APHINITY Trial for HER2+ Breast Cancer

Ruth O’Regan, MD:The APHINITY trial was designed to evaluate the use of or the addition of adjuvant pertuzumab to trastuzumab-based chemotherapy regimens. It was based on the very impressive results of the CLEOPATRA study in the metastatic setting and also the results of the NeoSphere study, where adding pertuzumab to trastuzumab and chemotherapy quite markedly improved the complete response rate. So, basically, patients were given adjuvant chemotherapy with trastuzumab with or without pertuzumab. They could get adriamycin/Cytoxan followed by a taxane with trastuzumab plus or minus pertuzumab or docetaxel/carboplatin/trastuzumab with or without pertuzumab. Overall, it met its primary endpoint. There was a significant improvement of disease-free survival with the patients who got pertuzumab, but it was probably more modest than perhaps had been anticipated. Although, in reality, these patients do so well overall, it’s hard to show the benefit of a new therapy.

Looking at subset analysis on the APHINITY study, the benefit of adding in pertuzumab was really restricted to patients with node-positive breast cancer. And there was really no benefit in patients with node-negative breast cancer. There was also a trend toward patients with estrogen receptor-negative cancers, like this lady’s cancer, doing better with the addition of pertuzumab, but really that wasn’t statistically significant. So, I think there was some disappointment about these results overall. However, I think it’s just that because the treatments that we have are so effective, it’s just hard to see a huge benefit when you add a new drug like this.

I think, overall, it brings up quite a few questions. I think, for a patient like this with node-positive breast cancer, particularly because it’s estrogen receptor-negative, I wouldn’t hesitate to use pertuzumab. If you look at the APHINITY study, the toxicity was more diarrhea with pertuzumab than trastuzumab, but it was manageable. And there were a little bit more cardiac events, but that wasn’t statistically significant. There’s not a huge risk to the patients apart from the cost of the drug. And they are going to be coming in every 3 weeks to get trastuzumab. So, getting another treatment really doesn’t impact their quality of life. For a patient like this, I would certainly recommend it.

I think that where you get into difficulty is where you’ve got patients with node-negative breast cancer. I think it’s hard to perhaps justify the use of pertuzumab in all those patients. And the other area where we don’t have an answer for is, what do you do in patients who you’ve given trastuzumab/pertuzumab and chemotherapy to preoperatively—which we do commonly—if they don’t have a great response rate or they do have a great response rate? Do you continue the pertuzumab in that scenario or not? And we just don’t have a right answer to that. So, again, I think we will probably base that on what the clinical stage of the cancer was at the initial diagnosis. If we know that the patient had positive lymph nodes, even if she had a good response to preoperative chemotherapy, you might consider adding pertuzumab in with the trastuzumab after surgery.

The regimen of docetaxel/carboplatin/trastuzumab with or without pertuzumab, overall, it’s generally reasonably well tolerated. The issues really with it are that it does cause fairly significant neutropenia, so you have to be very careful in terms of asking patients to watch for fevers and considering growth factors if appropriate. The other thing I think that you need to watch out for with this is, when you give pertuzumab and trastuzumab together, there is an increased risk of diarrhea. And one of the things you really need to watch out for is the development of typhlitis, which is where you get fevers and diarrhea, because that’s a very serious situation that requires really urgent hospital admission. That’s very rare, but I’ve certainly seen it with this regimen and I think we just have to be careful to watch out for signs like that. Apart from that, not a lot of nausea. The hair loss with the docetaxel/carboplatin can actually be prevented in the majority of patients by using cold caps, whereas they don’t work for anthracycline-based regimens as well. So, that’s something else that you can tell patients. Overall, it is manageable, but there are just a few warning signs, if you like, that you have to look out for that you really have to take seriously when you’re using that regimen.

Just to summarize: I think we’ve made huge strides in treatingHER2-positive breast cancer. Actually, the APHINITY trial is an example of how well these patients are doing because you just weren’t able to show, I think, a markedly improved outcome by adding in a drug that we know has improved survival in the metastatic setting. So, I think for most patients withHER2-positive breast cancer, they’re actually going to do fine with the regimens that we have right now. The questions are: do all patients need pertuzumab? Should it be restricted to node-positive breast cancer? We then have the issue of neratinib, which is given after a year of trastuzumab. That drug primarily is effective in hormone receptor-positive cancers, not hormone receptor-negative cancers. It is quite toxic and causes quite a lot of diarrhea. So, there are questions around where we would use that as well. But I think, although most patients do well, there are some patients who do not do as well. They’re the ones we need to focus on and work out why their cancers are resistant to the agents that we have right now. A good example of that is there are some estrogen receptor-positive breast cancers that are alsoHER2-positive that don’t respond as well to chemotherapy andHER2-directed therapy. They’d probably do fine just with endocrine therapy, but there is a group of those cancers that we need to focus on. Because, I think forHER2-positive breast cancer, it’s almost like we need to focus on giving less treatment rather than more treatment because the patients are doing so well. And I do wonder, if there areER-positive,HER2-positive cancers that maybe could be treated withHER2-directed therapy and endocrine therapy without chemotherapy. That would be something, I think, that would be worthwhile evaluating going forward.

Transcript edited for clarity.

• A 49-year-old women was referred for biopsy after routine mammography showed a 2.4-cm diameter spiculated mass in the left breast
• PE: revealed a well-circumscribed, non-tender firm mass in the lower-outer quadrant of the left breast; singular palpable nodal enlargement in the left axilla
• Excisional biopsy of the breast and axillary lymph nodes showed high grade lobular carcinoma
  • ER-/PR-; HER2 IHC 3+; Ki-67, 89%
  • Staging, pT2N3M0
• She underwent right mastectomy and lymph node dissection
• The patient was started on adjuvant chemotherapy with docetaxel + carboplatin with 12 months of trastuzumab + pertuzumab