Moving Forward With Biomarkers in Non–Small Cell Lung Cancer

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Markus Joerger, MD, PhD

Rohit Lal, MD

Nasser Hanna, MD

Young-Chul Kim, MD, PhD

We saw a clinically meaningful improvement with the addition of vintafolide across all endpoints, but the most robust improvement was in the predefined adenocarcinoma patients.

—Rohit Lal, MD

The effort to identify new biomarkers for response and outcomes in lung cancer is advancing, according to studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid. Immunohistochemical expression of folate receptor for vintafolide and thymidylate synthase for pemetrexed (Alimta) holds promise for individualizing second-line treatment of metastatic non–small cell lung cancer (NSCLC), in keeping with the theme of “precision medicine” at this year’s Congress.

Second-line therapy with vintafolide added to docetaxel vs docetaxel alone made no difference in overall survival in patients with NSCLC in the phase II TARGET trial population, but vintafolide improved overall survival in a subgroup of patients with adenocarcinoma.1

TARGET Trial Details

Vintafolide is an investigational small-molecule drug conjugate targeted to the folate receptor. The 199 patients included in this trial were selected for folate receptor expression, and results provide a clue that folate receptor overexpression may be useful for therapy selection in patients with adenocarcinoma, suggested Markus Joerger, MD, PhD, Associate Professor of Medical Oncology and Clinical Pharmacology at Cantonal Hospital, St. Gallen, Switzerland, who wrote about these results in the Congress Daily.

Rohit Lal, MD, Consultant Medical Oncologist at Guy’s and St. Thomas’ Hospital, London, presented the TARGET results, standing in for lead author Nasser Hanna, MD. “We saw a clinically meaningful improvement with the addition of vintafolide across all endpoints, but the most robust improvement was in the predefined adenocarcinoma patients. The safety was manageable and as expected with both single agents. Going forward, we need to figure out the best trial design for this drug and patient selection,” Dr. Lal said.

The rationale for the study was partly based on preclinical data showing complete suppression of tumor growth with the combination of docetaxel plus vintafolide. Rodryg Ramlau, MD, PhD, a study coauthor from the Lung Disease Centre in Poznan, Poland, said that an early trial showed that single-agent vintafolide exerted disease control in 57.1% of 14 heavily pretreated patients.

Patients selected for the trial had target lesions that were folate receptor–positive on imaging, and they were randomly assigned 1:1:1 (n = 199) to vintafolide, the combination of both drugs at the same dose and schedule as the monotherapy arms, and docetaxel monotherapy. Treatment was continued until disease progression or unacceptable toxicity. Treatment arms were well balanced for all patient characteristics.

Median progression-free survival was 1.6 months with vintafolide, 4.2 months for the combination, and 3.3 months with docetaxel monotherapy. Median overall survival was 8.4 months for vintafolide, 11.5 months for the combination, and 8.8 months for docetaxel. The disease control rate was 40% for vintafolide, 70% for the combination, and 60% for docetaxel.

In the subgroup of patients with adenocarcinoma, combination therapy reduced the risk of disease progression by 32% and reduced the risk of death by 49% compared with monotherapy with either drug (P = .0147).

No unexpected adverse events occurred. Neutropenia and peripheral neuropathy were increased with the combination.

Doublets Comparable

A small phase III noninferiority trial showed that pemetrexed/cisplatin and docetaxel/cisplatin had comparable outcomes as first-line treatment of stage IV nonsquamous NSCLC, but pemetrexed/cisplatin had an improved safety profile, with less severe febrile neutropenia compared with docetaxel/cisplatin.2 Grade 3/4 neutropenia were reported in 1.3% of the pemetrexed/cisplain arm vs 13.9% of the docetaxel/cisplatin arm. Febrile neutropenia occurred in 1.3% vs 11.1%.

Among 149 evaluable patients enrolled in the trial, median progression-free survival was 4.7 months with pemetrexed/cisplatin and 4.6 months with docetaxel/cisplatin. Patients with EGFR-activating mutations were excluded from the trial.

Lead author Young-Chul Kim, MD, PhD, of Chonnam National University Hwasun Hospital, Hwasun Gun, Korea, explained that the study was designed when maintenance was not standard of care and four cycles of chemotherapy was preferred over six cycles.

“We failed to show superiority of one doublet over another. Moreover, expected median progression-free survival was 6.4 months,” he said. “Response rates were not that different, and progression-free survival was almost identical,” he added.

He suggested that the disappointing results were related to giving only four cycles of chemotherapy in this trial.

Biomarker for Outcome?

A phase II study at the same ESMO session suggested that thymidylate synthase expression may be a potential biomarker for predicting outcome with pemetrexed treatment of metastatic NSCLC in the second-line setting.3

The patients were stratified for thymidylate synthase expression, which is a predictive factor for response in pemetrexed-treated patients, explained lead author Myung-Ju Ahn, MD, PhD, Sungkyunkwan University School of Medicine, Seoul, Korea. “This is the first [thymidylate synthase] biomarker study in NSCLC. The data suggest that [thymidylate synthase] is a predictive and prognostic biomarker,” she added.

In 315 patients with stage IIIB/IV nonsquamous NSCLC, thymidylate synthase–negative status on immunohistochemistry was significantly associated with improved response rates and improved progression-free survival in patients receiving pemetrexed/cisplatin vs those treated with gemcitabine/cisplatin.

Response rates were 38% vs 21%, respectively (P = .007), and median progression-free survival was 6.4 vs 5.5 months, respectively (P = .013).

Irrespective of treatment group, overall survival was related to thymidylate synthase status, she said. Thymidylate synthase–negative patients had survived a mean of 30.3 months, whereas thymidylate synthase–positive patients survived a mean of 15.2 months. Thymidylate synthase negativity was an independent prognostic factor for favorable overall survival, she said.

For the study, thymidylate synthase positivity was defined as expression of the enzyme in more than 10% of tumor cells, and thymidylate synthase negativity as expression in 10% or fewer tumor cells. Thymidylate synthase–negative patients tended to be female, younger, and never-smokers. ■

Disclosure: Dr. Joerger reported no potential conflicts of interest. Dr. Kim received funding for the trial and honoraria from Sanofi-Aventis Korea.


1. Hanna N, Juhász E, Cainap C, et al: TARGET: A randomized phase II trial comparing vintafolide versus vintafolide plus docetexel versus docetaxel alone in second-line treatment of folate receptor-positive non-small cell lung cancer patients. ESMO 2014 Congress. Abstract LBA40_PR. Presented September 27, 2014.

2. Kim Y, Oh I, Kim K, et al: A randomized phase II study of docetaxel plus cisplatin versus pemetrexed plus cisplatin in first-line non-squamous non-small cell lung cancer. ESMO 2014 Congress. Abstract LBA41_PR. Presented September 27, 2014.

3. Ahn M, Sun J, Ahn JS, et al: Cisplatin plus pemetrexed versus cisplatin plus gemcitabine according to thymidylate synthase expression in non-squamous NSCLC: A biomarker-stratified randomized phase II trial. ESMO 2014 Congress. Abstract LBA42_PR. Presented September 27, 2014.

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