DIMESNA FOR NSCLC?

January 26, 2010 — The investigational chemoprotective agent dimesna, also known as BNP7787 (Tavocept, BioNumerik), for advanced nonsmall-cell lung cancer (NSCLC) seems to improve survival, especially in patients with adenocarcinomas, according to a meta-analysis of 2 trials published in the December issue of European Journal of Clinical & Medical Oncology.

In other words, dimesna is also an "antitumor enhancing agent," according to the authors of the study.

"This doesn't happen," study coauthor Michael C. Perry, MD, told Medscape Oncology, referring to the fact that a chemoprotective agent might also provide survival benefit as an anticancer agent.

"The agent has been previously looked at to relieve toxicity — not as a primary therapy," said Dr. Perry, who is professor of medicine in the Division of Hematology and Oncology at the University of Missouri in Columbia, and a member of BioNumerik's scientific advisory board.

Dimesna was "envisioned" as an agent to reduce nephrotoxicity and neurotoxicity, and has been used in patients investigationally for "about 10 years," Dr. Perry added.

On the basis of the survival findings in the meta-analysis, BioNumerik has initiated an international phase 3 study of dimesna in patients with stage IIIB/IV primary adenocarcinoma of the lung.

The newly published meta-analysis examined overall survival outcomes for 346 newly diagnosed randomized patients with advanced NSCLC, including 211 with primary adenocarcinoma.

For the adenocarcinoma subtype in the combined analysis, patients treated with dimesna and taxane plus cisplatin chemotherapy (n = 107) had a median overall survival of 19.2 months, whereas those treated with chemotherapy alone (n=102) had a median overall survival of 11.5 months; the difference was statistically significant (P = .009).

Dimesna was not quite as impressive in all histopathologic subtypes of NCSLC included in the study but still showed effectiveness, write the study authors, led by Frederick Hausheer, MD, founder, chair, and chief executive officer of BioNumerik.

"Analysis of the combined study populations demonstrates a significant (P = .0392; power = .6588) overall survival benefit in favor of [dimesna]," write the study authors.

The survival benefit seen with dimesna is supported scientifically by "identified mechanisms of action," they report.

"We have elucidated that [dimesna] targets the thioredoxin and glutaredoxin systems, both of which are overexpressed in adenocarcinoma of the lung," the authors explain. "It is postulated that the presence of [dimesna] and its metabolites result in interference with the key components of the thioredoxin and glutaredoxin systems," they add.

Details of the 2 Studies in Meta-Analysis

Patients with advanced-stage IIIB/IV NSCLC were entered in 2 randomized, multicenter trials of dimesna — 1 in the United States (conducted by Cancer and Leukemia Group B [CALGB 30303]) and 1 in Japan.

In both studies, patients were treated with a taxane (docetaxel in the United States and paclitaxel in Japan) and cisplatin, administered with either dimesna vs no dimesna (United States) or dimesna vs placebo (Japan) for a maximum of 6 cycles. The 2 studies were very similar in design and included the same key inclusion criteria.

All patients enrolled in both trials were treatment naive and had not received any previous chemotherapy or primary therapy for their lung cancer.

All patients had a Zubrod performance status score of 0 to 1 and thus were among those "expected to do best on treatment," noted Dr. Perry. "Studies on anyone [with a Zubrod score] over 1 are not done," he added.

The mean age was 61.5 years in the American study and 60.6 years in the Japanese study. Again, the average ages were "typical" for lung cancer studies, said Dr. Perry.

All subtypes of NSCLC were represented in the study patients; however, adenocarcinoma was predominant.

"Adenocarcinoma was the largest of all of the NSCLC subtypes represented in each of the studies, and was equally distributed between treatment groups in each study," write the authors.

One of the limitations of the study was that data on second-line therapy was not gathered in the American study, say the authors. So, when patients failed in the study, they went back to community-based treatment. The only follow-up was to determine survival from the social security database. There might have been some kind of "substantial survival effect" from an "imbalanced" second-line treatment effect. But it is unlikely, said Dr. Perry, as is evidenced by the fact that, in the Japanese study, which collected second-line therapy data, no effect was seen.

All the authors of this study report being employed by, being in a leadership position at, or serving in a consultant/advisory role for BioNumerik Pharmaceuticals or ASKA Pharmaceuticals.

Eur J Clin Med Oncol. 2009;1:7-19.