Adjuvant Options Expand in HER2+ Breast Cancer, But Questions Remain

Vik Gorantla, MD

The outlook for HER2-positive breast cancer has significantly improved over the past few years, with the emergence of targeted therapies that have been shown to vastly improve patient outcomes. Moreover, recent FDA approvals in the adjuvant setting have added to the armamentarium, explained Vik Gorantla, MD.

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 who were at high risk for recurrence. The decision was based on data from the phase III APHINITY trial, in which the pertuzumab combination demonstrated a 3-year invasive disease-free survival (iDFS) rate of 94.1% compared with 93.2% seen in those who were given trastuzumab/placebo plus chemotherapy.

“Trastuzumab really changed the landscape of treatment for patients with HER2-positive breast cancer. We have done well in this patient population, but now, we want to see if we can do better,” Vik Gorantla, MD, said. “Pertuzumab has been approved in the metastatic setting and in the neoadjuvant setting, so logically, it makes sense to see if we can use it in the adjuvant setting to get even better results. Can we do better?”

The FDA also approved neratinib (Nerlynx) for the extended adjuvant treatment of patients with early stage, HER2-positive breast cancer following postoperative trastuzumab in July 2017.

OncLive^®: Could you share insight on the APHINITY trial and how this study’s results have informed your practice?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer, Gorantla, a clinical assistant professor at University of Pittsburgh Medical Center, Hillman Cancer Center, discussed ongoing developments in the adjuvant setting for patients with HER2-positive breast cancer.Gorantla: This clinical trial was started in 2011; it was an international trial with more than 500 centers and 4800 women who were randomized 1:1 to receive pertuzumab, trastuzumab, and chemotherapy versus trastuzumab plus chemotherapy and placebo. The primary endpoint was iDFS. The secondary endpoint was overall survival (OS) and the trial was adequately powered to meet this objective. The science was good science—it was a well-run and well-defined study.

Is the duration of the pertuzumab regimen up for debate, or is it strictly 1 full year?

What would you say are the unanswered questions with the APHINITY trial?

Again, randomization was performed, and, of course, the data were presented in 2017 and showed that the study met its primary endpoint by a couple of percentage points; it was statistically significant. The benefit was really seen in node-positive patients and also in potentially estrogen receptor (ER)— and progesterone receptor (PR)–negative patients; that’s where we saw the most benefit, and that is the population for which we most probably will be using this drug.It’s strictly 1 year at this point. But again, it has been a very controversial subject. Was the benefit really worth it? There has been a lot of debate about it. Again, it was a well-designed study; it met its primary endpoint. The FDA has approved the regimen. Now, patient selection is going to be the key. Personally, I think patients who have ER-/PR-negative, node-positive disease are the patients who I would recommend this regimen for.What do we do for patients who have residual disease? What do we do for those who received neoadjuvant therapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP)? Those are the questions that are unanswered. Again, the OS data are still maturing; it has only been 4 years since the data have come out.

Another question has to do with the long-term implications. If you were exposed to pertuzumab and if the disease comes back, what are you going to do? If you expose them again to pertuzumab, does prior exposure to pertuzumab affect your outcome when you add on pertuzumab later?

Moving forward, what is the biggest challenge that you would like to see addressed?

What is needed to drive subsequent progress in this patient population?

Of course, now, we live in a world where we have to look at the cost of therapy. Cost is not only physical and emotional toxicities, but also financial toxicities—the cost of the drug. That’s another aspect that we are looking at very closely now. When we talk about physical toxicities, overall, the biggest issue with this drug was really the diarrhea—approximately a 7% increase in diarrhea compared with trastuzumab—but it can be easily managed.What happens when the disease comes back? This is a disease that relapses in the visceral organs, especially in the brain. What do we do in those patients? We need drugs that have better blood-brain barrier penetration. We have had lapatinib in the past and there are some data for neratinib and potentially ado-trastuzumab emtansine (T-DM1; Kadcyla).We need to balance toxicity and benefit—that’s really the crux of it. [We need] better understanding of the biology and better understanding of the pathways. Additionally, we are only targeting 2 epitopes, if you think about it: trastuzumab targets one epitope, while pertuzumab targets another one. Are there other ways of doing this? What about the regions of HER1, HER3, HER4—is there any role there? That would be something to look at.

von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. doi: 10.1056/NEJMoa1703643.