NEW ORLEANSIn a phase II study, combined treatment with
Herceptin (trastuzumab) and vinorelbine (Navelbine) improved response
rates and survival in women with HER2-positive metastatic breast
The clinical trial finding supports preclinical research suggesting a
synergistic interaction between Herceptin and vinorelbine, Harold J.
Burstein, MD, of Harvard Medical School, said at the 36th
Annual Meeting of the American Society of Clinical Oncology (ASCO).
Dr. Burstein and his colleagues at Dana-Farber/Partners Cancer Care
were involved with this trial.
Further rationale for the study came from the fact that both agents
have activity in advanced breast cancer with side effect profiles
favorable for combination therapyand both are given on a weekly
schedule, Dr. Burstein said. He noted also that vinorelbine is not
associated with cardiotoxicity, nausea, vomiting, or alopecia, and
does not require steroid premedication.
The primary objective was to define a response rate to the
combination in women with HER2-positive metastatic breast cancer and
to characterize the safety/toxicity profile of the regimen. The study
included patients with measurable metastatic disease and tumors
(either primary or metastatic) that were HER2 positive at the +2 or
+3 level by immunohistochemistry.
While participants with up to two prior chemotherapy regimens for
advanced breast cancer were allowed, prior therapy with Herceptin or
vinorelbine was not permitted. Patients with impaired cardiac
function were also excluded. Sixty-five percent of patients had
either two or three metastatic sites.
Dr. Burstein noted that while the study opened with the
Herceptin/vinorelbine combination as a second- or third-line therapy,
eligibility was later extended to first-line treatment of metastatic
Forty patients (median age, 51) received Herceptin (4 mg/kg first
dose, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m²/wk IV
push). Doses of vinorelbine were reduced to 15 mg/m² for
absolute neutrophil counts (ANC) between 750 and 1,250/µL or
withheld for a week if the ANC dropped below 750/µL. Restaging
and cardiac function tests were performed after every 8-week cycle.
Out of a total of 982 weeks of treatment for the entire cohort,
vinorelbine doses were reduced in 13% of weeks and omitted in 7%.
Complete responses, Dr. Burstein said, were seen in 2 patients (5%)
and partial responses in 28 (70%), for an overall response rate of
75%. Two patients (5%) had stable disease for more than 6 months, and
eight (20%) had progressive disease. The response rate was 80% among
the 30 patients with +3 HER2 status and 55% among the 9 patients with
Activity was noted regardless of prior chemotherapy for
metastatic disease, Dr. Burstein said. Among the patients who
had undergone two prior regimens, 71% responded, as did 64% of
patients who had undergone one prior regimen. The response rate was
84% for first-line-therapy patients.
The combination regimen was well tolerated, Dr. Burstein said, with
minimal alopecia (13% grade 1, 2% grade 2) and few gastrointestinal
side effects (44% grade 1 nausea, 15% grade 2). Leukopenia (grade
3-4) occurred in 36% of patients. While grade 1 sensory neuropathy
occurred in 31% of patients and grade 2 in 8%, there were no grade
3-4 neuropathies, he said.
Grade 1-2 cardiotoxicities occurred in 13% of patients. The three
patients who had grade 2 cardiotoxicities (asymptomatic declines in
left ventricular ejection fraction) were taken off study medications.
No symptomatic heart disease or heart failure occurred, and no
significant changes in ejection fraction were noted after the second
cycle of treatment.
It looks like this is going to be a valuable regimen, Dr.
Burstein said in an interview with ONI. Our study
doesnt allow us to say whether its better than anything
else, but we know that it is very well tolerated, which our patients like.
Dr. Burstein noted that further research is being conducted to answer
other key questions pertaining to the optimal use of Herceptin.
We really have no idea when to stop Herceptin, he said.
New studies will look at patients who have already undergone
chemotherapy with a taxanepaclitaxel (Taxol) or docetaxel
(Taxotere)and Herceptin, and have had disease progression.
Participants will receive vinorelbine with or without Herceptin.
Another study among chemotherapy-naïve women with advanced
breast cancer will evaluate Herceptin alone or with vinorelbine.
The question is, do you need to start chemotherapy right away
or can you defer it until Herceptin is clearly not working, Dr.