Pol Specenier

A Review of the Most Promising Biomarkers in Colorectal Cancer: One Step Closer to Targeted Therapy

Rapidly growing insights into the molecular biology of colorectal cancer (CRC) and recent developments in gene sequencing and molecular diagnostics have led to high expectations for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on molecular biomarkers are contradictory in their findings and the current reality is that no molecular marker, other than the KRAS gene in the case of epidermal growth factor receptor (EGFR)- targeted therapy for metastatic disease, has made it into clinical practice. Many markers investigated suffer from technical shortcomings, resulting from lack of quantitative techniques to capture the impact of the molecular alteration. This understanding has recently led to the more comprehensive approaches of global gene expression profiling or genome-wide analysis to determine prognostic and predictive signatures in tumors. In this review, an update of the most recent data on promising biological prognostic and/or predictive markers, including microsatellite instability, epidermal growth factor receptor, KRAS, BRAF, CpG island methylator phenotype, cytotoxic T lymphocytes, forkhead box P3-positive T cells, receptor for hyaluronic acid-mediated motility, phosphatase and tensin homolog, and T-cell originated protein kinase, in patients with CRC is provided.

Current concepts for the management of head and neck cancer: chemotherapy.

Chemotherapy can be administered in patients with locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) either concurrently with irradiation or as induction chemotherapy prior to local treatment or as palliative therapy in patients with recurrent and/or metastatic disease. Cisplatin-based chemoradiation is still the standard for LA-SCCHN. TPF has emerged as the new standard regimen when induction chemotherapy is indicated. Areas of active investigation in LA-SCCHN are the sequential administration of induction chemotherapy followed by chemoradiation and the integration of targeted therapies. None of the combination chemotherapy regimens demonstrated an overall survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil in recurrent/metastatic disease. Combination chemotherapy in this setting is preferably used in younger patients with a good performance status and with symptomatic disease who require prompt symptom relief. However, a survival benefit was observed when cetuximab was combined with platinum-5-fluorouracil.

A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma

BACKGROUND The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma. METHODS Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity. RESULTS One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of ∼2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS. CONCLUSIONS Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms. CLINICAL TRIAL REGISTRATION NCT01582269, ClinicalTrials.gov.

Anti-Epidermal Growth Factor Receptor Therapy in Head and Neck Squamous Cell Carcinoma: Focus on Potential Molecular Mechanisms of Drug Resistance

Targeted therapy against the epidermal growth factor receptor (EGFR) is one of the most promising molecular therapeutics for head and neck squamous cell carcinoma (HNSCC). EGFR is overexpressed in a wide range of malignancies, including HNSCC, and initiates important signal transduction pathways in HNSCC carcinogenesis. However, primary and acquired resistance are serious problems and are responsible for low single-agent response rate and tumor recurrence. Therefore, an improved understanding of the molecular mechanisms of resistance to EGFR inhibitors may provide valuable indications to identify biomarkers that can be used clinically to predict response to EGFR blockade and to establish new treatment options to overcome resistance. To date, no predictive biomarker for HNSCC is available in the clinic. Therapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signaling and/or mechanisms that can modulate EGFR-dependent signaling. In this review, we will summarize some of these molecular mechanisms and describe strategies to overcome that resistance.

Cetuximab: its unique place in head and neck cancer treatment

Head and neck cancer is the sixth most common cancer worldwide. At present, globally about 650,000 new cases of squamous cell carcinoma of the head and neck (SCCHN) are diagnosed each year. The epidermal growth factor receptor (EGFR) is almost invariably expressed in SCCHN. Overexpression of the EGFR is a strong and independent unfavorable prognostic factor in SCCHN. Cetuximab is a chimeric monoclonal antibody, which binds with high affinity to the extracellular domain of the human EGFR, blocking ligand binding, resulting in inhibition of the receptor function. It also targets cytotoxic immune effector cells towards EGFR-expressing tumor cells (antibody dependent cell-mediated cytotoxicity). The addition of cetuximab to radiotherapy (RT) improves locoregional control and survival when compared to RT alone. The addition of cetuximab to platinum-based chemoradiation (CRT) is feasible but does not lead to an improved outcome. Cetuximab plus RT has never been compared prospectively to CRT, which therefore remains the standard treatment for patients with locoregionally advanced SCCHN for whom surgery is not considered the optimal treatment, provided they can tolerate CRT. The addition of cetuximab to platinum-based chemotherapy prolongs survival in patients with recurrent or metastatic SCCHN. The combination of a platinum-based regimen and cetuximab should be considered as the standard first line regimen for patients who can tolerate this treatment.

Recurrent head and neck cancer: current treatment and future prospects

Recurrent and metastatic squamous cell carcinoma of the head and neck still carries a poor prognosis. Response rates with combination chemotherapy regimens are generally higher than those observed with single-agent chemotherapy. However, this did not translate into an overall survival benefit, not in even a single randomized trial. As none of the combination chemotherapy regimens demonstrated an overall survival benefit when compared with single-agent methotrexate, cisplatin or 5-fluorouracil, the use of combination chemotherapy outside clinical trials is usually restricted to younger patients with a good performance status and with symptomatic disease who require prompt symptom relief. After decades without real progress, a recent randomized trial showed that adding cetuximab, the first clinically available EGF receptor-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil), led to an important survival benefit. In addition, the response rate nearly doubled with this approach, which has great promise for the treatment of symptomatic disease. There is now a plethora of targeted therapies in various stages of preclinical and clinical development. The next challenge will be to sort out which of them have a clinically meaningful activity and find out how to incorporate them into existing treatment regimens.

Cetuximab in the treatment of squamous cell carcinoma of the head and neck

The majority of the head and neck cancers are squamous cell carcinomas, which commonly overexpress the EGF receptor (EGFR). Cetuximab is a chimeric monoclonal antibody that binds with high affinity to the extracellular domain of EGFR, and in addition induces antibody-dependent cellular cytoxicity. In a randomized Phase III trial in patients with locoregionally advanced squamous cell carcinoma of the head and neck, the addition of cetuximab to radiotherapy prolonged the median time of locoregional control from 14.9 to 24.4 months and increased the median overall survival from 29.3 to 49.0 months. In patients with platinum-refractory recurrent and/or metastatic disease, the objective response and disease-control rates in various studies ranged from 10 to 13% and from 46 to 56%, respectively. In the EXTREME trial, the addition of cetuximab to platinum/5-fluorouracil as first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck not only led to significant improvements in survival, response rate and disease control, but also induced a better symptom control in comparison with that observed with platinum/5-fluorouracil alone.

Bevacizumab in glioblastoma multiforme.

Bevacizumab is a humanized IgG1 monoclonal antibody that selectively binds with high affinity to human VEGF and neutralizes VEGF’ s biologic activity. Malignant gliomas are characterized by extensive microvascular proliferation and produce VEGF. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of malignant glioma cells. Promising response rates, progression-free survival rates at 6 months and median overall survival in patients with recurrent glioblastoma multiforme (GBM) have been reported with bevacizumab, both in retrospective analyses and in prospective Phase II studies. In the pivotal randomized but noncomparative Phase II trial, a non-negligible percentage of patients survived beyond 1 and 2 years after the start of bevacizumab administration. However, randomized Phase III trial data on bevacizumab in recurrent GBM are lacking. Currently, bevacizumab is being studied in combination with temozolomide and radiation in previously untreated GBM patients in two large randomized Phase III trials.

The role of taxanes and targeted therapies in locally advanced head and neck cancer

Purpose of review This review presents new data on the role of taxanes and targeted therapies in the management of squamous cell carcinoma of the head and neck. Recent findings Taxane-containing triplets are clearly superior as an induction regimen in locally advanced squamous cell carcinoma of the head and neck when compared with cisplatin/5 fluorouracil which has been the standard for two decades. Preliminary data suggest that the addition of a taxane to cisplatin/5 fluorouracil as induction regimen followed by chemoradiation may be superior to chemoradiation alone. The addition of cetuximab to radiation prolongs locoregional control and survival without increasing mucositis. Areas of active investigation are the search for epidermal growth factor receptor mutations and the optimal way of integrating epidermal growth factor receptor-directed therapies into standard management. Meanwhile new targets are explored. Summary Taxane/cisplatin/5 fluorouracil induction chemotherapy is clearly superior to cisplatin/5 fluorouracil. Epidermal growth factor receptor directed therapies can safely be combined with radiation and the combination shows encouraging results.

Biologic Therapy in Head and Neck Cancer: A Road with Hurdles

The epidermal growth factor receptor (EGFR) is overexpressed in the vast majority of cases of squamous cell carcinoma of the head and neck (SCCHN). A high EGFR expression is associated with an unfavorable prognosis. Cetuximab is a chimeric human/murine IgG1 antibody which binds with high affinity to the EGFR. It is the only targeted agent which got approval for the treatment of SCCHN from the regulatory agencies of Europe and the United States, both in locoregionally advanced disease, in association with radiation, and in recurrent/metastatic disease. The outcome of trials involving other EGFR-directed monoclonal antibodies, that is, zalutumumab and panitumumab, was consistent with the results with cetuximab. However these trials failed to meet their primary endpoint. The results with EGFR-directed tyrosine kinase inhibitors have been disappointing. Other potential targets for treatment in SCCHN include the entire ErbB family, the vascular endothelial growth factor (VEGF) and its receptor (VEGFR), the insulin-like growth factor 1 receptor (IGF-1R), the insulin receptor (IR), histone deacetylases (HDAC), the mammalian target of rapamycin (mTOR), the platelet-derived growth factor receptor (PDGFR), heat-shock protein 90 (HSP90), nuclear factor-kappa B (NF-κB), aurora A or B, and phosphatidylinositol 3-kinase (PIK3CA).