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Pegram Highlights Progress in HER2+ Breast Cancer

Danielle Bucco
Published: Monday, Apr 09, 2018

Mark Pegram, MD
Mark Pegram, MD
It is an exciting time in drug development for patients with HER2-positive breast cancer, which is leading to new therapeutic strategies and FDA approvals, says Mark D. Pegram, MD.

For example, in December 2017, the FDA approved pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy as an adjuvant treatment for patients with HER2-positive breast cancer, based on data from the phase III APHINITY trial. The study demonstrated a 3-year invasive disease-free survival (iDFS) rate of 94.1% with the pertuzumab regimen compared with 93.2% for patients receiving trastuzumab, chemotherapy, and placebo (HR, 0.82; 95% CI, 0.67-1.00; P = .047). The 4-year iDFS rates were 92.3% versus 90.6%, respectively.

In an interview during the 2018 OncLive® State of the Science SummitTM on Breast Cancer, Pegram, associate director for clinical research and director of the breast oncology program at Stanford Women’s Cancer Center, discussed the evolving treatment paradigm of HER2-positive breast cancer.

OncLive: Please provide an overview of your presentation on HER2-positive breast cancer.

Pegram: It is a very exciting time in drug development for patients with HER2-positive breast cancer. We have seen recent FDA approvals for new approaches to treat patients with early-stage HER2-positive breast cancer.

In particular, there are data from the APHINITY trial now available and published. This led to the FDA approval of pertuzumab for these patients. APHINITY investigated the adjuvant use of pertuzumab in combination with chemotherapy plus trastuzumab. The difficulty with the trial is that it is a low-risk patient population to begin with. A lot of node-negative patients were studied in that trial, which led to the event rate being low. However, the trial met its statistical endpoint with confidence, but the absolute benefit of adjuvant pertuzumab is small. That trial needs longer follow-up to see more events and whether there is any difference in long-term outcomes.

I discussed extended adjuvant therapy with the small molecule inhibitor neratinib (Nerlynx). This has also been approved by the FDA. It had a similar efficacy signal to pertuzumab, and one could argue in absolute terms that there was 2.5% difference in the intent-to-treat population. That was sufficient to merit FDA approval.

The challenge of that drug is the fact that it has significant toxicity, some of which can be mitigated by concomitant medication with loperamide as it can lower gastrointestinal toxicity. However, now that it is approved by the FDA, the burden is on us as clinicians to make patients aware of the toxicity when considering it in a balanced discussion. In some cases, it is important to mention whether the toxicity and expense merits the small efficacy signal. It is not for everybody, but one can envision where this would be a fair consideration for high-risk patients.

The same can be said with pertuzumab. It is going to be restricted to higher-risk subsets of patients and does not need to be used for everyone. Clinical judgement will be imperative. 

Next, I spoke about patients with HER2-positive breast cancer who have brain metastases. There was a study presented at the 2017 ASCO Annual Meeting looking at high doses of trastuzumab past the first step of a Simon’s two-stage study design. That has now finished enrolling 40 patients in a phase II trial, but the results are pending.

There are also new small molecule HER2 inhibitors that are more specific for HER2 and do not have as much [toxicity] as other drugs, such as lapatinib (Tykerb) or neratinib. In particular, tucatinib, previously known as ONT-380, is a pure HER2 inhibitor that doesn't inhibit EGFR. Therefore, the toxicities of diarrhea and skin rash are not there to the extent that you see with existing FDA-approved HER2 inhibitors. That might be an interesting path forward for patients with HER2-positive breast cancer who have brain metastases. That molecule is being studied in an ongoing randomized registration trial.

I also discussed published data with trastuzumab emtansine (T-DM1; Kadcyla) in HER2-positive breast cancer for patients with brain metastases, and our anecdotal responses to the drug. It is very well tolerated and is approved by the FDA. That could be a path forward for selected patients.

I spoke about new immune-oncology approaches. Everyone has heard about the PD-1/PD-L1 inhibitors, and certainly that is moving forward in all subtypes of breast cancer, including the HER2-positive subtype. That area is being covered with ongoing studies.

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