Novel Therapies on the Horizon in HER2-Positive Metastatic Breast Cancer

The treatment of patients with HER2-positive metastatic breast cancer is evolving rapidly. In a session at the 37th Annual Miami Breast Cancer Conference, Sara Hurvitz, MD, Director, Breast Cancer Clinical Trials Program, UCLA Health, Los Angeles, discussed novel therapies for patients with HER2-positive advanced breast cancer, noting that some have generated more hype, whereas others have flown more under the radar.

Novel Antibodies to Stimulate Immune Response: Margetuximab and PRS343

The phase 3 SOPHIA clinical trial confirmed the superiority of margetuximab over trastuzumab in the metastatic setting. In the trial, patients who had received ≥2 previous lines of anti-HER2 therapy, and up to 3 lines in the metastatic setting, were randomized to single-agent chemotherapy with either trastuzumab or margetuximab. The study had sequential primary end points of progression-free survival (PFS) and overall survival (OS).

Dr Hurvitz noted that in the overall population, the improvement in PFS was marginal but significant. “But, when you sort the data based on patients’ Fc gamma receptor genotype, you can see that the F carriers [FV or FF] are the ones who really are deriving benefit from the use of margetuximab. So maybe the patients [with VV genotype] wouldn’t be the best candidates for this,” she added.

There was no significant improvement in OS in the intent-to-treat population, but there has been a strong trend (although not yet significant) toward an improvement in OS among CD16A-185 F-carriers, with a median difference of 4.3 months. “So, this may be how we should select this therapy, should it be approved,” Dr Hurvitz said.

Margetuximab is also relatively well-tolerated and resulted in slightly increased infusion-related reactions and fatigue compared with trastuzumab.

Another HER2-targeting antibody, PRS343, is designed to stimulate the immune system and the tumor microenvironment. An ongoing phase 1 clinical trial has demonstrated an objective response rate (ORR) of 40% among patients treated with PRS343 at 8 mg/kg every 2 weeks.

“It’s not a chemotherapy, so patients are tolerating it really well,” Dr Hurvitz said. “We actually haven’t hit maximum tolerated dose.”

Antibody-Drug Conjugates: ARX788 and SYD985

ARX788 is a HER2-targeting antibody-drug conjugate. In a phase 1 study of 51 patients with metastatic HER2-positive breast cancer, the ORRs seen with ARX788 increased with dose escalation. Five of 8 patients treated with a dose of 1.5 mg/kg had an objective response, resulting in a 63% ORR.

Among all 51 patients, 8 (15.7%) cases of drug-related pulmonary toxicities were reported; 7 were grade 1/2 and 1 was grade 3.

“We’re going to have to watch for pneumonitis ILD [interstitial lung disease] with this one,” said Dr Hurvitz. “There have been no grade 5 events, but there is pneumonitis, so this will have to be monitored closely.”

SYD985 is a HER2-targeting antibody-drug conjugate that has demonstrated an ORR of 33% in the ongoing phase 3 TULIP randomized clinical trial. In January 2018, SYD985 was granted fast-track designation by the US Food and Drug Administration for use in patients whose disease has progressed during or following a minimum of 2 HER2-targeting regimens for locally advanced or metastatic disease, or progressed during or after treatment with [ado-]trastuzumab emtansine.

CDK4/6 Inhibition in HER2-Positive Disease

The phase 2 monarcHER study randomized heavily pretreated patients with hormone receptor–positive, HER2-positive advanced breast cancer to either abemaciclib plus trastuzumab plus fulvestrant, abemaciclib plus trastuzumab, or trastuzumab plus chemotherapy. The study is important because the use of CDK4/6 inhibitors has been confined to HER2-negative patients.

“These data kind of flew under the radar, but I think we need to pay attention to them,” said Dr Hurvitz. “The study met its primary end point of improved PFS by hitting CDK4/6, the estrogen receptor, and HER2 all in one shot.”

Approximately one-third (32.9%) of patients had an objective response, which beat out chemotherapy at a 13.9% ORR. “And I would argue that this is much less toxic than chemotherapy,” she added.

Related Articles

Subscribe to
Oncology Practice Management

Stay up to date with oncology news & updates by subscribing to recieve the free OPM print publications or weekly e‑Newsletter.

I'd like to recieve: