Lapatinib Shows Value Similar to Trastuzumab in Neoadjuvant Regimens for Breast Cancer, but with Greater Toxicity


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Lapatinib (Tykerb) proved valuable as a component of neoadjuvant chemotherapy for HER2-positive operable breast cancer in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 trial presented at the 2012 ASCO Annual Meeting by Andre Robidoux, MD, of the NSABP and the University of Montreal Hospital Center in Canada.1

Similar Complete Response Rates

“Substitution of lapatinib for trastuzumab [Herceptin] in combination with the chemotherapy program employed in this study resulted in similar high percentages of pathologic complete responses in both hormone receptor–positive and hormone receptor–negative cohorts. Combined HER2-targeted therapy produced a numerically higher [pathologic complete response] percentage than single-agent HER2-directed therapy, but the difference was not statistically significant,” said Dr. Robidoux.

The phase III NSABP B-41 evaluated whether dual HER2 inhibition with trastuzumab plus lapatinib improves pathologic complete response rates over trastuzumab alone as neoadjuvant chemotherapy. The study also compared the relative efficacy of the two anti-HER2 agents in this setting.

The 529 patients received four cycles of standard neoadjuvant chemotherapy with doxorubicin plus cyclophosphamide (AC) followed by weekly paclitaxel (P). Concurrent with the weekly paclitaxel, patients were randomly assigned to receive trastuzumab, lapatinib (1,250 mg/d), or trastuzumab plus lapatinib (750 mg/d) prior to surgery. After lumpectomy or mastectomy, all women received trastuzumab for 1 year.

Dual Inhibition

The pathologic complete response rate was 52.5% with AC→P plus trastuzumab, 53.2% with AC→P plus lapatinib, and 62% with AC→P plus trastuzumab and lapatinib. “A higher percentage receiving the combination had a [pathologic complete response], but the difference was not statistically significant (P = .095),” he noted. The combination also produced a numerically higher clinical complete response rate (76.8% vs 52% with trastuzumab and 69.9% with lapatinib), but there was no difference in rates of breast-conserving surgery.

By hormone receptor status as well, the addition of lapatinib to trastuzumab yielded a numeric, though not a statistically significant, benefit over the single agents. In hormone receptor–negative patients, the pathologic complete response rate was 73.0% with the combination, 65.5% with AC→P plus trastuzumab, and 60.6% with AC→P plus lapatinib. In the hormone receptor–positive cohort, pathologic complete responses were observed in 55.6% receiving the combination, in 46.7% receiving AC→P plus trastuzumab, and in 48.0% receiving AC→P plus lapatinib.

“Despite the fact that 73% of the hormone receptor–negative population obtained a pathologic complete response, this was not significant,” said Dr. Robidoux.

When pathologic complete response was defined as no residual disease in both the breast and nodal tissue, those rates were 49.4% with trastuzumab, 47.4% with lapatinib, and 60.2% with the combination, which was marginally significant (P = .056), he added.

Unplanned Analysis

“Intriguing findings” were made in an unplanned analysis based on immunohistochemistry (IHC) staining intensity, he said. In patients who were fluorescence in situ hybridization (FISH)-positive but IHC-low (0, 1, or 2), the pathologic complete response rate was 41.7% with trastuzumab, 60.9% with lapatinib, and 25% with the dual inhibition; the differences were not statistically significant.

However, in the IHC3+ group, pathologic complete responses were observed in 54.7%, 53.2%, and 71%, respectively (P = .006 for the combination vs single agents). The test for interaction with IHC level was also statistically significant (P = .021), Dr. Robidoux reported. “This suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression,” he maintained.

“It might be of importance for ongoing and future trials using dual inhibition of HER2 to confirm what has been suggested in B-41—ie, that the dual inhibition seems to work better in patients with tumors overexpressing HER2,” he told The ASCO Post.

Toxicity Concerns

While lapatinib was beneficial as a neoadjuvant agent, toxicity was a drawback, he acknowledged. Fewer patients receiving lapatinib completed treatment, compared to those receiving trastuzumab alone (63% vs 68%; P = .01). And grade 3 and 4 adverse events were more common in the lapatinib-containing arms (60% and 62%) compared to trastuzumab (50%). Diarrhea accounted for most of the toxicity with lapatinib but was rare with trastuzumab (P < .001). Other toxicities were similar. ■

Disclosure: Dr. Robidoux has served as consultant or advisor to GlaxoSmithKline and has received honoraria and research funding from GlaxoSmithKline and Roche.

Reference

1. Robidoux A, Tang G, Rastogi P, et al: Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. 2012 ASCO Annual Meeting. Abstract LBA506. Presented June 3, 2012.


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