Thymidylate synthase: a prognostic and predictive biomarker for response to pemetrexed-cisplatin in non-squamous NSCLC

A randomized phase II study showed that patients whose lung cancers express low levels of thymidylate synthase experience a greater benefit from treatment with the combination of pemetrexed and cisplatin than those whose tumours express high levels.

Thymidylate synthase, an enzyme involved in DNA synthesis, is one of the proteins that is targeted by pemetrexed which is the most widely used chemotherapeutic regimen in the treatment of non-squamous NSCLC. Hence, the presented study evaluated whether the expression of thymidylate synthase is a predictive factor for response to pemetrexed plus cisplatin chemotherapy compared with gemcitabine plus cisplatin in non-squamous cell lung cancer patients.

In total, 315 patients with non-squamous NSCLC with one or more measurable lesions who received no prior chemotherapy for advanced NSCLC were included in the study. The patients with more than 10% of tumors expressing TS were labelled as a TS+ and those with 10% or less were labelled as a TS-. After being stratified as TS+ or TS-, patients were randomized to either cisplatin plus pemetrexed (CP) or cisplatin plus gemcitabine (CG). CP or CG was administered until disease progression or unacceptable toxicity with maximum 6 cycles. The response rate of CP and CG arms evaluated by independent reviewers were 38,6% and 21,1% in the TS- group, and 40,3% and 48,1% in TS+ group (interaction p = 0,007). The median progression-free survival (PFS) of CP and CG were 6,4 and 5,5 months in the TS- group (p= 0,013), compared to 5,9 and 5,3 months in the TS+ group (p=0,64) (interaction p = 0,07). The median OS of CP and CG were similar in the TS- group (not reached vs. 28,3 months, p= 0,86) and the TS+ group (19,0 vs. 14,4 months, P=0,36) (interaction p = 0,31). However, irrespective of treatment, TS- patients had a significantly longer median OS of 30,3 months compared to 15,2 months for TS+ patients (p < 0,0001). In multivariate analyses, TS- expression was significantly associated with longer survival (HR[95%CI]: 0,64[0,45-0,90]) along with younger age (HR[95%CI]: 0,62[0,44-0,88]) and EGFR mutation (HR[95%CI]: 0,45[0,28-0,71]).

As such, the clinical benefits of the pemetrexed combination compared to other regimen were more prominent in those patients who expressed low levels of thymidylate synthase. This suggests that thymidylate synthase can be used as a predictive biomarker. Furthermore, low thymidylate synthase expression was associated with prolonged overall survival irrespective of which chemotherapeutic regimen the patients received, suggesting that its expression can also serve as a prognostic biomarker.

In summary, non-squamous cell NSCLC, thymidylate synthase-negative patients appear to get more clinical benefit from pemetrexed/cisplatin combination therapy. Furthermore, multivariate analysis of the present study showed that TS negative expression was significantly associated with longer survival, along with younger age and EGFR mutation, suggesting it is a good independent prognostic marker. As such, this study holds promise for TS-customized chemotherapy in advanced NSCLC.

Reference

Ahn M, Sun J, Ahn J et al. Cisplatin Plus Pemetrexed (CP) versus Cisplatin plus Gemcitabine (CG) According to Thymidylate Synthase Expression in Non-squamous NSCLC: A Biomarker-stratified Phase II Trial. Presented at ESMO 2014; Abstract LBA42.