Elena Elez

Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment

Although the prognosis of cancer remains poor recent advances in the diagnostic methods, new approaches in surgical procedures and the development of new therapeutic agents have had a significant impact in the outcome of cancer patients. A better understanding of the molecular pathways that characterize cell growth, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. The epidermal growth factor receptor (EGFR) mediated signal transduction has been one of the most studied pathways in carcinogenesis. The phosphorylation of EGFR activates multiple biological processes including apoptosis, differentiation, cellular proliferation, motility, invasion, adhesion, DNA repair and survival. Several therapies have been developed to inactivate the EGFR pathway including monoclonal antibodies against the extracellular domain of EGFR. In this review, the authors examine the development of monoclonal antibodies against EGFR and the effects of this blockage in cell cycle, as well as the most important trials with these monoclonal antibodies in several tumor types.

Oxaliplatin-based chemotherapy in the management of colorectal cancer

Oxaliplatin is the only third-generation platinum derivative compound that has found a place in the routine treatment of colorectal cancer (CRC). The appearance of oxaliplatin, as well as irinotecan, in the CRC treatment armamentarium has offered new standards for adjuvant treatment and greater hopes in metastatic disease. Moreover, the combination of oxaliplatin-based chemotherapy with new targeted drugs has improved response rates and survival of these patients. Despite these new approaches, the prognosis of CRC remains poor and a better understanding of the molecular pathways is needed to optimize the use of these new approaches. In this review, the authors examine the development of oxaliplatin as well as the main trials that have positioned oxaliplatin as a key drug in the treatment of CRC.

Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study

PURPOSE RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype. PATIENTS AND METHODS Patients with chemotherapy-refractory KRAS G13D mutation-positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m(2) loading dose and then 250 mg/m(2) once per week with or without irinotecan 180 mg/m(2) once every 2 weeks. The primary end point was 6-month progression-free survival; secondary end points were response rate, overall survival, quality of life, and toxicity. RESULTS Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar; toxicities were higher with combination therapy. CONCLUSION In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.

Understanding the Predictive Role of K-ras for Epidermal Growth Factor Receptor–Targeted Therapies in Colorectal Cancer

The prognosis of metastatic colorectal cancer (mCRC) remains poor regardless of the advances obtained in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Current use of irinotecan, oxaliplatin, and bevacizumab combined with the long-time standards 5-fluorouracil and leucovorin as first- or second-line treatment for patients with mCRC has resulted in median overall survival figures of > 20 months. Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumor cells, such as the epidermal growth factor receptor (EGFR). The activation of EGFR leads to the activation of intracellular effectors involved in intracellular signaling pathways such as the G protein K-Ras. The K-Ras oncoprotein controls transduction of signals required for proliferation, differentiation, and survival, mainly acting as guanosine diphosphate/guanosine triphosphate-regulated binary switches located at the inner surface of the plasma membrane. Monoclonal antibodies (MoAbs) designed to bind to the ectodomain of the EGFR have shown activity in chemorefractory mCRC and in the first-line setting. Cetuximab and panitumumab are MoAbs that bind to the EGFR and thereby inhibit cell proliferation, metastasis, and angiogenesis. Recent clinical data confirm that the efficacy of cetuximab and panitumumab is confined to patients bearing tumors with wild-type K-ras. K-ras mutation analysis may now be considered a new standard of care in the selection of patients for EGFR-targeted therapy.

New trends in epidermal growth factor receptor-directed monoclonal antibodies

The epidermal growth factor receptor (EGFR) has been the focus of much attention in the age of targeted cancer therapeutics. In addition to its role in signal transduction under physiological conditions, it has been of interest because it is highly expressed in many tumor types and influences growth and survival in malignant states. Advances in the understanding of the EGFR and in genetic engineering have led to the development of monoclonal antibodies targeting the extracellular domain of the membrane-bound receptor. Cetuximab and panitumumab are the two most advanced such compounds. Thus far, cetuximab has achieved regulatory approval in metastatic colorectal cancer, and locally advanced and metastatic squamous cell cancer of the head and neck; panitumumab has been approved for metastatic colorectal cancer. This review will focus on the EGFR signaling network, monoclonal antibodies against EGFR and the pertinent clinical trials in this field of oncology using such agents.

BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives

The MAPK cascade plays a crucial role in tumor cell proliferation and survival. Accumulating evidence suggests that mutations in the BRAF oncogene are not only associated with poor prognosis but also linked with less benefit when treated with anti-epidermal growth factor receptor antibodies in metastatic colorectal cancer (mCRC). Targeting this molecular aberration has thus become a matter of particular interest in mCRC drug development. In contrast to other malignances such as BRAF mutant melanoma, efficacy observed with BRAF inhibitors in monotherapy in mCRC is poor. Several mechanisms of resistance have been identified leading to the development of different treatment strategies that have shown promising activity in early clinical trials. Hence, rational combination of targeted therapies is expected to further increase the efficacy of selective BRAF inhibitors. Herein, we discuss the main clinical and molecular characteristics of BRAF mutant colorectal cancer and its translation into the clinic, with a focus on developmental therapeutics and combination strategies. In addition, we contextualize the available data with potential future approaches that include the extended access to next-generation sequencing platforms and gene expression strategies for molecular subtyping. These approaches will facilitate the identification of certain patient profiles providing more therapeutic possibilities.The MAPK cascade plays a crucial role in tumor cell proliferation and survival. Accumulating evidence suggests that mutations in the BRAF oncogene are not only associated with poor prognosis but also linked with less benefit when treated with anti-epidermal growth factor receptor antibodies in metastatic colorectal cancer (mCRC). Targeting this molecular aberration has thus become a matter of particular interest in mCRC drug development. In contrast to other malignances such as BRAF mutant melanoma, efficacy observed with BRAF inhibitors in monotherapy in mCRC is poor. Several mechanisms of resistance have been identified leading to the development of different treatment strategies that have shown promising activity in early clinical trials. Hence, rational combination of targeted therapies is expected to further increase the efficacy of selective BRAF inhibitors. Herein, we discuss the main clinical and molecular characteristics of BRAF mutant colorectal cancer and its translation into the clinic, with a focus on developmental therapeutics and combination strategies. In addition, we contextualize the available data with potential future approaches that include the extended access to next-generation sequencing platforms and gene expression strategies for molecular subtyping. These approaches will facilitate the identification of certain patient profiles providing more therapeutic possibilities.

Update on Novel Strategies to Optimize Cetuximab Therapy in Patients with Metastatic Colorectal Cancer

The prognosis of metastatic colorectal cancer (mCRC) remains poor despite the advances made in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed toward molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Cetuximab is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor and thereby inhibits cell proliferation, metastasis, and angiogenesis. Preclinical studies indicate that cetuximab induces synergistic antitumor activity when combined with chemotherapy or radiation. In pretreated patients with mCRC, cetuximab might restore sensitivity toward irinotecan and has therefore been registered for the treatment of patients with mCRC refractory to irinotecan. Moreover, cetuximab seems to add substantial benefit to standard oxaliplatin- and irinotecan-based combinations, resulting in high response rates in the first-line setting. Recent preclinical and clinical data have optimized cetuximab therapy. New targeted therapy combinations and the identification of biomarkers associated with disease control in patients treated with cetuximab are changing the current management of mCRC. Also, preliminary data suggest that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy.

535PENCORAFENIB (LGX818), AN ORAL BRAF INHIBITOR, IN PATIENTS (PTS) WITH BRAF V600E METASTATIC COLORECTAL CANCER (MCRC): RESULTS OF DOSE EXPANSION IN AN OPEN-LABEL, PHASE 1 STUDY

ABSTRACT Aim: Few treatment options exist for pts with BRAF-mutant mCRC. Encorafenib, a potent and selective oral BRAF inhibitor, showed signs of efficacy in pts with BRAF-mutant advanced melanoma in a phase 1 dose-escalation study. Here we present results from pts with BRAF-mutant mCRC enrolled in the dose-expansion phase of the same trial. Methods: Adult pts with nonresectable, advanced mCRC with a BRAF V600 mutation, for whom there was no existing effective therapy, received encorafenib 300 mg (n = 6) or 450 mg (n = 12) once daily. Responses were assessed by investigator per RECIST 1.1. Results: All 18 pts had a BRAF V600E mutation. Median age was 62 y (range, 34-73). Ten pts (55.6%) were female. Median number of prior treatment regimens was 3 (range, 1-8); 1 pt received prior therapy with a BRAF inhibitor (vemurafenib). At the data cutoff (7 Jan 2014), median treatment duration was 11 wks; 4 pts (22.2%) remained on treatment, and 14 (77.8%) discontinued due to progressive disease (PD; n = 10), adverse events (AEs; n = 3), and death (n = 1, not related to study drug). Twelve pts (66.7%) achieved a best response of stable disease (SD). No pt achieved confirmed complete response (CR) or confirmed partial response (PR) by the data cutoff (Table). Progression-free survival (PFS) events occurred in 13 pts (PD, n = 10; death, n = 3). Median PFS was 4.0 mo. The most common AEs of any grade were palmar-plantar erythrodysaesthesia syndrome (66.7%), myalgia (44.4%), and dry skin (44.4%). Three pts had dose-limiting toxicities (arthralgia and myalgia [n = 1]; insomnia and myalgia [n = 1]; bone pain and vomiting [n = 1]; all grade 3), all on encorafenib 450 mg. Encorafenib 300 mg n = 6 Encorafenib 450 mg n = 12 All pts N = 18 Best Overall Response, n (%) _CRa 0 0 0 _PRa 0 0 0 _SD 4 (66.7) 8 (66.7) 12 (66.7) __With unconfirmed CR/PR 1 (16.7) 2 (16.7) 3 (16.7) _PD 1 (16.7) 3 (25.0) 4 (22.2) __With unconfirmed CR/PR 0 2 (16.7) 2 (11.1) _Unknownb 1 (16.7) 1 (8.3) 2 (11.1) Median PFS, mo (95% CI) 2.3 (1.7-7.2) 4.0 (1.8-5.5) 4.0 (1.8-5.6) a CR and PR required confirmation in a second assessment at least 4 wks after the first. b Best response was unknown for 2 pts who achieved SD before 6 wks of treatment. Conclusions: Encorafenib showed modest activity in this difficult-to-treat population, with SD observed in two-thirds of pts. Studies in BRAF-mutant mCRC are ongoing in combination with epidermal growth factor receptor and phosphoinositide 3-kinase inhibitors. Disclosure: M. Hidalgo: has been on a board of directors and/or advisory board for and received research funding from Novartis; R. von Moos: has consulted for Novartis, Roche, GSK, BMS, MSD; received research funding from Amgen, Merck, Roche; received honoraria from Novartis, Roche, GSK, BMS, Sanofi; A. Arance: has received research funding from Roche; has consulted with Roche, BMS, GSK D. Michel, A. Seroutou and T. Demuth: is an employee of Novartis Pharma AG; J. Tabernero: has consulted for Amgen, Imclone, Lilly, Merck KGaA, Millenium, Novartis, Roche, Sanofi, Celgene, Chugai, Taiho and has received honoraria from Amgen, Merck KGaA, Novartis, Roche, Sanofi. All other authors have declared no conflicts of interest.

Phase Ib/II, open-label, dose-escalation study of LGX818, an oral selective BRAF inhibitor, in combination with MEK162, an oral MEK1/2 inhibitor, in patients with BRAF V600-dependent advanced solid tumors: preliminary results.

Phase Ib/II, open-label, dose-escalation study of LGX818, an oral selective BRAF inhibitor, in combination with MEK162, an oral MEK1/2 inhibitor, in patients with BRAF V600-dependent advanced solid tumors: preliminary results Richard Kefford, Ryan J Sullivan, Wilson H Miller Jr, Elena M Elez, Daniel Tan, Kevin B Kim, Georgina V Long, Keith T Flaherty, David Tai, Simone Stutvoet, Heiko Maacke, Matt Whiley, Laure Moutouh-de Parseval, Josep Tabernero

Handling side-effects of targeted therapies: safety of targeted therapies in solid tumours

Major advances with new molecular agents have translated in the last decade in a survival benefit in those patients with advanced cancer disease and in a cure rate improvement in those treated in the adjuvant setting. Some of these targeted agents have been approved by the regulatory agencies and are now used in daily clinical practice. In general, targeted molecular therapies have a good toxicity profile; nevertheless, new types of toxicity have been reported with the use of these new agents.