New Agent for Lymph Node Mapping in Breast Cancer, Melanoma

Zosia Chustecka

June 10, 2011

June 10, 2011 (Chicago, Illinois) — A novel receptor-targeted radioactive tracer for intraoperative lymphatic mapping (ILM) — 99mTc-tilmanocept (Lymphoseek) — beat a standard product in current use in a phase 3 clinical trial.

In patients with breast cancer and melanoma who were clinically node-negative, the novel product identified nodes that contained cancer cells that were missed by the standard product, which might have implications for treatment.

Results from the study were presented here at the American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting. The manufacturer (Neoprobe) intends to file these data with the US Food and Drug Administration (FDA) and begin the approval process before the end of the year.

The company held a briefing for analysts and journalists at the ASCO meeting, during which the 2 lead investigators involved in the clinical trial spoke enthusiastically about their experience with the product.

However, after the results were presented at the meeting, the discussant suggested that this trial is a "good first step," but that more work is needed and, in particular, questioned the choice of the control used in the study.

One analyst picked up on this, and has filed a Citizen Petition asking the FDA to refrain from approving the product until another trial is conducted.

Finding Tumor in Lymph Nodes That Were Missed

ILM is widely used for staging in breast cancer and melanoma patients who are clinically node-negative; the mapping can detect whether any nodes contain cancer cells.

The only FDA-approved product for ILM is vital blue dye (VBD); in this study, isosulfan blue (Lymphazurin) was used. In clinical practice, VBD is often used in combination with a radioactive tracer, technetium 99m–labeled sulfur colloid, which is not approved for use in ILM. Because its use is considered to be off-label, and so is not standardized, there is a wide variation in its use across different centers.

The new product comprises a radiopharmaceutical attached to a dextra core, which targets dextra-mannose receptors on the surface of lymphatic cells. This means that the tracer binds to and stays in the lymph nodes.

The product was designed specifically for use in ILM, because "we wanted to overcome the drawbacks of using VBD in combination with colloidal sulfur," explained Anne Wallace, MD, professor of surgery and director of the breast care unit at the Moores Cancer Center at the University of California, San Diego. She was involved in the early development of the product, about 12 years ago, and more recently took part in the phase 3 clinical trial. In the interim period, the product was acquired and developed by Neoprobe; during this time, Dr. Wallace had no access to it, and found that "I really missed using it."

The product is easier to use than the combination of VBD plus colloidal sulfur, she said. VBD can cause blue staining or tattooing of the breast, and colloidal sulfur can cause a burning sensation and pain when it is injected. The new product has neither of these adverse effects. It also more accurate, Dr. Wallace said — it identified a significant number of tumor-containing nodes that were not stained blue.

The trial used VBD and 99mTc-tilmanocept in each patient, and compared the nodes that were stained blue with those identified as "hot" by the radiotracer.

Among her cohort of breast cancer patients, 99mTc-tilmanocept independently upstaged 2 patients, Dr. Wallace said.

In those 2 patients, there was no blue signal, but there was a "subtle hot signal," Dr. Wallace noted. The finding of cancer cells in the nodes makes a difference in the treatment recommendation.

"This is huge in early breast cancer," Dr. Wallace explained. "The product made a difference — both of these women will go on to adjuvant therapy that they may not have otherwise received."

A similar experience was reported by Vernon Sondak, MD, chair of cutaneous surgery at the H. Lee Moffit Cancer Center in Tampa, Florida, and another principal investigator on the trial. He was treating melanoma patients, and also had 2 who were upstaged; 99mTc-tilmanocept found tumor in lymph nodes that were not identified by the blue dye.

The trial involved 153 patients with breast cancer or melanoma treated at 8 centers. In total, 99mTc-tilmanocept identified cancer in 373 lymph nodes, whereas VBD identified 227. The false-negative rate for VBD was 28% and for 99mTc-tilmanocept was 0% (P < .0001); sensitivity for VBD was 72% and for 99mTc-tilmanocept was 100% (P < .001).

The "Elephant in the Room"

After the poster presentation, Michael Sabel, MD, FACS, assistant professor of surgery at the University of Michigan in Ann Arbor, who acted as a discussant, described this trial as a "good first step." The product's unique point is that it binds to receptors on the surface of lymph node cells, which might give it an advantage, he said. The trial shows that it was equally effective when administered the day before surgery and when it was given on the day of surgery. This could be useful because "it is easier for both our patients and us if it can be given the day before," Dr. Sabel explained.

The trial also showed that 99mTc-tilmanocept is better than VBD, he said.

However, there is an "elephant in the room" here, Dr. Sabel pointed out. The 99mTc-tilmanocept was compared with VBD alone, but it is never used alone in clinical practice; it is always used in combination with colloidal sulfur, he said.

He noted that the real question is: How does 99mTc-tilmanocept with VBD compare with colloidal sulfur plus VBD?

According to Neoprobe, it designed and conducted the trials after consultation with the FDA. The comparator for the trial was chosen after long discussions with the agency, and VBD was used alone because it is the only FDA-approved agent.

Neoprobe was "in constant communication with the FDA," and reported that it is confident that the clinical trials that have been completed are suitable for the approval.

However, some analysts are not so certain. In fact, one of them, Martin Shkreli, chief investment officer at MSMB Capital Management, has gone so far as to file a Citizen Petition to the FDA. In it, he "respectfully requests that the FDA refrain from approving" the new product until there are data available from a trial that compares 99mTc-tilmanocept with a combination of VDB plus colloidal sulfur. At the end of the petition, he discloses that he is a hedge fund manager who will benefit financially from a decline in the stock price of Neoprobe.

On his Seeking Alpha blog, Mr. Shkreli says the company should "run a study reflecting the real world." He also says that VBD plus colloidal sulfur results in the identification of the sentinel lymph node about 95% of the time, and adds that "it is commonly believed that this identification rate cannot be improved upon. In addition, he provides a link to Dr. Sabel's slides.

Neoprobe has submitted a response to the Citizen Petition, pointing out key flaws in the arguments raised; it "respectfully requests that the FDA deny the Citizen Petition expeditiously."

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract LBA8526. Presented June 6, 2011.

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