A prospective observational study of on-treatment plasma homocysteine levels as a biomarker of toxicity, depression and vitamin supplementation lead-in time pre pemetrexed, in patients with non-small cell lung cancer and malignant mesothelioma.

OBJECTIVES: Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity. MATERIAL AND METHODS: Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities. RESULTS: Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities. CONCLUSION: On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short.

Eventual role of EGFR-tyrosine kinase inhibitors in early-stage non-small-cell lung cancer.

Nonadvanced non-small-cell lung cancer (NSCLC) has a poor long-term survival from surgery or definitive radiation that is minimally improved with induction/adjuvant conventional chemotherapy. EGFR-tyrosine kinase inhibitors (TKIs), which provide a significant benefit for molecularly selected EGFR-mutant patients with advanced NSCLC, have been infrequently explored in nonadvanced NSCLC to date. Current published studies reported no significant benefit from adding EGFR-TKI to the induction/adjuvant setting. However, many of them present eventual biases such as unpowered statistics, lack of molecular selection, recruitment of low-risk NSCLC, low sample size or unsuitable control arms. Results, strengths and deficiencies of completed and ongoing trials were fully discussed. Similarly, the selection of patients and control arms, the duration and risks of EGFR-TKI therapies in early-stage NSCLC, the evaluation of response and the diagnosis of EGFR status were considered and analyzed.

The role of afatinib in the management of non-small cell lung carcinoma.

INTRODUCTION: Despite initial patient benefit, drug resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) is inevitable. One of the key mechanisms responsible for the development of acquired drug resistance is the secondary T790M missense mutation in exon 20 of the EGFR kinase domain. Afatinib is an ATP-competitive small molecule inhibitor that potently and irreversibly inhibits EGFR and mutated EGFR including the T790M variant, as well as other members of the ErbB family in preclinical studies. AREAS COVERED: The authors describe the rationale and provide the preclinical background to afatinib and its potential as a NSCLC therapy. Specifically, the authors detail the drug's pharmaco-kinetic profile and review its clinical efficacy and toxicity profile. EXPERT OPINION: Afatinib is an effective treatment option for therapy-naive advanced NSCLC harboring an activating EGFR mutation. Furthermore, it is also of potential benefit to patients with acquired resistance to EGFR kinase inhibitors. In the future, the authors envision the clinical development of third-generation EGFR mutation-specific inhibitors in NSCLC, which may potentially spare normal tissue toxicity. Nevertheless, afatinib currently represents a bona fide treatment option in the NSCLC therapeutic armamentarium.

Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy.

INTRODUCTION: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data. METHODS: Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon's two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively. RESULTS: Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome. CONCLUSIONS: Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.