Hurvitz Heralds Next HER2+ Breast Cancer Breakthroughs

Sara A. Hurvitz, MD

The 5 FDA-approved HER2-targeted agents have altered the natural course of HER2-positive breast cancer, explained Sara A. Hurvitz, MD, at the 2018 Miami Breast Cancer Conference (MBCC).

“These therapies have altered the way patients can now live with this disease,” said Hurvitz, noting that the stage is now set for the next wave of treatment breakthroughs.

Tucatinib (ONT-380)

At the MBCC, Hurvitz, an associate professor in the Department of Medicine at the University of California, Los Angeles, highlighted several “exciting new agents” with the potential to further revolutionize the treatment of HER2-positive breast cancer. A phase Ib study examined the HER2 selective tyrosine kinase inhibitor tucatinib in combination with capecitabine and/or trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer.

Among 23 patients who received the triplet of tucatinib, capecitabine, and trastuzumab, the overall response rate (ORR) was 61% (n = 14), the median progression-free survival (PFS) was 7.8 months, and the median duration of response was 10 months.

“What was intriguing to many of us was the CNS responses that were seen in the study,” said Hurvitz. Among patients with brain metastases, the CNS ORR was 42% (5/12).

Margetuximab

An ongoing phase II trial, HER2CLIMB (NCT02614794), is randomizing patients with HER2-positive breast cancer with/without CNS metastases to tucatinib plus capecitabine and trastuzumab versus placebo plus capecitabine and trastuzumab. The primary endpoint of the study is PFS, with secondary outcomes including overall survival and quality of life.A phase I study showed that the Fc-optimized monoclonal antibody margetuximab was generally well tolerated, with a safety profile that Hurvitz described as “quite akin to that of trastuzumab.”

Among the 24 evaluable patients with HER2-positive metastatic breast cancer, there were 4 (17%) partial responses. Three patients remained on study for over 3 years.

Trastuzumab Deruxtecan (DS-8201)

The treatment is now being evaluated in larger trials, including the phase III SOPHIA trial (NCT02492711), which is randomizing patients with HER2-positive metastatic breast cancer who had prior anti-HER2 targeted treatment to receive chemotherapy plus either margetuximab or trastuzumab. The HER2-targeting antibody-drug conjugate trastuzumab deruxtecan is highly potent, with a drug-to-antibody ratio of 7-8. The ratio for the FDA-approved antibody-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla) is 3-5.

Results were presented at the 2017 San Antonio Breast Cancer Symposium for a phase I study of trastuzumab deruxtecan in heavily pretreated patients with HER2-expressing metastatic breast cancer who previously received T-DM1.

The ORR in 57 evaluable patients with HER2-positive tumors was 61.4% (n = 35) and the median PFS was 10.4 months. The ORR was 56.4% (22/39) among HR-positive patients, 75% (12/16) among HR-negative patients, and 62% (31/50) in patients with prior pertuzumab treatment.

Regarding safety, Hurvitz said, “In terms of the adverse event profile I would say it’s pretty well-tolerated. You see some cytopenias, but it’s unusual to have grade 3/4, and it’s not looking like it’s got a huge toxicity profile that requires concern.

An ongoing pivotal phase II trial called DESTINY-Breast01 (NCT03248492) is examining the efficacy and safety of trastuzumab deruxtecan in patients with HER2-positive unresectable and/or metastatic breast cancer who are resistant or refractory to T-DM1. There’s also a phase I study exploring the antibody-drug conjugate in combination with nivolumab (Opdivo).

Pyrotinib

In August 2017, the FDA granted trastuzumab deruxtecan a breakthrough therapy designation for the treatment of patients with HER2-positive locally advanced or metastatic breast cancer who have received trastuzumab and pertuzumab (Perjeta) and have disease progression after T-DM1.Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor with activity against EGFR/HER1, HER2, and HER4. In a phase I study, pyrotinib had an ORR of 50% (all partial responses) among 36 evaluable patients with HER2-positive breast cancer. The ORR in patients who had prior trastuzumab was 33.3%.

The median time to response was 8.0 weeks and the median duration of response for the 18 patients who had a partial response was 32.4 weeks. Grade 3 diarrhea was the one dose-limiting toxicity.

A phase II study assessed the combination of pyrotinib and capecitabine versus lapatinib (Tykerb) and capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes and anthracyclines, with or without prior trastuzumab.

The ORR was 78.5% for the pyrotinib arm compared with 57.1% for the lapatinib arm. The median PFS was 18 months versus 7 months, respectively (HR, 0.36; P <.0001).

Grade 3/4 toxicities were higher for the pyrotinib arm, including hand-foot syndrome (24.6% vs 20.6% in the lapatinib arm), diarrhea (15.4% vs 4.8%), decreased neutrophil (9.2% vs 3.2%), and vomiting (4.6% vs 1.6%). The rates of serious adverse events were 7.7% versus 6.3%, respectively.

An ongoing phase III trial (NCT02973737) is exploring pyrotinib in combination with capecitabine versus placebo plus capecitabine in HER2-positive metastatic breast cancer patients who have received an anthracycline, a taxane, and trastuzumab.

In 19 evaluable patients with HER2-low tumors, the ORR was 31.6% (n = 6) and the median PFS was not reached. The ORR was 31.3% (5/16) among HR-positive patients and 0% (0/2) in HR-negative patients.