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News Archive: Michigan Oncology Journal Spring 99

Herceptin: An Example of the Success of Translational Research

-Anne F. Schott, M.D.,
Assistant Professor of Internal Medicine
-Stephen P. Ethier, Ph.D.,
Associate Professor of Radiation Oncology
Associate Director, Breast Oncology Program

Those of us who see breast cancer patients in clinical practice can attest to the high level of public interest and awareness in the new cancer therapy trastuzumab (Herceptin®). The interest was fueled initially by the intense media coverage of the American Society of Clinical Oncology meeting in May 1998, where the results of the Phase III trials with trastuzumab were released in abstract form. The fire was stoked by the continuing media coverage of the FDA approval process and by the action of patient advocate groups in accelerating approval. The drug became available to clinicians in early October, although the pivotal Phase III trial has not yet been published. This article will review the molecular basis for the development of this new therapy and some results of published (and unpublished) clinical trials with trastuzumab.

HER2 and Cancer
Growth factors and their receptors are known to play critical roles in cell development, growth and differentiation. Many receptors possess intrinsic tyrosine kinase activity that is activated upon the receptor's interaction with its ligand. Abnormal expression of human epidermal growth factor receptor 2 (HER-2) is frequently observed in a number of primary tumors, suggesting that the overexpression of this growth factor receptor may contribute to transformation and tumorigenesis (Figure 1). In most cases, HER-2 protein overexpression is the result of gene amplification, and overexpression has been correlated with poor clinical outcome in patients with breast and ovarian cancers (1). Laboratory data have demonstrated that overexpression of HER-2 is sufficient to stimulate the tyrosine kinase activity of this receptor. Furthermore, high-level activation of the HER-2 kinase results in the activation of downstream signaling molecules, such as the MAP kinases and the PI 3/Akt kinases, which both drive proliferation and inhibit apoptosis of the cells.

Approximately 25% to 30% of patients with breast and ovarian cancers overexpress HER-2 (1). Similar associations may exist for lung adenocarcinoma and gastric cancers. These data encourage the exploitation of HER-2 as a potential target for cancer therapy.

muMAb 4D5
Murine monoclonal antibodies (muMAbs) were produced against the extracellular domain of the HER2 receptor to inhibit the proliferation of human tumor cells overexpressing p185HER2. The most encouraging results were obtained with muMAb 4D5, which produced significant anti-proliferative effects both in vitro and in vivo against human breast cancer that overexpresses the HER2 receptor (2). Trastuzumab, the humanized version of muMAb 4D5, was engineered by inserting the complementary-determining regions (CDRs) of muMAb 4D5 into the framework of a consensus human IgG1. Trastuzumab is comparable to muMAb 4D5 in blocking breast tumor cell proliferation; however, unlike muMAb 4D5, it induces antibody-dependent cellular cytotoxicity against tumor cell lines in the presence of human peripheral blood mononuclear cells. In addition, the humanized form of the antibody prevents or reduces the generation of an immune response directed against the antibody itself.

Clinical Studies of Trastuzumab
The clinical benefit of trastuzumab in women with metastatic breast cancer has been demonstrated by the results of two recent Phase III studies. A large randomized, controlled Phase III trial conducted to evaluate the efficacy and safety of trastuzumab with first-line chemotherapy (anthracycline plus cyclophosphamide, or paclitaxel) compared with chemotherapy alone, was recently completed in women with metastatic breast cancer (3). This study of 469 patients with HER-2 overexpressing tumors who had not received chemotherapy for metastatic disease demonstrated that the combination of trastuzumab and chemotherapy significantly prolongs the time to disease progression compared with chemotherapy alone (Table 1). The median time to disease progression for all enrolled patients who received trastuzumab plus chemotherapy was 7.2 months. The median time to disease progression for all enrolled patients who received chemotherapy alone was 4.5 months. Thus, the addition of trastuzumab to chemotherapy extended the median time to progression by 2.7 months. The difference between the overall time to disease progression for the two treatment groups was statistically significant (p<0.0001). The second study enrolled 222 patients with refractory metastatic breast cancer (4). The overall response rate for all 222 patients was 15% (95% CI 11, 21). There were 8 complete responses and 26 partial responses. The median duration of response was 9.1 months. Thus, trastuzumab has some activity as a single agent in women with metastatic breast cancer who have HER-2 overexpressing tumors.

Assessments of adverse events in these two studies indicated that several women developed signs and symptoms of cardiac dysfunction while receiving trastuzumab. The risk of cardiac dysfunction was highest in patients who received trastuzumab co-administered with anthracycline-based chemotherapy (Table 2), and the risk may have been influenced by increasing age. The nature of the observed cardiac dysfunction was similar to the syndrome of anthracycline-induced cardiomyopathy, and the signs and symptoms of cardiac dysfunction usually responded to treatment. Other adverse events observed in these two studies were generally mild to moderate in severity.

Summary
Trastuzumab (Herceptin®) was approved on September 25, 1998, for use in patients with metastatic breast cancer who have tumors that overexpress the HER-2 protein. It is indicated for treatment of patients both as first-line therapy in combination with paclitaxel, and as a single agent in second- and third-line therapy. Due to the increased incidence of cardiac toxicity, it is recommended that left ventricular function be evaluated in all patients prior to and during treatment with trastuzumab. This is an exciting time to be in the field of oncology. Trastuzumab is the first of hopefully many therapies that will target specific genetic alterations that contribute to the malignant progression of cancer. Although trastuzumab may benefit only a small subset of all cancer patients, the development of this drug is proof of the principle that discoveries in the basic science laboratory can be translated into promising cancer treatments.

References

1. Slamon DJ, et al. Studies of the HER-2/neu protooncogene in human breast and ovarian cancer. Science. 244(4905):707-12, 1989.
2. Hudziak R, et al. p185HER2 monoclonal antibody has anti-proliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 9:1165-72, 1989.
3. Slamon D, et al. Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer markedly increases anticancer activity: a randomized, multinational controlled Phase III trial. Proc of ASCO #377, 17:98A, 1998.
4. Cobleigh M, et al. Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc of ASCO #376, 17: 97A, 1998.

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Figure One

Table 1.
Phase III Clinical Efficacy in First-Line Treatment

(a) AC= anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
(b) Assessed by an independent Response Evaluation Committee
(c) Kaplan-Meier Estimate

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Table 2.
Incidence and Severity of Cardiac Dysfunction

(a) Open-label, single-agent Phase 2 study (94% received prior anthracyclines).
(b) Randomized Phase III study comparing chemotherapy plus trastuzumab to chemotherapy alone, where chemotherapy is either anthracycline/cyclophophamide or paclitaxel.

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