Pertuzumab Use Continues to Expand in Breast Cancer

Hope Rugo, MD

Treatment strategies that incorporate pertuzumab (Perjeta) continue to evolve as more clinical trial data becomes available. The FDA initially approved pertuzumab in combination with trastuzumab and docetaxel as a frontline treatment for patients with HER2-positive metastatic breast cancer in 2012, based on findings from the phase III CLEOPATRA trial. This was followed by the approval of pertuzumab, trastuzumab, and chemotherapy as a neoadjuvant therapy for early-stage HER2-positive breast cancer in 2013.

In addition to these settings, the combination of pertuzumab with trastuzumab and hormonal therapy has generated excitement as a potential option for patients with HER2 and ER-positive breast cancer, and represents an area for future research, according to an OncLive Peer Exchange discussion entitled Treating Advanced Breast Cancer in Community Settings.

"The CLEOPATRA trial continued both antibodies until progression, and that’s where we’re seeing this survival benefit and adding in the hormone therapy is a great thing," Hope S. Rugo, MD, the director of the Breast Oncology, Clinical Trials, and Education Program at the University of California San Francisco Comprehensive Cancer Center, said during the discussion. "We all have these patients who have been on that regimen for 10 years instead of dying of their cancer. It seems like a better option."

In the CLEOPATRA trial, 808 women were randomized to trastuzumab, docetaxel, and pertuzumab (n = 402) or trastuzumab, docetaxel, and placebo (n = 406). The primary endpoint was progression-free survival (PFS), with secondary outcome measures focused on overall survival (OS) and response.

"I’ve seen a lot of questions about how long do we continue the chemo," Sara Hurvitz, MD, director of the Hematology/Oncology Breast Cancer Program and an Associate Professor in the Department of Medicine at UCLA, said during the discussion. "The CLEOPATRA study did six cycles and then allowed patients to stop the chemotherapy, and that’s what I do routinely in my practice."

According to The New England Journal of Medicine, the median PFS was 18.5 versus 12.4 months in the pertuzumab and placebo arms, respectively (HR = 0.62; P <.0001).¹ The median OS with the triplet therapy was not reached compared with 37.6 months with placebo (HR = 0.66; P = .0008). A final OS analysis from the CLEOPATRA study will be presented at the 2014 ESMO Congress.

The objective response rate was 80.2% in the pertuzumab arm compared with 69.3% with placebo. The median duration of response was 20.2 versus 12.5 months, for the pertuzumab and placebo arms, respectively.

"I think you can’t argue with the response rate or with the progression-free survival of 18.5 months,” Hurvitz said. “I think that’s just incredibly impressive, and so you would want to give your patient that opportunity."

In the discussion, panelists noted that several questions exist regarding the standard of care for patients with HER2-positive and ER-positive metastatic breast cancer.

"I do incorporate endocrine therapy in patients who co-express the hormone receptors, even though CLEOPATRA did not do that. But I think it makes biological sense," Hurvitz said.

The collection of studies suggests that HER2 inhibitors work synergistically with hormonal agents. It has been hypothesized that this synergy is the result of MED1 inhibition, a key pathway that connects ER and HER2.

The combination of trastuzumab and fulvestrant was compared with fulvestrant alone in patients with ER-positive and HER2-positive metastatic breast cancer. According to an analysis presented at the 2014 Breast Cancer Symposium, the combination of trastuzumab and fulvestrant resulted in a dramatic prolongation in response.²

In the 85-patient study, 11 patients (13%) were treated with the combination. The median duration of fulvestrant therapy for HER2-positive patients was 772 days, compared with 360 days for HER2-negative patients (P = .059). The odds ratio for patients with HER2-positive breast cancer receiving a longer duration of treatment was 6.2 (P = .0249).

To explore this paradigm further, the phase II PERTAIN study is exploring the combination of pertuzumab, trastuzumab, and an aromatase inhibitor (AI) for postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer. This study plans to randomize patients in a 1:1 ratio to the triplet therapy or trastuzumab plus an AI (either letrozole or anastrozole). The study plans to enroll approximately 250 patients (NCT01491737).

"That trial is actually ongoing. It probably will be announced in about a year, 18 months, we’ll figure out,” Brufsky said. “And then hopefully that will be on guidelines and the insurance companies won’t reject it."

References:

1. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
2. Charif M, Lower EE, Kennedy D, et al. The effect of trastuzumab therapy on clinical benefit from fulvestrant treatment for metastatic estrogen receptor-positive breast cancer patients. Presented at: 2014 Breast Cancer Symposium; September 4 - 6, 2014; San Francisco, CA. Abstract 155.