Novel Agents May Overcome Resistance to Trastuzumab

ABSTRACT: Inhibitors of mTOR may restore sensitivity to trastuzumab and to aromatase inhibitors in breast cancer patients. Other novel agents are also showing promise in trastuzumab-resistant patients.

CHICAGO-For breast cancer patients whose tumors have become resistant to available agents, restoring the sensitivity to treatment is an important goal. Preclinical studies have suggested that drugs that inhibit the mTOR protein kinase-which acts as a central regulator of tumor cell division, cell metabolism, and blood vessel growth-may be able to do so.

At ASCO 2008, investigators described the activity of the investigational mTOR inhibitor RAD001 (everolimus) in treatment-refractory breast cancer patients and other novel agents that are demonstrating interesting activity in early trials.

Impressive Results with RAD001

RAD001 (everolimus), a once-daily oral therapy that continuously inhibits mTOR, exerts direct antitumor activity and can also influence the estrogen receptor and the HER2/neu pathways, which are both important in breast cancer. According to early clinical trials presented at ASCO, RAD001 appears able to overcome resistance to trastuzumab and to enhance the efficacy of endocrine therapy.

“The results of these trials underscore the promise of mTOR inhibitors across various subsets of breast cancers, as well as in other tumors [see ONI June 2008, p. 30, and this issue p. 34],” said Professor Peter Harper, consultant medical oncologist, Guy’s and St. Thomas’ Hospital, London.

In a phase I multicenter study, French investigators evaluated RAD001 given daily or weekly in combination with paclitaxel and trastuzumab (Herceptin) in heavily pretreated HER2-overexpressing metastatic breast cancer patients who were resistant to trastuzumab (abstract 1003).

Among 13 evaluable patients, partial responses were observed in 6 patients and stable disease in 6, for a disease control rate (responses plus stable disease greater than 16 weeks) of 83%, reported Fabrice Andre, MD, PhD, of the Institut Gustave Roussy, Villejuif, France.

One patient showed substantial reduction in lung metastasis and another had complete disappearance of brain metastasis.

“Only one patient in the study had progressive disease. These preliminary results are very exciting, given that the women were heavily pretreated, and had documented resistance to trastuzumab. Most were also taxane resistant,” Dr. Andre said.

Douglass Yee, MD, professor of medicine and pharmacology and chairman of Breast Cancer Research at the University of Minnesota, commented on the “substantial response” and called this a “very successful” phase I trial. “Trastuzumab may be sensitizing patients to mTOR inhibition. We should test this in trastuzumab-nave patients,” he suggested.

In another phase I European study, 22 heavily pretreated trastuzumab-resistant patients received RAD001 with vinorelbine (Navelbine) and trastuzumab (abstract 1057). Among 11 patients receiving daily treatment, there was 1 complete response, 1 partial response, and 6 patients with stable disease up to 39 weeks. In the 11 patients treated weekly, 1 patient responded and 7 remained stable.

mTOR Inhibitor Plus Letrozole

There is also evidence that mTOR inhibition might make endocrine therapy more effective, according to an international phase II study led by Jose Baselga, MD, of Hospital Vall D’Hebron, Barcelona, Spain (abstract 530).

RAD001 enhanced tumor shrinkage when given in combination with letrozole (Femara) vs placebo, to 270 postmenopausal women with newly diagnosed ER-positive disease. By ultrasound evaluation, the response rate to the combination was 68% vs 47% for letrozole alone (P = .035). In addition, the cell cycle response to the combination, as measured by reduction in the proliferation index Ki67, was twice the level seen with single-agent letrozole.

There Novel Approaches

International investigators reported other promising approaches to overcoming trastuzumab resistance. The most impressive results came from a multicenter phase I study of the first-in-class HER2 antibody-drug conjugate trastuzumab-DM-1.

T-DM-1 is designed to combine trastuzumab’s HER2-blocking activity with the delivery of a highly potent antimicrotubule agent to HER2-expressing cells. In heavily pretreated patients, it produced responses in 44% to 53%, depending on dosing schedule, and stable disease in 9% (abstract 1028).

Median progression-free survival with the maximum dose was 9.8 months, reported Muralidhar Beeram, MD, of the Institute for Drug Development, San Antonio.

In a phase II trial reported at ASCO, the monoclonal antibody pertuzumab, when combined with trastuzumab, produced responses in 24% of heavily pretreated patients (including 8% complete responses), with a median duration of response of 25 weeks, reported Karen Gelmon, MD, of the British Columbia Cancer Agency, Vancouver (abstract 1026).

Pertuzumab is the first agent in the class of HER dimerization inhibitors and has a mechanism of action that is complementary to trastuzumab.

Finally, the heat shock protein 90 inhibitor tanespimycin, combined with trastuzumab, achieved a 26% response rate in 27 patients in a phase II multicenter study, Shanu Modi, MD, of Memorial Sloan-Kettering, reported (abstract 1027). When HSP90 is inhibited, the HER2 receptor is degraded, she said.

Martine Piccart-Gebhart, MD, director of medicine, Institut Jules Bordet, Brussels, commented on these studies: "It is very exciting to see drugs that shrink tumors in patients progressing on trastuzumab. The response rate of 25% to 50% in early trials is very impressive."