Dual HER2-Blockade Plus AI Shows Promise in HER2+/ER+ Breast Cancer

Alberto Montero, MD

Data from the phase II PERTAIN trial presented late last year at the 2016 San Antonio Breast Cancer Symposium (SABCS) showed that adding an aromatase inhibitor (AI) to pertuzumab (Perjeta) and trastuzumab (Herceptin) extended progression-free survival (PFS) by over 3 months versus trastuzumab plus an AI in patients with HER2-positive, HR-positive locally advanced or metastatic breast cancer.

The median PFS was 18.89 months with the pertuzumab triplet compared with 15.80 months for trastuzumab and an AI alone (HR, 0.65; 95% CI, 0.48-0.89; P = .007). The objective response rates were 63.3% versus 55.7%, respectively.

OncLive: Could you provide an overview of the PERTAIN study?

In an interview with OncLive at SABCS, Alberto Montero, MD, a staff physician in the Department of Solid Tumor Oncology at Cleveland Clinic, discussed the significance of the PERTAIN study in estrogen-positive, HER2-positive patients.Montero: It’s a randomized phase II trial to answer a hypothesis that mechanisms of estrogen resistance really, in part, go through the HER2 pathways. So the hypothesis is by dual blockade of the HER2 pathway and in the estrogen-positive, HER2-positive population, perhaps, that’ll be better than just trastuzumab alone. Most of these patients received some form of chemo which is the standard of care, so a taxane—either docetaxel or paclitaxel—but not all of them received chemo.

This was interesting because there was a subset of patients that hadn’t received chemo, just antibody and aromatase inhibitor alone, and the PFS was around 21 months with the addition of pertuzumab.

With this combination, what are the concerns about safety?

What kind of clinical impact could you see this type of regimen having in the field?

What is the typical standard therapy for estrogen-positive, HER2-positive patients now, and what is the efficacy that is seen with that?

I think that the clinical relevance is that some patients who fit this population—HER2-positive and estrogen-positive—who aren’t good candidates for chemotherapy, can expect a PFS upwards of 20 months with a dual HER2 blockade and an aromatase inhibitor.They looked at cardiac toxicity—which is something to worry about—but there was nothing unexpected because we know that from CLEOPATRA and other studies, the incidents of heart failure with the addition of pertuzumab to trastuzumab is pretty low. As long as there are no anthracyclines that are administered with HER2 blockade, the cardiac toxicity is quite low.I think the main application or impact of the study is in patients in the metastatic stage where we can’t cure them and quality of life and side effect profile is really important. So, this study provides some clinical data looking at dual antibody blockade and an aromatase inhibitor in that triple-positive subset without any sort of cytotoxic chemo.The standard of care would be to start with chemo, because the FDA label with pertuzumab in the metastatic setting is in combination with a taxane and trastuzumab. Then typically you’d do some sort of initial chemotherapy and then at some point you would stop the taxane and continue the dual antibody treatment. Presumably, in someone who is estrogen-positive, you would also add some sort of anti-estrogen treatment along with that.

Are there any remaining challenges associated with this treatment?

Is there anything further that you would like to add?

To my knowledge, this is really the first study that is looking at that specific population and looking at what impact does the addition of pertuzumab have to trastuzumab in aromatase inhibitor therapy. And the answer is it does have a significant impact.Number one, cost—pertuzumab is a very expensive medication. From a cost-effectiveness standpoint, eliminating the taxane—although great in terms of minimizing toxicity—is not really going to change the equation because what’s driving the cost is the monoclonal antibodies. So, from a value standpoint, it’s not going to be more cost-effective, but there is more value from the point of view of less toxicity. If you get a really good outcome in a patient who can’t tolerate chemotherapy, it’s a value to the patient and to physicians to have data with a nonchemotherapy option.I think it’s important to keep in mind that this is a randomized phase II trial that was only in hormone receptor¬—positive, HER2-positive patients. HER2 is not a monolithic entity, so within HER2 there are those who are hormone receptive–negative and HER2-positive, which is a different biology and this study wouldn’t apply to those patients.

Arpino G, Ferrero J-M, de la Haba-Rodriguez J, et al. Primary analysis of PERTAIN: a randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10; San Antonio, TX. Abstract S3-04.