Combination Tx for HER2+ Breast Cancer Excites SABCS

High Cost A Downer

Nick Mulcahy

December 11, 2010

December 11, 2010 (San Antonio, Texas) — Combination targeted therapy appears to be more effective than using a single agent in the treatment of stages 1 to 3 HER2-positive breast cancer, according to 3 new clinical trials presented here at the 33rd Annual San Antonio Breast Cancer Symposium.

After meeting participants saw these promising data, however, one prominent expert questioned the affordability of the strategy, given the high cost of these drugs.

The clearest proof of the combination concept at the meeting was a neoadjuvant trial comparing the targeted agents trastuzumab (Herceptin; Genentech/Roche) and lapatinib (Tykerb; GlaxoSmithKline), given both alone and together before breast cancer surgery in women with primary HER2-positive breast cancer.

Dr. Jose Baselga

The combination of trastuzumab and lapatinib completely wiped out tumor cells in the breast, and thus achieved a pathological complete response (pCR) in 51.3% of women — about twice the response seen with either drug alone. The difference was statistically significant (P =.001).

These results from the Neo-ALLTO trial were presented by Jose Baselga, MD, who was at the Vall d'Hebron University Hospital in Barcelona, Spain, at the time of the trial start and is now at the Massachusetts General Hospital Cancer Center, in Boston. "Dual antiHER2 blockade is a valid concept," summarized Dr. Baselga.

"The combination is a lot better than either single agent," said Edith Perez, MD, from the Mayo Clinic, about Neo-ALLTO results.

An expert in targeted therapies, Dr. Perez was asked by Medscape Medical News to comment on the new trials. "We are not curing everybody with HER2-positive disease," said Dr. Perez about the need to improve on treatment with trastuzumab.

Dr. Luca Gianni

In the second of the presentations at the meeting session on targeted therapies, use of a trastuzumab and pertuzumab (Genentech/Roche) doublet showed, "most importantly," that "a proportion of HER2-positive tumors can be eradicated without the need for chemotherapy," said lead author Luca Gianni, MD, from the Istituto Nationale Tumori, in Milan, Italy. "Our study is the only study that indicates there is a subset of women who can do without chemotherapy," said Dr. Gianni at a meeting press conference.

However, Dr. Gianni's 4-group, phase 2, neoadjuvant trial, known as NeoSphere, also showed that the combination of trastuzumab, pertuzumab, and docetaxel was most effective, producing a pCR rate of 45.8% — the clear winner over the other 3 treatment groups, including the trastuzumab and pertuzumab doublet, which had a pCR rate of 17%.

In the third trial, the combination of neoadjuvant trastuzumab and chemotherapy achieved pCR in 31.3% of women with primary breast cancer compared with 21.7% in women treated with lapatinib and chemotherapy; the difference was statistically significant (P < .05). The definition of pCR used in the German study, known as GeparQuinto, was the "most stringent" used in medicine, pointed out lead author Michael Untch, MD, from Helios Klinikum Berlin-Buch in Germany. Trastuzumab and lapatinib were only used in combination with chemotherapy in this trial, and not alone or in combination with each other.

Dr. Michael Untch

The exact efficacy of lapatinib in GeparQuinto was clouded by the fact that about a third of the patients receiving lapatinib discontinued treatment because of adverse effects, including, most prominently, diarrhea. "We have to be prepared to teach patients how to deal with this side effect," said Dr. Untch.

Pathological Complete Response and Its Critics

Targeted therapy combinations for the treatment of early breast cancer are investigational at this point.

However, the pCR results in the trials were seen by a number of experts to be signs of likely eventual regulatory approval. The pCR measure, which was evaluated at the time of surgery, is a good surrogate for longer-term efficacy, said Dr. Untch, citing the other research. "All those patients [in the study] who had a pCR were, after 5 years, still alive," he said about another German study.

However, Eric Winer, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, said that pCR was "not ready for prime time" as a measure to be used for drug approval or practice change, as it is not always correlated with improved disease-free and overall survival. "We need further data," said Dr. Winer about the various targeted therapy combinations. He made his comments while acting as discussant of the 3 trials presented at the meeting.

Another expert agreed with Dr. Winer about the value of pCR and the targeted therapy studies presented at the meeting. "This data is promising, but it cannot be used to change clinical practice, because complete pathological response is not a perfect surrogate for long-term survival," said Leif Ellisen, MD, PhD, from the Gillette Center for Breast Cancer at Harvard Medical School, in Boston, Massachusetts.

"It's predicted survival in some trials of breast cancer, but not in all," he told Medscape Medical News. "And the [US Food and Drug Administration] has said that it will not allow pCR to be used as an endpoint."

However, these comments were in stark contrast to those of another presenter at the meeting: Michael Spector, MD, from the Duke Comprehensive Cancer Center in Durham, North Carolina. "I envision the next trial to be lapatinib plus trastuzumab plus pertuzumab," he said at a meeting press conference. "I've always believed total HER2 blockade is optimal," said Dr. Spector, who developed lapatinib while working at GlaxoSmithKline.

"People are starting to talk about curing the disease," said Dr. Spector, referring to nonmetastatic HER2-positive breast cancer.

Money, Money, Money

What are the possibilities for anti-HER2 agents in improving the most important measure in medicine, overall survival?

"With new therapies, we could easily go over curing 90% of patients at 5 years," said Dr. Baselga, noting that trastuzumab's 5-year survival rate is about 87% in an early trial.

Dr. Baselga also noted that before targeted therapy for HER2-positive disease, the 5-year survival rate was 40% to 50%.

"Remarkable," summarized Dr. Spector about the actual and possible improvements in survival.

After speaking so enthusiastically for targeted therapy, however, Dr. Spector then doused the high spirits with a strong dose of economic reality: What good are the therapies if they are not accessible to all HER2-positive women? he asked.

He also presented a slide to the symposium audience that listed the 3 targeted therapies — lapatinib, trastuzumab, and pertuzumab — and their possible combinations. The slide also listed corresponding dollar signs to signify approximate costs. The slide read:

T + L $$
T + P $$$
T + P + L [Image of a piggy bank being smashed; accompanied by the verbal comment from Dr. Spector, "We are going to bust the economy!"]

Dr. Untch offered a strategy that, although unproven, could lower future targeted therapy costs. "We can probably lower the cost if, after 12 weeks of very effective treatment, we achieve 50% or more eradication of tumor cells. Do we really need to treat for 12 more months?" he asked, referring to trastuzumab treatment schedules.

Dr. Baselga, Dr. Untch, and Dr. Spector have disclosed no relevant financial relationships. Dr. Gianni is on the advisory board of Roche, Genentech, Boehringer Ingelheim, and Pfizer.

33rd Annual San Antonio Breast Cancer Symposium: Abstracts S3-1, S3-2, S3-3, and S3-4. Presented December 10, 2010.

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