"Impressive,” “outstanding,” and “unprecedented” are among the terms used to describe the 56.5-month overall survival for women with HER2-positive metastatic breast cancer receiving first-line treatment with pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and docetaxel in the CLEOPATRA trial.¹ Pertuzumab was approved for this use by the U.S. Food and Drug Administration (FDA) 2 years ago, and an ASCO clinical practice guideline issued earlier this year recommends (with some exceptions) trastuzumab, pertuzumab, and a taxane for first-line treatment of patients with HER2-positive advanced breast cancer.²

Will these latest trial results, the overwhelming positive comments, and reports by major media, including The New York Times, The Wall Street Journal, and Reuters, as well as the medical press, be decisive factors in universal use of this regimen, which already has been called the standard of care?

“In spite of the fact that pertuzumab was already approved and is in the ASCO guidelines, I think just seeing the survival data being so strong excites physicians more about using it in the first line, and it is going to be standard every time,” the study’s lead author Sandra M. Swain, MD, FACP, said in an interview with The ASCO Post. A past President of ASCO, Dr. Swain is Medical Director of the Washington Cancer Institute at the MedStar Washington Hospital Center and Professor of Medicine at Georgetown University in Washington, DC.

“A lot of physicians just weren’t aware of the data and how exciting it is—that there was a survival benefit—because the last time that I presented it, there was no median reached for survival. Now there is, and knowing it is so long, and it is getting so much press, if physicians don’t yet know about it, patients certainly will bring it to their attention. If their tumors have HER2-positive overexpression, patients will wonder whether they are eligible to get this,” Dr. Swain noted.

Unexpectedly Large Survival Benefit

Dr. Swain presented the latest results from the CLEOPATRA study final overall survival analysis at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid. The median overall survival for patients receiving pertuzumab with trastuzumab and docetaxel was 15.7 months longer than for patients who received placebo instead of pertuzumab.

At the ESMO Congress, Dr. Swain declared that the overall survival result is “unprecedented in first-line treatment, and this substantial improvement confirms the pertuzumab-containing regimen as standard of care in this setting.” In the subsequent interview with The ASCO Post, Dr. Swain acknowledged that based on interim analyses, “there was expected to be a survival benefit, but we never imagined that it would be almost 16 months.”

Results Kept Getting Better

The FDA based its approval of pertuzumab in June 2012 on earlier results of the CLEOPATRA trial. The study involved 808 patients from 25 countries, including 135 from North America, randomly assigned to receive trastuzumab and docetaxel with either pertuzumab or placebo. (Details of the study are reported in the November 1 issue of The ASCO Post.)

A primary analysis in May 2011 showed a statistically significant 6.1-month improvement in median progression-free survival and a strong trend toward better overall survival for patients receiving pertuzumab. A second interim analysis in May 2012 showed that improvement in overall survival was statistically significant and clinically meaningful, but median overall survival had not yet been reached. Now it has and has exceeded expectations.

Patients receiving pertuzumab continue to have improved progression-free survival, although it is now assessed by investigator rather than independent review, which served as the basis for the FDA approval. “When I last updated progression-free survival, it was very similar, and now it is a 6.3-month median improvement,” Dr. Swain said.

Use Lagged Behind Approval

The FDA approval and the ASCO clinical practice guideline recommendation, published in the Journal of Clinical Oncology² this past summer, did not lead to universal use of pertuzumab along with trastuzumab and a taxane for women with advanced HER2-positive breast cancer. An article in The New York Times reporting the latest CLEOPATRA results noted that a spokesman for Roche said that only about half of the eligible women in the United States are being treated with pertuzumab. Moreover, according to the Times article, “doctors say use is lower in many countries where cost is more of an issue.”³

Media coverage of the results presented at the ESMO meeting “has brought a lot more interest in using pertuzumab, certainly in the first line for HER2-positive breast cancer,” Dr. Swain stated. This was especially true in Europe, where approvals and reimbursement may differ, she noted. “That was one great advantage to presenting it at ESMO.”

No New Safety Concerns

Longer follow-up raised no new safety concerns about using the combination of pertuzumab, trastuzumab, and docetaxel. “The side effects are what we have seen before—an increase in diarrhea and mouth sores and also some fever and infection,” Dr. Swain said. “Those things usually occur when the patient is getting chemotherapy with monoclonal antibodies. The way that physicians have worked with that is they change the chemotherapy, for example, using paclitaxel. That is one thing people have been doing if they have a lot toxicity with docetaxel,” she noted.

“The cardiac toxicity was not increased, but if a patient does have cardiac issues and a lower ejection fraction or some evidence of heart failure, then that patient should be seen by a cardiologist. Those would be the patients you would be concerned about giving these drugs, especially if they have had [doxorubicin] in the past,” Dr. Swain observed.

Unanswered Questions

Despite the clear evidence of survival benefits and overall safety with pertuzumab/trastuzumab, “there are unanswered questions” about the use of the combination in women with metastatic HER2-positive breast cancer, Dr. Swain said. “One question is, when patients using pertuzumab/trastuzumab have progression, should they continue those two drugs and then add a different chemotherapy? That’s being tested. We do that now with trastuzumab, but should we do that with pertuzumab, too? We don’t know the answer. Right now, you’d stop it and wouldn’t use it after progression,” she said.

“Another question is,” Dr. Swain continued, “if a patient has an estrogen receptor–positive tumor, and it’s very small, with maybe just a little bone disease, or some soft-tissue disease, can you use pertuzumab/trastuzumab with just hormonal therapy and not have to use chemotherapy? That question is also being looked at.” ■

Disclosure: Dr. Swain has received research funding (via her institution), travel expenses, and honoraria from Genentech/Roche, and is a Genentech/Roche steering committee member (uncompensated).

References

1. Swain S, Kim S, Cortes J, et al: Final overall survival analysis from the CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. ESMO 2014 Congress. Abstract 350O. Presented September 28, 2014.

2. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:2078-2099, 2014.

3. Pollack A: Roche breast cancer drug Perjeta appears to greatly extend patients’ lives. NY Times. September 28, 2014.