Emerging Alternatives in the Third-Line Setting for Metastatic HER2-Positive Breast Cancer

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Shanu Modi, MD

Shanu Modi, MD

In the post-trastuzumab era, a number of U.S. Food and Drug Administration (FDA)-approved targeted agents for metastatic HER2-positive breast cancer are available, but there is no preferred option for third-line treatment and beyond. At the 2019 Chemotherapy Foundation Symposium, Shanu Modi, MD, Section Head of HER2-Positive Breast Cancer, Memorial Sloan Kettering Cancer Center, New York, reviewed potential therapies after failure of first- and second-line HER2-directed therapies.1

“The HER2 story is a success story,” Dr. Modi said. “The HER2 oncogene was discovered in the late 1980s, and 2 decades later, we had trastuzumab. Since then, five HER2-targeted agents have been approved by the FDA. These new drugs have led to more than a doubling in overall survival in patients with HER2-positive metastatic disease—from about 20 months to up to 5 years. This is a tremendous achievement.”

Optimal Sequencing of Therapies

The current treatment algorithm for metastatic HER2-positive disease is first-line treatment with taxane/trastuzumab/pertuzumab, “based on unprecedented results from the CLEOPATRA trial,” she said. For second-line treatment, the antibody-drug conjugate ado-trastuzumab emtansine (commonly known as T-DM1) is recommended, based on the results of the EMILIA trial.

“Several options are available for third-line therapy, but none of them is preferred. Many of these treatments have not been directly compared with each other,” Dr. Modi noted. Third-line options include lapatinib/capecitabine, trastuzumab/capecitabine, trastuzumab/lapatinib, trastuzumab/chemotherapy, T-DM1 (if not received earlier), and pertuzumab (if not received earlier).

Treatments on the Horizon

“A number of promising emerging drugs are on the horizon for the third-line treatment of HER2-positive metastatic breast cancer. Some of them are in late-stage phase III trials, and some have reported positive results,” Dr. Modi told the audience.

A novel anti-HER2 antibody called margetuximab is characterized by enhanced binding to the activating low-affinity Fc receptor CD16A on immune effector cells. “This agent has the potential to mount a much more vigorous immune response against the cancer,” noted Dr. Modi.

Phase I results in 60 patients (40% with metastatic HER2-positive breast cancer) were reported. The drug’s safety profile was comparable to that of trastuzumab, with an objective response rate of 26% and a median progression-free survival of 5.5 months. All of these patients had prior anti-HER2 therapy, including a median of four lines of therapy for metastatic disease.

The phase III randomized SOPHIA trial enrolled patients treated with prior trastuzumab and pertuzumab and one to three prior lines of therapy for metastatic disease.2 They were randomly assigned 2:1 to standard chemotherapy plus margetuximab (n = 266) or chemotherapy plus trastuzumab (n = 270) and treated until progressive disease. Approximately 90% of these patients also had received T-DM1.

For the primary endpoint, the median progression-free survival was 5.8 months with the investigational drug vs 4.9 months in the control arm (P = .033). The absolute gain was 0.9 months, which Dr. Modi called a “very modest” absolute benefit. “Sometimes, a modest progression-free survival benefit can translate into better overall survival with immunotherapy. We need longer follow-up for this trial,” she said.

Three potent tyrosine kinase inhibitors are being investigated as third-line therapy in HER2-positive metastatic disease: neratinib, tucatinib, and pyrotinib. Neratinib is an oral pan-HER agent that binds irreversibly to HER1, HER2, and HER4. By contrast, lapatinib has reversible binding to HER1 and HER2. Neratinib is approved in early-stage HER2-positive breast cancer but does not have an indication for metastatic disease.

The phase III NALA trial is a registration trial for the metastatic setting.3 The study enrolled 621 patients with metastatic HER2-positive breast cancer treated with at least two lines of prior HER2-directed therapy. Patients were randomly assigned 1:1 to neratinib/capecitabine vs lapatinib/capecitabine (a standard of care). There was a 2.2-month difference in progression-free survival favoring neratinib, but this did not translate into an improved overall survival at 48 months, according to a restricted means analysis. An application for a third-line indication for neratinib has been submitted to the FDA.

Tucatinib is another oral tyrosine kinase inhibitor; however, it is selective for HER2 and therefore is associated with decreased gastrointestinal toxicity. In a phase Ib study, the triplet of tucatinib plus capecitabine and trastuzumab had antitumor activity in a heavily pretreated population, including those with brain metastases.

The HER2CLIMB study is a randomized phase II registration trial for the triplet combination as third-line therapy. The HER2CLIMB-02 phase III trial is accruing patients with HER2-positive metastatic breast cancer treated with prior trastuzumab and a taxane; it will compare tucatinib plus T-DM1 vs placebo and T-DM1 in the second-line setting.

Antibody-Drug Conjugates

Trastuzumab deruxtecan (DS-8201a) is a HER2 antibody-drug conjugate. Similar to T-DM1, trastuzumab deruxtecan has a trastuzumab-like monoclonal antibody backbone, but its payload is different—a topoisomerase I inhibitor with twice as many chemotherapy molecules per antibody (drug-antibody ratio of 8). In preclinical studies, this agent is “very potent” in tumors resistant to T-DM1 “and can eradicate tumors in animal models,” Dr. Modi explained.

A phase I dose-escalation/expansion trial showed that trastuzumab deruxtecan was active after T-DM1 in 110 patients with HER2-positive metastatic breast cancer and a median of five prior lines of therapy.4 The objective response rate was 60%. The duration of response was 20 months, and progression-free survival was 22.1 months. “In this setting, the expected progression-free survival is 3 to 6 months. We find this result pretty exciting,” Dr. Modi said.

DESTINY-Breast01 is a phase II registration trial of trastuzumab deruxtecan. Patients who are resistant or refractory to T-DM1 were randomly assigned to different dose levels of the antibody-drug conjugate in the first part of the trial to identify the optimal dose; all patients were then treated with the recommended phase II dose to define the overall response rate.

Two other phase III trials of trastuzumab-deruxtecan are actively recruiting patients: DESTINY-Breast02 and -DESTINY-Breast03. The DESTINY-Breast02 trial will randomly assign patients previously treated with T-DM1 for metastatic HER2-positive breast cancer 2:1 to trastuzumab deruxtecan (n = 400) vs investigator’s choice of treatment (n = 200). The DESTINY-Breast03 trial will enroll patients previously treated with trastuzumab plus taxane therapy for HER2-positive metastatic breast cancer and randomly assign them 1:1 to T-DM1 (n = 250) vs trastuzumab deruxtecan (n = 250).

HER2-Positive Breast Cancer

First- and second-line therapies for metastatic HER2-positive breast cancer have been defined. Although several regimens are used in the third-line setting, none is
preferred. Several new compounds are under study in the third-line setting; some have shown activity in phase III trials.

“There is a lot of clinical research ongoing in the third-line setting [of HER2-positive breast cancer], and we may soon see new exciting options for our patients. Ultimately, if multiple new drugs become available, we will be left with the task of sequencing and selecting these therapies based on an individual’s particular circumstances,” Dr. Modi stated. 

DISCLOSURE: Dr. Modi reported financial relationships (research, consultancy, and advisory) with Novartis, AstraZeneca/Medmmune, Seattle Genetics, Daiichi Sankyo, Carrick, Eli Lilly, and MacroGenics and has served on a speakers bureau for Genentech.


1. Modi S: Third-line therapy and beyond for HER2-positive breast cancer. 2019 Chemotherapy Foundation Symposium. Presented Novermber 7, 2019.

2. Rugo HS, Im SA, Wright GLS, et al: SOPHIA primary analysis: A phase 3 study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies. 2019 ASCO Annual Meeting. Abstract 1000. Presented June 4, 2019.

3. Saura C, Oliveira M, Feng YH, et al: Neratinib + capecitabine versus lapatinib + capecitabine in patients with metastatic HER2+ breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized phase III NALA trial. 2019 ASCO Annual Meeting. Abstract 1002. Presented June 4, 2019.

4. Tamura K, Tsurutani J, Takahashi S, et al: Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: A dose-expansion, phase 1 study. Lancet Oncol 20:816-826, 2019.