A multicenter Phase II study reported at the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO), held May 18-21, 2002 in Orlando, Florida has confirmed that the combination of vinorelbine (Navelbine, GlaxoSmithKline) and trastuzumab (Herceptin, Genentech) is a highly effective first-line treatment for metastatic breast cancer patients overexpressing the HER2/neu protein.¹ The overall response rate of 68.5% validates the encouraging findings from a previous single-center experience² and builds upon preclinical data suggesting there is synergy between these two active agents. In addition to its activity, the combination of vinorelbine and trastuzumab offers a favorable tolerability profile and therefore constitutes an appropriate new treatment option in metastatic breast cancer.

Principal investigator Harold J. Burstein, MD, PhD, Assistant Professor of Medicine, Harvard Medical School, Breast Oncology Center, Dana-Farber/Partners Cancer Care, Boston, Massachusetts, said it was important to confirm the initial encouraging results with a larger multicenter study.

Susana M. Campos, MD, MPH, Instructor in Medicine, Harvard Medical School, Breast Oncology Center, Dana-Farber/Partners Cancer Care, Boston, Massachusetts, a co-investigator, agreed, "Single institutions often report high response rates with a regimen they are studying. A multicenter study is often useful to validate and reproduce initial findings."

In the original single-center study headed by Dr. Burstein², trastuzumab and vinorelbine combination chemotherapy achieved responses in 30 of 40 HER2-positive patients, for an overall response rate of 75% (95% Confidence Interval (CI), 57%-89%), including 3 complete responses. The response rate was 84% (95% CI, 60%-97%) in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% (95% CI, 61%-92%) among HER2 3+ patients. High response rates were also seen in women treated with trastuzumab and vinorelbine as second- (64%, 95% CI, 35%-87%) or third-line (71%, 95% CI, 29%-96%) therapy, and among patients previously treated with anthracyclines (88%, 95% CI, 47%-99%) and/or taxanes (50%, 95% CI, 12%-88%).

The current multicenter study involved 15 sites and enrolled 54 patients who tested positive for HER2 overexpression by either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC 3+). The patients, who had received no prior treatment for metastatic disease, were given trastuzumab (4 mg/kg intravenous (IV) loading dose, 2 mg/kg IV weekly thereafter) and vinorelbine (25 mg/m²/week IV push) until disease progression or undue toxicity. Vinorelbine dose was reduced to 15 mg/m² for absolute neutrophil count (ANC) of 750-1250 cells/mm³ or held for ANC < 750. Patients were re-staged every 8 weeks and left ventricular ejection fraction (LVEF) was assessed at 16 weeks.

"Importantly, in 90% of the treatment weeks we were able to get both Navelbine and Herceptin in. So if you really believe there is synergy or interaction, you see that you can deliver both drugs very reliably on this schedule," Dr. Burstein said. "The second important point is that the response continues to be very impressive, 68.5% in this trial, which is very encouraging."

Among the 54 patients, there were 4 complete responses (7%) and 33 partial responses (61%) (see Table). Stable disease was noted in 9 patients (17%), and 8 patients (15%) progressed on treatment, he reported.

The good response rates achieved with trastuzumab and vinorelbine combination chemotherapy were not significantly affected by prior adjuvant chemotherapy, hormone receptor status, or HER2 testing methodology.

"We looked at prior adjuvant chemotherapy, and as far as we could tell there was no difference in response rate according to the presence or absence of chemotherapy or whether patients had anthracyclines or not," he said. "Our feeling is that any woman with HER2-positive advanced disease would be a candidate for this regimen."

Table. Response Rates (n = 54)

The response rate observed with trastuzumab and vinorelbine combination chemotherapy compares favorably to that seen with taxanes plus trastuzumab, Dr. Burstein pointed out. In a study recently published in the Journal of Clinical Oncology, weekly docetaxel with trastuzumab showed a response rate of 63%³, he said.

Dr. Campos said she is particularly impressed with the safety and ease of administration of this regimen.

"Phase II studies with a taxane plus trastuzumab and vinorelbine plus trastuzumab have yielded similar responses (randomized study ongoing-TRAVIOTA) [see below]. However, the side effect profile of the vinorelbine plus trastuzumab combination differs from early Phase II studies, i.e., cardiac toxicity, tolerability, hair loss and neuropathy," she said, indicating that there is a need for a less toxic chemotherapeutic regimen in metastatic breast cancer.

"I am encouraged with the response of the vinorelbine/ trastuzumab combination. This combination achieves our goals in metastatic breast cancer--it is an effective regimen that minimizes toxicity and enhances the quality of life of women with metastatic breast cancer," advised Dr. Campos.

The only notable side effect in the current study was neutropenia, which occurred in 54% (grade 3 or 4) of patients; only 2 patients developed febrile neutropenia. There was no grade 3 or 4 neuropathy, grade 3 or 4 nausea or vomiting, and only minimal alopecia (grade 2 = 4%). Essentially, the regimen was quite well tolerated and could be given for a sustained period of time with very few side effects, Dr. Burstein said.

Of note, there was minimal cardiac toxicity, with only two patients demonstrating a decline in LVEF to ≤ 50% (grade 3 in one patient resolving with therapy). A cardiac surveillance strategy that remeasured LVEF at 16 weeks successfully identified patients at risk for grade 2 or greater cardiotoxicity, he reported.

"This study confirms that this is a very active and very well-tolerated regimen, and we hope it will be further developed in randomized trials and be used to set standards for management of HER2-positive breast cancer," Dr. Burstein said. Dr. Burstein is currently leading a randomized trial, the TRAVIOTA [01087] study (Trastuzumab and Vinorelbine Or Taxane), to compare vinorelbine and trastuzumab to trastuzumab plus a weekly taxane. The study will define the activity for the two different regimens and compare the side effect profiles.

Docetaxel Plus Trastuzumab Study Reported

In another multicenter Phase II study reported at ASCO 2002, Italian investigators showed good activity for the concurrent administration of trastuzumab (4 mg/kg IV loading dose, 2 mg/kg IV weekly thereafter) and docetaxel (75 mg/m² IV every 3 weeks for 6 cycles). ⁴ In 25 patients with HER2-positive metastatic breast cancer (IHC 2+ n = 9; or 3+ n = 16), the overall response rate was 70% in 23 evaluable patients, including one complete response and 15 partial responses, reported Filippo Montemurro, MD, of Candiolo, Italy.

In women with HER2 3+ amplification (n = 14), the overall response rate was 79% (one complete response, 10 partial responses), whereas it was 56% (5 partial responses) in the 9 patients with HER2 2+ tumors.

Symptomatic grade 3 cardiotoxicity occurred in one patient, and grade 3 or 4 neutropenia occurred in 80% of the cycles administered, although there were no reported cases of febrile neutropenia.

Dr. Montemurro concluded that this combination has relevant antitumor activity and good tolerability. Moreover, he advised that patients determined for HER2 status by FISH and not IHC, the therapeutic ratio of this regimen would be optimized. A larger Phase II trial in patients selected by FISH positivity is underway, he said.

References

1. Burstein HJ, Marcom PK, Lambert-Falls R et al. Multicenter Phase II Study of Trastuzumab (T) and Vinorelbine (V) as First-Line Therapy for HER2-Overexpressing Metastatic Breast Cancer. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 211.
2. Burstein HJ, Kuter I, Campos SM, et al. Clinical Activity of Trastuzumab and Vinorelbine in Women with HER2-Overexpressing Metastatic Breast Cancer. J Clin Oncol 2001;19(10):2722-2730.
3. Esteva FJ, Valero V, Booser D, et al. Phase II Study of Weekly Docetaxel and Trastuzumab for Patients with HER2-Overexpressing Metastatic Breast Cancer. J Clin Oncol 2202;20(7):1800-1808.
4. Montemurro F, Choa G, Faggiuolo R, et al. Safety and Activity of Docetaxel and Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer. A Pilot Phase II Study. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2009.