Phase I Trial of Erlotinib-Based Multimodality Therapy for Inoperable Stage III Non-small Cell Lung Cancer

Abstract

Introduction This Phase I trial aimed to determine the maximum-tolerated-dose of erlotinib administered with two standard chemoradiotherapy regimens for non-small cell lung cancer. Methods Unresectable stage III non-small cell lung cancer patients were enrolled in this 2-arm dose-escalation study. Erlotinib, given only during chemoradiotherapy, was escalated from 50 to 150 mg/d in 3 to 6 patient cohorts. Arm A: erlotinib with cisplatin (50 mg/m2 IV days 1, 8, 29, 36), etoposide (50 mg/m2 IV days 1–5, 29–33) and chest radiotherapy (66 Gy, 2 Gy/d) followed by docetaxel (75 mg/m2 IV Q21 d) for 3 cycles. Arm B: induction carboplatin (AUC 6) and paclitaxel (200 mg/m2) for two 21-d cycles then radiotherapy with erlotinib, carboplatin (AUC = 2/wk) and paclitaxel (50 mg/m2/wk). Results Seventeen patients were treated in each arm. Patient characteristics: performance status 0 to 24 patients, 1 to 10 patients, median age 63 years, adenocarcinoma 21% and female 14 patients. Dose-escalation of erlotinib to 150 mg/d was possible on both chemoradiotherapy regimens. Grade 3/4 leukopenia and neutropenia were predominant toxicities in both arms. Grade 3 chemoradiotherapy toxicities in arm A were esophagitis (3 patients), vomiting (1), ototoxicity (1), diarrhea (2), dehydration (3), pneumonitis (1); and arm B was esophagitis (6). Seven patients (21%) developed rash (all grade 1/2). Median survival times for patients on Arm A and B were 10.2 and 13.7 months, respectively. Three-year overall survival in patients with and without rash were 53% and 10%, respectively (log-rank P = 0.0807). Epidermal growth factor receptor IHC or FISH positive patients showed no significant overall survival difference. Conclusion Addition of standard-dose erlotinib to chemoradiotherapy is feasible without evident increase in toxicities. However, the survival data are disappointing in this unselected patient population and does not support further investigation of this approach.

Evaluation of concurrent chemoradiotherapy for locally advanced NSCLC according to EGFR mutation status

“…Accordingly, it may be appropriate to suggest that a combined therapy of EGFR inhibitor and TRT may improve the probability of a cure in patients with LA-NSCLC who possess an EGFR mutation. However, few clinical trials have been able to demonstrate a clear benefit of combined EGFR-TKI therapy with TRT in patients with LA-NSCLC (24)(25)(26)(27)(28)(29). In an attempt to obtain an answer to this question, the WJOG6911L trial is currently in progress in Japan, which is a multicenter phase II trial of gefitinib administration in combination with radiotherapy in patients with LA-NSCLC who possess sensitizing EGFR mutations (trial no., UMIN000008366).…”

Conflito de interesses em ensaios clínicos iniciais envolvendo pacientes com neoplasia de pulmão

“…Em recente metanálise 11 , observou-se que, até aquele momento, se considerados todos os estudos de fase I, I/II ou II nos quais havia o emprego de terapia-alvo com RQT em pacientes com NPNPC localmente avançada [12][13][14][15][16][17][18] , quando os resultados eram comparados com o tratamento-padrão, os pacientes não apresentavam melhora clinicamente relevante, como sobrevida livre de doença ou sobrevida global. Apresentavam, no entanto, aumento estatisticamente significativo do nível de efeitos secundários graves (grau III a V) 19 durante o tratamento -o que é bastante preocupante, já que esses pacientes tinham, no momento do estudo, diagnós-tico de enfermidade com potencial curativo.…”

“…A metanálise reuniu um total de sete ensaios clínicos de fase I/II realizados nos Estados Unidos e em países europeus, durante o período de 2000 a 2011, empregando terapia-alvo e RQT, em pacientes com NPNPC localmente avançada [12][13][14][15][16][17][18] . As conclusões apresentadas foram então classificadas, pelos autores do presente estudo, em favorável, desfavorável ou neutra em relação à terapia-alvo testada, de acordo com a recomendação (ou não) da utilização da droga em ensaios clínicos posteriores ou, eventualmente, na prá-tica clínica cotidiana, posteriormente ao estudo.…”

Current status of and future strategies for multimodality treatment of unresectable stage III nonsmall cell lung cancer

“…The addition of erlotinib to chemoradiotherapy did not appear to increase toxicity but survival was disappointing with both regimens (median survival of 10.2 and 13.7 months) [65].…”