A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: The NVALT-10 study

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. Patients and methods: A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). Results: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49-0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7%versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively. Conclusions: PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology. Study Registration number: NCT00835471.