metastatic colorectal cancers (mCRCs) with limited benefit from cytotoxic agents. Their sensitivity to anti-epithelial growth factor receptors (EGFRs) is not clear. We retrospectively identified patients with RAS/BRAF wild-type mCRC treated with anti-EGFRs. Our findings suggest no benefit from anti-EGFRs in mCRC with mucinous histology or mucinous component, irrespective of sidedness

Early rhythm-control ablation therapy to prevent atrial fibrillation recurrences: Insights from the CHARISMA Registry

Background An early, comprehensive rhythm-control therapy is needed in order to treat atrial fibrillation (AF) effectively and to improve ablation outcomes. Methods A total of 153 consecutive patients from the CHARISMA registry undergoing AF ablation at eight centers were included. Patients with de novo PVI were classified as having undergone early treatment (ET) if the procedure was performed within 6 months after the first AF episode, and as having undergone delayed treatment (DT) if ablation was performed over 6 months after the first AF episode. Results One-hundred fifty-three patients were enrolled (69.9% male, 59 +/- 10 years, 61.4% paroxysmal AF, 38.6% persistent AF). The time from the first AF episode to the ablation procedure was 1034 +/- 1483 days. The ET group comprised 36 patients (25.3%), the DT group 60 (39.2%) and Redo cases were 57 (37.3%). During a mean follow-up of 366 +/- 130 days, 18 patients (11.8%) suffered an AF/AT recurrence. More DT patients than ET patients suffered recurrences (15.7% vs. 2.2%, p = 0.0452) and the time to AT/AF recurrence was shorter in the group of patients who received an ablation treatment after 6 months (HR = 6.19, 95% CI: 1.7 to 21.9; p = 0.0474). On multivariate Cox analysis, only hypertension (HR = 4.86, 95% CI: 1.6 to 14.98, p = 0.0062) was independently associated with recurrences. Beyond the hypertension risk factor, ET was associated with a low risk of recurrence; recurrence rate ranged from 0% (ET patients without hypertension) to 25.0% (DT patients with hypertension). Conclusions An early rhythm-control ablation therapy in the absence of common risk factors was associated with the lowest rate of recurrences