Adjuvant Treatment Options for HER2+ Breast Cancer Continue to Expand


Although much success has been seen, 15% of patients with HER2-positive breast cancer will recur. Outcomes for those patients need to be improved, said Sara M. Tolaney, MD.

Advancements in 2017, including the FDA approval of neratinib (Nerlynx) and the recent priority review designation of pertuzumab (Perjeta), showcase an evolving treatment landscape for patients with HER2-positive breast cancer.

In September 2017, a supplemental biologics license application for pertuzumab in combination with trastuzumab (Herceptin) and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer was granted priority review. Pertuzumab was initially approved for use in combination with trastuzumab and docetaxel as a neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer.

Although much success has been seen, 15% of patients with HER2-positive breast cancer will recur. Outcomes for those patients need to be improved, said Sara M. Tolaney, MD.

In an interview with Oncology Nursing News, Tolaney, instructor of medicine, Harvard Medical School, attending physician of medical oncology, Dana-Farber Cancer Institute, discussed the state of adjuvant treatment for patients with HER2-positive breast cancer.

What does the adjuvant landscape look like in HER2-positive disease?

Tolaney: [Adjuvant treatment for HER2-positive breast cancer] has evolved over the past few years. We have seen outcomes from 6 pivotal studies that have shown that adding trastuzumab to chemotherapy dramatically improves disease-free and overall survival. Despite this, 15% of patients with HER2-positive cancer still recur. There has been a need to try to do more to improve outcomes. There are 2 particular drugs that I focused on; one was pertuzumab and the other was neratinib.

With pertuzumab, we have data in the metastatic setting from the CLEOPATRA study, which demonstrated that adding pertuzumab to a taxane and trastuzumab dramatically improves survival by about 16 months. We then had data in the preoperative setting from both NeoSphere and TRYPHAENA, which suggested that adding pertuzumab improved rates of pathologic complete response.

This led to the FDA approval of pertuzumab in the preoperative setting, but we are still waiting for data from the definitive study, which is the APHINITY trial—that was just presented earlier this year. This was a positive study, in the sense that it did technically show that there was a benefit to adding pertuzumab to chemotherapy and trastuzumab, with about a 20% reduction in rates of invasive disease-free survival (DFS). However, if you look at the absolute benefit—if you look at 4-year outcomes—you can see that the absolute difference is only 1.7%. The majority of benefit occurs in those patients with node-positive tumors and those with hormone receptor (HR)-negative disease.

This has left us with the question, “How do we clinically incorporate pertuzumab in our patients who have HER2-positive tumors?” Which patients should be getting it? It becomes even more complicated since we usually administer preoperative therapy in the HER2-positive setting, particularly in patients with stage II and III tumors. One way that I have interpreted it is using pertuzumab in those patients who are at a particularly high-risk for recurrence. These are those patients who have node-positive tumors and those who have HR-negative tumors.

The other agent that has also achieved an FDA approval recently was neratinib. This was based on the ExteNET trial, which looked at 1 year of neratinib after a patient has completed standard chemotherapy and trastuzumab. This study showed that adding neratinib was associated with a significant improvement in DFS—a little over a 2% absolute difference in the 2 arms. What I thought was interesting in the ExteNET trial was that the majority of benefit was seen in the patients who had HR-positive disease. The 5-year outcomes were recently presented at [the 2017 ESMO Annual Congress], and the absolute difference in the arms in the HR-positive group was a little over 4%, which was pretty significant.

The catch with neratinib has been the toxicity, which has been about a 40% rate of grade 3 diarrhea. It is important to note that this trial did not use any antidiarrheal prophylactics, so there are some data to suggest that if you use Imodium, budesonide, or colestipol, the rates of diarrhea are lower—but it is still a real toxicity.

Using neratinib in the adjuvant setting is reasonable in patients who are at high risk, such as those who have node-positive disease and, given the subgroup analysis, patients who have HR-positive disease. It is important to realize that the ExteNET population is a pertuzumab-naïve population, so it shouldn't be used in patients who have previously received pertuzumab.

What should physicians take into consideration if they decide to take this route?

It is hard because APHINITY is a positive study that showed benefit, but the benefit was small. Honestly, the financial cost is high. Pertuzumab costs $100,000 and, when they calculated the number for the amount that you would need to prevent just 1 recurrence, it comes out at $5.6 million. Therefore, the costs for society, if we started adapting and using pertuzumab in all of our stage II/III HER2-positive patients, is enormous. We need to figure out which patients need pertuzumab, so the biomarker work that will come out of APHINITY will be very important. For now, given the data that we do have, picking those patients who are thought to be at highest risk is probably the way to go.

What studies are investigating neratinib in combination?

In the metastatic setting, there is a trial that compared capecitabine and lapatinib (Tykerb) to capecitabine and neratinib. Certainly, one would think that a potential problem with this combination would be a lot of diarrhea, given that both agents by themselves can give a lot of diarrhea. However, this trial did institute an Imodium prophylaxis throughout, so it was tolerable. We are awaiting the results of that trial, and that will be interesting.

There is also an ongoing study combining neratinib with hormonal therapy in the metastatic setting. Given the subgroup analysis that we saw from ExteNET, suggesting that the majority of benefit was in the ER-positive population, this trial is randomizing metastatic HR-positive/HER2-positive patients to either neratinib and fulvestrant (Faslodex) or neratinib alone. This is to tease out whether this activity may be from synergistic activity with hormonal therapy. That will be interesting to see.

Anecdotally, how have you seen the approval of neratinib impact clinical practice?

I had treated a lot of patients on the ExteNET trial, and the diarrhea that occurred tended to occur early. Therefore, [use it] if you can manage it; we have since learned how to use Imodium to prevent diarrhea. You have to keep in mind that these are patients who are in the adjuvant setting and they have already completed 1 year of chemotherapy and trastuzumab. It is a long road to go through another year of HER2-directed therapy, particularly an agent that is associated with diarrhea, requires management of toxicity, and sometimes [requires] dose modification. It is a lot to put a patient through, so we have to be mindful about selecting which patients need such extended treatment.

Are there any other novel HER-targeted agents in the pipeline?

One interesting novel HER2 agent is tucatinib (ONT-380). That agent targets HER2, but it does not seem to have the toxicity that we see with lapatinib, where you also hit EGFR and patients get rash and diarrhea. Therefore, it’s a potent HER2 inhibitor, but without the diarrhea toxicity. That agent looks very promising; it also has CNS penetration. There is a randomized trial, the HER2CLIMB study, which is currently enrolling patients who have metastatic HER2-positive disease. The trial is randomizing these patients to capecitabine and trastuzumab, or capecitabine, trastuzumab, and tucatinib. We will see; it is an exciting drug.

Looking toward the future, how is the treatment of HER2-positive breast cancer progressing?

There are a lot of interesting drugs being tested, particularly right now in the metastatic setting. Two additional areas that will possibly change the future of management are immunotherapy and CDK 4/6 inhibition. We will see data at the 2017 San Antonio Breast Cancer Symposium from the PANACEA trial, which looked at the combination of pembrolizumab (Keytruda) and trastuzumab in patients who have metastatic HER2-positive disease. There has also been a bunch of data that have been done looking at CDK 4/6 inhibition in HER2-positive disease. Some early preclinical work has suggested that trastuzumab-resistant patients may particularly be sensitive to CDK 4/6 inhibition. Currently, there is an ongoing randomized trial—the monarcHER trial—which is looking at abemaciclib (Verzenio) in the trastuzumab-resistant population, and comparing with physicians-choice chemotherapy. That trial should, hopefully, complete accrual early next year, so we will see.

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