SABCS--in neoadjuvant setting herceptin more effective vs her2 than lapatinib

[Lani]

SABCS: HER2-Targeted Drugs Not Equal in Breast CA

SAN ANTONIO -- For presurgical treatment of HER2-positive early breast cancer, lapatinib (Tykerb) doesn't measure up to standard trastuzumab (Herceptin), according to head-to-head trial results.
The addition of lapatinib to neoadjuvant anthracycline-based chemotherapy cured 29.9% of tumors, compared with the 45.0% pathologic complete response rate with trastuzumab added to the same cytotoxic regimen, Michael Untch, MD, of the Helios Clinic in Berlin, and colleagues found.

One reason may have been the greater toxicity of lapatinib in the study, predominantly diarrhea, that led to discontinuation of treatment in 23% of patients compared with 13% in the trastuzumab arm, they reported here at the San Antonio Breast Cancer Symposium.

Trastuzumab with chemotherapy has been the standard for neoadjuvant therapy, typically limited in use outside the clinical trial setting to shrink large or locally advanced tumors and avoid mastectomy, noted Leif Ellisen, MD, PhD, of Massachusetts General Hospital in Boston, who was not involved in the study.

And based on these results, that standard isn't going to change for either the neoadjuvant or adjuvant setting.
Neoadjuvant results are often seen as a quick barometer of how well a drug or combination is likely to do in the adjuvant setting, with pathological complete response used as a surrogate for disease-free survival.

But questions have arisen about how good a surrogate it is.

"The results suggested lapatinib alone was not quite as good as trastuzumab," Ellisen said in an interview. "The big question we have is whether that will mean ultimately lapatinib is inferior."

He pointed out that the results of Neo-ALTTO -- another neoadjuvant trial reported at the same session comparing the addition of lapatinib, trastuzumab, or the combination to chemotherapy -- suggested no significant difference between the biologic drugs overall and an advantage for lapatinib at six weeks before chemotherapy initiation.

But Untch cautioned that there were differences between the trials, in that Neo-ALTTO used a higher dose of lapatinib (1,500 mg per day) but a shorter duration of treatment.

Untch's group conducted the HER2-positive portion of the GeparQuinto trial in 620 treatment-naïve patients with early or locally advanced primary breast cancer.

The women were randomized to treatment with trastuzumab (6 mg/kg every three weeks) or lapatinib (1,000 to 1,250 mg per day) concurrent with four, three-week cycles of cyclophosphamide (Cytoxan, 600 mg/m2) and epirubicin (Ellence, 90 mg/m2) followed by another four cycles of docetaxel (Taxotere, 100 mg/m2).

The run-in phase in the first 60 patients indicated some problems:

Severe neutropenia in 82% led the researchers to make growth factor support mandatory with docetaxel
Treatment discontinuation in 34.5% required a reduction in the lapatinib dose from 1,250 to 1,000 mg per day
Severe diarrhea in 6.9% led the researchers to start giving patients the anti-diarrheal medication loperamide as a stand-by medication
Untch called this a learning process, but noted that the lapatinib's greater diarrhea-related adverse effects and dose reductions may have hampered its apparent efficacy.

Trastuzumab held the advantage using a strict definition of pathologic complete response that allowed neither invasive nor non-invasive residual tumor in breast or lymph nodes (31.3% versus 21.7%, P<0.05).

To match other published studies, the researchers also used two other definitions of pathologic complete response, including the definition from the National Surgical Adjuvant Breast and Bowel Project. Both significantly favored trastuzumab.

Discontinuation of both chemotherapy and anti-HER2 medication occurred in 16.0% of the lapatinib group and 10.0% of the trastuzumab group. Another 7.0% and 3.1% stopped their trastuzumab or lapatinib, respectively, without an interruption in chemotherapy.

Breast-conserving surgery, potentially reflecting tumor shrinkage, was somewhat more common in women given trastuzumab in the trial, at 65.6% compared with 56.0% in those on lapatinib.

The trial also included adjuvant trastuzumab for both groups of women, who the researchers plan to follow up to determine the effect of early differences in anti-HER2 therapy on longer-term outcomes, such as progression-free survival.

Combinations of anti-HER2 garnered more attention at the conference, with leading oncologists suggesting dual or triple blockade as more likely to be the future of neoadjuvant treatment.

However, Untch noted that the 45% cure rate with trastuzumab plus chemotherapy was nothing to sniff at for HER2-positive disease.

"Please do not forget this is a patient population which 10 years ago had the worst prognosis," he told reporters at a press conference.

The study was supported by GlaxoSmithKline, Roche, and Sanofi-Aventis.


Primary source: San Antonio Breast Cancer Symposium
Source reference:
Untch M, et al "Lapatinib vs trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy: primary efficacy endpoint analysis of the GEPARQUINTO STUDY (GBG 44)" SABCS 2010; Abstract 240