Alice Goodman, Medical Writer

San Antonio, TX—The long-awaited final results of the BCIRG 006 trial of adjuvant chemotherapy show that a regimen of concurrent anthracycline chemotherapy plus trastuzumab (Herceptin) outperformed anthracycline-containing chemotherapy alone and performed similarly to a non-anthracycline-containing regimen in patients with early HER2-amplified breast cancer. However, the non-anthracycline regimen had a much better adverse-effects profile, especially with respect to longer-term life-threatening adverse effects.

“Our interpretation of the study results is that trastuzumab provides similar disease-free survival and overall survival with an anthracycline and a non-anthracycline regimen in low- and high-risk patients.

Acute and chronic toxicity favors TCH, the non-anthracycline regimen. The advantage of slightly fewer events with the anthracycline regimen plus trastuzumab comes with a cost of cardiotoxicity and leukemia,” said Dennis Slamon, MD, UCLA, CA, a pioneer in the development of trastuzumab for the treatment of HER2-positive breast cancer.

Although Dr Slamon said that, based on results of the trial, the benefit of anthracyclines appears to be restricted to higher-risk patients (those with topoisomerase II amplification), other experts said they were not ready to abandon anthracyclines for patients with breast cancer.

Anthracyclines are used worldwide because they improve disease-free survival (DFS) by 3.5% and overall survival (OS) by 4% according to the Oxford overview, the “bible” for oncologists; furthermore, they are much cheaper than newer drugs, which is important for counties with nationalized health coverage.

BCIRG 006 randomized 3222 patients with documented HER2-positive early breast cancer to one of three treatment arms:

anthracycline (doxorubicin) plus cyclophosphamide followed by docetaxel (AC › T); 4 cycles of AC › T plus trastuzumab (AC > TH); or 6 cycles of docetaxel and carboplatin plus trastuzumab (TCH).

Patients were enrolled from April 2001 to March 2004. Median age was around 53 years; about 60% had a mastectomy, about 68% had radiotherapy, and about 51% had hormone therapy. Twenty-nine percent of all patients were node-negative. 

About 38% had 1 to 3 nodes involved, about 23% had 4 to 10 nodes involved, and about 10% had more than 10 nodes involved.

Forty percent had tumors ≤2 cm; 53% had tumors between 2 and 5 cm in size; and 6% had tumors >5 cm. Patients were stratified for hormone receptor—positive and negative status and for tumor size. After April 2005, 23 patients (2.3% of those randomized to the control arm, crossed over to receive trastuzumab, leaving 97.5% of the control arm intact for comparisons of DFS, OS, and safety.

At the San Antonio Breast Cancer Symposium, Dr Slamon presented results of the third planned analysis of the trial. Median follow-up was 65 months; 656 DFS events (breast cancer relapse, second primary cancer, or death) had occurred; 348 deaths occurred. He said that in 2005, at the first planned analysis, DFS was 84% for AC-TH (

 <.0001 compared to control arm), 80% for TCH (

 = .0002), and 73% for the control arm. The updated DFS was 84% for AC › TH (

 =.04), and 75% for the control arm. The total number of DFS events in each arm was 257, 185, and 214, respectively. The difference between the two study arms was not statistically different, Dr. Slamon noted, although it was slightly numerically superior for AC › TH.

The third planned analysis of OS showed that 92%, 91%, and 87% of patients, respectively, were alive at 5 years. The number of deaths due to any cause was 141 in the control arm, 94 in the AC › TH arm, and 113 in the TCH arm. Again, the difference in OS between the two experimental arms was not statistically significant.

For node-negative disease, 5-year DFS in the three arms was 93%, 90%, and 85%, respectively. The difference was statistically significant favoring anthracycline-containing arm over the control arm (

 =.02), with a trend favoring TCH. OS in node-negative patients was 97%, 96%, and 93%, respectively.

Looking at higher risk, node-positive disease, 5-year DFS was 80%, 78%, and 71%, respectively. Both experimental arms were significantly superior to control (

 = .013 for TCH). In high-risk patients with ≥4 positive nodes, 5-year DFS was 73%, 72%, and 61%, respectively, which was highly significant for both arms versus control (

 = .002 for both arms). OS in those with ≥4 positive nodes was 84%, 83%, and 76%, respectively. Only the anthracycline-containing arm was significantly superior to control (

TCH won out when toxicity was analyzed. Both non-hematological and hematological toxicities occurred significantly less frequently with TCH, including Grade 3 and 4 arthralgia, myalgia, hand-foot syndrome, stomatitis, vomiting,

neutropenia and leucopenia.. Acute leukemias were reported in 6, 1, and 1 patients, respectively. 

“All patients who developed leukemia has prior anthracycline exposure” Dr Slamon told listeners.

As has been shown previously, cardiac toxicity was more frequent in patients receiving an anthracycline, with a four- to five-fold increase in clinical congestive heart failure in the two arms that contained doxorubicin. “No surprise here,” Dr Slamon said. Although mean left ventricular ejection fraction (LVEF) declined at the beginning of treatment, patients treated with TCH recovered to normal at 5 years, while LVEF in patients randomized to the other two arms has not yet returned to normal. 

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Anthracycline chemotherapy plus trastuzumab outperformed anthracycline alone, and performed similarly to a non-anthracycline regimen in breast cancer patients. 

Anthracyclines and Trastuzumab Bests Taxane/Carboplatin/Trastuzumab

San Antonio, TX — Updated results of the AVADO trial confirm previously reported interim findings: the addition of bevacizumab (Avastin) to docetaxel (Taxotere) as first-line treatment of locally recurrent or metastatic breast cancer improves progression-free survival (PFS) and objective response rates (ORR). The addition of bevacizumab did not appear to affect the safety profile of docetaxel treatment. 

Although overall survival (OS) was not significantly different between patients who received a lower dose of bevacizumab and those who took a higher dose, David Miles, MD, said that OS may have been influenced by crossover in this trial and the affect of subsequent therapies. Dr Miles is consultant medical oncologist at Mount Vernon Hospital in Northwood, Middlesex, U.K.

AVADO is the most recent of three trials that show adding bevacizumab to chemotherapy in the first-line setting improves PFS and ORR in metastatic breast cancer. The results Dr Miles presented at the San Antonio Breast Cancer Symposium were the final OS data, along with updated data on other endpoints, including time to progression (TTP) and duration of response. He did not have time to present quality of life data, but at a press conference, he said patients on bevacizumab had improved quality of life in this trial.

Within 1 year, AVADO had recruited 736 patients from 104 sites across 26 countries. Median age was 55 years; two-thirds of the patients received adjuvant chemotherapy (25% were treated with taxanes); more than 80% had measurable disease at study entry.

Patients were randomized to one of three arms: docetaxel plus placebo; docetaxel plus 7.5 mg/kg of bevacizumab every 3 weeks or docetaxel plus 15 mg/kg of bevacizumab every 3 weeks. Patients could receive a maximum of 9 cycles but could stop after 6 cycles. If chemotherapy was discontinued, placebo and bevacizumab were continued until disease progression. Crossover was allowed after unblinding of study results, Dr Miles said.

At a median follow-up of 25 months, updated data showed median PFS was 9 months for the lower-dose bevacizumab group versus 8.2 months for docetaxel alone, representing a 14% risk reduction in disease progression or death. Median PFS was significantly improved with the higher dose of bevacizumab compared with placebo, at >10 months compared with 8.2 months (

 = .006), representing a 23% risk reduction.

A separate analysis censored for non-protocol therapy before disease progression (encompassing only 3% of patients) found that median PFS was 10 months for the 15-mg dose of bevacizumab group versus >8 months for the placebo arm, representing a 33% risk reduction (

=.002). A similar censored analysis for the 7.5-mg arm of the trial showed a median PFS of 8.1 months for the placebo arm and 9 months for the bevacizumab arm.

The ORR was 64.1% for the higher dose of bevacizumab, 55% for the lower dose, and 46% for placebo. The difference in ORR between bevacizumab and placebo was considered highly significant (

The rate of 1-year survival was 84% in the group receiving the higher dose of bevacizumab compared with 76% for the placebo group (

No significant differences were seen in OS between the two bevacizumab groups.

Neutropenia was an expected complication, Dr Miles said. Grade 3 or higher neutropenia was reported in 17.3% of the control arm and 19.8% in each of the two bevacizumab-containing arms. Grade 3 or higher hypertension was seen in 1.3% of the placebo group compared with 0.8%, and 4.8% in the bevacizumab arms. Hypertension requiring treatment was reported in 11% of patients in the lower-dose bevacizumab arm and 18% of patients in the higher-dose arm. No increase in GI perforation, wound healing, bleeding, or thrombotic events was reported with bevacizumab treatment. “This is reassuring,” Dr Miles said. SABCS Abstract 41.

: The study was supported by Hoffman-LaRoche.

Updated results confirm that addition of bevacizumab to docetaxel as first-line breast cancer treatment improves survival and response rates.

Update Shows Adding Bevacizumab to Chemotherapy Improves Survival

SAN ANTONIO — Sorafenib (Nexavar), a multi-targeted tyrosine kinase inhibitor (TKI), showed promise when combined with chemotherapy for locally advanced or metastatic breast cancer in the phase IIb Solti-0701 trial reported at the San Antonio Breast Cancer Symposium. Based on the promising results of this trial, a phase III registration trial will begin in 2010 to evaluate the combination of sorafenib plus capecitabine for treatment of advanced breast cancer.

“The combination of sorafenib and capecitabine was tolerable, with clinically manageable toxicities, and no unexpected toxicity signal. The combination achieved a 42% reduction in disease progression and death, with confirmed robust findings across subgroups when used in both first- and second-line therapy. We conclude that sorafenib may be a valuable addition when given in combination with chemotherapy,” stated Jose Baselga, MD, Vall D’Hebron University Hospital, Barcelona, Spain.

Soliti-0701 was a multinational, double-blind, placebo-controlled, randomized, phase IIb study that enrolled 220 women with locally advanced unresectable or metastatic HER2-negative breast cancer. Women were allowed on 1 prior chemotherapy for advanced disease. They were stratified according to lines of therapy (first- or second-line) and visceral metastasis (presence or absence) and randomized 1:1 to receive either 400 mg 

of sorafenib orally twice a day plus 1000 mg/m

 of capecitabine orally twice a day for 14 out of every 21-day cycle or to placebo plus capecitabine at the same dose and schedule.

The dose of capecitabine was lower than the approved dose, which is 1250 mg/m

 twice daily for 14 out of every 21 days, Dr Baselga said. Treatment was continued until disease progression or unacceptable toxicity. 

At baseline, both groups were well balanced for demographic and disease characteristics. Median age was 55 years. Seventy percent were both estrogen receptor—positive and progesterone receptor–positive. Eighty percent had prior adjuvant or neoadjuvant therapy; of these, 40% were treated with taxanes and 90% with anthracyclines. No previous bevacizumab was allowed.

Fifty-seven percent of patients in the experimental arm and 45% in the capecitabine plus placebo arm had 1 prior chemotherapy regimen for advanced/metastatic disease.

With the exception of hand/foot syndrome, there were few grade 3 adverse events in either group and virtually no grade 4 adverse events. However, 45% of patients in the sorafenib/capecitabine arm developed grade 3 hand/foot syndrome compared with 13% in the comparator arm. These patients were treated with pre-defined management, as this is an expected toxicity with sorafenib, Dr Baselga explained.

No dose adjustments were made for grade 1 hand/foot syndrome, but for grades 2 and 3, sorafenib was withheld until symptom resolution. Dose adjustments were made for grade 3.

Treatment discontinuations due to adverse events were reported in 65% of those on sorafenib and 79% for placebo; discontinuations due to progressive disease occurred in 45% and 66%, respectively. 

For the primary endpoint of progression-free survival (PFS), median PFS was

6.4 months for sorafenib/capecitabine versus 4.1 months for capecitabine/placebo. This difference of almost 2 months was highly statistically significant (

 = .0006). Response rates were 38% and 30.7%, respectively.

In a pre-specified subgroup analysis of those being treated first-line for advanced/metastatic disease, PFS was 7.6 months for sorafenib/capecitabine and 4.1 months for capecitabine/placebo, representing a statistically significant 50% reduction in disease progression/death (

 = .0022). In the second-line setting, PFS

was 5.7 months versus 4.1 months, respectively, representing a 35% reduction (

Sorafenib showed promise when combined with chemotherapy for locally advanced or metastatic breast cancer.

Sorafenib Works Well With Chemotherapy in Advanced Breast Cancer

San Antonio, TX — The addition of bevacizumab (Avastin) to chemotherapy improved progression-free survival (PFS) compared with chemotherapy alone in patients with metastatic breast cancer whose cancer has progressed on first-line therapy. “This is the first Phase III study to show that bevacizumab plus chemotherapy is effective as second-line therapy for metastatic breast cancer. These results are clinically meaningful. We have few options for second-line chemotherapy in metastatic disease,” said Adam Brufsky, MD, University of Pittsburgh, PA. Dr Brufsky discussed this study at an official press conference remotely from his home while recovering from illness.

The study, called Ribbon-2, included 684 women with metastatic breast cancer that progressed on first-line chemotherapy. The women received chemotherapy of the investigators’ choice (taxane [44%], gemcitabine [23%], capecitabine [21%], or vinorelbine [12%]). Women were then randomized 2:1 to receive chemotherapy plus bevacizumab or chemotherapy alone. They were treated until disease progression.

Treatment arms were well balanced for demographic and disease characteristics. Median age was 55 years. A slight imbalance was observed for patients with triple- negative breast cancer (estrogen receptor—negative, progesterone receptor–negative, and HER2-negative): 20% in the chemotherapy arm and 24% in the bevacizumab-containing arm.

For the primary endpoint of progression-free survival (PFS), the addition of bevacizumab achieved a highly statistically significant 22% improvement (P = .0072), from a median of 5.1 months with chemotherapy alone to 7.2 months with the addition of bevacizumab. An exploratory analysis that looked at PFS results according to type of chemotherapy received suggested that the choice of chemotherapy matters. 

“As a class, there was a benefit with taxanes and with capecitabine. Patients on gemcitabine or vinorelbine did not appear to benefit from the addition of bevacizumab. But this was a preliminary analysis in very small numbers of patients,” Dr Brufsky told listeners.

Response rates were also much higher with the addition of bevacizumab. Overall response rates were 39.5% with the combination therapy versus 29.6% with chemotherapy alone. No difference in overall survival was seen in this interim analysis. Only 57% of the patients have died, Dr Brufsky said.

“A difference in overall survival may emerge with longer follow-up,” he said. 

“We now know that bevacizumab is clearly beneficial as first-line and as second-line therapy. We are interested in a study of continuous bevacizumab in metastatic breast cancer, the so-called Ribbon-3 trial.” 

Toxicity with bevacizumab was consistent with previous experience in metastatic breast cancer and other tumor types. No new toxicity signals emerged. 

Edith Perez, MD, Mayo Clinic, Jacksonville, FL, who moderated the official press conference where this abstract was discussed, said that a previous study in second-line therapy of metastatic breast cancer showed no benefit for the addition of bevacizumab to capecitabine. “It is an important finding that bevacizumab plus several options of chemotherapy improved PFS in patients who did not get it as first line,” Dr Perez commented.

When asked whether the cost of bevacizumab was worth an extra 2.1 months of PFS, Dr Brufsky acknowledged that cost is an issue. “When we compare trial results, 2.1 months is a mean. There are patients who do much better at one end of the curve. We want to identify characteristics that predict better response,” he commented. 

Adding bevacizumab to chemotherapy improved survival compared with chemotherapy alone in breast cancer patients.

Alice Goodman, Medical Writer

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