Herceptin Trials Usher in New Era in Adjuvant Therapy

ASCO — Interim findings from two phase III studies, one a North American joint analysis and the other a large international trial, have changed the standard of care for women with early invasive HER2-positive breast cancer. Trastuzumab (Herceptin) used in addition to standard adjuvant chemotherapy yielded dramatic responses in these patients, cutting the risk of both locoregional and distant recurrence in half, and significantly improving overall survival time. Both studies were reported in a late-breaking scientific symposium at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO), "Advances in Monoclonal Antibody Therapy for Breast Cancer."

The joint analysis combined data from 3,351 patients in two National Cancer Institute-sponsored trials, NSABP (National Surgical Adjuvant Breast and Bowel Project)-B31 and NCCTG (North Central Cancer Treatment Group)-N9831. Each study evaluated a combination of doxorubicin (Adriamycin) and cyclophosphamide (AC), followed by paclitaxel , with or without trastuzumab, using different schedules of paclitaxel. The international trial, HERA (HERceptin Adjuvant), is a 39-country, 5,090-patient study of Herceptin vs observation following a wide range of primary chemotherapy options.

Efficacy results of the NSABP-B31/NCCTG-N9831 joint analysis and of the HERA trial were first made public in late April, shortly after they became available to the investigators, and both trials were stopped early, with about 2 years and 1 year of median follow-up, respectively, because they had met their efficacy endpoints (see Table).

Commenting on the "strikingly positive" findings in the two trials, discussant George W. Sledge, Jr., of the Indiana University Cancer Center, told a packed ASCO audience: "Ladies and gentlemen, biology has spoken—and we should listen." In particular, he noted, the extraordinarily high disease-free-survival (DFS) response seen with trastuzumab in the joint analysis "is certainly the most stunning result that I have seen in an adjuvant trial during my entire professional career . . . with a P value astonishing beyond belief."

Joint Analysis Permitted

Because NSABP-B31 and NCCTG-N9831 were so similar in design, FDA permitted a joint analysis, said NSABP study chair Edward Romond, MD. Dr. Romond, associate professor of medicine, University of Kentucky, Lexington, presented the findings from the joint analysis. NCCTG chair Edith Perez, MD, presented further analysis of NCCTG-N9831, and in a poster presentation she discussed interim cardiac safety data from that trial (abstract 556). Dr. Perez is professor of medicine, Mayo Medical School; director, Clinical Investigations; and director of the Breast Cancer Program, in the Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.

Women with operable breast cancer whose tumors overexpressed HER2 were enrolled in NSABP-B31 and NCCTG-N9831 in early 2000. The joint analysis is on data from 3,351 patients: 1,736 women in NSABP-B31 and 1,615 women in NCCTG-N9831. Half of the women in all arms had 1 to 3 positive nodes, and about 25% had 4 to 9 positive nodes. Half were ER+ and 40% were PR+. Tumor size was less than 4 cm in about 80% and less than 2 cm in about 40% of patients; 15% of patients had tumors larger than 4 cm.

In both trials, Dr. Romond said, AC was given as 60 mg/m² doxorubicin every 3 weeks and 600 mg/m² cyclophosphamide every 3 weeks, for four cycles, followed by paclitaxel. In NSABP-B31, paclitaxel was given at 175 mg/m² every 3 weeks for four cycles; in NCCTG-N9831, paclitaxel was given at 80 mg/m² every week for 12 cycles. Women with hormone-positive tumors received adjuvant hormonal therapy.

In both trials, trastuzumab was administered at a 4 mg/kg loading dose plus 2 mg/kg weekly for 51 cycles. NCCTG-N9831 had three study arms, two of which included trastuzumab given either sequentially (arm B) or concurrently (arm C) with paclitaxel at the 80 mg/m² dose. Data from arm B of N9831 were not included in the joint analysis, Dr. Romond explained, because the NSABP-B31 trial only looked at trastuzumab concurrent with paclitaxel. The study arm for the joint analysis, therefore, was AC followed by paclitaxel plus trastuzumab, and the control arm was AC followed by paclitaxel.

Unprecedented Results

Findings of the first interim intent-to-treat analysis of 395 DFS events were dramatic: Use of trastuzumab reduced the overall risk of local recurrence at 3 years by 52% (hazard ratio [HR] = 0.48, 2P = 3 ´ 10^-12), with 261 recurrences in women on chemotherapy alone vs 134 in those on trastuzumab. The absolute reduction in risk of recurrence by Kaplan-Meier analysis was 12% with trastuzumab at 3 years, and 18% at 4 years. No difference was seen in relative benefit from trastuzumab by age, hormone-receptor status, tumor size, number of positive nodes, or the trastuzumab protocol in which the patient was enrolled.

Time to first distant recurrence, assessed as a surrogate for overall survival, showed that trastuzumab plus chemotherapy reduced the overall probability of distant metastases by 53% at 3 years, (HR = 0.47, 2P = 8 ´ 10^-10). The estimated absolute reduction in risk with trastuzumab was 9% at 3 years and 16% at 4 years. Results at a median overall follow-up time of 2 years showed trastuzumab conferred a 33% reduction in mortality (HR = 0.67, 2P = .015). The estimated absolute reduction in risk of death with trastuzumab was 2.5% at 3 years and 4.8% at 4 years.

In a separate discussion of findings from NCCTG-9831, which assessed benefits of trastuzumab given sequentially vs concurrent with chemotherapy, Dr. Perez commented that "a 36% improvement in [disease-free] survival was seen with the concurrent vs the sequential approach" (P = .0114), with 84 recurrences seen among patients who received trastuzumab sequentially vs 53 among women who received it concurrently with chemotherapy, though "more follow-up is needed to determine whether this trend continues." A 13% decreased recurrence was seen with sequential vs control treatment (P = .2936, NS).

Cardiac Risk

While chemotherapy of the type given in the NCCTG and NSABP trials carries a risk of congestive heart failure (CHF) of less than 1%, investigators found in the joint analysis that the risk of CHF in women receiving chemotherapy plus trastuzumab was increased by 3% to 4%. In the separate cardiac safety analysis of NCCTG-N9831, a 2.2% greater incidence of cardiac events vs control was seen with sequential therapy, and a 3.3% increased incidence was seen with concurrent therapy, but at this point in the analysis the confidence intervals overlap, Dr. Perez pointed out.

Drs. Romond and Perez both underscored the importance of general cardiac monitoring in all patients if trastuzumab is to be used in this regimen in the adjuvant setting.

New Standard

"I’m very honored to have been a part of this trial," Dr. Perez told ONI. "These [HER2-positive women] are patients who might have poor prognosis despite antiestrogen treatment and the chemotherapeutic agents available. As physicians, we work in the hope that we will be able to positively impact people’s lives. It has been 7 years since we devised this study, but the results will affect treatment for breast cancer for years to come. We have changed the standard of care: Patients following resection should have chemotherapy plus Herceptin to minimize the risk that cancer could return. We may be able to improve on the answer, but now we have the answer."

In an interview, Dr. Perez said that many physicians and patients have contacted her about starting trastuzumab even if their chemotherapy was completed several years ago. "At this time, she said, "we do not know if there is a benefit of adding Herceptin beyond 7 weeks of completion of chemotherapy [as was done in the HERA study, described below], but our preliminary data suggest that it is best to add Herceptin along with paclitaxel instead of waiting to complete chemotherapy."

The randomized phase III HERA study evaluated duration of trastuzumab treatment in women with early-stage HER2-positive invasive breast cancer, and was conducted by investigators from the Breast International Group (BIG) and other non-BIG groups in collaboration with Roche.

HERA evaluated use of adjuvant trastuzumab given every 3 weeks for 12 or 24 months vs observation following a variety of standard adjuvant chemotherapy regimens given before or after surgery, and radiotherapy as applicable.

Both lymph-node-positive and lymph- node-negative patients were included in the trial, with about one-third of patients being node negative. Most patients received an anthracycline but did not receive a taxane.

The findings were presented at ASCO by lead investigator and chair of BIG Martine J. Piccart-Gebhart, MD, PhD, associate professor of oncology, Universite Libre de Bruxelles, and head of the Department of Medicine, Jules Bordet Institute, Brussels, Belgium.

The interim analysis in 3,387 women compared Herceptin vs observation but did not include a comparison of 12 months vs 24 months; these data are not mature but will become available later in the study.

An interim intent-to-treat analysis at 475 DFS events in 3,387 women at 1-year follow-up met its primary efficacy endpoint by showing that patients who received trastuzumab had significant improvement in DFS, with a 46% reduction in likelihood of recurrence (HR = 0.54, P < .0001); recurrences of all types (two-thirds, however, were distant metastases) were seen in 127 patients randomized to 12-month trastuzumab vs 220 randomized to observation. This reduction translates to an absolute improvement in 2-year DFS of 8%.

In discussing the DFS benefit according to subgroups, Dr. Piccart commented, "There does not appear to be significant heterogeneity of the impressive treatment benefit observed according to nodal status, type of prior adjuvant chemotherapy, receptor status, age, and region of the world." The secondary endpoint of overall survival has not yet been reached, possibly owing to short follow up, with 37 deaths in the observation group and 29 in the 12-month trastuzumab group.

Incidence of CHF was 0.5% in the 12-month trastuzumab group vs 0 for patients randomized to observation. The study’s Independent Data Monitoring Committee found no safety concerns, and patients will continue to be followed for side effects.

Breast Cancer Endgame

In discussing results of both the joint analysis and HERA, Dr. Sledge noted that "we can now see the outlines of the breast cancer endgame," with treatment targeting based on biological subsets of patients, such as those with ER and HER2 positivity; "upstream-downstream" targeting of the HER2 pathway; combinations with novel therapeutics such as anti-VEGF agents; and genomic/proteomic tailored strategies using older agents, eg, CMF [cyclophosphamide-methotrexate-fluorouracil] in NSABP-B20.

It is telling that in both the joint analysis and HERA, trastuzumab not only significantly reduced the risk of locoregional recurrence but also cut the risk of distant metastases, he said, pointing out that both trials illustrate "how rapidly patients suffer a recurrence of their disease in the absence of Herceptin."

Regarding cardiac risk , he said, "there is no question that the benefits of Herceptin far outweigh the risks here, but the price is real, and it has to be discussed with every patient receiving an anthracycline in close proximity to trastuzumab."