Reports

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30th Annual San Antonio Breast Cancer Symposium

San Antonio, Texas / December 13-16, 2007

First-line Metastatic Treatment

A study reported at the San Antonio meeting affirmed the activity of the current first-line regimen of the monoclonal antibody (MAb) trastuzumab plus a taxane for metastatic breast cancer but also demonstrated a strategy to achieve further improvement in outcomes. Adding capecitabine to the standard first-line trastuzumab/docetaxel regimen significantly improved time to disease progression (TTP) and progression-free survival (PFS). Both regimens led to response rates in excess of 70%.

“Trastuzumab’s ability to increase survival changed the treatment landscape for advanced breast cancer patients,” stated Dr. Andrew Wardley, Christie Hospital, Manchester, UK. “Adding capecitabine to the most commonly used first-line regimen of trastuzumab and taxanes allows patients to live even longer without disease progression.”

The findings came from the randomized, open-label Capecitabine, Herceptin and Taxotere (CHAT) trial, which involved 222 patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. None of the patients had prior exposure to docetaxel, capecitabine or trastuzumab. The patients were randomized to docetaxel (100 mg/m2 every three weeks) plus trastuzumab (loading dose 8 mg/kg, then 6 mg/kg every three weeks) or to the same two agents (docetaxel at 75 mg/m2) plus capecitabine (950 mg/m2 b.i.d. days 1 to 14, every 21 days). Treatment continued until disease progression or intolerable toxicity.

The primary study end point was overall response rate. Secondary end points consisted of TTP, PFS, overall survival (OS) and safety. Dr. Wardley presented data on all major end points except OS.

In designing the study, investigators had assumed a 50% overall response rate with the two-drug regimen and projected improvement to 70% with the addition of capecitabine. Instead, the two-drug regimen resulted in a response rate of 72.5%, more than 40% higher than expected. The capecitabine regimen met projections by achieving a response rate of 70.5%. It was also associated with a median TTP of 18.6 vs. 13.6 months (P=0.0290) and a median PFS of 17.9 vs. 12.8 months (P=0.0402). Additionally, adding capecitabine to trastuzumab and docetaxel led to a higher proportion of complete responses (23.2% vs. 16.4%) and stable disease (25.0% vs. 16.4%).

“The significant improvement in TTP and PFS plus the higher rate of complete response suggest the three-drug combination has better efficacy, but that remains to be determined with a larger number of patients and longer follow-up,” Dr. Wardley noted.

The three-drug regimen had manageable toxicity, and the addition of capecitabine did not result in any unexpected adverse effects, he added.

Improved Survival Following Brain Metastasis

In a retrospective review of 56 patient records with HER2-positive breast cancer that had metastasized to the brain, Dr. Byung Ho Nam, National Cancer Center, Goyang-si, South Korea, and colleagues reported that treatment with trastuzumab was associated with significant improvement in OS.

The study group consisted of 36 patients who never received trastuzumab or who discontinued it after the diagnosis of brain metastases and 20 patients who received the MAb continuously or started it after diagnosis of brain metastases. The analysis revealed a median survival of 3.8 months in patients who did not receive the MAb vs. 13.4 months in those who did (P=0.0003). The best survival (19.3 months) was seen in patients with either estrogen or progesterone receptor-positive tumours treated with trastuzumab. Although Dr. Nam acknowledged that the results appeared intriguing, he cautioned that they would require confirmation in prospective clinical studies.

Treatment Beyond Progression

According to Dr. Gunter von Minckwitz, University of Frankfurt, Germany, preclinical studies have shown that the antiproliferative activity of trastuzumab persists as long as the agent remains present. Additionally, its withdrawal results in the return of rapid cell growth (Oncogene 1998;17:2235-49).

In an extension phase of the pivotal trial, continued treatment with trastuzumab (alone or in combination with another agent) beyond progression led to an overall clinical benefit of 22% and a median response duration of 6.7 months (J Clin Oncol 2004;22:1063-70). The principle of continuing anti-HER therapy after progression was supported in a recent trial wherein the addition of an epidermal growth factor inhibitor to chemotherapy proved more effective than chemotherapy alone (N Engl J Med 2006;355:2733-43).

Dr. von Minckwitz presented interim findings from a prospective, randomized phase III study involving patients with metastatic HER2-positive breast cancer previously treated with first-line or adjuvant trastuzumab and who had prior exposure to anthracyclines or taxanes. Patients received capecitabine 2500 mg/m2 on days 1 to 14 every 21 days alone or in combination with trastuzumab 6 mg/kg every three weeks.

Investigators randomized 156 patients to the two treatment arms. The addition of the MAb to capecitabine led to a 52% improvement in PFS (8.5 months vs. 5.6 months). The difference was associated with a hazard ratio of 0.71 in favour of the MAb arm. Median OS was 20.3 months with the combination and 19.9 months with capecitabine alone. Twice as many patients had objective responses with trastuzumab compared with capecitabine alone (48.9% vs. 24.6%).

All patients had normal left ventricular ejection fraction (LVEF) at baseline, and only one patient had a decline in LVEF during treatment to <40%. Two patients (2.9%) in the capecitabine arm and three (4.9%) in the combination arm had other serious cardiac events, consisting of one case each of cardiac insufficiency and tachycardia and three cases of hypertension.

Neutropenia, anemia and thrombocytopenia occurred in about 30% to 60% of patients in each arm, but grade 3/4 hematologic toxicity was uncommon, Dr. von Minckwitz reported. The most common grade 3/4 non-hematologic toxicities were hand-foot syndrome (24% to 30%) and diarrhea (15% to 20%). Other grade 3/4 non-hematologic toxicities occurred in fewer than 10% of patients.

“Treatment with trastuzumab beyond progression in addition to capecitabine was associated with numerically fewer events,” Dr. von Minckwitz concluded. “Simultaneous application of trastuzumab and capecitabine in metastatic breast cancer is a feasible schedule without unexpected severe toxicities, especially without long-term cardiac toxicity.”

Real-world Experience

Additional support for continuation of the MAb treatment emerged from an analysis of outcomes among breast cancer patients treated with trastuzumab-containing regimens (or monotherapy) in clinical oncology practices and adds to existing literature on that topic. The findings involved 910 patients treated at 142 centres in Germany. The patients received the agent as monotherapy (n=102), in addition to chemotherapy (n=715), or in addition to hormonal therapy (n=93), reported Dr. Christian Jackisch, Klinikum-Offenbach, Germany.

The MAb-containing regimens were associated with an overall response rate of 56%. Its addition to chemotherapy resulted in a higher response rate (59%) compared with trastuzumab alone (45%) or trastuzumab plus hormonal therapy (38%). As first-line therapy, patients who received a trastuzumab/taxane combination had the highest overall response rate (62%), whereas those with prior anthracycline and taxane exposure had the lowest response rate (47%).

The median PFS for all patients was 9.8 months and was longest in patients who received the MAb in addition to hormonal therapy (11.9 months). Median OS was 30 months overall, 27 months with trastuzumab monotherapy, 28 months with trastuzumab/chemotherapy combinations, and 44 months with trastuzumab/hormonal combinations.

A subset of 112 patients who continued MAb therapy beyond progression was compared with a similar group of 81 patients who stopped trastuzumab at progression. Patients who continued treatment had a 50% improvement in OS (20.1 months vs. 13.4 months, P=0.0014).

“Trastuzumab is commonly used beyond disease progression in routine clinical practice,” Dr. Jackisch commented. “The results presented here show a significant increase in OS in patients receiving trastuzumab after disease progression.”