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

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Aflibercept Plus FOLFIRI in the Real-life Setting: Safety and Quality of Life Data From the Italian Patient Cohort of the Aflibercept Safety and Quality-of-Life Program Study

Abstract Background Aflibercept combined with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) as second-line treatment of metastatic colorectal cancer (mCRC) significantly improved survival compared with FOLFIRI alone in the pivotal VELOUR (aflibercept vs. placebo in combination with irinotecan and 5-fluorouracil in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin-based regimen) trial. No quality-of-life assessment was performed in VELOUR; therefore, the ASQoP (Aflibercept Safety and Quality-of-Life Program) trial was designed to capture the safety and health-related quality of life (HRQL). Patients and Methods ASQoP was an international, open-label, single-arm trial evaluating the safety and HRQL of aflibercept combined with FOLFIRI administered in a real-life setting to 781 patients with mCRC, pretreated with an oxaliplatin-based regimen with or without bevacizumab. The Italian subset of ASQoP enrolled 200 patients from 28 institutions. The primary endpoint was safety; HRQL was a secondary endpoint, assessed by validated questionnaires (European quality of life 5-dimension instrument 3-level; European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30, version 3; and EORTC-CR29) at baseline, during treatment, and at the end of treatment. Results The median age of the Italian ASQoP population was 63 years; the median number of aflibercept and FOLFIRI cycles was 7. Treatment-emergent adverse events were reported in 97.5% of patients. Hypertension (28.5%), neutropenia (27.5%; from laboratory data), asthenic conditions (20.0%), diarrhea (17.0%), and stomatitis (13.0%) were the most frequent (incidence, ≥ 5%) grade 3/4 toxicities. One toxic death occurred during the study period due to sepsis, without neutropenic complications. No significant worsening of HRQL was shown during treatment. Conclusion Aflibercept combined with FOLFIRI was well tolerated when administered as second-line treatment for patients with mCRC in a real-life setting. It did not affect HRQL and showed similar rates of treatment-emergent adverse events as those observed in the VELOUR trial. No new safety signals were identified

Location of primary tumor and benefit from anti-epidermal growth factorreceptor monoclonalantibodies in patients with RAS and BRAF wild-typemetastatic colorectal cancer

Introduction. Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients and Methods. Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Results. Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p 5 .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p, .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97;95%confidence interval: 2.09–7.53; p,.0001). Conclusion. Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti- EGFRs

TRIBE-2: A phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Background: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. Methods/design: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. Discussion: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. Trial registration: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014

Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

PURPOSE To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).METHODS TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect >= 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).RESULTS From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P= .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in RO resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).CONCLUSION The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC. (C) 2022 by American Society of Clinical Oncolog

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

NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients

Background: Macrophages play a crucial role in the interaction between tumor and immune system, and iNOS is known as a surrogate marker of M1 macrophages activation. The goal of the study was to investigate the role of iNOS polymorphisms as prognostic marker in mCRC patients. Materials and methods: Functional significant polymorphisms in the promoter of INOS gene were analyzed by PCR-based and direct DNA sequencing in 4 cohorts of patients receiving bevacizumab based first-line chemotherapy: two evaluation cohorts (TRIBE ARM A and ARM B) and two validation cohorts (FIRE 3 arm A and MOMA). The relation of the SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test. Subgroup analyses according to RAS status were preplanned. Results: In the exploratory cohort 1 (TRIBE A), patients with CCTTT any> 13repeats (N = 57) showed improved median PFS compared with patients carrying the 26repeats/ 13 repeats (N = 24) had improved PFS results compared with those carrying the 26 repeats/26 repeats vs repeats/<= 2626 repeats (N = 205) patients. However, these data were not confirmed in the two validation cohorts. Conclusion: We failed to replicate the exploratory findings in both validation sets. The CCTTT polymorphic region of the INOS gene does not predict outcome in mCRC receiving bevacizumab based first line chemotherapy. Further investigations are needed to reveal mechanisms between tumor, immune system and chemotherapy response

Modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab, followed by cetuximab or bevacizumab maintenance, in RAS/BRAF wild-type metastatic colorectal cancer: the phase II randomized MACBETH trial

Background: The combination of triple chemotherapy regimens with an anti-EGFR monoclonal antibody (moAb) reported promising activity with some safety concerns in phase II trials. MACBETH trial aimed at evaluating the activity and safety of first-line modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab and at exploring the role of maintenance with cetuximab or bevacizumab in metastatic colorectal (mCRC) patients. The study initially enrolled KRAS wild-type patients and after an amendment in October 2013 only RAS and BRAF wild-type. Patients and methods: Eligibility criteria included measurable, unresectable, RAS and BRAF wild-type mCRC, age 18-75 years. Patients were randomized 1:1 to receive up to 8 cycles of first-line induction with mFOLFOXIRI plus cetuximab repeated every 2 weeks, followed by maintenance with cetuximab (arm A) or bevacizumab (arm B) until progression. MACBETH was a phase II randomized non-comparative study, with primary endpoint 10 months-Progression Free Rate (10m-PFR). Results: Between October 2011 and March 2015, 323 patients from 21 Italian centers were screened. Out of 143 randomized patients, 116 were RAS and BRAF wild-type and were included in the modified ITT (mITT) population, evaluable for primary and secondary endpoints. At a median follow-up of 40.0 months, 10m-PFR were 50.9% and 40.4% in arm A and B, respectively. Objective response rate was 71.6%; 45 patients (38.8%) underwent secondary surgery of metastases, and R0 resection was achieved in 33 cases (28.4%). Among patients with liver-only disease, the R0 resection rate was 51.9%. Main grade 3-4 adverse events during induction treatment were neutropenia (31.0%), diarrhea (18.1%), skin toxicity (15.5%), asthenia (9.5%), stomatitis (6.0%), and febrile neutropenia (2.6%). Conclusions: Neither of the two arms met the primary endpoint. However, four months-induction with mFOLFOXIRI plus cetuximab is feasible and has relevant activity, leading to high conversion rate. Continuing cetuximab as maintenance until progression seems to affect positively progression-free survival

Upfront folfoxiri plus bevacizumab for metastatic colorectal cancer: program of translational analyses of the phase III randomized tribe2 trial

The present work focuses on clinical and translational results from the no-profit phase III randomized TRIBE2 trial conducted by the Gruppo Oncologico del Nord Ovest (GONO) and coordinated by the Unit of Medical Oncology 2 at the Azienda Ospedaliero-Universitaria Pisana. The study aimed at comparing the efficacy of a preplanned strategy of upfront exposure to the three cytotoxic drugs in the FOLFOXIRI (fluorouracil, leucovorin, irinotecan and oxaliplatin) regimen followed by the reintroduction of doublets (first-line mFOLFOX6 [fluorouracil, leucovorin, and oxaliplatin], followed by FOLFIRI [fluorouracil, leucovorin, and irinotecan] after disease progression), with a sustained inhibition of angiogenesis with bevacizumab, in previously untreated metastatic colorectal cancer patients. During the last three years I was in charge of following patients enrolled in the TRIBE2 trial and I was responsible for data collection and monitoring not only at the Azienda Ospedaliero-Universitaria Pisana, but also at the other 58 Italian participating centres. Main inclusion TRIBE2 trial criteria included the availability of tumour specimens collected before study treatment. These procedures allowed us to collect tissue samples of metastatic colorectal cancer patients, that were, therefore, available for translational analyses. The first chapter of the present thesis describes the current landscape of the first-line treatment of metastatic colorectal cancer patients and illustrates an evidence-based algorithm that summarizes an updated perspective on the choice of the best therapy for each patient. The aim of this chapter is to provide the reader with a frame to properly understand the background of the design of the TRIBE2 trial and the unmet needs that the study attempted to address. The second chapter focuses on the elucidation of the TRIBE2 trial’s procedures and the summary of the trial’s results about primary and secondary endpoints, and their interpretation for the application to the clinical practice. The third chapter reports the results of an individual patient data-based meta-analysis from five randomized trials, including the TRIBE2 study, providing a robust estimation of the added value of FOLFOXIRI plus bevacizumab over conventional doublets plus bevacizumab. Finally, the fourth and the fifth chapter describe the results of two translational projects moving from the TRIBE2 study: a comprehensive genomic profiling by means of a next-generation sequencing (NGS) approach, including the assessment of microsatellite instability (MSI) status, tumour mutational load (TML) and actionable genomic alterations; the evaluation of two distinct molecular classifications based on gene expression profiles on tumour tissues, including the consensus molecular subtypes (CMS) and CRCA subtypes. Other translational projects including samples from patients enrolled in the TRIBE2 study are currently ongoing and will help to throw light on the complex molecular landscape of metastatic colorectal cancer and on the optimization of the treatment with FOLFOXIRI plus bevacizumab, by an improved selection of candidate patients

Validazione prospettica del polimorfismo -1498 C/T di VEGF come fattore predittivo di efficacia di bevacizumab in pazienti con carcinoma colorettale metastatico, in trattamento di prima linea con FOLFIRI e bevacizumab.

Il fenomeno dell’angiogenesi, inteso come formazione di neovasi da una rete vascolare preesistente, rappresenta un evento fondamentale nella cancerogenesi, necessario per fornire al tumore il supporto indispensabile per la sua crescita e progressione. In ragione di ciò, l’angiogenesi costituisce un target farmacologico nella terapia anti-neoplastica. Lo sviluppo e la successiva introduzione nella pratica clinica di agenti ad azione anti-angiogenica hanno rivoluzionato la terapia di molte neoplasie solide, tra cui il carcinoma colorettale (Colorectal cancer, CRC). Ad oggi, l’unico farmaco anti-angiogenico registrato per il trattamento in prima e seconda linea di questa neoplasia in stadio metastatico, in associazione a chemioterapia a base di fluoropirimidine, è bevacizumab. Si tratta di un anticorpo monoclonale ricombinante umanizzato diretto contro Vascular Endothelial Growth Factor (VEGF), principale mediatore ad azione pro-angiogenica. Studi clinici di fase III hanno dimostrato che l’associazione di bevacizumab a chemioterapici convenzionali, in prima linea di trattamento, migliora significativamente l’outcome di pazienti affetti da carcinoma colorettale metastatico (metastatic Colorectal cancer, mCRC), rispetto alla sola chemioterapia. Attualmente, i pazienti da sottoporre a trattamento con bevacizumab sono selezionati esclusivamente in base a criteri clinici, legati alle tossicità del farmaco. Questo dato, assieme al fatto che appare evidente che non tutti i pazienti beneficiano del trattamento con l’anti-VEGF o comunque non in eguale misura, rende necessaria l’identificazione di biomarcatori predittivi di efficacia di bevacizumab. È ipotizzabile che, in questo modo, il beneficio derivato dall’anti-angiogenico possa essere ottimizzato da una più accurata selezione dei pazienti, consentendo, allo stesso tempo, un risparmio sulle tossicità e sui costi legati al trattamento. Recenti studi hanno indicato come potenziali predittori di beneficio da bevacizumab polimorfismi germinali del gene VEGF, che codifica il target dell’anticorpo. Specifiche varianti alleliche del gene sono in grado di modularne l’espressione e verosimilmente condizionare, in modo indiretto, la risposta all’anti-VEGF. Esperienze condotte nell’ambito di diverse neoplasie in fase metastatica, compreso il CRC, hanno investigato il ruolo predittivo e prognostico di alcuni polimorfismi a singolo nucleotide (Single nucleotide Polymorphisms, SNPs) di VEGF su DNA genomico in pazienti trattati con bevacizumab. I risultati emersi, nel complesso piuttosto eterogenei, devono considerarsi non conclusivi e, quindi, non applicabili alla pratica clinica. Si tratta, infatti, di indagini condotte in modo retrospettivo e spesso carenti di un confronto con un gruppo di pazienti non trattati con bevacizumab. Inoltre, deve considerarsi che l’effetto di specifiche varianti geniche può essere variabile in patologie differenti, così come in relazione al trattamento chemioterapico somministrato insieme all’anti-VEGF. Sulla base di queste premesse, al fine di superare le criticità metodologiche delle esperienze presenti in letteratura, è stato condotto uno studio esplorativo retrospettivo per valutare il ruolo di quattro polimorfismi di VEGF nel predire l’efficacia di bevacizumab, in pazienti con mCRC in terapia di prima linea con FOLFIRI (5FU, leucovorin e irinotecano) e bevacizumab (“gruppo bevacizumab”). I polimorfismi in studio erano localizzati due nella regione del promotore (-2578 C/A e -1498 C/T), uno nella 5’UTR (untraslated region) (+405 G/C) ed uno nella regione 3’UTR (+936 C/T). Allo scopo di stimare la possibile interazione tra l’effetto della terapia anti-VEGF ed i polimorfismi candidati, questi ultimi sono stati valutati anche in una popolazione di controllo (“gruppo controllo”), costituita da una coorte storica, trattata con sola chemioterapia FOLFIRI. Di tutti le varianti alleliche del gene VEGF in studio, nella popolazione di pazienti trattati con bevacizumab, l’unica a risultare correlata significativamente con l’outcome è stata VEGF -1498 C/T. Nella stessa popolazione, la mediana della sopravvivenza libera da progressione (median Progression Free Survival, mPFS) e della sopravvivenza globale (median Overall Survival, mOS) dei pazienti portatori dei genotipi VEGF -1498 C/C, C/T e T/T sono risultate, rispettivamente 12.8, 10.5, 7.5 mesi (p=0.0046, log-rank test) e 27.3, 20.5, 18.6 mesi (p=0.038, log-rank test). I portatori del genotipo VEGF -1498 T/T presentavano una PFS significativamente peggiore ed un trend negativo in OS rispetto ai portatori di almeno un allele C (mPFS 7.5 versus 11.1 mesi, p=0.0027; mOS 18.6 versus 23.1 mesi, p=0.155). Diversamente, nel “gruppo controllo”, nessuna delle varianti alleliche del polimorfismo VEGF -1498 C/T ha mostrato alcuna relazione significativa né con la PFS (Progression Free Survival), né con OS (Overall Survival). Il test d’interazione tra le varianti del polimorfismo VEGF -1498 C/T e l’effetto del trattamento suggerisce che la relazione del genotipo VEGF -1498 T/T con una PFS più breve possa essere ricondotta all’effetto del bevacizumab (p=0.018). Poiché il polimorfismo VEGF -1498 C/T sembra condizioni il beneficio derivante dalla terapia soltanto nel gruppo di pazienti trattati con bevacizumab, è possibile ipotizzare che questo rappresenti un fattore predittivo di efficacia dell’anti-angiogenico. La natura esplorativa ed il disegno retrospettivo del presente studio, assieme all’assenza di randomizzazione nel confronto tra i pazienti trattati e non con bevacizumab, implicano la necessità di una conferma prospettica dei risultati. È stato, quindi, condotto uno studio di tipo prospettico che valutasse il ruolo predittivo di efficacia di bevacizumab del polimorfismo VEGF -1498 C/T, in una popolazione di 265 pazienti con mCRC, in trattamento di prima linea con FOLFIRI e bevacizumab. Ad oggi, si dispone di risultati preliminari, derivati da un’analisi condotta su 246 pazienti valutabili. La mPFS dei pazienti portatori del genotipo VEGF -1498 T/T (N=78) e dei portatori di almeno un allele C (N=168) è risultata, rispettivamente, di 10.1 e 10.9 mesi (HR=1.20, 95% CI 0.87-1.72, p=0.26). Non confermando prospetticamente una correlazione statistica significativa tra le varianti alleliche di VEGF -1498 C/T e la PFS, questo dato, seppur preliminare, decreta verosimilmente il fallimento del polimorfismo come fattore predittivo di efficacia da bevacizumab