Practice Update | Onology

EDITOR’S PICKS 8

Adjuvant pertuzumab and trastuzumab in early HER2+ breast cancer The New England Journal of Medicine Take-home message

COMMENT By Lee S. Schwartzberg MD, FACP D oes dual anti-HER2 blockade add enough benefit to justify its use in the adjuvant setting of HER2-positive early-stage breast can- cer (ESBC)? The APHINITY trial tested the addition of pertuzumab to standard chemotherapy and 1 year of adjuvant trastuzumab. A statistically significant but clinically small benefit was seen at 3 years of follow-up, with a 1% improve- ment in invasive disease-free survival from 1 year of pertuzumab. The dis- tant recurrence rate was also 1% better. In subgroup analysis, node-positive patients and ER-negative patients had more (~2%) benefit with pertuzumab added. On the negative side of the ledger, pertuzumab added more all grade and grade 3 diarrhea, and a small increase in cardiac events. It can be argued that, based on these results, the decision to add pertuzumab to a standard adjuvant regimen for HER2-positive ESBC should be made carefully and not indiscriminately. Cer- tain clinically high-risk groups, such as patients with stage III or lower node-positive ER-negative/HER2-pos- itive cancers appear to derive benefit from the dual HER2 blockade. On the other hand, smaller, stage I HER2-posi- tive breast cancers do very well with just 12 weeks of paclitaxel and 1 year of tras- tuzumab, as evidenced by the long-term follow-up of the APT trial presented at ASCO 2017; so, additional therapy is unlikely to show a benefit. Like in all of medicine, one size does not fit all in the adjuvant treatment of ESBC. Some HER2-positive patients require dual anti-HER2 therapy, but many do well without incremental therapy, and, considering the additional cost and life impact of more treatment, they should not receive it. Overall, pertuzumab is a small step for- ward in HER2-positive ESBC compared with a big jump in the first-line metastatic setting with this drug as evidenced by the CLEOPATRA results.

• This study investigated whether pertuzumab added to adjuvant trastuzumab and chemotherapy would improve clinical outcomes among patients with node-positive or high-risk node-negative HER2-positive operable breast cancer. Disease recurred among 7.1% of patients in the pertuzumab group and 8.7% of patients in the placebo group (HR, 0.81; P = 0.045). The 3-year rate of invasive disease-free survival in the node-positive cohort was 92.0% with pertuzumab compared with 90.2% with placebo (HR for an invasive-disease event, 0.77; P=0.02). The 3-year rate of invasive disease-free survival in the node-negative cohort was 97.5% with pertuzumab and 98.4% with placebo (HR for an invasive-disease event, 1.13; P=0.64). The treatment effect was more evident among patients at higher relapse risk because of nodal involvement or hormone receptor-negative status, although it was homogeneous statistically among all the subgroups. • The results demonstrate that pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival rates among patients with HER2-positive breast cancer.

Abstract BACKGROUND Pertuzumab increases the rate of pathological complete response in the preop- erative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemother- apy, improves outcomes among patients with HER2-positive early breast cancer. METHODS We randomly assigned patients with node-positive or high-risk node-nega- tive HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed

a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Dis- ease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-dis- ease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as com- pared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunc- tion were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%). CONCLUSIONS Pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 2017 Jun 05;[EPub Ahead of Print], G von Minckwitz, M Procter, E de Azambuja, et al.

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