Dual HER2-Targeted Approach Delivers Greatest Neoadjuvant Benefit in HER2+ Breast Cancer

Frankie Ann Holmes, MD

In terms of neoadjuvant therapies for patients with HER2-positive breast cancer, dual anti—HER2-directed agents seem to have the most benefit, said Frankie Ann Holes, MD, a physician at Texas Oncology.

For example, the NOAH trial,¹ which explored neoadjuvant chemotherapy with or without trastuzumab (Herceptin) in women with HER2-positive locally advanced or inflammatory breast cancer, there was a clear difference in the trastuzumab arm that showed benefit of the combination regimen. 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.

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

Secondly, a number of clinical trials have explored lapatinib (Tykerb) and trastuzumab in the neoadjuvant setting, including the phase III GBG 44 trial² that compared lapatinib to trastuzumab in combination with an anthracycline-taxane—based chemotherapy regimen. The 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.³ The trastuzumab arm showed a pCR rate of 52.5% and the lapatinib arm had a similar rate of 53.2%. This similar lack of difference between trastuzumab and lapatinib separately was seen in various other studies comparing the treatments, such as the smaller USOR 05-074 trial from Holmes et al. ⁴

The combination arm in NSABP B-41 showed a numerical difference with a pCR rate of 62% but a relatively low statistical rate (P = .095).³ The 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," Holmes said during her presentation. "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."

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

The phase II NeoSphere trial looked at neoadjuvant pertuzumab and trastuzumab in breast cancer.⁵ The cohort of patients who 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 investigated neoadjuvant ado-trastuzumab emtansine plus pertuzumab (T-DM1+P) versus trastuzumab, carboplatin, and docetaxel plus pertuzumab (TCH+P).⁶ The 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.

“One of the themes that we’ve heard…is that we have to identify who are these subgroups of patients who really don’t need the more aggressive chemotherapy,” Holmes said.

Identifying those subgroups, however, would require a greater understanding of the gene signatures and biomarkers of HER2-positive 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 Oncol 34, 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 Oncol 34, 2016 (suppl; abstr 500).