Novel HER2-Targeted Therapies Pose Sequencing Challenges

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With three new HER2-targeted therapies approved over the past year or two alone, the treatment landscape for patients with metastatic breast cancer has become increasingly crowded. In the third-line setting and beyond, there are now at least eight HER2-targeted agents approved by the U.S. Food and Drug Administration (FDA) for metastatic disease, including three monoclonal antibodies, three tyrosine kinase inhibitors, and two antibody-drug conjugates.

During a presentation at the Miami Breast Cancer Conference, which was held virtually this year, Sara A. Hurvitz, MD, discussed the latest approvals in HER2-positive breast cancer, which have led to significant improvements in overall survival while raising questions about optimal sequencing.1

“This continues to be an incredibly exciting time for the treatment of HER2-positive breast cancer, given all these new agents, but we are challenged to understand how best to sequence these agents….”
— Sara A. Hurvitz, MD

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“This continues to be an incredibly exciting time for the treatment of HER2-positive breast cancer, given all these new agents, but we are challenged to understand how best to sequence these agents, which will require us to take into account the unique safety profile and efficacy profile of each of these agents,” said Dr. Hurvitz, Director of the Breast Cancer Clinical Research Program, Co-Director of the Santa Monica–UCLA Outpatient Hematology/Oncology Practice, and Professor of Medicine at David Geffen School of Medicine at the University of California, Los Angeles.

As Dr. Hurvitz reported, median overall survival for hormone receptor–positive and triple-negative breast cancers has remained relatively unchanged since 2008. Median overall survival for HER2-positive breast cancer, on the other hand, has improved dramatically in the past decade, from 39 months in 2008, to 58 months in 2013, to not having been reached in more recent years.

“The therapies we have now are so effective that overall survival associated with this disease subtype is better than the other two subtypes, which is in stark contrast to the outcomes with HER2-positive breast cancer in the pre-trastuzumab era,” said Dr. Hurvitz.

In the first-line setting, the gold standard of treatment for patients diagnosed with metastatic HER2-positive breast cancer remains the combination of trastuzumab, pertuzumab, and a taxane. In the second-line setting, the first choice is ado-trastuzumab emtansine (T-DM1), but the recently approved triplet regimen of tucatinib plus trastuzumab and capecitabine has become another option. Along with tucatinib, other additions in the third-line setting include fam-trastuzumab deruxtecan-nxki monotherapy, margetuximab-cmkb plus chemotherapy, and an expanded indication for neratinib in combination with capecitabine.

Trastuzumab Deruxtecan

Trastuzumab deruxtecan, an antibody-drug conjugate, was granted accelerated approval in December 2019 for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting. The decision was based on findings from the phase II DESTINY-Breast01 trial, a multicenter, single-arm study in which 184 patients received trastuzumab deruxtecan. Dr. Hurvitz reported that more than 90% of participants had visceral -disease, and the study population had a median of six prior lines of therapy.

“In this population of very heavily pretreated disease, we would have been excited to see a 20% objective response rate and a median progression-free survival of 6 months,” said Dr. Hurvitz. “We were blown away to see the objective response rate of 61% and median progression-free survival of more than 16 months.”

Updated data presented at the 2020 San Antonio Breast Cancer Symposium showed a median progression-free survival of 19.4 months and a median overall survival of 24.6 months.2 Patients receiving trastuzumab deruxtecan should be monitored for interstitial lung disease, which was fatal in 2.7% of patients, said Dr. Hurvitz.

A number of phase III trials, including DESTINY-Breast02, which is comparing trastuzumab deruxtecan vs investigator’s choice of capecitabine plus either trastuzumab or lapatinib in patients with metastatic breast cancer who previously received trastuzumab deruxtecan, are continuing to evaluate the drug.


In February 2020, the tyrosine kinase inhibitor neratinib received an expanded indication in combination with capecitabine for patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior HER2-targeted regimens in the metastatic setting. Approval was based on the phase II NALA trial, which randomly assigned patients to receive capecitabine with either neratinib or lapatinib.3

Due to concerns about diarrhea, the dose of capecitabine was lower in the neratinib arm (1,500 mg/m2) than in the lapatinib arm (2,000 mg/m2). Although patients in the neratinib arm also received loperamide starting with the first dose, 24% of patients on neratinib developed grade 3 or 4 diarrhea vs 13% of those in the lapatinib arm.

“This is a big limiting factor for the use of this agent,” said Dr. Hurvitz, who noted that findings from the original analysis showed progression-free survival of 8.8 months in the neratinib arm vs 6.6 months with lapatinib (P = .003).4 Neratinib also improved outcomes for patients with stable central nervous system (CNS) disease at baseline, she added.


Another recently approved tyrosine kinase inhibitor, tucatinib mitigates the risk of diarrhea from off-target EGFR inhibition given its selectivity for HER2. FDA approval of tucatinib was granted in May 2020 for patients with HER2-positive metastatic breast cancer who have received one or more anti-HER2 regimens in the metastatic setting, including patients with brain metastases. This approval was based on the results of the phase II HER2CLIMB trial, which randomly assigned patients to receive capecitabine plus trastuzumab in combination with either tucatinib or placebo.5 Nearly half (48%) of the study’s 612 patients had CNS metastases that were stable or actively progressing.

“This drug hit a home run at its first reporting,” said Dr. Hurvitz, who noted that median progression-free survival in the tucatinib arm was 7.8 months vs 5.6 months for patients who received placebo (hazard ratio [HR] = 0.54; P < .001). The median overall survival was 21.9 months in patients receiving tucatinib vs 17.4 months in the control arm (HR = 0.66; P = .005). Among patients with brain metastases, progression-free survival was 24.9% at 1 year in the tucatinib arm and 0% in the placebo arm (HR = 0.48; P < .001).

Although the HER2CLIMB study was a third-line trial, the regimen was approved in the second line, likely because of its “incredible activity in patients with brain metastases,” said Dr. Hurvitz. “The question now is whether tucatinib can advance past trastuzumab deruxtecan monotherapy in the second-line setting,” she added. The combination of tucatinib plus [T-DM1] is being compared with placebo plus [T-DM1] in the ongoing phase III HER2CLIMB-02 trial.


Finally, margetuximab, a chimeric monoclonal antibody, was approved in December 2020 in combination with chemotherapy for patients with HER2-positive breast cancer who have received two or more prior anti-HER2 regimens. According to Dr. Hurvitz, margetuximab is “a uniquely designed trastuzumab, which has the same Fab portion that targets HER2, but the Fc portion is engineered to more tightly bind to the patient’s immune effector cells, natural killer cells, and dendritic cells at the Fc receptor.” She noted that approximately 85% of patients will have an Fc receptor genotype that indicates weaker binding affinity for antibodies, and “engineering this to more tightly bind may benefit patients.”

The approval of margetuximab was based on data from the phase III SOPHIA trial, which showed a progression-free survival benefit for margetuximab plus chemotherapy vs trastuzumab plus chemotherapy.6 Median progression-free survival in patients receiving margetuximab improved by approximately 5 weeks compared with the control arm, which met the primary endpoint (HR = 0.76; P = .033).

However, Dr. Hurvitz noted that the survival benefit of this drug appears to be restricted to patients who were carriers of the CD16A receptor with a 158F allele. Although the finding was not statistically significant, she added, there was a median 4-month difference in overall survival in the margetuximab arm compared with the control arm (23.7 vs 19.4 months, respectively) in patients who were CD16A-158F carriers.

Dr. Hurvitz anticipates that margetuximab will be used more frequently in patients who are F allele carriers. She noted that an assay will be available to identify these patients in the near future.

“The tolerability of this agent is very good,” she concluded. “The only thing that increased compared with trastuzumab were infusion-related reactions.” 

DISCLOSURE: Dr. Hurvitz has received research funding from Ambrx, Amgen, Arvinas, Bayer, Daiichi Sankyo, Dignitana, Genentech, GSK, Immunomedics, Lilly, MacroGenics, Novartis, OBI Pharma, Pfizer, Pieris, Puma, Radius, Roche, Sanofi, and Seattle Genetics; and has ownership interest in NKMax.


1. Hurvitz SA: Novel therapies for HER2+ metastatic breast cancer. 2021 Miami Breast Cancer Conference. Presented March 5, 2021.

2. Modi S, Saura C, Yamashita T, et al: Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. 2020 San Antonio Breast Cancer Symposium. Abstract PD3-06. Accessed March 6, 2021. 

3. Saura C, Oliveira M, Feng YH, et al: Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Phase III NALA Trial. J Clin Oncol 38:3138-3149, 2020.

4. Saura C: Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial. 2020 San Antonio Breast Cancer Symposium. Abstract PD13-09. Presented December 11, 2020. Accessed March 6, 2021. 

5. Murthy RK, Loi S, Okines S, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-603, 2020. 

6. Rugo HS, Im SA, Cardoso F, et al: Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: A phase 3 randomized clinical trial. JAMA Oncol. January 22, 2021 (early release online).