NeoALTTO Analysis Finds Significant Link Between pCR and Survival

Photo Courtesy © SABCS/Todd Buchanan 2013

Martine Piccart-Gebhart, MD, PhD

Pathologic complete response (pCR) to neoadjuvant chemotherapy had a significant correlation with survival in early HER2-positive breast cancer after 4 years of follow-up, according to a new analysis of the NeoALTTO trial presented at the 36th Annual San Antonio Breast Cancer Symposium (SABCS).

The hazard for event-free survival (EFS) was 65%-70% lower for patients who achieved pCR than for those who did not. The follow-up analysis also confirmed the primary outcome of NeoALTTO: dual HER2 blockade with trastuzumab and lapatinib led to a significantly higher pCR rate than did either drug by itself, Martine Piccart-Gebhart, MD, PhD, lead author of the study reported.

“Patients who achieved pCR had significantly better event-free survival and overall survival compared with no pCR, irrespective of the treatment arm,” said Piccart-Gebhart, section head in breast diseases at the Free University of Brussels in Belgium and chair of the Breast International Group. “I believe that our results will be vital for the process of drug development in the field of early HER2-positive breast cancer.”

Her presentation provided an update of the multicenter NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization), involving 455 patients with HER2-positive breast tumors >2 cm in diameter. Patients were randomly assigned to preoperative therapy with paclitaxel and lapatinib, paclitaxel and trastuzumab, or paclitaxel plus both anti-HER2 drugs.

Neoadjuvant therapy with dual HER2 inhibition significantly improved the odds of pCR in patients with early HER2-positive breast cancer. Patients who received a single anti-HER2 agent had similar rates of pCR.

These results did not address the question of whether the higher pCR rate achieved with lapatinib plus trastuzumab translated into better overall survival (OS) or EFS, however. The NeoALTTO trial was powered to detect pCR differences, but underpowered to detect moderate differences in EFS and OS, noted Piccart-Gebhart. The prespecified follow-up analysis of secondary endpoints reported here examined the relationship between pCR, EFS, and OS, after a median follow-up of approximately 4 years.

For this analysis investigators employed the following definitions:

• No invasive disease in the breast or axilla
• EFS events—for patients who had primary breast surgery (n = 427): postoperative recurrence, second primary cancers, and death. For patients who did not undergo primary breast cancer surgery (n = 28): regional or distant progression or second primary cancers during neoadjuvant treatment or death during clinical follow-up.
• Overall survival events—death

The data were analyzed in two ways: a 30-week landmark analysis, which included 90% of patients, and a Cox model with pCR as a time-dependent covariate. Both models showed similar results, and Piccart-Gebhart presented the results of the landmark analysis at this year’s SABCS.

Among patients who achieved a pCR with neoadjuvant therapy, the 3-year EFS was 86% compared with 72% for patients who did not have a pCR (HR = .38; P = .0003). The landmark analysis of OS by pCR status also showed significantly higher 3-year OS in patients who achieved pCR with neoadjuvant therapy (94% vs. 87%, HR 0.35, P = .005). The landmark analysis did not demonstrate an association between pCR and survival according to treatment assignment.

Despite results favoring dual HER2 inhibition, Piccart-Gebhart said the analysis should not change current standard of care neoadjuvant therapy, which is chemotherapy plus trastuzumab.

In 2014, the results of NeoALTTO’s “sister” trial in the adjuvant setting—ALTTO—will become available, which Piccart-Gebhart predicts will provide a robust answer on the effect of dual HER2 blockade on long-term outcome.

“If the results of both studies are in line with each other, and depending on the strength of the results, we could witness a new standard of care for managing primary HER2-positive breast cancer,” she concluded.

Piccart-Gebhart M, Holmes AP, de Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab, or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study. Presented at: the 36^th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S1-01.

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