Hanping Wang

Nimotuzumab combined with chemotherapy as first-line treatment for advanced lung squamous cell carcinoma: Nimotuzumab in advanced LSCC

This study was conducted to evaluate the efficacy and safety of nimotuzumab combined with chemotherapy as first‐line therapy in advanced lung squamous cell carcinoma (LSCC), and to explore predictive biomarkers of the efficacy of nimotuzumab.

Quality of life results from a randomized, double-blinded, placebo-controlled, multi-center phase III trial of anlotinib in patients with advanced non-small cell lung cancer

OBJECTIVES Anlotinib is a novel multi-target tyrosine Kinase inhibitor that inhibits VEGFR2/3, FGFR1-4, PDGFD α/β, c-Kit and Ret. In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small-cell lung cancer (NSCLC) patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study assessed quality of life (QoL) in these patients. METHODS Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. The QoL were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the associated EORTC Quality of Life Lung Cancer Specific Module (QLQ-LC13) at baseline, end of cycle 1, end of every two cycles, and at the final visit. The analyses were conducted in the first 6 cycles. Differences in scores of 10 points or more between two arms or from baseline were considered clinically meaningful. RESULTS A total of 437 patients were assigned to anlotinib (n = 294) and placebo (n = 143). The completion rates of the QoL questionnaires were from 69.9% to 97.0%. Mean scores of QLQ-C30 and QLQ-LC13 subscales were similar in the anlotinib and placebo arms at baseline. Compared to placebo, anlotinib improved role functioning, social functioning, dyspnea, insomnia, constipation and financial problems. Only sore mouth or tongue symptom was worse in the anlotinib arm than in the placebo arm. CONCLUSIONS Anlotinib improved quality of life versus placebo in advanced NSCLC patients who had received at least two previous chemotherapies. The QoL analyses provided evidence that anlotinib should be a choice for the third-line treatment or beyond in advanced NSCLC.

Prospective study revealed prognostic significance of responses in leptomeningeal metastasis and clinical value of cerebrospinal fluid-based liquid biopsy

OBJECTIVE Leptomeningeal metastasis (LM) secondary to non-small cell lung cancer (NSCLC) is a devastating complication associated with poor prognosis. Diagnosis and assessment of responses in LM have been challenging due to limitation of traditional imaging tools and lack of standard evaluation criteria until very recently. To bridge this gap, we conducted the first prospective, observational study in cytologically diagnosed NSCLC-LM patients (NCT02803619). PATIENTS AND METHODS A total of 49 NSCLC-LM patients were enrolled. LM responses were evaluated with a composite endpoint integrating neurological symptoms, cerebrospinal fluid (CSF) parameters and central nervous system (CNS) imaging. Primary outcome was overall survival (OS) after diagnosis of LM. Exploratory endpoint was the association between OS and prognostic factors. Primary tumor and CSF samples were collected for biomarker analysis. RESULTS 93.9% of the cohort carried oncogenic drivers, and 85.7% harbored EGFR activating mutations. Median OS since LM diagnosis of the overall population was 9.7 months. EGFR mutant LM patients had a longer survival compared with wildtype ones. LM clinical responses assessed by the composite endpoint showed significant correlation with OS. Status of EGFR activating mutations was highly concordant between primary tumor and CSF. T790 M occurrence in CNS lesions was relatively rare and associated with intracranial exposure level of EGFR-TKIs. CONCLUSION Our results supported the composite endpoint for objective response evaluation of LM was valid, suggested LM outweighed peripheral lesions on the impact to patient survival, and emphasized the urge and promise of development of CNS-penetrant targeted therapies to improve clinical outcome of NSCLC-LM patients.

Penetration of the blood–brain barrier by avitinib and its control of intra/extra-cranial disease in non-small cell lung cancer harboring the T790M mutation

BACKGROUND Avitinib is an oral, potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for the EGFR T790 M mutation. We report the safety, intra-/extracranial efficacy, and the blood-brain barrier (BBB) penetration rate of avitinib (NCT02330367). METHODS Non-small cell lung cancer (NSCLC) patients with the EGFR T790 M mutation were orally administered avitinib (150-300 mg) twice daily for cycles of 28 continuous days. Blood and cerebrospinal fluid samples (2 ml each) were collected on day 29 in available patients with brain metastases, and the tumor response was assessed. RESULTS Sixteen NSCLC patients were included, of whom nine (60.0%) achieved a partial response, and five (33.3%) achieved stable disease. Median progression-free survival (PFS) and overall survival were 247 days (95% confidence interval (CI): 154.8-339.2) and 536 days (95%CI: 363.6-708.4), respectively. The median intracranial PFS of seven brain metastases patients was 142 days (95% CI 31.1-252.9). Blood and cerebrospinal fluid analysis of five brain metastases patients showed the BBB penetration rate to be 0.046%-0.146%. The most frequent adverse events were mild and reversible hepatic transaminases elevating (10/16, 62.5%) and diarrhea (4/16, 25.0%). CONCLUSIONS Avitinib is well tolerated and efficacious in T790M-positive patients. Its penetrability to the BBB is weak, but it showed good control of asymptomatic brain metastases. Further studies are proceeding.