Rechallenge with Anti-EGFR Treatment in RAS/BRAF wt Metastatic Colorectal Cancer (mCRC) in Real Clinical Practice: Experience of the GITuD Group.

BACKGROUND: There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative. OBJECTIVE: The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice. PATIENTS AND METHODS: A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed. RESULTS: Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5 months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); < 5% grade ≥ 3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade > 1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥ 3 days) and reduction (≥ 20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively. CONCLUSIONS: In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.

Effect of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF v600-mutated metastatic colorectal cancer: a real-world study in Spain.

BACKGROUND: Outcomes are poorer in metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations than those without it, but the effect of these mutations on treatment response is unclear. This real-world study assessed the effects of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF V600-mutated mCRC. METHODS: This real-world, multicenter, retrospective, observational study included patients with BRAF V600-mutated mCRC treated in eight hospitals in Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS); overall response rate (ORR) and disease control rate (DCR) were also assessed. The effect of first- and second-line treatment type on OS, PFS, ORR, and DCR were evaluated, plus the impact of systemic inflammatory markers on these outcomes. A systemic inflammation score (SIS) of 1-3 was assigned based on one point each for platelet-lymphocyte ratio (PLR) ≥200, neutrophil-lymphocyte ratio (NLR) ≥3, and serum albumin < 3.6 g/dL. RESULTS: Of 72 patients, data from 64 were analyzed. After a median of 69.1 months, median OS was 11.9 months and median first-line PFS was 4.4 months. First-line treatment was triplet chemotherapy-antiangiogenic (12.5%), doublet chemotherapy-antiangiogenic (47.2%), doublet chemotherapy-anti-EGFR (11.1%), or doublet chemotherapy (18.1%). Although first-line treatment showed no significant effect on OS, antiangiogenic-based regimens were associated with prolonged median PFS versus non-antiangiogenic regimens. Negative predictors of survival with antiangiogenic-based treatment were NLR, serum albumin, and SIS 1-3, but not PLR. Patients with SIS 1-3 showed significantly prolonged PFS with antiangiogenic-based treatment versus non-antiangiogenic-based treatment, while those with SIS=0 showed no PFS benefit. CONCLUSIONS: Antiangiogenic-based regimens, SIS, NLR, and albumin were predictors of survival in patients with mCRC, while SIS, NLR and serum albumin may predict response to antiangiogenic-based chemotherapy. TRIAL REGISTRATION: GIT-BRAF-2017-01.

Efficacy and safety of FOLFIRI/aflibercept in second-line treatment of metastatic colorectal cancer in a real-world population: Prognostic and predictive markers.

PURPOSE: The phase III VELOUR trial demonstrated efficacy with combined FOLFIRI-aflibercept in patients with metastatic colorectal cancer previously treated with oxaliplatin with or without bevacizumab versus placebo. The effect of FOLFIRI-aflibercept in routine clinical practice was evaluated. METHODS/PATIENTS: Overall survival (OS), progression-free survival (PFS), response and safety were analysed for 78 patients treated with FOLFIRI-aflibercept at six GITuD institutions. Exploratory analyses of prognostic and predictive markers of efficacy were performed. RESULTS: Patients had good general status (PS 0-1 96.2%), tumours were mostly RAS-mutant (75.6%), synchronous (71.8%), and left-sided (71.8%). Prior therapy included bevacizumab (47.4%) and anti-EGFR agents (12.8%). PFS was longer for metachronous than synchronous tumours (11.0 vs 5.0 months, P = 0.028), and for left-colon tumours (7.0 vs 3.0 months, P = 0.044). RAS-mutant status, first-line treatment and primary tumour surgery did not impact PFS. The disease control rate was 70.5%. The most common grade 3/4 toxicities were neutropenia (15.3%), asthenia (10.3%), diarrhea and mucositis (6.4% each). Dysphonia was reported in 39.7% of patients, and grade 3 hypertension in 3.8%. Development of hypertension (any grade) was significantly associated with a reduced risk of progression by multivariate analysis (HR = 2.7; 95%CI 1.3-5.4; P = 0.001). CONCLUSIONS: Efficacy with FOLFIRI-aflibercept in a real-life population was in line with results from the pivotal trial and toxicity was manageable with treatment adaptation. Survival outcomes were not impacted by primary tumour location, RAS-mutant status, first-line treatment or primary tumour surgery. Hypertension may be a surrogate marker of efficacy in this patient population.

Diagnosis delay and follow-up strategies in colorectal cancer. Prognosis implications: a study protocol.

BACKGROUND: Controversy exists with regard to the impact that the different components of diagnosis delay may have on the degree of invasion and prognosis in patients with colorectal cancer. The follow-up strategies after treatment also vary considerably. The aims of this study are: a) to determine if the symptoms-to-diagnosis interval and the treatment delay modify the survival of patients with colorectal cancer, and b) to determine if different follow-up strategies are associated with a higher survival rate. METHODS/DESIGN: Multi-centre study with prospective follow-up in five regions in Spain (Galicia, Balearic Islands, Catalonia, Aragón and Valencia) during the period 2010-2012. Incident cases are included with anatomopathological confirmation of colorectal cancer (International Classification of Diseases 9th revision codes 153-154) that formed a part of a previous study (n = 953).At the time of diagnosis, each patient was given a structured interview. Their clinical records will be reviewed during the follow-up period in order to obtain information on the explorations and tests carried out after treatment, and the progress of these patients.Symptoms-to-diagnosis interval is defined as the time calculated from the diagnosis of cancer and the first symptoms attributed to cancer. Treatment delay is defined as the time elapsed between diagnosis and treatment. In non-metastatic patients treated with curative intention, information will be obtained during the follow-up period on consultations performed in the digestive, surgery and oncology departments, as well as the endoscopies, tumour markers and imaging procedures carried out.Local recurrence, development of metastases in the follow-up, appearance of a new tumour and mortality will be included as outcome variables.Actuarial survival analysis with Kaplan-Meier curves, Cox regression and competitive risk survival analysis will be performed. DISCUSSION: This study will make it possible to verify if the different components of delay have an impact on survival rate in colon cancer and rectal cancer. In consequence, this multi-centre study will be able to detect the variability present in the follow-up of patients with colorectal cancer, and if this variability modifies the prognosis. Ideally, this study could determine which follow-up strategies are associated with a better prognosis in colorectal cancer.