Zosia Chustecka

October 08, 2014

MADRID — Searching for biomarkers that can predict a better response to therapy is a perennial hot topic in oncology. In the field of non-small cell lung cancer (NSCLC), a new approach is looking at the expression of thymidine synthase (TS) as a way of predicting a better response to chemotherapy.

"Thymidylate synthase is one of the proteins that is targeted by pemetrexed (Alimta), which is the most widely used chemotherapeutic regimen in the treatment of nonsquamous NSCLC," explained study author Myung-Ju Ahn MD, professor of hematology-oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, in Seoul, Korea.

Dr. Ahn and colleagues reported results from a phase 2 trial here at the European Society for Medical Oncology Congress 2014. The trial involved 315 patients with nonsquamous NSCLC who received first-line treatment with a chemotherapy doublet, either pemetrexed plus cisplatin or gemcitabine plus cisplatin. The chemotherapy was administered until disease progression or unacceptable toxicity, with a maximum of 6 cycles.

All patients had tumor samples tested by immunohistochemistry for TS expression status. Patients with more than 10% of tumors expressing TS were grouped as TS-positive, and those with 10% or less were grouped as TS-negative.

The results suggest that patients who were classed as TS-negative had a "more prominent" clinical benefit from pemetrexed and cisplatin, in terms of both response rates and progression-free survival, the researchers report.

For patients who were classed as TS-negative, the response rate was 47.0% for pemetrexed plus cisplatin and 21.1% for gemcitabine and cisplatin. Among patients who were classed as TS-positive, the response rate was 40.3% and 39.2%, respectively (interaction P = .008).

The median progression-free survival was 6.4 months with pemetrexed and cisplatin vs 5.5 months with gemcitabine plus cisplatin in patients who were TS-negative (P = .013), and 5.9 and 5.3 months, respectively, in patients who were TS-positive (P = .64) (interaction P = .07).

Hence, the team suggests that TS expression could be used as a predictive marker.

In addition, low TS expression was associated with prolonged overall survival, irrespective of chemotherapeutic regimens, the researchers note.

The median overall survival was not statistically different between the 2 different chemotherapy combinations, but patients in the TS-negative group showed a longer overall survival (not reached with pemetrexed and cisplatin vs. 28.3 months with gemcitabine plus cisplatin; P = .86) than patients in the TS-positive group (19.0 vs 14.4 months, respectively; P = .36) (interaction P = .31).

The researchers note that TS-negativity is an independent prognostic factor for overall survival (hazard ratio, 0.64; 95% confidence interval [CI], 0.45 - 0.90), and suggest that it can be used as a prognostic marker.

"In nonsquamous cell NSCLC, TS-negative patients get more clinical benefit from pemetrexed/cisplatin combination therapy," Dr. Ahn said in a statement.

"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."

However, a lung cancer expert who frequently contributes to Medscape Oncology is not convinced. Approached for comment, Giorgio V. Scagliotti, MD, PhD, chair of the Department of Medical Oncology at San Luigi Hospital, University of Torino, in Orbassano, Italy, said the study is reasonably well designed, "but the prognostic/predictive role of TS is unsolved. The study showed no significant interaction between TS level and progression-free survival."

"TS is not ready for clinical use," Dr. Scagliotti told Medscape Medical News.

The use of pharmacogenomic markers is still reserved for the clinical research setting, and no data support its use in clinical practice to select patients, he said.

Dr. Ahn and colleagues have disclosed no relevant financial relationships. Dr. Scagliotti reports serving as a speaker for Lilly, Roche, AstraZeneca, and Pfizer.

European Society for Medical Oncology (ESMO) Congress 2014: Abstract LBA42_PR. Presented September 27, 2014.

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