Cisplatin (Cis)/etoposide (VP16) compared to cis/irinotecan (CPT11) in extensive-stage small cell lung cancer (E-SCLC): Pharmacogenomic (PG) and comparative toxicity analysis of JCOG 9511 and SWOG 0124
7524 Introduction: J9511 demonstrated a significant survival benefit for Cis/CPT11 over Cis/VP16 in Japanese patients (pts) with E-SCLC (Noda, et al. NEJM 2002). S0124 is the confirmatory North American phase III trial (accrual completed) using the identical J9511 protocol. We hypothesized that toxicities would differ between North American & Japanese pts due in part to differences in the distribution of genetic polymorphisms involved in chemotherapy metabolism. Methods: Toxicity data were compared among 706 pts enrolled in J9511 & S0124 receiving common treatment using a logistic model adjusted for age, sex, and performance status (PS). Select polymorphisms of the UGT1A1, ABCB1, & OATP genes in genomic DNA were evaluated in 142 pts in S0124 only (67 Cis/CPT11; 75 Cis/VP16). Associations between toxicity & genotype within each arm were assessed using logistic regression. Results: Pt demographics for J9511 & S0124 respectively: Mean age − 61 & 62 years; Male sex − 131 (86%) & 315 (57%); PS 0 − 19 (13%) & 173 (31%); PS>0 − 133 (87%) & 372 (68%). Comparative toxicities (≥ grade 3) are summarized ( table ). PG analysis in S0124 pts: ABCB1 (C3435T) T/T was associated with an increased risk of CPT11 grade 3+ diarrhea (p=0.04) versus C/C and C/T. UGT1A1 (G3156A) A/A was associated with increased risk of CPT11 neutropenia (p=0.009) & leukopenia (p=0.05). UGT1A1*28 TA7, typically associated with increased CPT11 toxicity, was seen in only 4 pts (2 Cis/CPT11; 2 Cis/VP16); thus no correlation was done. No gene tested was associated with VP16 toxicity. Conclusions: Significant differences in treatment-related myelosuppression exist between J9511 and S0124 pt populations. Certain polymorphisms in genes involved in CPT11 metabolism are significantly associated with CPT11 toxicities in S0124. Additional analyses are ongoing. These results support the hypothesis that toxicities may be associated with distribution of genetic polymorphisms. No significant financial relationships to disclose. [Table: see text]