Epidermal growth factor tyrosine kinase inhibitor therapy inferior to second-line chemotherapy in EGFR wild-type non-small cell lung cancer patients: results of French nationwide observational study

In the recent issue of The European Respiratory Journal, Tomasini et al. report on an observational study comparing the clinical, biological, treatment and outcome data for epidermal growth factor wild-type (EGFR-wt) advanced non-small cell lung cancer (NSCLC) patients who received second-line treatment with an EGFR tyrosine kinase inhibitor (TKI) versus those that received second-line chemotherapy, collected in France over a 1 year period (1). Their central finding, that clinical outcomes with second-line EGFR TKI therapy in EGFR-wt patients were inferior to those with second-line chemotherapy, underscores the ineffectual nature of the treatment of EGFR-wt NSCLC with an EGFR TKI.

Data for Tomasini et al.’s study were generated from the French Cooperative Thoracic Intergroup (IFCT), representing a nationwide approach to genetic tumor profiling of NSCLC at 28 molecular genetics centers throughout France from April 2012–April 2013. The 868 EGFR-wt patients treated with second-line chemotherapy had a median PFS of 4.3 vs. 2.83 months in the 410 patients treated with second-line TKI (HR 0.66; 95% CI: 0.57–0.77; P<0.0001) and median OS was longer in the chemotherapy group at 8.38 vs. 4.99 months in the EGFR TKI group (HR 0.70; 95% CI: 0.59–0.83; P<0.0001). A clear limitation of this study, which the authors acknowledge, is its observational nature leading to demographic imbalances between the two treatment arms (1).

Specifically, more non-smoking, ECOG performance status ≥2, elderly (≥65 years old) patients were treated with an EGFR TKI, rather than chemotherapy (nonsmokers: 16.3% in TKI group vs. 8.8% in chemotherapy group, P<0.0001; ECOG ≥2: 27.1% in TKI group vs. 18.2% in chemotherapy group, P<0.0001; age ≥65 years old: 46.8% in TKI group vs. 32.7% in chemotherapy group, P<0.0001). This is not surprising, since EGFR TKIs are generally considered to be less toxic than cytotoxic chemotherapy and were thus likely preferentially selected by clinicians in frail patients and non-smokers. However, when controlling for these confounding characteristics, the survival benefit observed in the chemotherapy group remained (1).

Although the efficacy of an EGFR TKI in NSCLC was first established in a biomarker agnostic fashion (2), subsequent studies have prospectively evaluated the relevance of an EGFR mutation in relation to EGFR TKI response. The landmark IPASS (Iressa Pan-Asia Study) compared gefitinib with carboplatin/paclitaxel as first-line therapy in advanced NSCLC. The findings of the study were striking, with EGFR-mutant (EGFR-mt) patients evidencing a 71.2% objective response rate (ORR) compared to 1.1% in EGFR-wt patients (P=0.001) (3). In the TAILOR (Tarceva Italian Lung Optimization Trail), erlotinib was compared to docetaxel in EGFR-wt patients as second line therapy and the ORR in EGFR-wt patients to erlotinib was only 3.0%, compared to 15.5% in the docetaxel arm (P=0.003) (4). This difference in ORR between the two treatment arms translated into a median OS of 8.2 months in the docetaxel arm compared to 5.4 months in the erlotinib arm (adjusted HR 0.73; 95% CI: 0.53–1.00; P=0.05), similar to the OS benefit observed in the current study (4). In the U.S., EGFR TKIs are no longer approved for use in EGFR-wt patients (5). In October 2016, the U.S. FDA modified erlotinib’s indication, limiting its use to only those patients whose tumors harbor an EGFR mutation, based upon the IUNO trial that found that overall survival with maintenance erlotinib was no better than placebo as second-line therapy in EGFR-wt patients (5,6).

Tomasini et al.’s observational study presented in the recent issue of The European Respiratory Journal further emphasizes the inferior nature of TKI therapy in EGFR-wt patients. Importantly, a number of more appealing therapeutic options are currently available as second-line therapies in EGFR-wt patients, including immunotherapy, chemotherapy +/− angiogenesis inhibitors, and single agent chemotherapy (7-10). In the current treatment landscape there appears to be no role for an EGFR TKI in the treatment of EGFR-wt patients.

Acknowledgements

Dr. Garon reports funds to his institution from AstraZenca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genentech, Mirati, Merck, Pfizer, and Novartis.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

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