Panelists expand upon the most important clinical factors that inform selection amongst available systemic therapy regimens in the neoadjuvant setting of HER2+ eBC, comment on the potential for treatment de-escalation in lower-risk patients, and discuss exciting treatments on the horizon.
Sara Hurvitz, MD: Virginia, what clinical and nonclinical factors are you using to select among the available agents? Can you take us through that?
Virginia G. Kaklamani, MD, DSc: When we look at the patient before they’ve had surgery, many of the things that we have available are going to be our clinical factors. You’re going to look at tumor size and node positivity to decide whether this patient should be treated neoadjuvantly. Interestingly, at ASCO [American Society of Clinical Oncology Annual Meeting], the PHERGain trial was presented. This was a very interesting trial. It took patients randomized to receive our standard TCHP regimen [docetaxel, carboplatin, trastuzumab, pertuzumab] and gave them a more tailored approach with no chemotherapy, just HP [trastuzumab, pertuzumab] plus endocrine therapy if they were ER [endocrine receptor]–positive. Based on PET [positron emission tomography] imaging and whether patients’ tumors were responding to treatment, they were continuing on HP [trastuzumab, pertuzumab] or switching to TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab]. It’s interesting because the outcomes were very good. When you looked at patients who had PET responses, their 3-year IDFS [invasive disease-free survival] rate was 98.8%, which is very impressive. With this approach, we’re not necessarily escalating or de-escalating but optimizing based on tumor response.
Sara Hurvitz, MD: Absolutely. Do you think it’s appropriate to use the neoadjuvant setting to de-escalate? Are you doing that in your clinical practice? What do we know about that?
Virginia G. Kaklamani, MD, DSc: I don’t know if we’re there yet. I’d love to get there, and PHERGain is a wonderful trial to get us there. Typically I’ll use my TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] regimen for 6 cycles. Then I’ll take patients to surgery and decide based on pCR [pathologic complete response] rate whether to continue with trastuzumab-based antibody therapy or switch to T-DM1 [trastuzumab emtansine].
Sara Hurvitz, MD: Sounds good. Melinda, tell us about other exciting developments or studies that are ongoing in the neoadjuvant setting.
Melinda Telli, MD: I’m really excited about the CompassHER2-pCR study. We’ve documented that we can do a briefer chemotherapy treatment in our patients with stage I [disease]. This is the next step, to say, “What about patients with stage II and up to IIIA disease? Can we achieve an excellent response rate with a single-agent taxane for 4 cycles with trastuzumab-pertuzumab prior to surgery?” This is a very large study that’s being run through the cooperative group [with] over 2100 patients. It’s nearly at its enrollment goal. It has enrolled very quickly [and has] been popular with patients. I’m excited to see the results. Hopefully not too long from now we’ll see the pCR data. That strategy question is what we’re all interested in.
But many new drugs have entered into the metastatic setting in the last few years. We’re seeing those drugs moving into the preoperative setting. We’re all excited about T-DXd [trastuzumab deruxtecan] and its potential as it moves further forward in treatment. But there are some ongoing studies looking at T-DXd [trastuzumab deruxtecan] as monotherapy or in combination with other agents in the preoperative setting. That’s exciting. We’re seeing some other agents move forward too from the advanced disease setting. I/O [immuno-oncology] strategies for some patients. For our hormone receptor–positive, HER2 [human epidermal growth factor receptor 2]–positive patients, we’re seeing endocrine therapy–HER2-directed therapy combinations with CDK4/6 inhibition and PI3 kinase inhibitors. There’s lots going on there.
Sara Hurvitz, MD: It’s very exciting time, with a lot of novel therapies. There was even an abstract on intratumoral vaccine–based therapy. They were small numbers, but there were very exciting data, with some novel agents being tested. Virginia, I want to ask about your use of subcutaneous trastuzumab-pertuzumab. That’s something available to our patients now. I can’t always get it for my patients based on insurance, but what do we know about this formulation? Are you using it in your practice?
Virginia G. Kaklamani, MD, DSc: This is extremely convenient, especially for patients who are going to be on another 6 months of therapy after surgery. Instead of coming to the office and spending an hour or an hour and a half waiting in a chair, they have their subcutaneous injection for HP [trastuzumab, pertuzumab] over 5 minutes and then go home. There are data from 2 clinical trials, PHranceSCa and FeDeriCa, looking at the subcutaneous injection.
The first 1 looked at efficacy. It was in the neoadjuvant setting, and it showed that the pCR rate was exactly the same. Also, the PK [pharmacokinetics] was very similar between the 2 preparations. The second 1 looked at patient convenience. Do patients like 1 better than the other? Eighty-five percent of patients preferred the subcutaneous preparation, 1% preferred the IV [intravenously], and the rest didn’t have a preference. Based on those data, I discuss it with my patients. The majority want to try it. I keep the port in for that [first] dose to make sure they’re still OK with it. If they are, I take that port out and continue with it.
Sara Hurvitz, MD: That’s great. I want to circle back to you for a moment, Heather. Many areas have a shortage of carboplatin, so I wanted to hear from you on a practical standpoint in the neoadjuvant setting for HER2+ breast cancer. How are you managing this? Are you using the APT [adjuvant paclitaxel-trastuzumab] regimen? Any other clues you can give our practicing clinicians?
Heather McArthur, MD: That’s a great question because the platinum shortage has challenged us in many spaces, including HER2+ disease. We’re participating in the CompassHER2-pCR study. That’s neoadjuvant THP [docetaxel, trastuzumab, pertuzumab] for 4 cycles, and it’s a platinum-free regimen. If they have residual disease, they participate in the residual disease version of the COMPASS trial. We have to give 2 additional cycles of the taxane-based regimen before they can enroll, and then they get access to T-DM1 [trastuzumab emtansine] plus or minus tucatinib in that setting. Those are all platinum-free regimens.
We also have a multicenter investigator-initiated trial looking at THP [docetaxel, trastuzumab, pertuzumab] plus or minus pembrolizumab, combining immunotherapy to see if you can harness that synergy between HER2-directed therapy. We have standard-of-care options and clinical trial options for patients who are platinum-free.
Sara Hurvitz, MD: It’s a challenging situation. Debu, we’ve moved away from the use of anthracyclines in the neoadjuvant and adjuvant setting for HER2+ breast cancer. If you have a patient who’s appropriate for neoadjuvant therapy with a little higher risk, are you going to do a THP [docetaxel, trastuzumab, pertuzumab]–type regimen outside a clinical trial to see how they do? Are you inclined to go back to an anthracycline regimen if you don’t have access to platinum?
Debu Tripathy, MD: I feel comfortable with THP [docetaxel, trastuzumab, pertuzumab] in most cases. There are going to be higher-risk, maybe stage III, cases where a platinum as needed. At our institution [The University of Texas MD Anderson Cancer Center], we have reserved the supply that we have for patients who we feel have an outcomes difference. This may fall into that category, but we have to remember that we haven’t formally investigated the use of platinum. There haven’t been randomized trials in the metastatic setting. There have been [trials that] didn’t show a benefit from platinum. For most cases, I’d feel comfortable with the THP [docetaxel, trastuzumab, pertuzumab] regimen if it was absolutely not available.
Sara Hurvitz, MD: Excellent. Thank you all for your thoughts on this section.
Transcript edited for clarity.