TS Expression Could Guide Treatment in Nonsquamous NSCLC


The combination of pemetrexed/cisplatin was superior to gemcitabine/cisplatin in non-squamous NSCLC patients negative for the thymidylate synthase enzyme.

The combination of pemetrexed and cisplatin was superior to gemcitabine and cisplatin only in those non-squamous non–small-cell lung cancer (NSCLC) patients who were negative for the enzyme thymidylate synthase (TS), suggesting it could be used as a predictive marker to guide treatment.

Previous research has shown that pemetrexed/cisplatin offers superior survival in nonsquamous NSCLC, while gemcitabine/cisplatin was better in squamous NSCLC. “A plausible mechanism for the histotype-dependent efficacy of pemetrexed-based chemotherapy can be explained by the presence of different levels of TS according to histologic types, with adenocarcinoma of lung cancer exhibiting a lower TS protein expression level than squamous cell carcinoma or neuroendocrine carcinoma,” wrote study authors led by Myung-Ju Ahn, MD, PhD, of Sungkyunkwan University School of Medicine in Seoul.

TS is involved in de novo DNA synthesis, and inhibiting the enzyme leads to arrested cell proliferation; pemetrexed’s antitumor effects arise from inhibition of TS. The new study’s results were published online ahead of print in the Journal of Clinical Oncology.

In the new study, 321 patients with nonsquamous NSCLC were stratified by TS expression levels into either TS-positive (161 patients) or TS-negative (160 patients) groups, and then randomized 1:1 to either pemetrexed/cisplatin or gemcitabine/cisplatin. The analysis included 315 of these patients who received at least one dose of study drug.

The response rate in the TS-negative group was 47% with pemetrexed and 21% with gemcitabine; in the TS-positive group, meanwhile, the response rates were 40% for pemetrexed and 39% for gemcitabine (interaction P = .0084).

Similarly, in the TS-negative group the median progression-free survival was 6.4 months for pemetrexed/cisplatin and 5.5 months for gemcitabine/cisplatin, for a hazard ratio (HR) of 0.65 (95% CI, 0.46–0.91; P = .01). In the TS-positive group, the median progression-free survival was 5.9 months for pemetrexed and 5.3 months for gemcitabine, for an HR of 0.91 (95% CI, 0.65–1.27; P = .57).

The median overall survival time was not reached for the pemetrexed/cisplatin group in the TS-negative cohort, and it was 28.3 months in the gemcitabine patients. In the TS-positive patients, median overall survival was 19 months for pemetrexed and 14.4 months for gemcitabine (P = .36).

On a multivariable analysis, TS-negative expression was significantly associated with longer survival, with an HR of 0.60 (95% CI, 0.42–0.84); younger age, having never smoked, and having an EGFR mutation were also significantly associated with survival. When patients were stratified into four groups based on TS expression, overall survival decreased with increasing TS expression levels (P < .001).

“This biomarker-stratified, randomized trial shows that clinical benefits of pemetrexed/cisplatin compared with gemcitabine/cisplatin were more pronounced in the TS-negative group than in the TS-positive group, and TS-negative tumor was independently associated with longer survival, suggesting TS expression status as a potential predictive or prognostic role in NSCLC,” the authors concluded. They added that larger phase III trials are still warranted to confirm the role of TS expression.

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