William J. Gradishar, MD
The roles of CD4/6 and PI3K inhibitors and immunotherapy are being defined in subsets of patients with estrogen receptor (ER)–positive, HER2-negative breast cancer and triple-negative breast cancer (TNBC), respectively, leading to updates in the breast cancer space.
For example, the addition of the PI3K inhibitor alpelisib to fulvestrant (Faslodex) as a treatment for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer who harbor PIK3CA mutations demonstrated an improvement in median progression-free survival (PFS) in the phase III SOLAR-1 trial.1
Most recently, in March 2019, the FDA approved atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) for the frontline treatment of patients with PD-L1–positive TNBC. The decision is based on results of the phase III IMpassion130 study, in which the combination led to a 40% reduction in the risk of progression or death versus nab-paclitaxel alone in this patient population.2
“We will now be graced with the dilemma of which patients should receive these drugs,” said William J. Gradishar, MD, on the atezolizumab approval. “Clearly TNBC, clearly PD-L1–positive [tumors], but every one of these checkpoint inhibitor trials has their own unique diagnostic to define PD-L1-positivity.”
In addition to this approval, Gradishar discussed some of the latest updates for both patients with ER-positive or -negative and HER2-negative breast cancer during his presentation at the 2019 NCCN Annual Conference. He also focused on agents emerging in the pipeline for these patient subsets and how they will fit into the treatment landscape.
In an interview with OncLive
during the meeting, Gradishar, chief of hematology and oncology, Department of Medicine, Betsy Bramsen Professorship of Breast Oncology, professor of medicine (hematology and oncology), Northwestern University's Feinberg School of Medicine, discussed the latest updates in HER2-negative advanced breast cancer and the role of molecular assays in this space.
OncLive: What are the updates in the ER-positive breast cancer space?
: Within this space of ER-positive disease, we’ve seen the evolution of endocrine therapy go from a list of monotherapy options—meaning endocrine therapy alone—to the introduction of a targeted therapy added to endocrine therapy about 5 years ago. In this case, it was the mTOR inhibitor everolimus (Afinitor). In the last few years, there has sort of been this explosion within the area of CD4/6 inhibitors and how their addition to endocrine therapy has markedly enhanced PFS, be it in the frontline setting or the second-line setting.
We now have 3 approved CD4/6 inhibitors, although there are subtleties between them in terms of their pharmacokinetics or their toxicities. The clinical trials were designed in a similar fashion, and they are all perfectly consistent in showing that by adding a CD4/6 inhibitor, you significantly improve PFS compared with endocrine therapy alone. The effect is more profound in the first-line setting than in the second-line setting, but there is a consistent effect seen wherever you use them.
What has happened is that they are much more commonly used with endocrine therapy than using endocrine therapy alone. That said, there are still patients who are appropriate for endocrine therapy alone. We are not dogmatically told that we must use a CD4/6 inhibitor, but if we have an appropriate patient, adding it will incrementally improve outcomes.
One of the issues is whether the PFS benefit translates into overall survival (OS) benefit. We don’t know that yet. There are some hints that it is going in that direction with the palbociclib (Ibrance) trial; we will hear more data on that at the 2019 ASCO Annual Meeting with ribociclib (Kisqali). We also don’t necessarily know if a CD4/6 inhibitor should be continued after disease progression or switch to a different CD4/6 inhibitor. These questions are being addressed in clinical trials now.
The other area in ER-positive disease is new drugs for which we might anticipate approvals in the next year or 2. PI3K inhibitors have been looked at in clinical trials for the last couple of years, and early trials showed a hint of activity but not sufficient to get too excited about. Furthermore, some of the off-target side effects made them unattractive.
However, now with the SOLAR-1 trial, we see that in those patients who are ER positive and have a PIK3CA
mutation, the addition of the PI3K inhibitor alpelisib can add to the effects of endocrine therapy and significantly improve PFS. If you use it in a patient [who does not have a PIK3CA
mutation], you won’t see that effect. It speaks to the issue of tailoring your therapy.
Again, there are some side effects, such as hyperglycemia, but these are generally manageable. In the earlier trials with PI3K inhibitors, gastrointestinal symptoms were much more common. If one was predicting, this could very well be the next drug that is approved in this space. I don’t have any inside knowledge, but the “tea leaves” speak to this sort of a trial getting the attention of the FDA, perhaps in a favorable way.
There are oral selective estrogen receptor degraders (SERDs); we have an intramuscular SERD fulvestrant, that has been around for 20 years. However, oral SERDs have developed and demonstrated activity in patients who have received prior endocrine therapy. There is no approved drug, but that class of drugs is being evaluated.
What updates have we seen for patients with ER-negative, HER2- negative breast cancer?
In the area of ER-negative, HER2-negative breast cancer—sort of TNBC—it has sort of been chemotherapy forever. We haven’t had any new therapies. Generally, if you look at the guidelines, it’s a list of chemotherapy drugs.
That began to change about 1 or 2 years ago because PARP inhibitors were reevaluated after the early enthusiasm waned and other drugs in that class were evaluated in clinical trials. Olaparib (Lynparza) was approved [last year] for patients with germline BRCA-mutated tumors, and the trial [results showed that if] you gave olaparib monotherapy versus chemotherapy of physician’s choice in patients with metastatic disease, olaparib performed better. PFS was improved, overall response rate (ORR) was improved, and so that became a part of the guideline.
More recently, talazoparib (Talzenna) another PARP inhibitor, was also approved and showed the same sort of effect of improving PFS and ORR. Again, there are subtleties between the drugs, both in terms of toxicities and how they are administered, but the effects seem similar.
The biggest thing that has been introduced in the guidelines in the last 10 days is the approval of atezolizumab for breast cancer. We’ve had checkpoint inhibitors available in other malignancies for some time. Breast cancer did not appear to be the obvious attractive malignancy where these drugs might be useful. In certain ER-positive TNBC subsets, there were some hints of higher tumor-infiltrating lymphocytes; checkpoint inhibitor monotherapy trials done in that population showed some modest activity. The IMpassion130 trial looked at nab-paclitaxel alone or nab-paclitaxel plus atezolizumab. What the data showed is that in those patients who had PD-L1–positive tumors, there seemed to be an impact in using a checkpoint inhibitor. In fact, there is a trend suggesting that there may even be a survival benefit.
As more of these drugs become available, it might turn out that you need to have a panel of different assays to judge which [assay] you should use with which drug. Those are the most recent updates to the guidelines. There is a lot of work going on with antibody-drug conjugates in TNBC, and with checkpoint inhibitors plus other immunotherapies, so none of that is ready for guideline introduction. However, it is going to be the subject of a lot of the trials that are going to be presented over the next few years.
How could these updates in the field impact these patient subsets?
The use of checkpoint inhibitors will probably be significantly adopted. In the community, physicians have been using checkpoint inhibitors in melanoma, lung cancer, and other diseases for some time because they have been approved for a long time. They are very familiar with these drugs, and my guess is that in the TNBC population, these drugs will probably be used fairly frequently. How widespread, for how long, and in what setting still needs to be defined. We have data supporting their use in the first-line setting, [but there are] trials in the adjuvant setting and beyond the first-line setting in metastatic disease, but the only data we have now are for first-line therapy.
In ER-positive disease, the CD4/6 inhibitors are widely used. Not every patient needs one, but my guess is that as we go forward, it might be PI3K inhibitors—if they get approved.
Is there anything else going on in the breast cancer space that is important to discuss?
With respect to updates, there is more nuance to the use of molecular assays. There are a number of assays that clinicians can order. The panel that is most to date [is] the 21-gene recurrence score, but there is also equal support and level 1 evidence for the 70-gene assay. What the guidelines have done in the last year is they have essentially made a table that lists all the molecular assays currently clinically available to physicians and what the level of support is. We are not saying, “You must order this one or that one,” but we provide the level of evidence for all of them. The issue that physicians will face going forward is how to best implement these, and whether they should order one. We don’t necessarily recommend you order more than one. It often only adds to confusion, but as we go forward, this again speaks to the idea of being more precise with our treatment recommendations. This might be another way of refining how we make our recommendations to individual patients.
<<< 2019 NCCN Annual Meeting
- André F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA3.
- Schmid P. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA1_PR.