Correlation between thymidylate synthetase (TS) expression and progression-free survival (PFS) in patients receiving pemetrexed (pem) for advanced NSCLC: A prospective study.

Abstract

7583 Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to be associated with TS expression. Our primary objective was to assess the correlation between TS and PFS, prospectively. Methods: Context: A Phase II, single-arm, exploratory, multicenter, UK study with appropriate approvals and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC histology, stage IIIB/IV. Patients (n=70) received pem/cisplatin induction x 4. Non-progressive patients continued on maintenance pem until tumor progression or discontinuation. All patients were followed until death or study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized) were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for median PFS (mPFS) and Cox regression to determine the statistical correlation between PFS and TS IHC nuclear score, (continuous variable) were performed. Maximal Chi-square analysis identified the optimal association cutpoints between PFS and low vs. high TS scores. Results: Patient demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%) had adenocarcinoma; 15 were not otherwise specified. Maintenance pem was started in 43/70 (61.4%) patients. Evaluable patients had at least one dose of study treatment and a valid TS score (n=60). For the evaluable population, the mPFS from start of induction was 5.5 months (95% CI 3.9-6.9). A statistically significant correlation between PFS and TS IHC nuclear scores was observed [p<0.0001, HR= 1.01 (95% CI 1.01, 1.02)], suggesting higher TS values are associated with shorter PFS. When the population was dichotomized at the identified optimal H-score cutpoint of 70, the mPFS in the low expression group (n=40) was 7.1 months (5.7-8.3) compared to 2.6 months (1.3-4.1) in the high expression group (n=20) [adjusted p=0.0015, HR=0.28 (95% CI 0.16-0.52)]. Similar trends with cytoplasmic TS IHC (p=0.09) and TS qPCR (p=0.05) levels were observed. Statistical correlations were seen among the TS levels. Data is preliminary. Conclusions: Study suggests statistically significant association between low TS IHC nuclear expression and improved PFS in this Phase 2 single-arm trial.