Expert Describes Discouraging Neoadjuvant Data in HER2+ Breast Cancer

Gunter von Minckwitz, MD, PhD

Neoadjuvant treatment regimens in HER2-positive breast cancer are being investigated, but early results presented at the 2015 San Antonio Breast Cancer Symposium demonstrate that the therapies may not elicit a significant benefit in patients.

An early survival analysis of the phase II GeparSixto study, which examined the addition of carboplatin to neoadjuvant therapy for patients with triple-negative breast cancer (TNBC) and those with HER2-positive breast cancer, showed a survival benefit in TNBC, though the same could not be said for HER2-positive disease, explained Gunter von Minckwitz, MD.

In this study, HER2-positive patients (n = 273) received concurrently trastuzumab 6(8)mg/kg every 3 weeks and lapatinib at 750 mg daily. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2.0 q1w versus no carboplatin, stratified by subtype (HER2-positive vs TNBC).

Secondly, an analysis of BRCA mutations, therapy response, and prognosis of three subgroups of patients—including HER2-positive, HER2-negative, and TNBC—enrolled in the GeparQuinto study, will be reported.

HER2-positive patients who received lapatinib instead of trastuzumab experienced significantly lower pathological complete response (pCR) rates. Moreover, survival data do not show a significant inferior survival for the laparinib patients, explained von Minckwitz.

Also being reported during the meeting is a 3-year analysis of results from the phase III randomized, placebo-controlled, double-blind ExteNET study, which examined neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. In the 2-year analysis, the disease-free survival rate was 93.9% in the neratinib arm versus 91.6% with placebo, representing a 33% reduction in the risk of recurrence (HR, 0.67; 95% CI, 0.50-0.91; P = .009). However, 95.4% of patients treated with neratinib experienced all-grade diarrhea, including 39.9% experiencing grade 3/4.

OncLive: What were the goals of the GeparSixto study?

What were the significant findings of the study?

In an interview with OncLive during the symposium in San Antonio, Texas, von Minckwitz, professor and president of German Breast Group research GmbH, discussed these less-than-encouraging results and what next steps lie ahead in neoadjuvant therapy regimens for HER2-positive breast cancer.von Minckwitz: The goal of the GeparSixto study was to explore how far the addition of carboplatin to standard or a full chemotherapy-targeted backbone treatment can improve pCR in either HER2-positive breast cancer or TNBC. Patients with HER2-positive disease received weekly paclitaxel and non—pegylated-liposomal doxorubicin, and were concurrently scheduled to receive trastuzumab and pertuzumab. Patients with TNBC received bevacizumab as a targeted agent. In the experimental arm, carboplatin was added. In the weekly schedule, we started it at a dose of AUC 2, but then reduced it after half of the patients were recruited to AUC 1.5. This appeared to be better tolerated by patients.Two years ago, we reported that the pCR rate of this study was significantly higher when carboplatin was added. We saw that this effect was mainly in patients with TNBC. There was no effect, even in numerically, even somewhat lower pCR rate, in HER2-positive patients.

Is there an understanding of why the addition of carboplatin was not found to be effective in patients with HER2-positive disease?

Now, at this meeting, we are presenting survival data of this study. Again, we see that carboplatin significantly improves disease-free survival in TNBC patients but not in patients with HER2-positive disease. The hazard ratio in TNBC patients is 0.56, which demonstrated a very extensive beneficial effect of carboplatin in this population.We can only hypothesize. There is only one other study looking into that. Here, carboplatin was not given in addition; it was a replacement of anthracycline and cyclophosphamide, so it is a different situation.

Can you discuss updated findings from the ExteNET trial which are being presented at this meeting?

What do these findings demonstrate about the administration of neratinib?

Can you provide an overview of the GeparQuinto study and the reported results?

Also, we did a step analysis to examine if there was a dose relationship with carboplatin. We saw that only in the HER2-positive patients was there a dose relationship. The higher dose of carboplatin resulted in a higher pCR. Perhaps not a sufficient number of patients received the full dose of carboplatin, so maybe we missed the effect. On the other hand, it was not feasible to give this agent to patients. In patients with TNBC, there was no dose response relationship, so dose reductions were less relevant in this subgroup.The ExteNET study has a long story, as it went through various sponsors. The initial report was only an observation period that was cut at 2 years, so it was very early. The effect that was seen was an initial effect. Here, 3-year data is being released and, so far, the data look quite confirmatory to the initial analysis.It is a question of risk and benefits, as neratinib is not such an easily handled drug. It has a high rate of diarrhea, which might be preventable by using an antidiarrheal up front. However, that was not the case in the ExteNET study, so we cannot truly assess how far a 1-year treatment with this compound can be more manageable. It is the negative point of this drug, and to me it is still an issue in recommending this treatment for some additional benefit, which is still short-term. The trial will collect further follow-up.We have published this study several times. It was a neoadjuvant study with three randomizations in various subgroups of patients with breast cancer being treated with neoadjuvant treatment. The largest group was HER2-negative patients who received standard anthracycline taxane sequential chemotherapy with or without bevacizumab. Those patients who did not respond after four cycles were re-randomized to receive the mTOR inhibitor everolimus together with the taxane treatment. The third randomization was in HER2-positive disease, looking at how trastuzumab and lapatinib are effective in addition to standard anthracycline taxane-based chemotherapy.

What is the status of the HER2-positive group?

At this meeting, we reported data on the HER2-negative cohort where we have analyzed the germline BRCA status, and we wanted to find out how prognoses of patients with a pCR is somehow dependent on the BRCA status, as this was initially reported by a small retrospective monocentric cohort study from Israel. What we see is that the mutant patients may have somewhat have more relapses despite having a pCR but, in this study which included almost 700 patients where we had the germline BRCA information available, there was no clear significant difference in this. We believe that pCR is a relevant prognostic marker in all of these patients, independently of the BRCA status.We have seen that those patients who received lapatinib instead of trastuzumab had significantly lower pCR rates and we are reporting survival data that does not show a significant inferior survival for the lapatinib arm.

However, two aspects have to be considered. The trial was never powered to show survival effects, so the lapatinib curve is somewhat below the trastuzumab curve, but not significantly. On the other hand, the patients in the lapatinib arm received trastuzumab after surgery, so it is not a pure trastuzumab versus lapatinib comparison; it is a trastuzumab versus lapatinib followed up by trastuzumab comparison.

References

1. von Minckwitz G, Loibl S, Schneeweiss A, et al. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Presented at: San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S2-04.
2. Fasching PA, Loibl S, Eidtmann H, et al. BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study. Presented at: San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S5-06.