Pertuzumab and Other Agents Continue Progress in HER2+ Breast Cancer

Adam M. Brufsky, MD, PhD

The adjuvant treatment landscape for patients with HER2-positive breast cancer continues to grow, particularly following the recent FDA approval of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy, which was based on findings from the APHINITY trial.

In the phase III trial, the combination demonstrated a 3-year invasive disease-free survival (DFS) rate of 94.1%, which represented an 18% reduction in the risk of developing invasive disease or death. The benefit was more pronounced among higher-risk patients. The DFS rate for patients with node-positive disease was 92.0% with pertuzumab versus 90.2% with standard therapy.

OncLive: Can you discuss the impact of pertuzumab on the treatment landscape for patients with HER2-positive breast cancer?

In an interview with OncLive, Adam M. Brufsky, MD, PhD, a professor of medicine, associate chief of hematology/oncology, co-director of the Comprehensive Breast Care Center, associate director of clinical investigation, University of Pittsburgh, discussed the developing role of pertuzumab in HER2-positive breast cancer, as well as the impact of other agents in the field.Brufsky: Many oncologists in the United States will treat patients with neoadjuvant chemotherapy. The reason we have done that is because it was the only setting in which pertuzumab was approved until recently. If we decide someone needs anti-HER2 therapy and chemotherapy, we generally will give them either docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (TCHP) or Adriamycin and cyclophosphamide (AC) times 4 followed by THP. That would be 4 to 6 cycles of a pertuzumab-containing regimen.

[With the approval], another 11 to 13 doses can be given, which was the NCCN guideline. Many of us thought they were jumping the gun when they initially stated this without clinical data, but this has been proven to be true to some degree. There is a benefit with that since many are already using pertuzumab and this is just adding more.

However, we are not sure if it is necessary. Therefore, this becomes a test of 6 doses of pertuzumab, which has benefits in terms of pathologic complete response (pCR) and DFS versus an adjuvant trial where no one received pertuzumab. It is a 6- versus 17-dose issue. I am not sure how many of us are going to interpret this. The data from APHINITY, which this approval is based on, shows a modest or minimal benefit because the control arm did so well and we already have a 91% 5-year DFS.

Neratinib was also approved in this space in 2017. Can you discuss its role?

We are not sure if extra pertuzumab is necessary and many of us will struggle with that question. If an oncologist does not think it is necessary, instead of getting upfront adjuvant chemotherapy, many women will have surgery first. If they are lymph node negative with a 2-cm tumor, they will receive adjuvant paclitaxel or trastuzumab for 12 weeks. This will spare them more intensive chemotherapy and patients will still see a 4- or 5-year DFS. Many of us will give neoadjuvant therapy upfront with pertuzumab and decide whether we are going to give the next several doses. Mostly everyone will receive trastuzumab, whereas some patients may also receive pertuzumab if they are node-positive after neoadjuvant therapy or after surgery without neoadjuvant therapy. The women who will likely receive this are high-risk upfront. Women with positive lymph nodes who do not have a pCR rate, will receive 1 year of trastuzumab or pertuzumab and then will likely receive 1 year of neratinib.

Will neratinib be combined with other agents for this patient population?

Neratinib’s major adverse event (AE) is diarrhea. Even with intensive prophylaxis, it is still seen in 10% to 15% of patients as a grade 3 AE. A couple of months of antidiarrheal medications are needed to get the patient through the tachyphylaxis stage. I would not prescribe neratinib for women with node-negative estrogen receptor (ER)-positive or HER2-positive breast cancer. However, for someone who has a 5-cm tumor and it is still at 3- to 4-cm after 1 year of trastuzumab or pertuzumab, I would then give neratinib. This is around 20% to 25% of women.We don’t know. We could see that giving neratinib upfront with trastuzumab is the way to go. People are probably going to give it as [indicated] in the label. I do not believe that people will start giving it earlier.

Can you discuss tucatinib (ONT-380) for the treatment of patients with brain metastases in the HER2-positive population?

Again, it is important to see a patient through that 1 year of trastuzumab and/or pertuzumab. You will not want to combine pertuzumab with neratinib since they both have a diarrhea-associated risk. I interpret the neratinib data as something you give to women with higher-risk disease after 1 year of trastuzumab.All of the second- and third-generation HER2 tyrosine kinase inhibitors (TKIs) have more activity in brain metastases than lapatinib (Tykerb). Lapatinib was not an effective systemic therapy. It had very bad diarrhea that was not as controllable as it is with some of the newer agents.

Neratinib also treats brain metastases. In the NEfERT-T trial, women were treated upfront with neratinib and paclitaxel. The instances of brain metastases fell by 50%. There is clearly activity in the brain with those regimens. Additionally, ONT-380 does have activity and there are many trials investigating it in the metastatic setting.

What does the future treatment landscape look like for HER2-positive breast cancer?

In lung cancer, poziotinib has been successful for patients who have progressed on neratinib and have HER2-insertion mutations. The second-generation class of HER2 TKIs will likely be effective against brain metastases. The landscape looks exciting. We have taken a disease that was uniformly progressive and fatal within 1 year in the absence of trastuzumab to one that now has a median survival of close to 5 years with trastuzumab, pertuzumab, and chemotherapy as a first-line treatment. We have already made a huge difference.

Overall, we are at a point where the majority of early-stage HER2 disease is essentially cured. Those women who develop metastatic HER2-positive breast cancer can expect a median survival of 5 years or more.

The second-line therapies are also quite effective. We know that more than 50% of women with HER2-positive metastatic disease relapse in their brain. That is the next big movement. HER2 TKIs are a start, but we will have to see where we take them. There will possibly be an agent that we can combine with them or use in place of TKIs, which will also be important. There is a lot of interest in combining checkpoint inhibitors in HER2-positive breast cancer. Finally, there are new antibody-drug conjugates coming down the pipeline. The next big thing will be, what do we treat the brain with? [We need to] deal with the brain successfully—we are talking 7 to 8 years, if not longer of overall survival for metastatic disease. I am optimistic.

von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). J Clin Oncol. 2017;35(suppl; abstr LBA500).