Promising Adjuvant Therapies Emerge in HER2+ Breast Cancer

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).

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

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.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.

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

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.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.

What would you like to see occur in the next 5 to 10 years in the adjuvant setting?

The other question is, “If it’s causing this much toxicity, is the additional 2%, 4%, or 9% benefit worth it?” Historically, when we look at things we don’t question anymore after they become standard of care, such as use of taxanes after anthracyclines in node-positive patients, the benefit, in terms of survival benefit, has been 3% to 5% by those maneuvers. It does not hit double digits. If you look at some of the pivotal trastuzumab-based trials, the benefit, in terms of lives saved or additional patients cured at the end of a 10-year follow-up, is 4% to 9%. Single-digit survival improvement has been the ballpark, and neratinib falls right into that ballpark.Relapses are fewer and fewer, now that our therapies are more effective, and it takes a very long time to get to the event number, and you need to have lots of events to detect small differences.

A recent article published in the Journal of Clinical Oncology concluded that pertuzumab was found to not be a cost-effective drug. Do you agree or disagree with the authors’ findings?

What potential could margetuximab have in the adjuvant setting?

Perhaps, the neoadjuvant setting is where we ought to be testing more things to get those treatments to patients faster. The prime example with this is pertuzumab being proven effective in the neoadjuvant setting. Now, an expert panel is endorsing it for use in the adjuvant setting.Those are very important considerations; the cost of drugs is becoming increasingly important and it is going up. For the first time, the NCCN is coming up with cost-conscious recommendations. In other words, they are giving tiered recommendations by cost, and it will be interesting to see what that is. Previously, we have taken the position that this is something for society to decide, congress to decide, and politicians to decide—not for doctors to decide. We only need to focus on the scientific part of treatments.It is showing efficacy, so that is a good start. When something is effective and well tolerated, then you hope to either combine it or concurrently sequence it with the existing therapies. We really need to first see robust data in the metastatic setting that shows the extent of its efficacy and tolerability, and I don’t think there will be any problem showing that. Then, you have to know how to combine it and with what in the adjuvant setting.

References

1. Chan A, Delaloge S, Holmes FA, et al. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). J Clin Oncol. 2015;33 (suppl; abstr 508).
2. O'Sullivan CC, Bradbury I, Campbell C, et al. Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2—positive early breast cancer and tumors ≤2 cm: A meta-analysis of the randomized trastuzumab Trials. J Clin Oncol. 2015;33(24):2600-2608.