Trial Information

A Randomized Phase II Study of Induction Chemotherapy Followed by Concurrent Chemoradiation Therapy According to EGFR Mutation Status in Patients With Unresectable Stage III NSCLC

Concurrent Chemoradiation therapy is widely accepted as a standard treatment of locally
advanced unresectable stage III NSCLC. When compared with the result of radiation therapy
alone of CALGB 8433 trial (i.e., 9.7 months), the median survival times have almost doubled
over the last 2 decades, but rarely exceeded 18 months after chemoradiation therapy in most
randomized trials. On the other hand, a significant portion of patients had to endure the
side effects of grade 3/4 esophagitis and also pneumonitis, which resulted in
treatment-related deaths in some cases. There is a great need to develop more effective but
less toxic treatment strategies. Recently, molecular-targeted therapy using EGFR-TKIs
brought new enthusiasm to the NSCLC therapy. The investigators observed a median survival
time of 20.1 months in chemo-naïve never-smoker Korean patients with adenocarcinoma of the
lung. The benefit of EGFR-TKI was also demonstrated in never-smokers who participated in the
phase III trial of carboplatin/paclitaxel with or without Erlotinib (TRIBUTE). Despite a
lack of benefit in the overall patient population, Erlotinib conferred a survival benefit to
those who had never smoked cigarettes, In this analysis, 105 patients who were identified as
never smokers had a median survival of 10 months, similar to the entire study population,
when treated with carboplatin/paclitaxel plus placebo. However, for the patients in this
subpopulation who were treated with Erlotinib and the same chemotherapy regimen, the median
survival increased to 22.5 months (P = 0.01). Furthermore, EGFR mutation was associated with
significantly higher response rate and longer survival as compared with those without EGFR
mutation. More importantly, the median survival time of those patients with EGFR
mutation-positive tumors exceeded 20 months in the majority of the studies. These results
are very provocative given the fact that only the patients with stage IIIb not amenable to
chemoradiation therapy and stage IV NSCLC patients were included in the study and in many
studies, the majority of the patients were heavily pre-treated with multiple chemotherapy
regimens. The investigators postulate that if the case were properly selected, EGFR-TKI
would significantly improve the overall survival of the patients with locally advanced
unresectable stage III NSCLC. The investigators therefore propose a randomized phase II
trial to evaluate the efficacy and toxicity of EGFR-TKI Erlotinib in selected group of NSCLC
patients with EGFR mutation-positive stage III tumors. The use of induction chemotherapy is
feasible and effective. It is also logistically beneficial for decreasing micrometastases
and radiation-related toxicity by decreasing tumor burden before definite locoregional
concurrent therapy. Previously the investigators conducted several phase II study of IP
chemotherapy in advanced NSCLC and demonstrated that IP chemotherapy has a promising
activity and readily manageable toxicity profile. Given the encouraging activity of IP
chemotherapy in the advanced stage setting, the investigators postulated that their further
investigation in the stage III setting might lead to further prolongation of survival times.
In addition to cisplatin, Irinotecan has been demonstrated to act as radiation sensitizers
in preclinical and clinical setting. Therefore, their use with concurrent radiotherapy might
lead to radiation sensitization and improved locoregional control.