Expert Says pCR Data Support Neoadjuvant Therapy in HER2-Positive Breast Cancer

Frankie Ann Holmes, MD

Substantial clinical trial evidence supports the use of pathologic complete response (pCR) as a measure for evaluating neoadjuvant therapies for patients with HER2-positive breast cancer, suggesting that preoperative treatment should be the standard of care, according to Frankie Ann Holmes, MD.

Holmes said recent research has shown that pCR to neoadjuvant chemotherapy is a significant predictor of long-term outcomes. Along with the FDA’s approval of a neoadjuvant pertuzumab (Perjeta) combination regimen based on favorable pCR outcomes, this research emphasizes the importance of neoadjuvant treatment for HER2-positive breast cancer to clinicians and may serve as a platform for accelerated approval of future agents, said Holmes.

Holmes, associate director of Breast Oncology Research at Texas Oncology, offered these insights during a presentation at the 13th Annual International Congress on the Future of Breast Cancer®. Physicians’ Education Resource (PER®) hosted the conference in Huntington Beach, California, in July.

The efficacy of pCR as a measure of evaluating therapies for breast cancer has been a closely watched issue in oncology drug development. In September 2013, the FDA approved an expanded indication for pertuzumab in combination with trastuzumab (Herceptin) and docetaxel preoperatively in patients with high-risk, HER2-positive early-stage breast cancer. The decision marked the first time that the FDA has formally approved a neoadjuvant breast cancer treatment.

Clinical Trial Patterns Dissected

Although results of one clinical trial have been disappointing, Holmes maintained that several studies support the prognostic value of pCR using a standard definition (ie, ypTis ypT0 ypN0). In October, the FDA issued a guidance document defining pCR as either the absence of residual invasive cancer (ypT0/Tis ypN0) or the absence of residual invasive and in situ cancer (ypT0 ypN0) on complete resected tumor specimens and all sampled regional lymph nodes following the completion of neoadjuvant systemic therapy.¹

Holmes said the CTNeoBC meta-analysis² showed that achieving pCR following preoperative chemotherapy was an especially strong predictor of event-free survival in aggressive forms of breast cancer. Attaining pCR reduced the risk of death by 92% in cancers that were HER2-positive and hormone receptor—negative cancers and by 84% in triple-negative breast cancers (TNBCs).

According to Holmes, these results were clinically significant because they showed pCR predicted outcomes regardless of treatment and emphasized the importance of neoadjuvant therapy in breast cancer treatment.

Holmes noted that the NeoSphere trial³, which investigated neoadjuvant pertuzumab use in combination with trastuzumab and docetaxel, was pivotal for accelerated FDA approval of the regimen.

The trial showed a pCR of 45.8% in patients with HER2-positive, locally advanced, inflammatory tumors who underwent the three-drug regimen, compared with 29% of the patients who received trastuzumab plus docetaxel treatment. The median tumor size across all arms was approximately 5 cm and about 30% of the participants had a node 0 status.

The TRYPHANEA trial⁴, which included patients with T2-4 tumors and any nodal status, confirmed the cardiac safety of this regimen, further supporting the accelerated FDA approval of the three-drug therapy; and the APHINITY trial is expected to produce additional efficacy and safety data by 2016.

"Preoperative chemotherapy with trastuzumab and pertuzumab should be considered as a standard of care in all newly diagnosed HER2-positive breast cancers," said Holmes.

Like the NeoSphere trial, the NeoALTTO trial⁵ showed an approximate 20% increase in pCR with the dual HER2-blockade strategy of concurrent or sequential lapatinib (Tykerb) and trastuzumab compared with trastuzumab alone.

However, the pCR data failed to translate into a significant improvement in disease-free survival (DFS) over trastuzumab alone in the phase III ALTTO trial after a median follow-up of 4.5 years.⁶ This finding caused some clinicians to question the validity of pCR as a predictor of long-term outcomes.

Holmes noted the number of events (550) was lower than the 850 events the trial was initially powered for. Additionally, the ALTTO patients were a low-risk cancer group with relatively high DFS among all treatments (88% in the lapatinib plus trastuzumab arm, 87% in the trastuzumab followed by lapatinib arm, and 86% in the trastuzumab-only arm), which may have contributed to the lack of significance in this trial. Holmes emphasized the ALTTO trial should not completely discount pCR as a predictor of long-term outcomes across all neoadjuvant therapies and breast cancer types.

Holmes indicated that even if the pCR in the NeoALTTO trial did not translate to improved DFS, the benefits of dual HER2 blockade in this trial suggest such neoadjuvant trials may serve as a model for future discovery of drugs and methods to target HER2-positive breast cancer. These include using immune response mRNA markers to predict the carboplatin-based chemotherapy response in HER2-positive and TNBC tumors, adding trebananib to a paclitaxel—trastuzumab chemotherapy regimen to inhibit angiogenesis, and using PET response to predict pCR after one cycle of chemotherapy with the addition of a second agent in the next treatment cycle if necessary.

According to Holmes, determination of pCR to neoadjuvant therapy will help accelerate approval of new agents and several strategies are "right around the corner" for targeting HER2-positive breast cancer. However, she stated that improving trial design is essential to assess how agents operate in combination.

References

1. US Food and Drug Administration. Pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. http://goo.gl/33oJ. Published October 6, 2014. Accessed October 17, 2014.
2. Cortazar P, Zhang L, Prowell T. Potential of neoadjuvant trials to support drug approval in high-risk early breast cancer. Breast Diseases: A Year Book Quarterly. 2014;25(2):112-115.
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial [published online December 6, 2011]. Lancet Oncol. 2012;13(1):25-32.
4. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA) [published online May 22, 2013]. Ann Oncol. 2013;24(9):2278-2284.
5. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [published online January 17, 2012]. Lancet. 2012;379(9816):633-640.
6. Piccart-Gebhart M, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL. Abstract LBA4.