Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small-cell lung cancer.

BACKGROUND: Axitinib is an orally active and potent tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. This phase II study assessed the efficacy and safety of axitinib combined with cisplatin/gemcitabine in chemotherapy-naïve patients with advanced/metastatic (stage IIIB/IV) squamous non-small-cell lung cancer (NSCLC). METHODS: Axitinib (starting dose 5 mg twice daily [bid]; titrated up or down to 2-10 mg bid) was administered orally on a continuous schedule with cisplatin (80 mg/m(2) intravenously [i.v.] every 3 weeks) and gemcitabine (1,250 mg/m(2) i.v. on days 1 and 8 of each 3-week cycle), and was continued as monotherapy after completion of six cycles (maximum) of chemotherapy. The primary study endpoint was objective response rate, as defined by Response Evaluation Criteria in Solid Tumours. RESULTS: Of the 38 patients treated, one (2.6%) patient achieved a complete response and 14 (36.8%) patients had a partial response; nine (23.7%) patients showed stable disease and three (7.9%) patients had disease progression. Median progression-free survival was 6.2 months, and median overall survival was 14.2 months. The estimated probability of survival at 12 months and 24 months was 63.2% and 30.8%, respectively. The most frequent grade ≥3 toxicities were neutropaenia and hypertension (13.2% each). Three (7.9%) patients experienced haemoptysis, of which one case (2.6%) was fatal. CONCLUSIONS: Treatment with the combination of axitinib and cisplatin/gemcitabine demonstrated anti-tumour activity in patients with advanced/metastatic squamous NSCLC and the fatal haemoptysis rate was low. However, without a reference arm (cisplatin/gemcitabine alone), it is not conclusive whether the combination is better than chemotherapy alone. This study was registered at ClinicalTrials.gov, registration # NCT00735904, on August 13, 2008.

Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

BACKGROUND: This phase II study examined the efficacy of mapatumumab in combination with paclitaxel and carboplatin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB or stage IV advanced primary NSCLC were randomly assigned (1:1:1) to receive up to 6 courses of standard-dose paclitaxel and carboplatin or a combination of paclitaxel, carboplatin, and mapatumumab (10 mg/kg or 30 mg/kg). Primary efficacy end points were overall response rate and median progression-free survival (PFS). Secondary efficacy end points included disease control rate, overall survival (OS), time to response, and duration of response. Exploratory studies included evaluation of historical biopsy materials for TRAIL-R1 expression by immunohistochemical analysis and serum levels of M30, a marker of apoptosis, before and after the first 2 doses of mapatumumab. Safety parameters, including adverse events (AEs), laboratory tests, and immunogenicity, were assessed. RESULTS: The majority of patients had stage IV disease (79%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%); baseline characteristics were similar across treatment arms. No improvements in response or disease control rates, PFS, or OS were gained from the addition of mapatumumab. Adverse events in the mapatumumab arms were generally consistent with toxicities seen in the carboplatin and paclitaxel control arm. Levels of M30 were highly variable, and consistent patterns were not seen across treatment arms. CONCLUSION: This study showed no clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC. The combination was generally well tolerated. The possibility of subgroups sensitive to mapatumumab is discussed.

A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens.

INTRODUCTION: AZD6244 (ARRY-142886) is a potent, selective MEK inhibitor. This study aimed to evaluate the efficacy and safety of AZD6244 versus pemetrexed as second- or third-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: In this randomized phase II study, patients received either 100 mg oral AZD6244 free-base suspension twice daily or 500 mg/m(2) intravenous pemetrexed once every 3 weeks after pretreatment with a corticosteroid, folic acid, and vitamin B12. The primary end point of the study was the disease progression event count. RESULTS: Eighty-four patients were randomized. Disease progression events were experienced by 28 (70%) and 26 (59%) patients in the AZD6244 and pemetrexed groups, respectively. Median progression-free survival was not statistically significantly different between the AZD6244 and pemetrexed groups (67 versus 90 days, respectively; hazard ratio 1.08, two-sided 80% confidence interval = 0.75-1.54; p = 0.79). Two patients in the AZD6244 group had a best response to treatment of partial response. In the pemetrexed group, one patient achieved a complete response and one patient a partial response. Dermatitis acneiform, diarrhea, nausea, and vomiting were the most frequently reported adverse events with AZD6244, compared with fatigue, anemia, nausea, anorexia, and dermatitis acneiform with pemetrexed. CONCLUSIONS: Oral AZD6244 showed clinical activity as second- or third-line therapy for patients with advanced NSCLC. In an unselected NSCLC population, there is no suggestion that AZD6244 monotherapy offers any advantage over standard treatment with pemetrexed. Based on preclinical data and recent clinical observations, further development of AZD6244 in NSCLC should focus on BRAF or RAS mutation-positive patients and/or AZD6244-based combination regimens.