NOVEL HER2 DRUGS INCREASE TREATMENT COST 

American clinicians are excited about adding the newly approved ado-trastuzumab emtansine (Kadcyla, Roche/Genentech) to their treatment options for patients withHER2-positive metastatic breast cancer, according to comments from experts received by Medscape Medical News.

At the same time, there is concern and frustration that the drug, known as T-DM1, is very expensive.

"I am thrilled about the approval of T-DM1," said Ann Partridge, MD, from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, in an email. Dr. Partridge called the new drug a "very effective agent with relatively limited side effects," and said it "will to add to the armamentarium for women living with metastatic HER2-positive breast cancer."

The approval by the US Food and Drug Administration (FDA) was a "momentous" day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog last week.

"This is the classic light-beer scenario; it's less filling and tastes great," she summarized, referring to the combination of reasonable adverse effects and considerable efficacy.

"There will be great temptation to use T-DM1 earlier in the course of the disease," Dr. Miller said in an email. However, before this use can be recommended, results from clinical trials, which are underway, are needed, she added.

T-DM1 is expensive, leading to speculation that there will be a backlash against it, as there was with aflibercept (Zaltrap, Regeneron/Sanofi). In October, the Memorial Sloan-Kettering Cancer Center in New York City very publicly refused to use aflibercept because it was much more expensive than another approved drug for the treatment of colorectal cancer, which had similar efficacy.

"All of these drugs are very expensive, making it difficult for some patients to get them even when they are approved and available," said Dr. Partridge. She added that all 4 of the targeted therapies approved by the FDA for the treatment of HER2-positive metastatic breast cancer come with a high price tag.

The first of these HER2-targeted products, trastuzumab (Herceptin, Genentech), was launched in 1998, followed by lapatinib (Tykerb, GlaxoSmithKline), pertuzumab last year (Perjeta, Genentech), and T-DM1 last week.

In the 3 Genentech products, there has been a big jump in price over time. According to media reports, trastuzumab costs around $4500 per month, pertuzumab costs around $6000 per month, and T-DM1 costs around $9800 per month.

Steven Vogl, MD, a private practitioner in the Bronx, New York, is disturbed about the price of the new drug. "I will use T-DM1 [but] I am upset about the high price," he said in an email.

Dr. Vogl predicted the high price of T-DM1 in an essay published last year on ClinicalOncology.com.

The company will likely "charge a steep premium for T-DM1 compared with trastuzumab plus chemotherapy," he wrote. "Drug prices now seem to be set at the estimated maximum the market will bear."

Despite her concerns about price, Dr. Partridge tempered her comments about T-DM1 because of its efficacy. "The cost is high, but that doesn't feel as bad when the data are so clear that the drug helps these women," she said.

But, in the opinion of Dr. Vogl, the data are not as clear as they should be.

He has been critical of the pivotal clinical trial of T-DM1, known as EMILIA. The study's control regimen (lapatinib and capecitabine) was "distinctly suboptimal" and not a standard of care, even though it is an FDA-approved treatment option in this setting, he said. The 5.8 month difference in overall survival in the 2 study groups might have been inflated by this control regimen, he explained. Dr. Vogl would have preferred to see the control patients also receive trastuzumab, which he believes to be a necessary complement to lapatinib.

"T-DM1 does not meet [the] goals of a major advance," Dr. Vogl has written, explaining that such an advance, in his opinion, must cure some patients, increase the rate of clinical complete remission, or produce a high rate of very long partial response.

Off-Label Use Likely

The news about T-DM1 is not limited to enthusiasm about a new treatment option and criticism about the price. There is also the practical matter of when to use it in the clinic.

The FDA has indicated that T-DM1 is a second-line therapy, after patients progress on trastuzumab and a taxane chemotherapy.

However, as a recent study showed, in 2009, about one third of the total use of patented intravenous chemotherapies, which include targeted therapies such as trastuzumab, was "off-label."

Dr. Vogl plans on using off-label T-DM1, at times, before the current first-line option of trastuzumab plus chemotherapy. "I will use T-DM1 over [trastuzumab] plus docetaxel," he said. But he expressed uncertainty about where pertuzumab fits into decision making. It is indicated for use in combination with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer who have not received previous therapy for metastatic disease.

"Pertuzumab makes everything complicated. We need data on the safety and efficacy of pertuzumab plus T-DM1," he said. Furthermore, there is the ever-present question of what insurers will cover regarding pertuzumab. "I do not know what payers are doing with pertuzumab. I fear they are restricting it to first line; this saves them money, which is usually their greatest interest," he said.

As noted above, Dr. Miller hinted that there might be a role for T-DM1 in earlier disease. The source of the "great temptation" of off-label use comes from an early-phase clinical trial. "There is a tantalizing randomized phase 2 trial suggesting that T-DM1 has greater efficacy and less toxicity than docetaxel plus trastuzumab as first-line therapy," she said.

However, Dr. Miller ultimately toed the regulatory line. "We need definitive phase 3 data from the MARIANNE trial before standard first-line use can be recommended," she said. That trial compares 3 regimens in patients with HER2-positive progressive breast cancer, recurrent locally advanced breast cancer, or previously untreated metastatic breast cancer: T-DM1 plus pertuzumab, T-DM1 plus pertuzumab-placebo (blinded for pertuzumab), and trastuzumab plus a taxane (docetaxel or paclitaxel).

"My colleagues and I will definitely be using T-DM1," said Dr. Partridge, "likely after first-line treatment with another regimen such as [paclitaxel], [trastuzumab], and pertuzumab."

Dr. Partridge and Dr. Vogl have disclosed no relevant financial relationships. Dr. Miller reports financial ties with Genentech, Bristol-Myers Squibb, AstraZeneca, Roche, and Clovis Oncology.