Sara Tolaney, MD, MPH
With the FDA approval of neratinib (Nerlynx) earlier this year, and the recent priority review designation of pertuzumab (Perjeta), treatment options for patients with HER2-positive breast cancer continue to advance.
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 OncLive
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.
OncLive: 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 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.