Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy

Background: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of ~7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting. Methods/Design Patients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m2 once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will also be performed. Discussion If the LUX-Head & Neck 1 trial meets its primary endpoint, it will demonstrate the ability of afatinib to elicit an improved treatment benefit versus a commonly used chemotherapy agent in the second-line treatment of R/M HNSCC patients who have failed on first-line platinum-based therapy, confirm the clinical efficacy of afatinib observed in the Phase II proof-of-concept study, and establish a new standard of care for this patient population

Long-lasting responses with chemotherapy followed by T-cell therapy in recurrent or metastatic EBV-related nasopharyngeal carcinoma

BackgroundRefractory or metastatic nasopharyngeal carcinoma (NPC) patients have a poor prognosis due to the lack of effective salvage treatments and prolonged survival by means of combination chemotherapy being described only for a minority of younger patients with oligometastatic disease. Targeting the Epstein - Barr virus (EBV) proteins expressed in NPC cells has been shown to be a feasible strategy that could help control systemic disease.Patients and MethodsBetween 2011 and 2014, 16 patients with recurrent/metastatic EBV-NPC received first-line chemotherapy (CT) followed by 2 doses of autologous cytotoxic EBV specific T-lymphocytes (15-25 x 107 total cells/dose, 2 weeks apart), based on our previous studies showing the feasibility and efficacy of this infusion regimen. Cumulative overall survival (OS) and median OS were analysed in the whole population and according to specific clinical and biological parameters.ResultsAll patients received the planned T-cell therapy schedule, 9 after reaching partial (n=5) or complete (n=4) disease remission with CT, and 7 after failing to obtain benefit from chemotherapy. No severe adverse events were recorded. Patients who received cytotoxic T-lymphocytes (CTLs) had a cumulative 10-year OS of 44%, with a median OS of 60 months (95% CI 42-62). Patients responding to CT, with oligometastatic disease (<3 disease sites), and plasma EBV-DNA <1000 copies/mL had a better outcome.ConclusionsAutologous EBV-specific CTLs transplanted following conventional first-line CT demonstrated promising efficacy with several patients obtaining long-lasting disease control. The rationale provided by this study, with the crucial role likely played by the timing of CTL administration when trying to induce synergy with conventional treatment needs to be confirmed in a prospective controlled trial

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC)

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC)

Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy.

BackgroundPatients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of ~7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting.Methods/designPatients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m(2) once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will also be performed.DiscussionIf the LUX-Head & Neck 1 trial meets its primary endpoint, it will demonstrate the ability of afatinib to elicit an improved treatment benefit versus a commonly used chemotherapy agent in the second-line treatment of R/M HNSCC patients who have failed on first-line platinum-based therapy, confirm the clinical efficacy of afatinib observed in the Phase II proof-of-concept study, and establish a new standard of care for this patient population