KEEP TRASTUZUMAB AND ADD LAPATINIB

December 14, 2009 (San Antonio, Texas) — For the first time, an improvement in overall survival has been seen in women with metastatic breast cancer who responded to but then progressed on trastuzumab (Herceptin, Genentech/Roche). Continuing with trastuzumab and adding on lapatinib (Tykerb, GlaxoSmithKline) produced a significant survival advantage of 4.5 months, compared with treatment with lapatinib alone, and resulted in a median overall survival of 14 months, which is "astonishing," according to one breast cancer expert.

These results come from the EGF104900 phase 3 clinical trial of dual HER2 blockade, and were presented here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS) by Kimberly Blackwell, MD, from Duke University Medical Centre in Durham, North Carolina.

"This is a very impressive improvement in overall survival," Dr. Blackwell said. It compares with what has been seen in first-line therapy in metastatic breast cancer when trastuzumab is added to chemotherapy, but the patients in this trial were heavily pretreated, so this is second-, third-, even fourth-line use, and this result was achieved without using chemotherapy, she pointed out.

Trastuzumab and lapatinib might be "acting together to form a sort of 'dual blockade' to obstruct the HER2 pathways necessary for the tumor to thrive," Dr. Blackwell suggested. Both agents are specific for HER2, but lapatinib works inside the cell and trastuzumab works on the outside of the cell, and this combination might "provide a more complete antitumor attack," she said in a statement.

"This is a refreshing study for all of us," Dr. Blackwell told Medscape Oncology. "The last time there was such an impact [was] the original trastuzumab study."

The improvement in overall survival in this patient population "is astonishing," said Claudine Isaacs, MD, director of the Clinical Breast Cancer Program at the Lombardi Comprehensive Cancer Center in Washington, DC, in an interview with Medscape Oncology.

Edith Perez, MD, director of the Breast Cancer Program at the Mayo Clinic in Jacksonville, Florida, who moderated the press briefing at which these results were discussed, said the breast cancer community has been "eagerly awaiting these results."

In an interview with Medscape Oncology, Dr. Perez said she agrees that this is an "impressive" improvement in overall survival, and pointed out that this is the first time a survival advantage has been demonstrated in metastatic breast cancer that has progressed after trastuzumab. The trial that resulted in the approval of lapatinib for this indication, in combination with capcitebine, showed an effect on progression-free survival but not on overall survival, she pointed out.

Dr. Perez said that she would now recommend use of the combination of lapatinib and continuing with trastuzumab in women who have already progressed on trastuzumab, noting that this combination was less toxic than lapatinib and capcitebine.

Dr. Blackwell also said that, in her clinical practice, she would now consider using this combination in women who had "previously done well on HER2-based therapy."

Benefit From Continuation of Trastuzumab?

There was some discussion over how much of the benefit seen in this trial came from continuing trastuzumab after progression, and how much from the addition of lapatinib.

Dr. Perez told reporters that this study validates the idea of continuing on trastuzumab therapy, even after progression on the drug. "This is important, because there are many physicians who stop trastuzumab once the patient progresses," she said.

Eric Winer, MD, chief of the Division of Women's Cancers at the Dana-Farber Cancer Institute in Boston, Massachusetts, who was approached for comment, said he was surprised by the overall survival result. He agreed that this is the first improvement in survival that has been seen in this patient population, but pointed out that "it hasn't been looked for that often."

His take was that this study shows that continuing trastuzumab after a patient has progressed is beneficial; this has also been shown in several other studies. "This is another study that shows that trastuzumab is a remarkable drug, and is a better drug than we ever thought when it was first approved," he said. The product has changed the natural history of the disease, he added.

However, Dr. Winer added, there does appear to be an interaction between trastuzumab and lapatinib, and said the combination should be studied further.

This combination is being studied further. The ALLTO trial is looking at lapatinib and trastuzumab in combination and in sequential use, and comparing both with chemotherapy, but is in a different patient population — women with early breast cancer. Another trial, the Neo-ALLTO study, will look at the same treatments but they will be administered prior to surgery, Dr. Blackwell told Medscape Oncology.

Unethical Not to Offer Lapatinib

The point about trastuzumab continuation was also raised after Dr. Blackwell's presentation. During the question period that followed, Kathy Pritchard, MD, from the Toronto-Sunnybrook Regional Cancer Center, in Ontario, said: "What you have shown is that continuing trastuzumab in this setting is useful." She suggested that the trial should have had a group in which the treatment was continuation of trastuzumab without the addition of lapatinib.

Dr. Blackwell countered that when the trial was being designed, such a treatment group had been considered but was discounted because it was thought to be unethical to offer women who had already progressed on trastuzumab only continuation of treatment with trastuzumab when there was another HER2-specific drug that was available. Hence, the trial offered these women treatment with lapatinib or lapatinib plus a continuation of trastuzumab, she explained.

The trial involved 296 women with HER2-positive metastatic breast cancer who had progressed on trastuzumab-containing regimens (the median number of previous regimens was 3). All women were treated with lapatinib, either alone (at a dose of 1500 mg once daily) or together with trastuzumab (in this group the dose of lapatinib was 1000 mg once daily, and trastuzumab was given at 2 mg/kg after a loading dose of 4 mg/kg).

Women in the lapatinib group who progressed were allowed to cross over to the combination group, and about half did so (77 of 148 patients; 52%).

The results that Dr. Blackwell presented come from an updated survival analysis conducted after 218 deaths (77%) had occurred.

They show a significant survival advantage for the combination group, in which the median overall survival was 14 months, compared with 9.5 months in the lapatinib group (hazard ratio [HR], 0.74; 95% confidence interval 0.57 - 0.97; P = .026).

This represents a 26% reduction in the risk of dying, Dr. Kimberley said. "After 1 year, there were 15 more women out of 100 who were still alive in the combination arm, compared with the lapatinib alone arm," she said.

"The actual survival benefit of the combination may be underestimated because of the high frequency of the crossover," Dr. Blackwell explained. If you take away the patients who crossed over, the reduction in the risk of dying on the combination rises to 36% (HR, 0.64), she told Medscape Oncology.

The combination had an acceptable tolerability profile and there was no increase in the cardiac signal. "As a practicing clinician, I found it remarkable that there was no safety issue," Dr. Blackwell said.

Dr. Blackwell reports receiving honoraria from GlaxoSmithKline and Genentech to conduct the study. Dr. Perez receives no direct funding from pharmaceutical companies, but has served on independent monitoring committees for Genentech and Novartis.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 61. Presented December 12, 2009.