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Neoadjuvant studies can demonstrate value of new agents in breast cancer
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Presurgical systemic — or neoadjuvant — therapy has been shown to induce pathologic complete response (pCR) rates in a substantial number of women with operable breast cancer.
Because pCR is associated with improved survival, improving pCR rates in breast cancer recently has served as a primary endpoint in several neoadjuvant trials. However, a meta-analysis of the published literature was unable to define the precise relationship between increases in pCR and increases in EFS.
Despite this limitation, the FDA has provided guidelines for drug approval based on enhanced pCR rates, with pertuzumab (Perjeta, Genentech) receiving the first approval of a HER-2–targeted therapy in the neoadjuvant setting under these guidelines. This approval was based on the results of the NeoSPHERE trial, which showed pertuzumab yielded improved pCR rates when combined with docetaxel and trastuzumab (Herceptin, Genentech) compared with docetaxel/trastuzumab alone.
Douglas Yee
Concerns about pCR serving as a surrogate marker have been raised with the presentation of the ALTTO trial at the 2014 ASCO Annual Meeting. This trial evaluated the benefit of adding lapatinib (Tykerb, GlaxoSmithKline) to a trastuzumab/chemotherapy-based regimen. Although the neoadjuvant trial (NeoALTTO) showed a statistically significant benefit for the addition of lapatinib, the ALTTO adjuvant trial failed to show a statistically significant improvement in EFS.
The interpretation of these two trials has been controversial. Although the discussion at ASCO raised concerns about the validity of pCR as a surrogate endpoint for survival in breast cancer, further statistical analysis suggested that NeoALTTO predicted the benefits of ALTTO with a high degree of precision. Even critics of the use of pCR as a surrogate endpoint agreed that ALTTO “was a seriously underpowered trial.”
So how do we solve the dilemma of understanding the relationship of improved pCR rates resulting from the inclusion of a new drug and survival? The NOAH trial provides a simple answer: perform the neoadjuvant study and the adjuvant trial together.
NOAH evaluated neoadjuvant trastuzumab/chemotherapy vs. chemotherapy alone in 235 patients with HER-2–positive disease. Additional trastuzumab was given after neoadjuvant therapy for a total of 12 months. Patients initially assigned to neoadjuvant chemotherapy alone were allowed to cross over to adjuvant trastuzumab given the positive results from the NSABP/HERA trials. Researchers reported pCR rates of 38% in the trastuzumab/chemotherapy group and 19% for chemotherapy alone. Patients who achieved a pCR had an HR of 0.29 for EFS, and a subgroup analysis suggested this relationship only was statistically significant in patients who received trastuzumab.
Thus, improvements in pCR rates driven by the inclusion of trastuzumab into the chemotherapy regimen resulted in improved EFS. Most importantly, these benefits could be detected in a small clinical trial of 235 patients enrolled during a period of less than 3 years. Given the large number of targeted therapies in development, the ability to detect a benefit in a small number of patients will shorten the time to approval, especially if pCR serves as a robust surrogate for EFS.
Finally, the ability to use a biomarker to predict benefit from any given therapy — in this case, HER-2 — can be most easily tested in the neoadjuvant setting, where pCR rates can be directly linked to the biomarker. Even within the HER2 positive subgroup, the intrinsic subtype of breast cancer is heterogeneous.
As recently shown, fewer than a third of HER-2–positive patients enrolled on a neoadjuvant clinical trial (CALGB 40601) were “HER-2–enriched” as defined by gene expression profiling. Clearly, refinements in biomarker analysis and appropriate assignment of therapy can be accomplished in the neoadjuvant therapy of breast cancer. NOAH has shown us how the neoadjuvant setting can efficiently demonstrate the value of new agents to improve survival in breast cancer.
References:
Berry D. In NeoALTTO and ALTTO trials, neoadjuvant response predicts adjuvant. Available at: www.cancerletter.com/articles/20140711_2. Accessed on Aug. 14, 2014.
Carey LA. Abstract #506. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Cortazar P. Lancet. 2014;384:164-172.
Gianni L. Lancet Oncol. 2014;15:640-647.
Lynce F. Cancer Invest. 2014;Published online ahead of print June 12.
Piccart-Gebhart MJ. Abstract #LBA4. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Sledge G. Neoadjuvant doesn’t predict adjuvant in breast cancer. Available at: www.cancerletter.com/articles/20140711_3. Accessed on Aug. 14, 2014.
For more information:
Douglas Yee, MD, is director of the Masonic Cancer Center, as well as professor of medicine and pharmacology at the University of Minnesota. He also is a HemOnc Today Editorial Board member. He can be reached at Division of Hematology, Oncology and Transplantation, 420 Delaware St. SE, MMC 480, Minneapolis, MN 55455; email: yeexx006@umn.edu.
Disclosure: Yee reports no relevant financial disclosures.