Efforts to build on the effectiveness of trastuzumab with a dual blockade of the HER2 pathway continue to suggest such a strategy has the potential to enhance outcomes for HER2-positive breast cancer patients.
Genentech announced this summer that the combination of trastuzumab (Herceptin) and docetaxel (Taxotere) with the investigational agent pertuzumab (Omnitarg) met the primary end point of improved progression-free survival in the randomized, double-blind, placebo-controlled phase III CLEOPATRA trial.
A monoclonal antibody, pertuzumab prevents the HER2 receptor from pairing with other HER receptors, including HER1/EGFR, HER3, and HER4, according to Genentech. The Roche-owned company released no data, but said it expects to submit the trial results for "global regulatory approval" this year. A spokesperson said the results will be submitted at "an upcoming medical meeting,"
Trastuzumab emtansine (formerly known as trastuzumab-DM1) is also in ongoing trials, assessing it in various combinations involving trastuzumab, pertuzumab, and lapatinib (Tykerb), the last of which is a dual inhibitor of HER2 and the epidermal growth factor receptor (EGFR). Genentech is developing this experimental antibody-drug conjugate, with Immunogen. It sought accelerated approval based on a positive phase II study last summer but was rebuffed by the Food and Drug Administration on grounds that patients in the trial had not exhausted other therapies.
Since then, the combination of trastuzumab and lapatinib – both approved for HER2-positive breast cancer – was shown to boost complete response rates to 74% when combined with preoperative chemotherapy in a phase II trial reported in June at the annual meeting of the American Society of Clinical Oncology (ASCO).
The study was one of a trio of neoadjuvant trials that evaluated whether complete responses rates could be bettered by adding lapatinib to chemotherapy plus trastuzumab or by combining lapatinib and trastuzumab without chemotherapy, but with the option of endocrine therapy.
Trastuzumab, Lapatinib, and Chemotherapy
Investigators in the phase II CHER-LOB study defined pathological complete response (pCR) as the complete disappearance of invasive residual disease in the breast and axillary nodes. Among 115 evaluable women, the pCR rate increased from 25.7% with chemotherapy plus trastuzumab (arm A) and 27.8% with chemotherapy plus lapatinib (arm B) to 43.1% with the addition of lapatinib to chemotherapy plus trastuzumab (arm C).
The cardiac safety data were reassuring, with no reports of heart failure or significant loss of left ventricular function. Diarrhea, however, was a significant toxicity that caused dose reductions and treatment interruptions in the majority of patients receiving chemotherapy plus lapatinib, acknowledged Dr. Valentina Guarneri of the Modena (Italy) University Hospital. Grade 3 or higher diarrhea was reported in 36% of 39 patients in arm B and 33% of 46 patients in arm C. Permanent lapatinib discontinuation occurred in 25.6% and 13%, respectively.
Because of the high incidence of diarrhea, the protocol was amended to reduce continuous daily dosing of lapatinib from 1,500 mg to 1,250 mg in arm B and from 1,000 mg to 750 mg in arm C. After the amendment, dose reductions fell from 80% to 54% in arm B and from 55% to 34% in arm C, she said.
Chemotherapy consisted of weekly paclitaxel 80 mg/m2 for 12 weeks followed by four cycles of fluorouracil 600 mg/m2 plus epirubicin 75 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks (FE75C). Trastuzumab 4 mg/m2 was given as a loading dose, followed by 2 mg/m2 every week.
A Similar Protocol but With Modifications
The second trial extended the 24-week preoperative FE75C chemotherapy sequence to 26 weeks after a 2-week run-in period of anti-HER2 therapy and used weekly paclitaxel after, rather than before, FE75C. Also, the daily lapatinib dose was set at 1,250 mg in arm B and increased from 750 mg-1,000 mg in arm C. Trastuzumab dosing was the same as above.
Using this protocol, pCR rates among 78 evaluable women reached 54% with chemotherapy plus trastuzumab (arm A), 45% with chemotherapy plus lapatinib (arm B), and 74% with double HER2 blockade plus chemotherapy (arm C), reported Dr. Frankie Ann Holmes with Texas Oncology in Houston.
Patients had stage II-III biopsy proven invasive HER2-positive breast cancer, whereas CHER-LOB limited enrollment to stage II-IIIA disease.
Headed in the Right Direction
Invited discussant Dr. Gunther von Minckwitz, with the German Breast Group, said that despite the small patient numbers, the pCR rates were quite impressive, especially for the study presented by Dr. Holmes, and are in range with previous trials using longer chemotherapy regimens.
Dr. Gunter von Minckwitz
The difference in pCR rates between the two studies could be explained by the small sample sizes and differences in patient characteristics. "Still the tendency is going in the same direction," he observed.