Experts Support Broader Pertuzumab Use in HER2-Positive Breast Cancer

Adam Brufsky, MD, PhD

The recent approval of pertuzumab (Perjeta) as part of a combination neoadjuvant treatment for patients with early-stage breast cancer has paved the way for wider use of the regimen in preoperative settings, experts indicated during a recent Peer Exchange panel discussion.

In September 2013, the FDA approved pertuzumab in combination with trastuzumab (Herceptin) and chemotherapy for patients with HER2-positive locally advanced or early-stage breast cancer, marking the first neoadjuvant indication in that disease setting. This accelerated approval was based on results from the phase II NeoSphere trial,1 which showed that pertuzumab, a HER dimerization inhibitor, combined with the HER2 inhibitor trastuzumab and the chemotherapy docetaxel, significantly improved pathologic complete response (pCR) when compared with three other neoadjuvant regimens. In the study, pCR was defined as the absence of invasive cancer in the breast and lymph nodes.

In a recent OncLive Peer Exchange roundtable entitled “Practical Considerations in Breast Cancer,” moderator Adam M. Brufsky, MD, PhD, Medical Director, Women’s Cancer Center, Magee-Womens Hospital of UPMC, University of Pittsburgh Cancer Institute, asked panelists which patients they would consider for neoadjuvant therapy in HER2-positive breast cancer, based on the recent approval.

Denise A. Yardley, MD

NeoSphere Trial

“In my own practice, I’ve actually lowered the bar of what I would have traditionally considered a patient who was locally advanced with a large tumor involvement of the skin or bulky axillary nodes almost to tumors that I think are eligible for adjuvant therapy,” replied Denise A. Yardley, MD, Senior Investigator, Breast Cancer Research, Sarah Cannon Research Institute, Tennessee Oncology. “From our own practice, I think tumors that have any degree of evidence of nodal involvement or tumors—if we look at size—we have some T1 tumors that are applicable for neoadjuvant strategies.”In the phase II NeoSphere trial,¹ 417 patients with newly diagnosed HER2-positive early-stage breast cancer were evenly randomized to one of four treatment arms: trastuzumab plus docetaxel (n = 107, group A), pertuzumab and trastuzumab plus docetaxel (n = 107, group B), pertuzumab plus trastuzumab (n = 107, group C), or pertuzumab plus docetaxel (n = 96, group D).

Patients who received pertuzumab/trastuzumab/ docetaxel experienced a significant improvement in pCR of 45.8% (95% CI, 36.1-55.7), compared with 29% (95% CI, 20.6-38.5), 24% (95% CI, 15.8-33.7), and 16.8% (95% CI, 10.3-25.3) for groups A, D, and C, respectively.

The most common grade 3 severity or higher adverse events (AEs) observed in the pertuzumab/ trastuzumab/docetaxel arm were neutropenia (48 of 107), febrile neutropenia (9 of 107), and leukopenia (5 of 107). The number of serious AEs was similar in groups A, B, and D, but was much lower in group C, which did not receive chemotherapy.

Joyce A. O’Shaughnessy, MD

The indication for pertuzumab specifies that it should be used in patients with node-positive T2 breast cancer. However, given the magnitude of benefit with administration of the drug, the panelists said it might be appropriate to treat patients with HER2-positive T2 N0 or T1 N1 tumors.

“What I’ve been doing in my practice is trying to get people on it because that pathologic CR rate is so important, particularly in the ER [estrogen receptor]—negative, where we know it does translate into benefit,” explained Joyce A. O’Shaughnessy, MD, Chair, Breast Cancer Research, Baylor Charles A. Sammons Cancer Center, Texas Oncology and US Oncology. “I think if they meet the label, T2 N0 or node positive clinically by however you get there, they should pertuzumab preoperative.”

In many situations, the panelists noted, a medical oncologist may not see a patient until after surgery. As a result, they stressed the importance of all members of a treatment team understanding the impact of neoadjuvant pertuzumab on the overall outcome so that it can be administered preoperatively. Moreover, pathologists should be made aware that HER2 status is important early in the process, even for small tumors. “I think that because we tend to see the patients after the surgeons, there may be certain patients who actually don’t have markers done before they have their primary surgery. So this is an educational process of working together with the surgeons and with our community colleagues,” noted Hope S. Rugo, MD, Professor of Medicine, Director of Breast Oncology Clinical Trials Program, UCSF Helen Diller Family Comprehensive Cancer Center.

Mark Pegram, MD

To improve access to pertuzumab, physicians at Stanford are beginning to use the same eligibility criteria used for adjuvant HER2-targeted therapies, stated Mark D. Pegram, MD, Professor, Medicine (Oncology) ,Stanford University Medical Center, Associate Director, Clinical Research Director, Breast Cancer Program, Stanford Cancer Institute. “We’re considering pertuzumab as neoadjuvant therapy for anybody who would be a candidate for standard adjuvant HER2-targeted therapy, irrespective of the cutoffs in the label in terms of size, for example,” explained Pegram. “We’ve shifted, in our practice at Stanford, to strong consideration for pertuzumab-based chemo up front for most any early-stage breast cancer that would be a candidate for standard adjuvant HER2-targeted therapy.”

TRYPHAENA Study

The regimens utilized to treat HER2-positive breast cancer continue to evolve as new therapies gain approval. By and large, HER2 status is being determined at a much earlier stage. Moreover, the increased efficacy of HER2-targeted therapies represents the potential to alter accompanying chemotherapeutic agents without significantly changing outcomes.In the phase II TRYPHAENA study,² 225 patients with HER2-positive early-stage breast cancer were were randomized to receive 6 neoadjuvant cycles in one of three treatment arms: (arm A) 5-fluorouracil, epirubicin, cyclophosphamide (FEC) + trastuzumab (H) + pertuzumab (P) x3→ docetaxel (T) + H + P x3; (arm B ) FEC x3 → T + H + P x3; or (arm C) T + carboplatin + H [TCH] + P x6. The primary endpoint was cardiac safety with a secondary endpoint of pCR.

In general, the pCR rates with these treatments were similar. In fact, the pCR with TCH plus pertuzumab was 63.6% compared with the anthracycline- based regimens, which had a pCR rate around 55%. The most common grade 3 or higher AEs associated with the TCH/pertuzumab combination were neutropenia (46.1%), febrile neutropenia (17.1%), and anemia (17.1%).

“[TRYPHAENA] convinced me that when it comes to a pertuzumab-based regimen, I can just give the TCHP. So that’s what I’ve been doing,” said O’Shaughnessy. “I’ve not been using the anthracycline anymore, because I think the TRYPHAENA was helpful in that regard.”

In terms of the chemotherapy used along with HER2-targeted therapies, Kimberly L. Blackwell, MD, Professor, Medicine Assistant Professor Radiation Oncology Duke Cancer Institute, said it is appropriate to administer docetaxel alone, without carboplatin. “I’m comfortable with single-agent docetaxel, especially in the neoadjuvant setting,” Blackwell noted. “If you get a pCR off that, you might spare these women the toxicity of carboplatin.”

Hope Rugo, MD

For patients who do not tolerate docetaxel/carboplatin, Rugo recommended a switch to weekly paclitaxel with low-dose carboplatin. In a single-arm phase II study, weekly paclitaxel with trastuzumab was explored for patients with low-risk HER2-positive breast cancer. This study demonstrated impressive findings, Rugo stated. A randomized follow-up trial will compare paclitaxel plus trastuzumab with the ado-trastuzumab emtansine (Kadcyla), or T-DM1.

Pertuzumab in Metastatic Breast Cancer

“We don’t have outcome data from TRYPHAENA or from the NeoSphere trial. So we don’t know yet what the outcome will be for these patients,” warned Rugo. “And we have to be a little bit cautious when we’re dropping drugs in patients who do not have the little cancers for which we’re talking about doing more neoadjuvant [therapy], but the more high-risk disease.”The FDA initially approved the combination of docetaxel, trastuzumab, and pertuzumab in 2012 to treat patients with HER2-positive metastatic breast cancer based on the phase III CLEOPATRA trial.³ The study provided ample category 1 evidence to support this regimen as the preferred first-line standard of care for patients in this setting, Brufsky stated.

In the study, 808 patients with HER2-positive metastatic breast cancer were evenly randomized to receive pertuzumab, trastuzumab, and docetaxel (n = 402) or trastuzumab, docetaxel, and placebo (n = 406). The pertuzumab combination demonstrated a median progression-free survival (PFS) of 18.5 months compared with 12.4 months in the control arm (HR = 0.62; 95% CI, 0.51-0.75; P <.001).

Kimberly L. Blackwell, MD

Adjustments to this regimen can be made without significantly impacting efficacy. A close analysis of the survival curves suggests that the majority of benefits are derived from the antibodies, said Blackwell. As a result, optimal outcomes are still achieved if the chemotherapy is stopped after 6 cycles. Moreover, in some situations, paclitaxel may need to be substituted for docetaxel in the combination.

Concerns over the optimal chemotherapy utilized and synchronizing schedules could be short-lived as newer trials explore chemotherapy-free options. The phase III MARIANNE trial is exploring T-DM1 plus pertuzumab or placebo versus trastuzumab plus a taxane for patients with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer. Results from this study are expected in the second half of 2014.⁴

The FDA-mandated confirmatory phase III APHINITY trial has enrolled more than 4800 patients with HER2-positive early-stage breast cancer. This trial is comparing pertuzumab, trastuzumab, and chemotherapy with trastuzumab and chemotherapy as an adjuvant treatment. Further data on efficacy, safety, and long-term outcomes from this trial are expected in 2016.

References

1. Gianni L, Pienkowski T, Im Y-H, 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.
2. Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline- containing or concurrent with an anthracycline-free standard regimen: a randomized phase II study (TRYPHAENA). 2011 CTRC-AACR San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, TX. Abstract S5-6.
3. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer [published online December 7, 2011]. N Engl J Med. 2012; 366(2):109-119.
4. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01120184.