Neoadjuvant Dual Anti-HER2 Therapies More Beneficial for HER2+ Breast Cancer

Frankie Ann Holmes, MD

Dual anti-HER2-directed therapies have emerged as the most beneficial neoadjuvant treatment option for patients with HER2-positive breast cancer, according to Frankie Ann Holmes, MD.

“Neoadjuvant directed therapy is seeing extremely high total pathological complete response rates, so for patients whose tumors are greater than 2 centimeters, or who are node positive, dual anti-HER2-directed therapy with trastuzumab and pertuzumab either with a taxane carboplatin backbone or, with the anthracycline cytoxan then taxane backbone, have shown to be very effective and are the optimal choices of therapy for those patients,” Holmes said in an interview withTargeted Oncologyfollowing her presentation on HER2-directed therapies at the 2016 International Congress on the Future of Breast Cancer.

In the NOAH trial,¹looking at neoadjuvant chemotherapy with or without trastuzumab in women with HER2+ locally advanced or inflammatory breast cancer, there was a clear difference in the trastuzumab arm that showed the benefit of the combination therapy. The 5-year event-free survival rate was 58% (95% CI, 48-66) for the trastuzumab group and 43% (95% CI, 34-52) for the chemotherapy control group. Overall survival (OS) rates at 5 years were 74% (95% CI, 64-81) for the experimental group and 63% (95% CI, 53-71) for the control.

A number of clinical trials have explored lapatinib and trastuzumab in the neoadjuvant setting, including the GBG 44 phase III trial which compared lapatinib to trastuzumab in combination with an anthracycline-taxane—based chemotherapy regimen.²The lapatinib arm was found to be inferior, with a pathological complete response (pCR) rate of 22.7%, and had a higher toxicity profile than the trastuzumab arm, which showed a pCR rate of 30.3% (P= .04).

The NSABP B-41 trial explored lapatinib and trastuzumab separately as well as in combination, all with weekly paclitaxel following doxorubicin and cyclophosphamide.³The trastuzumab arm showed a pCR rate of 52.5% and the lapatinib arm had a similar rate of 53.2%. This same lack of difference between trastuzumab and lapatinib separately was seen in various other trials comparing the treatments, such as the smaller USOR 05-074 trial from Holmes et al.⁴

The combination arm of the NSABP B-41 showed a numerical difference with a pCR rate of 62% but a relatively low statistical rate (P= .095).³The combination arm of the USOR 05-074 trial also had a higher pCR rate of 74%, versus 54% for the trastuzumab arm and 45% for the lapatinib arm.⁴

“One of the findings that all of these studies has shown is that pCR does correlate with relapse-free survival and overall survival. In the hormone receptor—negative subgroup … these are often the HER2-enriched subgroup, so they are more driven by HER2, there did seem to be an even more substantial benefit,” Holmes said during her presentation.

In the NSABP B-41 trial, the proportion of recurrence-free survival by breast pCR and hormone receptor—negative status showed a rate of 89.2% pCR versus 64.1% non-pCR (P<.0001). OS rates were 93.1% for pCR and 71% for non-pCR.³

The NeoSphere phase II trial looked at neoadjuvant pertuzumab and trastuzumab in breast cancer.⁵The cohort that received pertuzumab, trastuzumab, and docetaxel (n = 107) showed the highest 5-year progression-free survival rate of 86% (95% CI, 77-91) versus 81% for the docetaxel plus trastuzumab cohort and 73% each for the pertuzumab plus trastuzumab and docetaxel plus pertuzumab arms.

The KRISTINE trial studied neoadjuvant ado-trastuzumab emtansine plus pertuzumab (T-DM1+P) versus trastuzumab, carboplatin, and docetaxel plus pertuzumab (TCH+P).⁶The TCH+P arm showed a higher pCR rate of 56% versus 44% for the T-DM1+P group. The difference was even greater in the hormone receptor—negative subgroup, where TCH+P had a pCR rate of 73% versus 54% for the T-DM1+P cohort.

&ldquo;One of the themes that we&rsquo;ve heard &hellip; is that we have to identify who are these subgroups of patients who really don&rsquo;t need the more aggressive chemotherapy,&rdquo; Holmes said. Identifying those subgroups, however, would require a greater understanding of the gene signatures and biomarkers of HER2+ breast cancer.

References:

1. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort.Lancet Oncol.2014;15(6)640-647.
2. Untch M, Loibl S, Bischoff J, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial.Lancet Oncol.2012;13(2):135-144.
3. Robidoux A, Tang G, Rastogi P, et al. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: 5-year outcomes of NSABP protocol B-41.J Clin Oncol34, 2016 (suppl; abstr 501).
4. Holmes FA, Espina V, Liotta LA, et al. Pathological complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling.BMC Res Notes.2013;6:507.
5. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.Lancet Oncol.2016;17(6):791-800.
6. Hurvitz SA, Martin M, Symmans WF, et al. Pathological complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE).J Clin Oncol34, 2016 (suppl; abstr 500).