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Expert Discusses Latest Data in Neoadjuvant HER2+ Breast Cancer

Jason M. Broderick @jasoncology
Published: Tuesday, Sep 27, 2016

Stephen K. Chia, MD

Stephen K. Chia, MD

Results from the KRISTINE1 and NSABP B-412 trials presented at the 2016 ASCO Annual Meeting provided the latest data on the use of pertuzumab (Perjeta), trastuzumab (Herceptin), ado-trastuzumab emtansine (T-DM1; Kadcyla), and lapatinib (Tykerb) for the neoadjuvant treatment of patients with HER2-positive breast cancer.

In a lecture at the conference, Stephen K. Chia, MD, an assistant professor in the division of Medical Oncology at the University of British Columbia, highlighted the key findings from these trials and their implications for the treatment of HER2+ breast cancer.

KRISTINE

The phase III KRISTINE trial randomized 432 patients with HER2-positive early breast cancer to the neoadjuvant regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab (TCH+P), or T-DM1 plus pertuzumab (T-DM1+P).

The results showed a statistically significant inferiority for the T-DM1 arm. The pCR in the breast and lymph nodes was 56% with TCH+P versus 44% with T-DM1+P (P = .0155).

“KRISTINE does not support the use of neoadjuvant T-DM1, with or without pertuzumab,” Chia.

Neither of the subsequent regimens given in the adjuvant setting—trastuzumab plus pertuzumab in the TCH+P arm and T-DM1 plus pertuzumab in the T-DM1 arm—were standard of care. These treatments, Chia noted, could alter event-free survival and thus influence “concordance” between pCR and long-term outcomes, and physicians should keep this in mind when the long-term survival data become available.

Chia discussed the impact of the KRISTINE data, along with the previously reported MARIANNE data on his expectations for the KAITLIN trial. The KAITLIN trial is comparting T-DM1 plus pertuzumab to trastuzumab with pertuzumab plus a taxane as adjuvant therapy following anthracyclines for patients with HER2-positive breast cancer.

In the MARIANNE trial, T-DM1 plus or minus pertuzumab did not improve outcomes compared with trastuzumab plus either docetaxel or paclitaxel in the frontline setting for HER2+ breast cancer.

“Unfortunately I’m not optimistic, based on KRISTINE and MARIANNE, that you are going to see a superiority signal from KAITLIN,” said Chia. He added that when interpreting the results, it’s important to note that KAITLIN was not powered for a noninferiority statistical design.

Summarizing the current neoadjuvant landscape, Chia said data from KRISTINE, along with results from the NeoSphere, TRYPHAENA, and I-SPY 2 trials, support the use of neoadjuvant pertuzumab concurrent with a taxane.

However, he said at this time, there’s no data supporting the use of pertuzumab in the adjuvant setting. For this evidence, Chia is eagerly awaiting the results of the phase III APHINITY trial, comparing pertuzumab plus trastuzumab and chemotherapy with trastuzumab and chemotherapy alone.

NSABP B-41

The NSABP B-41 neoadjuvant trial in HER2-positive patients examined lapatinib and trastuzumab separately as well as in combination, all with weekly paclitaxel following doxorubicin and cyclophosphamide.

The pCR in breasts was 52.5% in the trastuzumab arm compared with 53.2% in the lapatinib arm, a difference that was not statistically significant (P = .99). The combination arm showed a numerical benefit with a 62% pCR in breasts, but the difference was not statistically significant compared with with the trastuzumab arm (P = .095).

Long-term follow-up data for the trial presented at ASCO were similar to these initial findings. The recurrence free interval (RFI) rate at 4.5 years was 80.7% for the lapatinib arm versus 86.9% for the trastuzumab arm (HR = 1.27; 95% CI, 0.74-2.2; P = .14). The RFI with the combination was 90%, representing a hazard ratio of 0.66 (95% CI, 0.34-1.25; P = 0.33) compared with trastuzumab.

The overall survival (OS) rate at 5 years was 89.4% with lapatinib compared with 94.5% with trastuzumab (HR = 1.52; 95% CI, 0.69-3.35; P = 0.11). The 5-year OS with the combination was 95.7%, representing a hazard ratio of 0.63 (95% CI, 0.24-1.67; P = .55) compared with trastuzumab.

Thus, when comparing trastuzumab with lapatinib in the neoadjuvant HER2-positive setting, there is a numerically, but not statistically significant, inferiority for lapatinib versus trastuzumab.

Chia also noted that while breast pCR was used as the pCR endpoint in the B-41 trial design, “If you use the preferred endpoint of pCR in breasts and nodes from the B-41, NeoALTTO, and CALGB 40601 [neoadjuvant] trials, all of them show numerically inferior, either statistically significant or not, pCR rates for the lapatinib arms.”

In his concluding remarks, Chia offered general advice about the approach to neoadjuvant research going forward.

“We need to embrace as a clinical community that the neoadjuvant model is the standard of care and enroll these patients into clinical trials.”

Focusing on the neoadjuvant model, Chia noted, will allow researchers to conduct residual disease trials; explore the potential that, in certain subtypes of breast cancer, neoadjuvant trials may replace adjuvant trials; and collaborate to discover predictive biomarkers.
 

References

  1. Hurvitz SA, Martin M, Symmans WF, et al. Pathologic 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).
  2. Robidoux A, Tang G, Priya 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).



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