Genomically matched therapy in refractory colorectal cancer according to ESMO Scale for Clinical Actionability of Molecular Targets: experience of a comprehensive cancer centre network.

Efficiency of expanded genomic profiling (EGP) programmes in terms of final inclusion of patients in genomically matched therapies is still unknown. Fit patients with advanced and refractory colorectal cancer (CRC) were selected for an EGP programme. Next-generation sequencing (NGS) analysis from formalin-fixed paraffin-embedded tumour samples was performed. The purpose was to describe the prevalence of genomic alterations defined by the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), as well as the percentage of patients finally included in genomically guided clinical trials. In total, 187 patients were recruited. Mutational profile was obtained in 177 patients (10 patients were failure due to insufficient tumour sample), copy number alterations in 41 patients and fusions in 31 patients. ESCAT-defined alterations were detected in 28.8% of the intention-to-analyse population. BRAF V600E was clustered in ESCAT I, with a prevalence of 3.7%, KRAS G12C and ERBB2 amplification were clustered in ESCAT II, whose prevalence was 4.2% and 1.6%, respectively. Most alterations were classified in ESCAT III (mutations in ERBB2, PIK3CA or FGFR genes and MET amplification) and IV (mutations in BRAF non-V600E, ERBB3, FBXW7, NOTCH, RNF43), with a single prevalence under 5%, except for PIK3CA mutation (9%). The final rate of inclusion into genomically guided clinical trials was 2.7%, including therapies targeting BRAF V600E or RNF43 mutations in two patients each, and ERBB2 mutation in one patient. In conclusion, EGP programmes in patients with advanced CRC are feasible and identify a subset of patients with potentially druggable genomic alterations. However, further efforts must be made to increase the rate of patients treated with genomically guided therapies.

Fluorouracil Bolus Use in Infusional Regimens Among Oncologists-A Survey by Brazilian Group of Gastrointestinal Tumors.

PURPOSE: The utility of administering fluorouracil (5-FU) in bolus in regimens of infusional 5-FU has been questioned. We aimed to quantify the use of 5-FU bolus in infusional regimens for gastrointestinal malignancies among Brazilian oncologists. METHODS: This was a cross-sectional electronic survey composed of eight multiple-choice questions sent to Brazilian oncologists during 14 days in February 2021. The survey instrument collected demographic data of participants and assessed practices in terms of 5-FU bolus use. We evaluated the association of demographic variables and 5-FU prescribing patterns with Fisher's exact test (odds ratio [OR]). RESULTS: The survey was completed by 332 medical oncologists. Overall, 37% were experienced oncologists and 32% were gastrointestinal specialists. In the first-line metastatic and in the adjuvant settings, 40% and 67% of oncologists always prescribe 5-FU bolus in infusional regimens, respectively. Experienced oncologists more frequently omit 5-FU bolus when compared with early-career oncologists, both in the metastatic (41% v 26%; OR, 1.98; P = .005) and adjuvant settings (28% v 14%; OR, 2.32; P = .003). In addition, more GI specialists remove 5-FU bolus when compared with generalists, but only in the metastatic setting (44% v 25%; OR, 2.33; P = .001). GI specialists are more likely to consider that treatment efficacy is not affected by 5-FU bolus withdrawal than are generalists (89% v 75%; OR, 2.65; P = .003). Most respondents (67%) keep leucovorin at the same doses when omitting 5-FU bolus, and only 16% always recommend dihydropyrimidine dehydrogenase testing. CONCLUSION: Our survey indicates that experience in oncology practice and percentage of time dedicated to treat GI cancers influence the prescription of 5-FU bolus in Brazil, with more frequent omission of it among experienced gastrointestinal specialists, particularly in the metastatic setting.

Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development.

INTRODUCTION: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity. AREAS COVERED: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing. EXPERT OPINION: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC.

BRAF as a target for cancer therapy.

Tumors with mutations in the gene encoding the serine-threonine protein kinase BRAF are dependent on the MAPK signaling pathway for their growth, what offers an opportunity to test oncogene-targeted therapy. Mutations at the position V600 of BRAF were described in approximately 8% of all solid tumors, including 50% of melanomas, 30 to 70% of papillary thyroid carcinomas and 5 to 8% of colorectal adenocarcinomas. Specific BRAF kinase inhibitors are undergoing rapid clinical development and promising data on efficacy have been demonstrated in activated mutant BRAF V600 melanomas. This review article will address: (a) preclinical data on the antitumor activity of BRAF inhibitors in cell lines/ in vivo models and their opposing functions as inhibitors or activators of the MAPK pathway, depending on the cellular context; (b) drug development from non-selective RAF inhibitors to selective BRAF inhibitors, such as PLX4032 and GSK2118436, with emphasis in the clinical efficacy and toxicity of these agents; and (c) possible mechanisms of resistance to BRAF inhibitors and strategies to overcome its development in BRAF mutant tumors.

Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer.

Necitumumab (IMC-11F8), under development by ImClone Systems in collaboration with Bristol-Myers Squibb, is a fully human IgG1 mAb targeting the epidermal growth factor receptor (EGFR), for the potential intravenous treatment of cancer, in particular NSCLC. In vitro studies demonstrate that necitumumab inhibits downstream targets in the EGFR pathway (eg, MAPK), which are important for cellular proliferation, differentiation, invasion and metastasis. Furthermore, because necitumumab is an IgG1 construct, it has the potential to induce antibody-dependent cell-mediated cytotoxicity against tumor cells. Preclinical studies indicated that the antitumor activity of necitumumab is either comparable with or superior to that of ImClone's chimeric anti-EGFR mAb cetuximab. In a phase I clinical trial in patients with advanced solid malignancies, necitumumab displayed nonlinear pharmacokinetic behavior. The toxicity profile of necitumumab is acceptable, with skin toxicity being the most frequently reported adverse event in the phase I and II clinical trials conducted to date. Preliminary data from a phase II clinical trial of necitumumab in combination with chemotherapy for the first-line treatment of advanced colon cancer are promising. Success in the ongoing phase III clinical trials in patients with advanced NSCLC would lead to necitumumab becoming a valuable addition to future therapeutic strategies in oncology.