Safety and Efficacy of Pertuzumab in HER2+ Breast Cancer

Ruth O’Regan, MD:The standard, currently, is to use pertuzumab and trastuzumab with chemotherapy in the preoperative setting. That’s really primarily based on the NeoSphere trial, which shows that if you added in pertuzumab with trastuzumab and a taxane, you significantly increase the pathologic complete response rate, which we know is very important prognostically compared to just using trastuzumab and a taxane. That’s essentially where that data came from. I think most of us would use pertuzumab or add pertuzumab to trastuzumab-based chemotherapy in a setting like this. I really can’t think of anybody that wouldn’t because pertuzumab, apart from maybe increasing some diarrhea when it’s given with trastuzumab, really doesn’t have much toxicity. So, there’s really no reason not to do it. We know it’s more likely to result in a higher response rate, but the toxicity is certainly acceptable in a scenario like this.

So, for a patient like this, I would either use a non-anthracycline—containing regimen with trastuzumab and pertuzumab or an anthracycline-containing regimen with pertuzumab and trastuzumab. I think specifically for this patient, I might lean towards an anthracycline/taxane/trastuzumab/pertuzumab approach just because of the fact that she’s younger, and that she may want to maintain fertility. We have more data with using anthracyclines and taxanes in that scenario.

In terms of the studies that I’ve looked at adding pertuzumab in with trastuzumab and docetaxel, none of them have shown a significant risk in toxicity with the addition of pertuzumab to the trastuzumab and docetaxel. The one thing that you do see sometimes is slight increase in diarrhea. That appears to be something that occurs when you do dual targeting of the HER2 receptor. There’s more diarrhea. That’s really the only thing that I’ve noticed. As far as the cardiotoxicity, neither in the metastatic setting nor in the preoperative setting has any increase in cardiotoxicity been noted. In fact, in the TRYPHAENA study, which is where the docetaxel/carboplatin/trastuzumab/pertuzumab regimen came from, the primary endpoint of that study was actually looking at cardiac toxicity, and they didn’t notice any increase compared to historical trials by adding in pertuzumab. So, overall, it’s a very safe approach, and I think most of us are very comfortable using this for patients.

The TRYPHAENA study was a study for patients with HER2-positive disease who were candidates for a preoperative approach with a primary endpoint of cardiotoxicity. There were 3 arms. The first arm was FEC (5-FU, epirubicin, cyclophosphamide) followed by docetaxel plus trastuzumab and pertuzumab. The second arm was FEC followed by docetaxel with the 2 antibodies given the whole way through the chemotherapy, and then continued afterwards. And then the third arm, which is really the one that was approved by the FDA, was docetaxel/carboplatin/trastuzumab/pertuzumab. Now, the pathologic complete response rate was not the primary endpoint of this study, but, in all the arms of the study, there was a very impressive pathologic complete response rate. And it was higher than what had been reported historically with using just trastuzumab and chemotherapy in this setting. So, based on this study, even though it was a smaller study than the NeoSphere study, the TRYPHAENA regimen, which is really docetaxel/carboplatin/trastuzumab/pertuzumab, was approved in the preoperative setting. Additionally, and importantly, with their primary endpoint, which was thinking of cardiotoxicity, they didn’t see any signal that it was worsening cardiotoxicity by adding the pertuzumab.

The AFFINITY trial is basically a trial looking to confirm what we’ve seen in the preoperative setting, that is that pertuzumab improves outcome when it’s added to trastuzumab and chemotherapy in patients with already stage HER2-positive breast cancer. But, in this case, this is an adjuvant trial. So, patients would have already had surgery, HER2-positive cancers, and they get randomized to, essentially, adjuvant chemotherapy with trastuzumab with or without pertuzumab. We’re not sure when it’s going to report because, historically, in these adjuvant HER2-positive trials, the event rate is very low. So, it may take quite a while to actually get results from this study. And so, we’re not really clear exactly when it’s going to report out. Presumably, they’re doing interim analysis to look at event rate, and maybe we’ll get some signal from that. The other thing to keep in mind is that these patients didn’t get preoperative treatment, so they may have slightly lower risk cancers, although the study was not designed that way. So, that could also decrease the number of events that you’re looking for going forward.

If it’s a positive study, it will basically confirm what we all hope, and that is that pertuzumab improves outcome, whether you’re give it preoperatively or postoperatively. I think the bigger question is if it’s a negative study, which it could be, then where are we at that time point? Because, the NCCN has already approved the use of adjuvant pertuzumab, or at least adding pertuzumab in with trastuzumab adjuvantly. That would certainly question those guidelines. So, we certainly hope it will be positive, but, at this point, we just don’t know when it’s going to report out. But, I think it will then allow us to use pertuzumab pretty much in all stages of HER2-positive disease—preoperatively, adjuvantly, and then also in the metastatic setting if it’s really shown to markedly improve survival compared to just using trastuzumab and chemotherapy alone.

Case Scenario 2:

• This is a 33-year old pre-menopausal woman who, after palpating a mass in her left breast, was referred for a mammogram by her primary care physician. Family history includes a sister who died of breast cancer at age 43 years.

• Her mammogram revealed a spiculated mass in the upper outer quadrant of the left breast. Targeted ultrasound showed a 2.6 x 3.4 x 2.1 cm irregular mass with an indistinct margin. Prominent appearing right axillary lymph nodes.
• Pathology: core biopsy revealed an invasive ductal carcinoma, poorly differentiated, lymphovascular invasion present. The tumor sample was mammaglobin-positive, ER/PR-negative, and HER2 3+ by IHC. Axillary ultrasound with fine-needle aspiration which was also positive for nodal involvement.
• The case was presented at the breast cancer multidisciplinary tumor board. The team recommended neoadjuvant therapy before surgery.