HER2+ BC: A Year in Review and Updates from SABCS - Episode 6

De-escalation in Neoadjuvant Setting for HER2+ BC

Updated findings on the use of neratinib for HER2+ breast cancer from the 2020 SABCS Virtual Symposium.

Hatem Soliman, MD: We have an interesting study from colleagues at Dana-Farber [Cancer Institute] looking at de-escalating therapy and seeing in the neoadjuvant setting if we can potentially de-escalate our standard neoadjuvant chemotherapy regimen, which is typically for these larger tumors that are stage II or III.

At Moffitt Cancer Center, we have been using the combination of docetaxel, carboplatin, trastuzumab, and pertuzumab. The investigators at Dana-Farber, based on interesting data, were asking if they could get away with using a taxane, trastuzumab, and pertuzumab, so this would be paclitaxel, trastuzumab, and pertuzumab for 12 weeks in lieu of the standard TCHP [docetaxel, carboplatin, trastuzumab, carboplatin] cycle that we use for 6 cycles once every 3 weeks. They enrolled patients who were stage II/III, with tumors at least over 1.5 cm, and they could have been hormone receptor positive or negative. They took both subtypes, treated them with 12 weeks of paclitaxel, trastuzumab, and pertuzumab for the standard dosing, then took them to definitive surgery. If they had a PCR [polymerase chain reaction], then they would complete their year total of HP [trastuzumab, pertuzumab]. But if no PCR, they would go on to get the adjuvant T-DM1 [trastuzumab emtansine], our standard approach.

If you looked at the breakdown of the patients in this study it was a representative population. There wasn’t anything that stood out from the group that was included that was unusual or not relevant to our practice. When looking at the number of patients who were node positive, it was about 33% of patients. The majority were T2—these were tumors between 2 and 5 cm—and 45% of them were hormone receptor positive, ER [estrogen receptor] and PR [progesterone] positive. Another 19% were ER positive and PR negative. About 32% were estrogen receptor negative, progesterone receptor negative. When looking at the type of surgery they had, it was a pretty evenly split between those who had lumpectomy and mastectomy. This is a pretty typical population for what we would see in the neoadjuvant setting.

Looking at the number of doses that were received, the treatment intensity and the intended dose was on target. They had 84% of the patients get their 12 doses of paclitaxel, which is good by most standards, and also get their trastuzumab and pertuzumab doses every 3 weeks, about the same proportion. When looking at patients who got additional non–THP [paclitaxel, trastuzumab, pertuzumab] neoadjuvant therapy, only about 5% got AC [doxorubicin, cyclophosphamide] for 4 cycles, before going to surgery. Not many patients needed to be rescued because of the omission of the carboplatin.

What was striking was that the pathologic complete response [pCR] rate for the combination was encouraging. If you look at all 97 patients, the pCR rate was 56%. When you look at the hormone receptor–positive, HER2-negative group, that percentage was 43%, which was lower, and that is what we would expect when they’re hormone receptor positive. The ER-/HER2+ group had an astounding 84% pCR rate, which stacks up favorably to TCHP [docetaxel, carboplatin, trastuzumab, carboplatin] in terms of pCR rate overall. Overall, this is an encouraging sign that we may be able to routinely de-escalate therapy in some of these stage II patients, even if they’re clinically node positive, and try to save our patients some of that additional toxicity from carboplatin.

The long-term efficacy though, in terms of follow-up, we have a compass, which is following similarly treated patients. We need to see how the event-free survival is on these patients. But if the pCR is any guide, they’re going to do pretty well.

Andrew Seidman, MD: It’s interesting that the primary end point was actually not pCR but rather whether doctors and patients would agree to adhere to just getting trastuzumab and pertuzumab if they had a pCR. The primary end point was adherence to HP [trastuzumab, pertuzumab] only if you had a pCR. Of those, only 1 patient ended up getting AC [doxorubicin, cyclophosphamide] postoperatively. The trial met its primary end point, and doctors and patients believe that if you get a pCR with de-escalated therapy, that’s good enough. For the patients who had residual cancer burden scores of 2 or 3, about half those patients did get further chemotherapy. They got AC [doxorubicin, cyclophosphamide] outback, which is reasonable. But those pCR rates are provocative, and 1 can conceive of kinder and gentler therapy when you optimize targeted therapy.

Hatem Soliman, MD: The one thing that would be interesting to see over time, is after KATHERINE, the discussion does come up as to what is the added value that adjuvant AC [doxorubicin, cyclophosphamide], in some of these scenarios where there’s residual disease and making that value judgment over switching over to T-DM1 [trastuzumab emtansine] in this setting. It remains to be seen.

Andrew Seidman, MD: We’re going to be learning how checkpoint inhibition plays out in this setting as well. In the HER2+ space, you could think of that as escalation because it’s escalating the number of agents and it’s escalating the cost. But giving a checkpoint inhibitor, for example, with a taxane and HER2-targeted therapy, would be relatively less toxic than giving an anthracycline and cyclophosphamide, or carboplatinum and docetaxel.

Transcript edited for clarity.