[MOL] Part 7 of series of 11 [01094]

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American Society of Clinical Oncology 35th Annual Meeting
Day 1 - May 15, 1999

Taxanes, Herceptin, and Weekly Therapy: New Options in Metastatic Breast Cancer

George W. Sledge, Jr, MD

There is growing evidence suggesting an important role for the use of taxanes and trastuzumab (Herceptin) as therapy for systemic breast cancer. Several presentations on the first day of the 35th ASCO conference suggested a possible path for future clinical development.

Potential Advantages of Weekly Taxane Therapy

Burstein and colleagues^[1] reported on their use of weekly docetaxel (Taxotere) in patients with metastatic breast cancer. This Phase II trial enrolled patients who had received no more than 1 prior chemotherapy regimen for overt metastatic disease, and treated patients with 40 mg/m²/week for 6/8 weeks. The results of this trial were consistent with those of other weekly taxane regimens (both for paclitaxel and docetaxel): Weekly taxane therapy is well tolerated, with minimal acute or cumulative neutropenia or anemia. The overall response rate observed was 41% (CI, 23.5% to 61.1 %).

There are several reasons to be interested in weekly taxane therapy. >From a pharmacokinetic standpoint, previous Phase I trials have suggested that weekly low-dose taxane therapy gives peak plasma concentrations and time above therapeutic threshold that is well within the ranges achieved with more standard (every 3 weeks) therapy. From a pharmacodynamic standpoint, bathing tumor tissues chronically with taxanes (which bind relatively avidly to tissues) may improve response.

Finally, recent preclinical studies suggest that endothelial cells are exquisitely sensitive to taxanes; therefore, weekly taxane therapy may represent a novel form of antiangiogenic therapy. In addition, weekly taxane therapy is a prime example of what has been called "dose-dense" therapy--therapy designed in response to the idea that frequent exposure offers less opportunity for the emergence and regrowth of drug-resistant clones. The battle cry for this approach could be akin to that of the storied Confederate Civil War general Nathan Bedford Forrest, who, when asked the secret to winning battles, reportedly answered, "Get thar the firstest with the mostest."

Burstein's study joins a growing roster of weekly taxane studies listed below:

Weekly Taxanes: Summary of Available Trials

Reference Prior Rx Dose & Schedule Response Rate

Chang Yes P 50-100 mg/m² 58%

Sikov No P 175 mg/m²/3h; 6/8 78%

Seidman Yes P 80-110 mg/m² 53%

Loffler Yes D 30-45 mg/m²; 6/8 50%

Burstein Yes D 40 mg/m² 6/8 41%

Reference	Prior Rx	Dose & Schedule	Response Rate
Chang	Yes	P 50-100 mg/m²	58%
Sikov	No	P 175 mg/m²/3h; 6/8	78%
Seidman	Yes	P 80-110 mg/m²	53%
Loffler	Yes	D 30-45 mg/m²; 6/8	50%
Burstein	Yes	D 40 mg/m² 6/8	41%

These trials have consistently shown good response rates and low hematopoietic toxicity. Still, several questions remain. Is there an optimum dose and schedule (or agent) for weekly taxane therapy? What other agents can be integrated into weekly regimens with the taxanes? Finally, and most importantly, what is the ultimate benefit of weekly taxane therapy? Specifically, is weekly taxane therapy superior to the more standard schedules with regard to response rate, time to progression, or overall survival? Phase III trials, now being planned, will be needed to answer these questions both for early and advanced breast cancer.

Confirming Survival Data

Norton and colleagues^[2] updated 1 of the more important trials from last year's meetings. HO648, the trial presented by Dr. Norton, took patients overexpressing HER-2 (as measured by an immunohistochemical assay) and randomized them to receive either chemotherapy alone or chemotherapy plus Herceptin, as front-line therapy for metastatic breast cancer. Herceptin is a humanized monoclonal antibody with high affinity and specificity for the extracellular membrane portion of HER-2. HER-2, in turn, is found on a quarter to a third of human breast cancers, where its presence predicts for impaired prognosis in both the adjuvant and metastatic settings.

Last year's presentation demonstrated a higher response rate and time to progression for patients receiving Herceptin and suggested a survival advantage. This year's update (with follow-up in excess of 2 years) confirmed the survival data and showed an improvement in median survival from 20.3 to 25.4 months.

With these results, Herceptin joins a very short list of agents proven to improve survival in metastatic breast cancer. As such, it seems reasonable to consider Herceptin as part of the routine standard of care for patients with metastatic breast cancer (particularly in combination with chemotherapy). As a corollary, it would make sense for all patients with metastatic breast cancer to have a HER-2 test (either by immunohistochemistry or fluorescence in situ hybridization) in their charts.

Questions Remain

This is not to say that we have all the answers when it comes to Herceptin therapy, however. We do not know the appropriate duration of therapy, for instance: Should the drug be given indefinitely (á la Tamoxifen), or for a brief period of time? What represents the optimal drug combination? Doxorubicin-Herceptin combinations clearly increase the rate of congestive heart failure; might we avoid this with agents such as liposomal doxorubicin or dexrazoxane? Numerous phase II trials are examining this possibility.

Fornier and colleagues^[3] from Memorial Sloan-Kettering provide a link between the studies of Burstein and Norton. These investigators combined weekly Herceptin with weekly paclitaxel (Taxol), and demonstrated that the combination is safe and appears effective. Patients were treated with paclitaxel at a dose of 90 mg/m² and Herceptin at 2 mg/kg weekly (after an initial 4-mg/kg loading dose). Patients could be either HER-2 positive or negative, and could have received up to 3 prior chemotherapy regimens. HER-2 status was judged by immunohistochemistry.

Therapy was well tolerated. Febrile neutropenias were rare, as was (importantly) congestive cardiomyopathy, suggesting that this regimen is worthy of consideration for adjuvant therapy trials. Responses were seen in 62% OF HER-2-positive patients and in 44% of HER-2-negative patients. This should not be taken as evidence for the use of Herceptin in HER-2-negative patients, where a strong biologic rationale for its use is lacking. The Memorial group recently published their work regarding weekly paclitaxel, reporting a 53% objective response rate for weekly paclitaxel in the absence of Herceptin.

Will weekly Herceptin plus weekly paclitaxel represent an important advance, or only 1 of the myriad alterations of dose and schedule reported in the medical oncology literature? Phase III trials, once again, may answer this question. Similarly, whether Herceptin has any role to play in HER-2 underexpressers remains an open question.

Therapy in the Adjuvant Setting

Taxane combination therapy was the subject of an interesting presentation by Nabholtz and colleagues.^[4] These investigators randomized front-line metastatic breast cancer patients to receive either AC (doxorubicin and cyclophosphamide, a standard combination in the past) or AT (doxorubicin and docetaxel). AT was statistically superior to AC with regard to overall response rates, time to progression, and time to treatment failure.

Should AT therefore represent a new standard of care for metastatic breast cancer? The data are insufficient to support this judgment at present. Follow-up is currently insufficient (and may never be sufficient) to demonstrate an overall survival advantage, and no quality-of-life data were available to suggest that patients receiving AT actually feel better than those receiving AC.

The real importance of the Nabholtz trial is for the adjuvant setting. The American Breast Intergroup, in a trial led by Dr. Lori Goldstein of the Eastern Cooperative Group, is currently comparing AC with AT in patients receiving adjuvant therapy for 0-3 positive lymph nodes. If AT were superior to AC in this setting (with regard to disease-free and overall survival), the implications would be significant for the large number of patients with minimal microscopic metastatic disease.

References

Burstein HJ, Younger J, Bunnell CA, et al: Weekly docetaxel (Taxotere) for metastatic breast cancer: A phase II trial [Abstract # 484]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Norton L, Slamon D, Leyland-Jones B, et al: Overall survival (OS) advantages to simultaneous chemotherapy (CRx) plus the humanized anti-HER2 monoclonal antibody Herceptin (H) in HER2-overexpressioning (HER2+) metastatic breast cancer (MBC) [Abstract #483]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Fornier M, Seidman AD, Esteva FJ, et al: Weekly (W) herceptin (H) + 1 hour taxol (T): Phase II study in HER2 overexpressing (H2+) and non-overexpressing (H2-) metastatic breast cancer (MBC) [Abstract #482]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Nabholtz JM, Falkson G, Campos D, et al: A phase III trial comparing doxorubicin (A) and docetaxel (T) (AT) to doxorubicin and cyclophosphamide (AC) as first line chemotherapy for MBC [Abstract #485]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.

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