Promising Adjuvant Therapies Emerge in HER2+ Breast Cancer

Gina Columbus @ginacolumbusonc
Published Online: Tuesday, Nov 24, 2015

Mohammad Jahanzeb, MD

Mohammad Jahanzeb, MD

Longer duration of treatment does not necessarily equal stronger benefit in patients with HER2-positive breast cancer, explains Mohammad Jahanzeb, MD.

Moreover, an emergence of therapies in the adjuvant setting, including trastuzumab (Herceptin) and neratinib, has shown more durable responses in patients.

For example, results from the phase III ExteNET study found that patients with early-stage, HER2-positive breast cancer who were treated with neratinib immediately following adjuvant trastuzumab plus chemotherapy resulted in a 33% reduction in the risk of disease recurrence.1 In a 2-year analysis, data showed that the invasive disease-free survival was 93.9% in the neratinib arm versus 91.6% in the placebo arm (HR, 0.67; 95% CI, 0.50-0.91; P = .009).

Trastuzumab has also shown efficacy in the adjuvant setting. In a meta-analysis of data from 5 clinical trials that was published in the Journal of Clinical Oncology,2 including the HERA, N9831, NSABP-B31, PACS-04, and FinHER trials, patients with HER2-positive breast cancer that was ≤2 cm experienced an improvement in disease-free and overall survival (OS) when treated with adjuvant trastuzumab.

Here, 8-year disease-free survival was improved by 9.4% for patients with HER2-positive and HR-negative tumors ≤2 cm treated with trastuzumab compared with those who did not receive HER2 inhibition (HR, 0.66; 95% CI, 0.49-0.88; P <.001). Also, OS at 8 years was increased by 8.8% with trastuzumab versus without (HR, 0.59; 95% CI, 0.47-0.74; P <.001).

In an interview with OncLive, Jahanzeb, medical director of Sylvester Comprehensive Cancer Center and professor of Medicine at University of Miami Miller School of Medicine, discussed emerging strategies in the adjuvant treatment of patients with HER2-positive breast cancer.

OncLive: What advancements have taken place in the adjuvant setting of HER2-positive breast cancer?

Jahanzeb: It is wonderful to have trastuzumab in the adjuvant space, which is the current standard treatment. It is standard of care to administer 12 months of trastuzumab-based therapy in addition to chemotherapy, ideally concurrently.

However, we still have upwards room because we do not cure everybody. Therefore, there have been several attempts made to improve the cure rate of HER2-positive breast cancer by adding things to trastuzumab, or extending its duration. We found that giving patients trastuzumab for 2 years instead of 1 does not matter. There is no additional benefit to extend the duration.

The opposite question has also been asked, “Could we get away with shorter duration?” An earlier trial has shown that 9 weeks of therapy is beneficial. Another trial from France showed that 6 months is not noninferior, so 12 months remains the standard until a couple of remaining trials that have not yet been reported show something different.

Meanwhile, the FDA approved pertuzumab in the neoadjuvant setting. However, the NCCN has included a footnote in their guidelines, which states that you can actually give pertuzumab in the adjuvant setting if the patient has not received it in the neoadjuvant setting. This has been a question in the adjuvant APHINITY trial, which accrued thousands of patients, and was closed to accrual in August 2013. We don’t know the results yet, but we already have a guideline to be able to use pertuzumab.

Please discuss the efficacy data for adjuvant neratinib and how should the drug is administered.

Most recently, we saw the results of the ExteNET study, which was a very large randomized trial. Patients received 12 months of neratinib, an oral tyrosine kinase inhibitor, following 12 months of trastuzumab. These women could have come off of trastuzumab within the past 12 months; on average, they had been off for about 4 months before they received neratinib. It was a placebo-controlled trial that, so far, has shown a 2% absolute benefit at the 2-year mark. In the hormone receptor–positive population, there was a 4% absolute benefit. There was an unplanned analysis, and if you looked at those patients who had centrally confirmed HER2-positivity by FISH and with hormone receptor positivity, their benefit was actually 9%.

The main problem was diarrhea. In the 95.4% who experienced the toxicity, 39.9% were grade 3/4 diarrhea, which can be managed by tapering down from 16 mg in the first month to 6 mg. Grade 3/4 diarrhea does not need to occur in nearly 40% of patients.




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