ADCs and Other Novel Agents Boost HER2+ Breast Cancer Paradigm

Partner | Cancer Centers | <b>Memorial Sloan Kettering Cancer Center </b>

Chau T. Dang, MD, discusses recent treatment breakthroughs and emerging agents in HER2-positive breast cancer.

Chau T. Dang, MD

Several FDA approvals over the past year have propelled progress in HER2-positive breast cancer, and other novel agents are rapidly advancing through the pipeline, explained Chau T. Dang, MD.

“Over the last 20 years, there's been an explosion of clinical trials that have led to the development of multiple drugs to improve the treatment of patients with metastatic HER2-positive breast cancer as well as early stage HER2-positive breast cancer,” said Dang. “The evolution has been striking.”

Among the key developments, antibody-drug conjugates (ADCs) continue to grow as a therapeutic option for patients with HER2-positive breast cancer. In May 2019, the FDA approved ado-trastuzumab emtansine (T-DM1; Kadcyla) for use as an adjuvant treatment for patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab (Herceptin) and chemotherapy. In December 2019, the FDA approved the ADC fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.

Beyond ADCs, in February 2020, the FDA approved the tyrosine kinase inhibitor neratinib (Nerlynx) in combination with capecitabine (Xeloda) for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.

In an interview with OncLive, Dang, the Regional Care Network Medical Site Director at Memorial Sloan Kettering Westchester, discussed recent treatment breakthroughs and emerging agents in HER2-positive breast cancer.

OncLive: What are your thoughts on ADCs and how do they function in treating patients with HER2-positive breast cancer?

Dang: [One of the ADCs we currently have is] ado-trastuzumab emtansine, which was initially approved for the treatment of patients with metastatic HER2-positive breast cancer, and recently was also approved for patients in the adjuvant setting who have residual disease after neoadjuvant therapy.

The antibody in T-DM1 is trastuzumab and the chemotherapy is linked to a linker, essentially creating targeted chemotherapy. The antibody delivers the drug directly to the cancer, it's internalized, and the chemotherapy is released. [The therapy] is missing most healthy parts of the body and targeting the tumor. It's an effective targeted therapy.

What steps are taken in the HER2-positive paradigm to create a personalized treatment approach for patients?

Our patients with metastatic HER2-positive breast cancer, in terms of creating a personalized approach for frontline treatment today, receive a taxane/trastuzumab (Herceptin)/pertuzumab (Perjeta) combination because it has led to significant improvement in progression-free survival (PFS) and overall survival (OS).

In the second-line setting, [patients receive] T-DM1. In the third-line space and beyond, we have a plethora of multiple combinations that are active for patients. In terms of personalization, we go through our frontline treatment, second-line treatment, and now we have a whole host of drugs that we will sequence to treat our patients in the metastatic setting.

Could you give an overview of the DESTINY-Breast01 trial and its findings?

The phase II DESTINY-Breast01 trial evaluated the efficacy of trastuzumab deruxtecan. This is a potent ADC with an extremely exciting, potent payload at an 8:1 ratio from drug to antibody. It's essentially a topoisomerase inhibitor. This trial was done to confirm the data from the phase I study where the heavily pretreated population was given the drug and was found to have a response rate of about 60%. In this trial, they were able to confirm the response rate of 60% in a very heavily pretreated population. That is striking. Additionally, the median PFS was 16 months and OS has not been reached. We are excited to see the development of this drug.

A small group of patients who had brain metastases entered the trial and we are anxiously waiting to see the activity of the drug in patients with brain metastases. As far as tolerability, the 1 toxicity that stood out was interstitial lung disease, which we are looking for guidance on how to monitor and manage our patients because our patients should be getting this very active drug in the third-line space.

How do you detect interstitial lung disease early and what are your management recommendations?

We are going to be looking for guidance when this drug gets approved, but any sign of interstitial lung disease warrants holding the drug. If it's mild grade 1, we hold the drug and we monitor. Our patients should see a pulmonary consultant to manage the symptoms and they will get steroids to help mitigate the symptoms. Any other higher-grade toxicity will mean stopping the drug. We need more guidance on how to monitor our patients and hold the drugs appropriately. This is an important toxicity that we want to learn how to capture early, hold drug, and institute steroids so our patients can get better quickly.

Could you also give an overview of the NALA trial, which recently led to the approval of neratinib (Nerlynx) plus capecitabine in HER2-positive breast cancer?

The NALA study is a randomized study evaluating neratinib with capecitabine versus the control of lapatinib (Tykerb) and capecitabine in patients being treated in the third-line space. The co-primary endpoints of PFS and OS saw that neratinib plus capecitabine was better than control with a PFS gain of about 2.2 months. In terms of OS, there was not a difference.

Regarding toxicity, the grade 3 diarrhea rate was about 24%. It's important to note that there needs to be antidiarrheal prophylaxis when neratinib combined with capecitabine is going to be used. There is going to be data coming out to help guide us on how to treat our patients.

A key thing that was notable from this trial was the incidence rate of central nervous system metastases. It was better in the neratinib combination at 22% versus 29% in the control, which is exciting to see that neratinib does cross the blood-brain barrier. We are excited to see how this combination will become available for our patients in the third-line space.

Could you give an overview of the HER2CLIMB data?

Tucatinib is a TKI against HER2 selectively. This is a very exciting drug that has been found to cross the blood-brain barrier. In the HER2CLIMB study, patients were enrolled and were receiving the drugs in the third-line space, and half the patients had brain metastasis. This is the only trial that had enrolled this number of patients with brain metastases and they were randomized to standard treatment, which is capecitabine, trastuzumab, and placebo versus capecitabine, trastuzumab, and tucatinib. The outcomes showed there was significant gain in PFS with a hazard ratio of 0.54, with the absolute gain of about 2.2 months. This is an all patients, including patients with brain metastases.

We saw an OS gain in patients with brain metastases and non-brain metastases, which is striking. It's exciting to see a small molecule that is so active, cranially and extracranially, for our patients. Unfortunately, half of our patients with metastatic disease will suffer brain metastases and we are excited to see the drug get approved for patients.

In terms of toxicity, diarrhea is always a concern for our patients, but the grade 3 diarrhea rate wasn't that high at only 13% and it was short-lived and very manageable.

Could you give an overview of the SOPHIA trial?

The SOPHIA trial is a randomized study of margetuximab with chemotherapy against trastuzumab and chemotherapy in patients being treated in the third-line space and beyond. Margetuximab is an anti-HER2 antibody with enhanced Fc component that is immune modulating. In this study, they found that margetuximab with chemotherapy was better than control with an improvement in PFS. Although it was statistically significant, the benefit was small at about 0.9 months.

In further follow up, the magnitude of benefit was a little bit larger in the order of about 1.3 months. As far as survival benefit, there seemed to be a trend favoring margetuximab, but it was not statistically significant. We await further data on this antibody.

It seems to be very well tolerated, not very different than trastuzumab, creating another combination in a third-line space. We will have to see how it is going to stack up against the other options that we've spoken about, especially with a PFS gain that is modest compared to what we're seeing with trastuzumab deruxtecan and the tucatinib combination.

Could you give an update on the APHINITY trial findings?

We saw an update from the APHINITY trial in the early setting. The APHINITY study randomized patients with high-risk HER2-positive breast cancer to chemotherapy, trastuzumab, and placebo or chemotherapy, trastuzumab, and pertuzumab. With a longer follow-up, we showed that the invasive disease-free survival (DFS) was in favor with the pertuzumab-containing arm. The magnitude of benefit was greater and, though the survival was not significant, the benefit in node-positive patients remains.

This study shows that dual antibody therapy is necessary for patients with high burden disease, such as patients with node-positive breast cancer. They also showed that there was benefit in patients with HR&shy;—positive breast cancer as well with longer follow-up. These patients have later events and it was not surprising to see some benefit in patients with HR-positive breast cancer. There still was no benefit in patients with node-negative breast cancer.

How are the data from the APHINITY trial impacting the breast cancer paradigm?

The APHINITY trial was done at a time when patients were having surgery with node-positive breast cancer. Today, most if not all of our patients with node-positive breast cancer will have dual antibody neoadjuvant therapy upfront. At the time of surgery, if there is pathologic complete response (pCR), then patients should still complete their 1 year of pertuzumab/trastuzumab based treatment because we saw that 1 year of trastuzumab/pertuzumab lead to an improvement in terms of DFS for patients with node-positive disease. This combination of trastuzumab/pertuzumab is important to give over the course of 1 year for patients with node-positive disease, whether they get their treatment all as adjuvant therapy or as neoadjuvant treatment.

How could these newer targeted therapies shift treatment decisions for clinical practice?

Right now in the third-line space, there are so many options for patients, including chemotherapy plus trastuzumab or hormone therapy plus trastuzumab for patients with hormone receptor (HR)—positive breast cancer, or even the doublet of trastuzumab and lapatinib or T-DM1 in the third-line space if patients have not had it in the second-line. There are so many options and there's no one standard option. These newer therapies will make their way into that third-line space, including tucatinib plus capecitabine/trastuzumab from the HER2CLIMB study, trastuzumab deruxtecan from DESTINY-Breast01, neratinib/capecitabine combination from NALA, and margetuximab with chemotherapy from SOPHIA.