Lapatinib Shows Promise in Early Trials


SAN ANTONIO — The investigational drug lapatinib shows promise for the treatment of inflammatory breast cancer, the most aggressive form of primary breast cancer, Dr. Massimo Cristofanilli said at the annual breast cancer symposium sponsored by the Cancer Therapy and Research Center.

Inflammatory breast cancer (IBC) accounts for just 1%–2% of all primary breast cancers. But it hasn't received the research attention it deserves, given that it is notoriously difficult to treat and has a 5-year overall survival of only 40%, said Dr. Cristofanilli, codirector of the IBC clinic at M.D. Anderson Cancer Center, Houston.

The clinic, which opened last October, is the world's first center dedicated to IBC research and treatment.

A retrospective analysis of nearly 400 patients with IBC who were treated using a multidisciplinary approach at M.D. Anderson during 1974–2005 underscores the long-standing lack of therapeutic progress, with no significant improvement seen in prognosis over the last 30 years.

Women with IBC haven't benefited from the advances in locoregional and systemic therapies that have led to enormous improvements in outcome for noninflammatory breast cancer, he said.

Up to 30% of women with IBC already have metastatic disease at the time of diagnosis of their primary breast cancer. Although IBC is a very rapidly growing form of breast cancer, that's only part of the reason for the high rate of metastases at initial diagnosis.

The fact is IBC is often diagnosed relatively late. Patients with IBC initially present with redness, swelling, tenderness, and pain that rapidly extends to the entire breast.

The breast skin has ridges and pits, like that of an orange, and the nipple is often inverted. Affected patients are often initially misdiagnosed as having mastitis and given antibiotics, the physician said.

Lapatinib (Tykerb) is an oral small-molecule tyrosine kinase inhibitor with activity against both the epidermal growth factor receptor (EGFR) and the HER2 receptor. Like trastuzumab (Herceptin), lapatinib appears to be effective in the treatment of HER2-positive breast cancers.

In addition, lapatinib has shown activity in patients with trastuzumab-resistant metastatic HER2-positive breast cancer. HER-2 overexpression has been reported in 30%–60% of cases of IBC.

Dr. Cristofanilli presented a phase II study involving neoadjuvant chemotherapy with lapatinib combined with paclitaxel in 35 patients newly diagnosed with IBC, including 9 who already had metastatic disease. A total of 30 patients had HER2-overexpressing tumors and the other 5 had HER2-negative disease that overexpressed EGFR.

Patients received 1,500 mg/day of lapatinib alone for 2 weeks, followed by 3 months of daily lapatinib plus once-weekly paclitaxel, then surgery.

The results exceeded anything previously seen in the treatment of IBC.

Among a total of 30 women with HER2-positive tumors, 23 patients showed a complete or partial clinical response, as did 4 of 5 women with EGFR-positive disease.

Among the patients who have undergone definitive surgery, 3 of 18 women with HER2-positive and none of 3 patients with EGFR-overexpressing IBC had a pathologic complete response, defined as no residual invasive tumor in the breast or axillary lymph nodes.

Particularly encouraging was the finding that three patients—all in the HER2-positive cohort—had a complete clinical response during the first 2 weeks of lapatinib monotherapy, the physician continued.

Grade 3 or 4 toxicities with lapatinib plus paclitaxel included diarrhea in 21 patients, fatigue in 7 and asthenia in another 7 patients, and skin rash in 3 patients.

Further studies are planned using lapatinib in combination with a variety of chemotherapy regimens in patients with HER2-positive rather than EGFR-positive IBC, according to Dr. Cristofanilli.

The phase II trial was sponsored by GlaxoSmithKline.

Three patients in the HER2-positive cohort had a complete clinical response while on lapatinib therapy. DR. CRISTOFANILLI

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