Treatment Options Expanding in HER2-Positive Breast Cancer

Treatment options for patients with HER2-positive breast cancer continue to expand, especially after the Food and Drug Administration (FDA) approval of Nerlynx (neratinib) earlier in 2017 and the more recent priority review designation of Perjeta (pertuzumab).

In September 2017, a supplemental biologics license application for Perjeta in combination with Herceptin (trastuzumab) and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer was granted priority review. Perjeta was initially approved for use in combination with Herceptin 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 percent of patients with HER2-positive breast cancer will recur. Outcomes for those patients need to be improved, said Sara M. Tolaney, M.D.

In an interview with CURE during the 35th annual CFS^®, 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?

[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 Herceptin to chemotherapy dramatically improves disease-free and overall survival. Despite this, 15 percent 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 Perjeta and the other was Nerlynx.

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

This led to the FDA approval of Perjeta 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 Perjeta to chemotherapy and Herceptin, with about a 20 percent reduction in rates of invasive disease-free survival (DFS). However, if you look at the absolute benefit — if you look at four-year outcomes — you can see that the absolute difference is only 1.7 percent. 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 Perjeta 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 2 and 3 tumors. One way that I have interpreted it is using Perjeta 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 Nerlynx. This was based on the ExteNET trial, which looked at one year of Nerlynx after a patient has completed standard chemotherapy and Herceptin. This study showed that adding Nerlynx was associated with a significant improvement in DFS—a little over a 2 percent absolute difference in the two 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 five-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 percent, which was pretty significant.

The catch with Nerlynx has been the toxicity, which has been about a 40 percent 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 Nerlynx 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 Perjeta -naïve population, so it shouldn't be used in patients who have previously received Perjeta.

What studies are investigating Nerlynx in combination?

In the metastatic setting, there is a trial that compared capecitabine and Tykerb (lapatinib) to capecitabine and Nerlynx. 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 Nerlynx 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 Nerlynx and Faslodex (fulvestrant) or Nerlynx 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 Nerlynx 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 one year of chemotherapy and Herceptin. 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 Tykerb, 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 Herceptin, or capecitabine, Herceptin 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 Keytruda (pembrolizumab) and Herceptin 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 Herceptin -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 Verzenio (abemaciclib) in the Herceptin -resistant population, and comparing with physicians-choice chemotherapy. That trial should, hopefully, complete accrual early next year, so we will see.