Concurrent Trastuzumab with Chemotherapy Optimal Regimen

San Antonio, TX—Based on a positive risk/benefit ratio in long-awaited results of the NCCTG N9831 trial, investigators recommend incorporation of trastuzumab (Herceptin) concurrently with the taxane (paclitaxel) portion of chemotherapy in adjuvant treatment of women with HER2-positive breast cancer. NCCTG N9831 tested chemotherapy alone versus sequential or concurrent addition of 52 weeks of trastuzumab in 3505 women (Table). “This is the only trial developed to define the optimal way to incorporate Herceptin in the context of adjuvant chemotherapy,” said lead investigator Edith A. Perez, MD, Mayo Clinic, Jacksonville, Florida.

Table. N9831 Schema (N = 3505)

A. Dosage

Drug

Abbreviation

Doxorubicin 60 mg/m²

A

Cyclophosphamide 600 mg/m²

C

Paclitaxel 80 mg/m²

T

Herceptin 4 mg/kg loading dose followed by 2 mg/kg

H

B. Treatment Arms

Cohort

First

Second

Third

Arm A (n = 1087)

AC every 3 weeks for 4 cycles

T weekly for 12 weeks

Arm B (n = 1097)

AC every 3 weeks for 4 cycles

T weekly for 12 weeks

H weekly for 52 weeks

Arm C (n = 949)

AC every 3 weeks for 4 cycles

TH weekly for 12 weeks

H weekly for 40 weeks

Reporting earlier study milestones, Dr Perez noted that 2 years after the trial’s 2000 inception, Arm C of the trial was closed temporarily for cardiac analysis, which revealed cardiac toxicity rates of 0.3%, 2.8%, and 3.3% for Arms A, B, and C, respectively.

This year, the Independent Data Monitoring Committee released the second interim analysis of control Arm A versus Arm B and the first interim analysis of Arm B versus Arm C. Regarding the Arm A versus Arm B comparison, Dr Perez said data from patients who had been allowed to crossover in 2005 from Arm A to therapy with H or from Arm B to concurrent H were censored.

In the arm A versus arm B comparison, after a median follow-up of 5.5 years (with 75% of patients followed for a minimum of 5 years), disease-free survival (DFS) improved with the addition of sequential trastuzumab (P = .0005) with an estimated hazard ratio (HR) of 0.70 (95% confidence interval, 0.57-0.86). DFS was 80.1% in the sequential therapy arm (AC

→

T

→

H, 164 events) and 71.9% in the AC

→

T arm (222 events). Further analysis adjusted DFS for patient characteristics and showed significant benefits for Arm B for older women; those with a higher number of positive nodes, larger tumor size, and estrogen—receptor negativity; and for sequential treatment versus chemotherapy alone.

DFS did differ with respect to the timing of trastuzumab therapy added to AC

→

T. Comparing sequential therapy versus concurrent therapy (AC

→

T H

→

H), Dr Perez said DFS was 84.2% for concurrent therapy (138 events) and 79.8% for sequential therapy (174 events; HR, 0.77; P = .0190). After adjustments for patient characteristics, standing out as predictive parameters were number of positive nodes, tumor size, estrogen receptor—negativity and treatment regimen (concurrent versus sequential).

HRs for overall survival favored adding trastuzumab to chemotherapy and using concurrent trastuzumab over sequential, but differences were not statistically significant (AC

→

T versus AC

→

T

→

H: unadjusted HR, 0.86; 95% CI, 0.65-1.13; AC

→

T

→

H versus AC

→

T H

→

H: unadjusted HR, 0.79, 95% CI 0.59-1.08).

Dr Perez concluded that DFS is significantly improved with the addition of 52 weeks of trastuzumab to AC

→

T. In addition, there is a statistically significant 33% reduction in the risk of an event with the sequential addition of trastuzumab following AC

→

T. Starting trastuzumab concurrently with a taxane rather than sequentially is associated with a strong favoring trend in event risk reduction (25%). “We recommend that adjuvant trastuzumab be incorporated in a concurrent fashion with the taxane portion of chemotherapy,” Dr Perez said. “The goal was to decrease the risk of cancer recurrence, and we have shown that concurrent use is the best way to achieve that,” she said. SABCS Abstract 80.