LBA42_PR - Cisplatin plus pemetrexed (CP) versus cisplatin plus gemcitabine (CG) according to thymidylate synthase expression in non-squamous NSCLC: A biomark...

Date 27 September 2014
Event ESMO 2014
Session NSCLC, metastatic 1
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Myung-Ju Ahn
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors M. Ahn1, J. Sun2, J.S. Ahn3, S. Jung4, K. Park3
  • 1Department Of Internal Medicine, Hematology, Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, 135-710 - Seoul/KR
  • 2Division Of Haematology/oncology, Department Of Medicine, Sungkyunkwan University, School of Medicine, 135-710 - Seoul/KR
  • 3Division Of Hematology/oncology, Department Of Medicine, Sungkyunkwan University, School of Medicine, 135-710 - Seoul/KR
  • 4Department Of Biostatistics And Bioinformatics, Duke University, Durham/US

Abstract

Aim

JMDB trial showed CP was significantly superior to CG in non-squamous NSCLC, while CP was inferior in squamous NSCLC. Thymidylate synthase (TS) is one of target proteins of pemetrexed and the efficacy of pemetrexed-based chemotherapy could depend on TS expression. The primary endpoint is to determine the predictive value of TS in non-squamous NSCLC in terms of objective response rate (RR) by testing on the interaction between treatment arm and TS positivity.

Methods

Main inclusion criteria are non-squamous NSCLC excepting for large cell neuroendocrine carcinoma, one or more measurable lesions, and no prior chemotherapy for advanced NSCLC. Written consents were obtained from eligible patients, and TS expression was collected by IHC. The patients with more than 10% of tumors expressing TS were grouped as a TS(+) and those with 10% or less were grouped as a TS(-). After being stratified as TS(+) or TS(-), patients were randomized to either CP or CG arms by 1: 1 fashion. CP or CG was administered until disease progression or unacceptable toxicity with maximum 6 cycles. Response evaluation was done every 2 cycles during treatment and every 2 months after completion of study chemotherapy. One-sided alpha of 0.1 was used for testing on the interaction term. Otherwise, all p-values are two-sided.

Results

For 315 evaluable patients, the RR of CP and CG were 47.0% and 21.1% in TS (-) group, whereas 40.3% and 39.2% in TS (+) group (interaction P = 0.008). The RR of CP and CG arms evaluated by independent reviewers were 38.6% and 21.1% in TS(-) group, and 40.3% and 48.1% in TS(+) group (interaction P = 0.007). The median PFS of CP and CG were 6.4 and 5.5 months in TS (-) group (P = 0.013), whereas 5.9 and 5.3 months in TS (+) group (P = 0.64) (interaction P = 0.07). The median OS of CP and CG were not different in TS (-) group (not reached vs. 28.3 months, P = 0.86) and in TS (+) group (19.0 vs. 14.4 months, P = 0.36) (interaction P = 0.31). TS-negativity was an independent prognostic factor for OS (HR = 0.64, 95% CI 0.45-0.90).

Conclusions

In terms of RR and PFS, clinical benefits of CP chemotherapy compared to CG were more prominent in TS (-) group than in TS (+) group, suggesting that TS can be used as a predictive biomarker. Furthermore, given that low TS expression was associated with prolonged OS irrespective of chemotherapeutic regimens, TS expression can also serve as a prognostic biomarker.

Disclosure

All authors have declared no conflicts of interest.