Expert Highlights Emerging Agents for Metastatic HER2+ Breast Cancer

Charles Geyer, MD

Charles Geyer, MD

A number of new agents are currently being investigated for the treatment of patients with metastatic HER2-positive breast cancer, including antibody—drug conjugates, tyrosine kinase inhibitors (TKIs), and combination therapies, as well as others. Although many of these are still under investigation, some have already begun making an impact in the field, and some initial findings have been presented at recent meetings.

“The most immediate data that can be applied to practice probably comes from the NALA study that compared neratinib (Nerlynx)/capecitabine with lapatinib (Tykerb)/capecitabine,” said Charles Geyer, MD.A supplemental New Drug Application for neratinib was accepted by the FDA for potential approvalbased on the findings from the NALA study in September 2019. This agent has previously been approved by the FDA for the adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer.

In therandomized, international, open-label phase III NALA trial,621 patients metastatic HER2-positive breast cancer were randomized 1:1 to receive either neratinib plus capecitabine or lapatinib plus capecitabine in the third-line setting or beyond. The results from this trial were presented at the 2019 ASCO Annual Meeting.

Overall, 69% of patients had received 2 prior lines of therapy and 31% had received at least 3 prior lines. These therapies included HER2-targeted agents, such as single-agent trastuzumab (Herceptin), trastuzumab plus pertuzumab (Perjeta), trastuzumab plus T-DM1 (ado-trastuzumab emtansine; Kadcyla), and trastuzumab plus pertuzumab and T-DM1.

Investigators noted a statistically significant improvement in progression-free survival (PFS) in the neratinib arm. At 1 year, the PFS rate was 29% with neratinib versus 15% in the control arm. Overall survival (OS) was improved but did not lead to a statistically significant improvement in the neratinib arm versus control, where the mean OS was 24.0 months versus 22.2 months, respectively.

Additionally, the objective response rate in patients that received the neratinib combination was 33% versus 27% in the control. Just over 10% of patients discontinued treatment due to treatment-emergent adverse events (TEAEs), such as diarrhea, nausea, vomiting, hand-foot syndrome, decreased appetite, and fatigue. Approximately 83% of any grade diarrhea was noted in the neratinib arm versus 66% in the control, while grade 3 diarrhea occurred in 24% versus 13%, respectively.

“The encouraging thing right now is that there are a number of phase III studies that are being done in the first-line setting,” Geyer concluded. “I think we have some promising therapies that could significantly improve [upon the impressive results we already have].”

In an interview withTargeted Oncology, Geyer, associate director for clinical research at the VCU Massey Cancer in Richmond, Virginia, discussed the potential role of neratinib as well as other new agents that are coming down the pipeline for the treatment of patients with metastatic HER2-positive breast cancer. He also addressed the biggest challenges oncologists face in managing this disease.

TARGETED ONCOLOGY: What novel agents are emerging now formetastatic HER2-positive breast cancer?

Geyer:There are a couple of interesting new agents. We saw 1, in particular, presented at ASCO in the SOPHIA study. [In this study], we finally saw results of margetuximab versus trastuzumab in patients who were heavily pretreated. I think this will hopefully lead to an FDA approval. There wasn’t a huge difference, but in that very refractory patient population, it shows us that there is something going on there that we may need to pull margetuximab into earlier lines of therapy. I am hopeful that will get approval and will continue to develop, but I think this is a very logical drug that makes a lot of sense.

The most interesting new drug that we have only seen preliminary [data] on is DS-8201, an immune conjugate. We have seen reports from the phase I study at last year’s ASCO looking at a number of patient cohorts, all of which show a remarkable degree of activity for the immune conjugate. It had a patient cohort of [patients with] HER2-positive breast cancer who had all received T-DM1, high degree of activity. They looked at HER2-low patients with breast cancer, high degree of activity and they looked at non-breast HER2-positive, high degree of activity. They have also launched a series of DESTINY studies, phase III studies, looking at specific cohorts that we all await with a great deal of interest.

The last agent is tucatinib in the HER2CLIMB study that is looking at, again, adding tucatinib in late line therapy to capecitabine and trastuzumab for that initial signal efficacy. The drug does seem to be very well tolerated but quite active. Particularly, it seems to have activity in brain metastases, so I think tucatinib is another drug that we are looking forward to seeing the results of in the HER2CLIMB study sometime within the next year, if not sooner than that.

TARGETED ONCOLOGY: Could you discuss some of the most compelling data you’ve seen so far in this setting?

Geyer:The most immediate data that can be applied to practice probably comes from the NALA study that compared neratinib/capecitabine with lapatinib/capecitabine. The data do show us that of the 2 small molecules/TKI inhibitors, neratinib is the more effective of the 2. I think, for me, that had an immediate impact. I had already started to move towards a capecitabine plus neratinib combination in my patients with metastatic HER2-positive breast cancer. I think the results of the NALA study support that, and I’ll continue to do that.

The study of margetuximab, of course, depends on if the FDA feels that the clinical difference is significant enough to approve the drug. My hope and expectations are that they will, so that 1 won’t really impact us now. I think the thing that will impact practice now of the most recently reported studies is the NALA trial. HER2CLIMB, if tucatinib gets approval, would, of course, be a very effective competitor for neratinib, I suspect.

TARGETED ONCOLOGY: What challenges do oncologists face when treating patients with metastatic HER2-positive breast cancer?

Geyer:Our problem with metastatic HER2-positive breast cancer is that, unfortunately, most of the patients with this disease ultimately develop resistance and die from their disease. We did see the final report from the landmark CLEOPATRA study that does show the remarkable impact of adding pertuzumab to trastuzumab in the first-line setting, but if you look long-term, there is only a minority of patients that are free from progression.

For metastatic patients, we have had very effective therapies that have allowed them to live for years, but they are chronically on therapy, so it’s very important to manage adverse effects and choose drugs based on that. The antibodies are well tolerated. The immune conjugate that we have available, T-DM1, is generally well tolerated, but it eventually causes neuropathy. Neuropathy is a big problem for patients who have been on long-term therapy with trastuzumab because they’ve received taxanes or T-DM1, and that’s a challenging thing to manage when it occurs. We really don’t have a lot of effective measures to prevent it. These are active areas of research.

Of course, the biggest challenge in metastatic HER2-positive breast cancer remains the problem of brain metastases. These patients are at high risk for developing brain metastases. Our therapies have improved with stereotactic surgery. There’s a lot more our neurosurgeons and radiation oncologists are able to do for our patients, but systemically, we are still lacking in effective therapies. The small molecules have respectable response rates around 30% to 45%, but they are relatively short lived, so for me, I think the best thing we can do for metastatic HER2-positive breast cancer is get better at managing early HER2-positive breast cancer so fewer women relapse. However, there are still women that present with de novo disease that will continue to be a challenge for us.

Reference:

Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.J Clin Oncol.2019;37(suppl; abstr 1002).