TS Expression Explored in ALK-positive NSCLC

David R. Gandara, MD

Professor of Medicine Division of Hematology and Oncology Director, Thoracic Oncology Program, Associate Director, Clinical Research, UC Davis Cancer Center Sacramento, CA

Expression levels of thymidylate synthase (TS), an enzyme important to DNA replication, may help point the way to new treatment options for patients with ALK-positive non-small cell lung cancer (NSCLC), including combination therapy, according to David R . Gandara, MD.

An analysis that Gandara presented in a poster at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago in June suggests that patients whose tumors exhibit ALK mutations and low TS expression would benefit from treatment with pemetrexed (Alimta), possibly in combination with crizotinib (Xalkori).

Research has shown that pemetrexed appears to have some activity in ALK-positive patients. However, patients who overexpress TS tend to have reduced sensitivity to pemetrexed, suggesting that TS could be a marker to determine sensitivity or likelihood of developing resistance.

“What we found is that the target enzyme for pemetrexed, thymidylate synthase, was especially low in the patients with ALK-positive cancers,” said Gandara, lead author of the study. “This would give a biologic rationale for the reports of pemetrexed activity in ALK-positive non-small cell lung cancer.”

The study assessed TS expression levels in 63 patients with ALK-positive NSCLC and 1698 patients with ALK-negative adenocarcinomas using reverse transcriptase- polymerase chain reaction (RT-PCR) technology. All patients with ALK-positive tumors had adenocarcinomas without EGFR or KRAS mutations, two other mutations commonly associated with NSCLC.

The authors established a threshold TS level of 2.33 as the cutoff point for sensitivity. The study found that the majority of ALK-positive patients (n = 43, 68%) had a TS level less than 2.33, compared with 32% of ALK-negative patients (n = 551, P < .0001). (Table)

Table. TS Expression in NSCLC Patients¹

ALK Status

(patients)

TS Median

(range)

TS Prevalence

<2.33

(patients)

P Value

ALK+

(63)

2.02

(0.55-19.44)

68%

(43)

P < .0001

ALK-

(1698)

3.32

(0.36-53.51)

32%

(551)

Gandara said that the study provides enough evidence to proceed with the submission of a trial design to the National Cancer Institute. He said that the Southwest Oncology Group (SWOG) has submitted a proposal for a randomized phase II trial in which patients on crizotinib whose disease progressed would be randomized to receive either pemetrexed alone or pemetrexed combined with maintenance crizotinib.

“The rationale here is that there may be clones of the cancer which are still crizotinib-sensitive, and those patients will benefit from the combination,” Gandara said. “We will rebiopsy patients at the time they progress on crizotinib so that we can study the underlying molecular pathways.”

The approval of crizotinib last August represented a major step forward in the treatment of late-stage NSCLC in patients who test positive for an abnormal version of the ALK gene.

The FDA approved pemetrexed in 2008 to treat locally advanced or metastatic nonsquamous NSCLC when given in combination with cisplatin.

Gandara DR, Huang E, Desai S, et al. Thymidylate synthase (TS) gene expression in patients with ALK positive (+) non-small cell lung cancer (NSCLC): Implications for therapy. J Clin Oncol. 2012;30(suppl; abstr 7582).