Pemetrexed-Erlotinib, Pemetrexed Alone, or Erlotinib Alone as Second-Line Treatment for East Asian and Non-East Asian Never-Smokers with Locally Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer: Exploratory Subgroup Analysis of a Phase II Trial

Abstract

Purpose: This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC).

Materials and methods: Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model.

Results: Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months).

Conclusion: The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients.

Keywords: East Asian; Erlotinib; Nonsquamous non-small cell lung cancer; Pemetrexed.

Appendix 1.

Box and scatter plots of progression-free survival (PFS) and overall survival (OS) for epidermal growth factor receptor (EGFR) mutation positive and EGFR mutation-negative subsets. (A, B) Box plot of PFS and OS, respectively, for the entire population. (C, D) Box plot of PFS and OS, respectively, for East Asian (EA) population. (E, F) Scatter plot of PFS and OS, respectively, by treatment group in the EA population. (G, H) Scatter plot of PFS and OS, respectively, by treatment group in the non-EA population. Note: Patient with any EGFR mutation detected was categorized as mutated (positive); patient without EGFR mutations detected was categorized as non-mutated (negative); (A-D) the distribution of the middle half of the data was displayed by a box with the bottom, center, and top lines indicating quartile 1, median, and quartile 3, respectively. Potential outliers are plotted as individual points. The vertical lines extend from the bottom and top of the box to the smallest or largest non-outliers. (G, H) There were no non-EA erlotinib-treated EGFR mutation positive patients or non-EA pemetrexed-treated EGFR mutation-negative patients. Erl, erlotinib; Pem, pemetrexed.

Fig. 1.

Kaplan-Meier plots of progression-free survival (PFS) and overall survival (OS) for East Asian (EA) and non-EA populations. (A) Kaplan-Meier plot of PFS for EA population. (B) Kaplan-Meier plot of OS for EA population. (C) Kaplan-Meier plot of PFS for non-EA population. (D) Kaplan-Meier plot of OS for non-EA population. For OS, 53.7%, 37.2% and 53.1% of EA patients and 35.1%, 40.5% and 54.5% of non-EA patients treated with pemetrexed-erlotinib, pemetrexed or erlotinib, respectively, were censored.

Fig. 2.

Forest plots by clinical subgroups (qualified intention-to-treat population). (A, B) Forest plots of progression-free survival (PFS) for East Asian (EA) population by clinical subgroups. (C, D) Forest plots of overall survival (OS) for EA population by clinical subgroups. (E, F) Forest plots of PFS for non-EA population by clinical subgroups. (G, H) Forest plots of OS for non-EA population by clinical subgroups. CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio. ^a)Patient with any EGFR mutation detected was categorized as mutated (positive); patient without EGFR mutations detected was categorized as non-mutated (negative); patient without EGFR samples or without valid EGFR samples was categorized as unknown. Note: The results for Eastern Cooperative Oncology Group performance status (ECOG PS) 2 subgroup were removed from the plot due to the extremely small number of patients in the EA (n=6) and non-EA (n=10) populations.