activating mutations were described in lung cancer over a decade ago, and in that time, targeted therapy with epidermal growth factor receptor (EGFR
) tyrosine kinase inhibitors (TKIs) have become the treatment of choice as first-line therapy. Targeted therapy improves responses and progression-free survival when compared with chemotherapy in these patients with advanced disease. Despite improvements in outcomes, resistance develops and the majority of patients expe- rience tumor progression and are not cured. The intro- duction of third-generation EGFR
TKIs that effectively block activating mutations and the T790M resistance mutation while sparing wild-type EGFR
has led to improved outcomes following the development of resis- tance. The future of EGFR
therapy will explore the use of these agents and combinations to potentially delay or eliminate resistance to increase efficacy and ultimately survival. This review will focus on current therapies used in the first-line setting for advanced EGFR
mutation positive non–small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.
Lung cancer is the leading cause of cancer related mortality worldwide in both men and women.1
Patients with advanced epidermal growth factor receptor (EGFR) mutated non–small- cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, show improved progression-free survival (PFS) compared with standard chemo- therapy as first-line therapy.2-5
Unfortunately, patients develop resistance through multiple routes, including acquired EGFR
mutations such as T790M.6
In order to combat this resistance, second- and third-generation EGFR
TKIs have been developed. In order to prevent or delay the development of resistance, multiple strategies have been investigated, such as the combina- tion of high-dose pulses with low-dose continuous EGFR
TKI therapy or co-targeting bypass signaling pathways as in the com- bined inhibition of both EGFR
The development of third-generation TKIs has improved patient outcomes; however, therapeutic resistance still occurs. As the options for therapy increase, the available data should be considered in choosing a frontline treatment.
Current Options for First-Line TherapyEGFR
TKIs have been established as frontline therapy for patients with metastatic EGFR
mutant lung. Differentiating between these treatment options requires an evaluation of the studies that have been performed.
The IPASS trial led the field, and was a randomized, phase 3 trial that compared gefitinib to carboplatin and paclitaxel in 1217 previously untreated never or light ex-smokers with advanced NSCLC, but did not require EGFR
mutation. The pri- mary endpoint was PFS, and at 12 months, the PFS was 24.9% with gefitinib and 6.7% with carboplatin/paclitaxel. In the sub- group of patients with an EGFR
mutation, PFS was significantly longer among those who received gefitinib.2
Importantly, those without EGFR
mutation had improved PFS with chemotherapy, highlighting the importance of molecularly testing for activating EGFR
A randomized, phase 3 trial compared gefitinib versus carboplatin/paclitaxel in previously untreated patients with EGFR-
mutated metastatic NSCLC.8
Analysis of the first 200 patients revealed that PFS was significantly longer in patients in the gefitinib group resulting in early termination. The gefitinib group had a median PFS of 10.8 versus 5.4 months in the chemotherapy group and a higher response rate of 73.7% versus 30.7%.
A third study comparing gefitinib and cisplatin plus docetaxel had similar results.9
This randomized, phase 3 study involved 177 previously untreated patients diagnosed with stage IIIB/IV NSCLC or postoperative recurrence with EGFR
mutations and evaluated PFS as the primary endpoint. The gefitinib group had significantly longer median PFS compared with the cisplatin plus docetaxel group (9.2 versus 6.3 months).
A randomized, phase 3 trial compared erlotinib with carbo- platin/gemcitabine in 165 patients with stage IIIB/IV NSCLC and EGFR
mutations.5 The analysis of PFS included 82 patients in the erlotinib group and 72 in the chemotherapy group. Median PFS was significantly longer in the patients treated with erlotinib than those treated with chemotherapy (13.1 versus 4.6 months).
The EURTAC trial compared erlotinib versus platinum-based chemotherapy for first-line treatment of patients with advanced NSCLC with EGFR
mutations in a randomized, phase 3 trial.10
In that study, 86 patients received erlotinib and 87 received standard chemotherapy. The preplanned interim analysis showed the study met its primary endpoint and enrollment was stopped. The median PFS in the erlotinib group was 9.7 months com- pared with 5.2 months in the chemotherapy group.
The LUX-Lung 3 study was a randomized, phase 3 trial that compared afatinib to pemetrexed/cisplatin in previously