Ying Cheng¹, Haruyasu Murakami², Pan-Chyr Yang³, Jianxing He⁴, Kazuhiko Nakagawa⁵, Jin Hyoung Kang⁶, Joo-Hang Kim⁷, Tarun Puri⁸, Xin Wang⁹, Sotaro Enatsu¹⁰, James Chih-Hsin Yang³

¹changchun Jilin Provincial Cancer Hospital,Changchun, China

²Shizuoka, Japan Shizuoka Cancer Center

³Taipei, Taiwan National Taiwan UniversityHospital

⁴Guangdong, China The First AffiliatedHospital of Guangzhou Medical College

⁵Osaka, Japan Kinki University School ofMedicine

⁶Seoul, Korea The Catholic University ofKorea

⁷Seoul, Korea Yonsei Cancer Center, YonseiUniversity Health System

⁸Haryana, India Eli Lilly and Company, Gurgaon

⁹Shanghai, China; Eli Lilly and Company

¹⁰Kobe, Japan Eli Lilly Japan K.K.

Objective: Pemetrexed(P) is the standard of care for non-squamous non-small cell lung cancer (NS NSCLC),whereas epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors(TKIs), such as gefitinib (G), are the standard of care for advanced NSCLC withEGFR mutations. Clinical and nonclinical studies have demonstratedsynergistic effects of EGFR TKIs and P. Based on these observations, theefficacy and safety of G+P was compared with G monotherapy in patients with NSNSCLC positive for activating EGFR mutations. The primary objective of thisrandomized, multicenter, open-label, parallel-arm, phase 2 East-Asian study wasto assess whether G+P prolongs progression-freesurvival (PFS) versus G alone.Secondary endpoints included overall survival (OS), overall response rate, diseasecontrol rate, time to progressive disease, duration of response, andtreatment-emergent adverse events (TEAEs).

Method: Eligible patients hadstage IV NS NSCLC with activating EGFR mutations, were chemonaïve, and had anEastern Cooperative Oncology Group performance status (ECOG PS) of 0 or1. Patients were randomized in a 2: 1 ratio (G+P: G). Dosing schedulewas concurrent G (250mg/day) and P (500mg/m² every 3 weeks) in theG+P arm and G monotherapy (250mg/day) in the G arm. Treatment continueduntil progression or unacceptable toxicity. The primary endpoint wasanalyzed after 144 events, which provided 70% power at a 1-sided 20%significance level, assuming a true hazard ratio (HR) of 0.79. 

Result: BetweenFebruary 2012 and August 2013, 191 patients were randomized and treated (G+P: N=126;G: N=65). Patients were mostly female (64.4%) with a mean age of 62 years;most were never-smokers (67.0%), had confirmed stage IV disease (84.8%), andECOG PS of 1 (68.6%). Overall, 55.0% had exon 19 deletions, 39.3% had exon21 L858R mutations, and 5.8% had other activating EGFR mutations. Baselinecharacteristics were balanced between treatment arms. Patients in the G+Parm received 96.3% and 92.9% of the planned mean dose of G and P, respectively;patients in the G arm received 97.9% of the planned mean dose of G. MedianPFS for G+P (15.8months) was significantly longer than for G (10.9months);HR=0.68; 95% confidence interval 0.48, 0.96; 1-sided P=0.014; 2-sided P=0.029. OSdata are immature and will be reported at study completion. The incidenceof grade 3/4 study drug-related TEAEs was significantly higher for G+P (42.1%)than for G (18.5%); P=0.001. The most common study drug-related TEAEsfor G+P were diarrhea (44.4%), aspartate aminotransferase increased (41.3%),and dermatitis acneiform and alanine aminotransferase increased (38.1% foreach), and for G were diarrhea (47.7%), dermatitis acneiform (43.1%), and dryskin (35.4%). The proportion of treatment discontinuations due to TEAEswas 16.7% in the G+P arm and 9.2% in the G arm; 2 patients (G+P arm) died dueto study drug-related adverse events. 

Conclusion：Thecombination of G+P led to a significant improvement in PFS compared with Gmonotherapy for East-Asian patients with EGFR mutation-positive NS NSCLC, andmet the primary study endpoint. The incidence of grade 3/4 studydrug-related AEs was higher for G+P than for G. ClinicalTrials.govidentifier: NCT01469000.

Key Words：Non-squamous non-small cell lung cancer Pemetrexed