Mark D. Pegram, MD, discusses the evolving treatment paradigm of HER2-positive breast cancer.
Mark Pegram, MD
It is an exciting time in drug development for patients with HER2-positive breast cancer, which is leading to new therapeutic strategies and FDA approvals, says Mark D. Pegram, MD.
For example, in December 2017, the FDA approved pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy as an adjuvant treatment for patients with HER2-positive breast cancer, based on data from the phase III APHINITY trial. The study demonstrated a 3-year invasive disease-free survival (iDFS) rate of 94.1% with the pertuzumab regimen compared with 93.2% for patients receiving trastuzumab, chemotherapy, and placebo (HR, 0.82; 95% CI, 0.67-1.00; P = .047). The 4-year iDFS rates were 92.3% versus 90.6%, respectively.
In an interview during the 2018 OncLive® State of the Science SummitTM on Breast Cancer, Pegram, associate director for clinical research and director of the breast oncology program at Stanford Women’s Cancer Center, discussed the evolving treatment paradigm of HER2-positive breast cancer.Pegram: It is a very exciting time in drug development for patients with HER2-positive breast cancer. We have seen recent FDA approvals for new approaches to treat patients with early-stage HER2-positive breast cancer.
In particular, there are data from the APHINITY trial now available and published. This led to the FDA approval of pertuzumab for these patients. APHINITY investigated the adjuvant use of pertuzumab in combination with chemotherapy plus trastuzumab. The difficulty with the trial is that it is a low-risk patient population to begin with. A lot of node-negative patients were studied in that trial, which led to the event rate being low. However, the trial met its statistical endpoint with confidence, but the absolute benefit of adjuvant pertuzumab is small. That trial needs longer follow-up to see more events and whether there is any difference in long-term outcomes.
I discussed extended adjuvant therapy with the small molecule inhibitor neratinib (Nerlynx). This has also been approved by the FDA. It had a similar efficacy signal to pertuzumab, and one could argue in absolute terms that there was 2.5% difference in the intent-to-treat population. That was sufficient to merit FDA approval.
The challenge of that drug is the fact that it has significant toxicity, some of which can be mitigated by concomitant medication with loperamide as it can lower gastrointestinal toxicity. However, now that it is approved by the FDA, the burden is on us as clinicians to make patients aware of the toxicity when considering it in a balanced discussion. In some cases, it is important to mention whether the toxicity and expense merits the small efficacy signal. It is not for everybody, but one can envision where this would be a fair consideration for high-risk patients.
The same can be said with pertuzumab. It is going to be restricted to higher-risk subsets of patients and does not need to be used for everyone. Clinical judgement will be imperative.
Next, I spoke about patients with HER2-positive breast cancer who have brain metastases. There was a study presented at the 2017 ASCO Annual Meeting looking at high doses of trastuzumab past the first step of a Simon’s two-stage study design. That has now finished enrolling 40 patients in a phase II trial, but the results are pending.
There are also new small molecule HER2 inhibitors that are more specific for HER2 and do not have as much [toxicity] as other drugs, such as lapatinib (Tykerb) or neratinib. In particular, tucatinib, previously known as ONT-380, is a pure HER2 inhibitor that doesn't inhibit EGFR. Therefore, the toxicities of diarrhea and skin rash are not there to the extent that you see with existing FDA-approved HER2 inhibitors. That might be an interesting path forward for patients with HER2-positive breast cancer who have brain metastases. That molecule is being studied in an ongoing randomized registration trial.
I also discussed published data with trastuzumab emtansine (T-DM1; Kadcyla) in HER2-positive breast cancer for patients with brain metastases, and our anecdotal responses to the drug. It is very well tolerated and is approved by the FDA. That could be a path forward for selected patients.
I spoke about new immune-oncology approaches. Everyone has heard about the PD-1/PD-L1 inhibitors, and certainly that is moving forward in all subtypes of breast cancer, including the HER2-positive subtype. That area is being covered with ongoing studies.
There are also other opportunities, specifically Fc-modified human-engineered antibodies. Margetuximab is a prototype that is in clinical development in the randomized, pivotal registrational [SOPHIA] trial in metastatic disease. The Fc-engineered antibody has a higher affinity to activate Fc receptors on natural killer cells and lower affinity to the decoy receptors. It has more of an immunologic effect to promote antibody-dependent cell killing of HER2-positive tumor targets. I am excited about that molecule and we will see what the pivotal trial looks like.
There is another approach with CD137 to augment antibody-dependent cell killing. The CD137 agonist causes a more potent release of perforin/granzyme. We have an open investigator-initiated trial of a CD137 agonist plus HER2 antibodies that is currently ongoing.
I discussed CD47, which is the macrophage checkpoint. The macrophage acts as the human immune system. CD47 is upregulated in virtually every tumor type, including liquid tumors, hematologic malignancies, and all solid tumors. This masks the tumor cells, so that they are not recognized by macrophages. Tumors are easily able to escape this access of the human immune system, but if you block CD47 with the blocking antibody, then you can lose the disguise of these tumors causing macrophages to recognize them. In preclinical models, a humanized anti-CD47 agent was developed at Stanford Medicine and has potent activity in multiple tumor types in xenograft models.
It also tends to combine well with other existing therapeutic antibodies, such as trastuzumab. Cetuximab (Erbitux) combinations are another promising path forward for that molecule, as well.
In summary, immune-oncology is not just PD-1/PD-L1. There are a lot of other checkpoints out there and other interactions in the human immune system that might still offer opportunities to exploit. That is exciting, and HER2 is an exciting model to test some of these new pathways and systems for the betterment of our patients. Sequencing of treatment for HER2-positive breast cancer has always been an issue. It is never easy, and we lack carefully controlled randomized trials testing sequences rigorously. Therefore, we are left to “read the tea leaves” of what little data seem to be available or it is up to the clinician’s judgement to decide the order in which we use some of these active agents.
That is going to remain a problem as more agents become available. In the CLEOPATRA trial of pertuzumab in the first-line setting for patients with HER2-positive metastatic disease, there was a robust survival benefit—making it easy to acknowledge that it should be a first-line choice for these patients.
Moreover, T-DM1 plus pertuzumab failed to beat trastuzumab plus pertuzumab and chemotherapy in a randomized trial. Therefore, second-line T-DM1 is well poised to lock in the second-line metastatic disease treatment. It is very well tolerated and has remarkable efficacy, even in trastuzumab-pretreated patients.
What we don't have are data on pertuzumab in patients pretreated with T-DM1. The available data suggest that the activity is less than pertuzumab-naïve disease but is still active. It still has locked in that second-line position in term of therapeutic index, which is activity divided by toxicity. T-DM1 is solidly for second-line use.
That is followed by HER2 inhibitors, such as lapatinib-based therapies, lapatinib in combination with capecitabine—which is FDA approved—or lapatinib plus trastuzumab, which has been published to be a robust and effective regimen in selected patients. That would be another good example of a lapatinib-based third-line regimen.
After that, we are looking at phase I/Ib trials and new combinations after the first 3 lines of therapy in metastatic disease. In the adjuvant setting, we just had the first approval of pertuzumab in that setting. We are still awaiting an adjuvant T-DM1 trial that has completed enrollment and is in follow-up. That should report sometime within the coming year. We will see what that data look like and if that offers future opportunities for early-stage breast cancer.
There are also the other antibodies that are ongoing, such as margetuximab and Fc-engineered antibodies. If the pivotal trial in patients with metastatic disease is positive, then there will be high enthusiasm to move that earlier in the disease setting, perhaps to the neoadjuvant or adjuvant setting as well.I don't think the FDA was confused by the data in the APHINITY trial, but they were acknowledging that there is no clear high-risk group that one can find. One would think that bigger tumors would do better by adding pertuzumab. The converse was observed on the point estimates of the hazard ratios. You might think to treat younger patients more aggressively, as they might have a higher risk and longer life expectancies. That notion wasn't supported by the data in the subset analysis.
In fact, there was a trend in the opposite direction based on the point estimates of the hazard ratios. Certainly, the node-positive subsets stood out as an important subset but, for node-negative patients, it is not clear that they derive any benefit. Even though that is a retrospective analysis, it is a large subset because the trial was huge. I don't discount that observation at all.
For most node-negative cases, pertuzumab is simply not necessary. For high-risk disease in terms of tumor burden and lots of nodes, the FDA left the label pretty open. It is going to be up to us as clinicians to decide what that risk should be and explain that to patients. They are going to have a preference too—whether or not they want to have some added toxicity and added expense for the relatively small absolute benefits that we are seeing so far, which could change with longer follow-up.
The FDA, in this case, was very progressive by acknowledging that since the data didn't say a particular high-risk group needs pertuzumab; they left it up to practicing physicians. That is very progressive in recognizing that there is still some art left in medicine.The NSABP B-47 trial was an optimistic study design hoping that trastuzumab would work in combination with chemotherapy against HER2 low-expressing early-stage breast cancer. These are patients who were follicle stimulating hormone-negative and had HER2 expression at the protein level by immunohistochemistry.
There was some retrospective subset analyses from the pivotal NSABP B-31 adjuvant trastuzumab trial, which suggested that there were a few patients who were misclassified as being HER2-positive; on retesting, they were actually negative for HER2.
To test that hypothesis, a study was done. This was a large randomized, controlled study that was negative. In hindsight, this might have been predicted because in the lab there is no efficacy with trastuzumab on HER2-negative cell lines.We hope so, since these Fc-engineered antibodies have more immunologic effects inducing antibody-dependent tumor cell killing. The hope is that we might be able to replace the existing repertoire of the therapeutic antibodies targeting HER2. If the engineered antibody margetuximab is superior, then perhaps this will replace those antibodies and will set the stage for a second generation of HER2-targeted antibodies with enhanced defector function.
von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017; 377:122-131. doi: 10.1056/NEJMoa1703643.