Potential Novel Therapies Emerge for Third-Line Setting in Patients with HER2+ Metastatic Breast Cancer

Sara A. Hurvitz, MD, FACP, of the University of California, Los Angeles, discussed a number of emerging novel therapies with the potential to treat patients with HER2-positive metastatic breast cancer in the third-line setting.

The gold standards of treatment for HER2-positive metastatic breast cancer currently are taxanes and trastuzumab (Herceptin) plus pertuzumab (Perjeta; THP) in the first-line setting and trastuzumab emtansine (T-DM1; Kadcyla) as second-line treatment, with emerging novel therapies being introduced for their potential as alternative therapeutic options in the third-line setting.

According to a presentation at the 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®), these therapeutic options include trastuzumab deruxtecan (Enhertu), neratinib (Nerlynx) plus capecitabine, tucatinib (Tucatinib) plus trastuzumab and capecitabine, margetuximab (Margenza) plus chemotherapy, and more.1

“This continues to be an incredibly exciting time for the treatment of HER2-positive breast cancer given all of these new agents,” explained Sara A. Hurvitz, MD, FACP, in her presentation of the data. “But we are challenged to understand how to best sequence these agents which really will require us to take into account the unique safety and efficacy profiles of each of these agents.”

First, the antibody-drug conjugate trastuzumab deruxtecan received accelerated approval in December 2019 in patients receiving 2 or more prior therapies based off of positive data from the single-agent, single-arm DESTINY-Breast01 study (NCT03248492) evaluating a heavily pretreated population (median of 6 prior lines of therapy) of 184 patients with unresectable and/or metastatic breast cancer. The cohort of patients received 5.4 mg/kg of therapy with trastuzumab deruxtecan.2

Updated data presented at the 2020 San Antonio Breast Cancer Symposium (SABCS) found that patients achieved an overall response rate (ORR) of 61.4% with a median progression-free survival (PFS) of over 19.4 months. More, the median duration of response was 20.8 months and median overall survival was recorded at 24.6 months.3

Next, the tyrosine kinase inhibitor (TKI) neratinib in combination with capecitabine received an expanded indication for patients with advanced/metastatic HER2-positive breast cancer who received 2 or more prior anti-HER2 based regimens based off of data from the phase 3 NALA trial (NCT01808573) which compared the combination with lapatinib plus capecitabine.4 The co-primary end points of the research were PFS and OS, with secondary end points including ORR, duration of response, and safety.

The data found that the mean PFS of the neratinib combination was 8.8 months compared with 6.6 months (HR, 0.76; 95% CI, 0.63-0.93; P = .0003). Even with the increase of 2 months in PFS, 24% of patients receiving the neratinib combination, which used a lower dose of capecitabine than the lapatinib combination, had grade 3/4 diarrhea compared with just 13% of patients in the lapatinib group.5

“There was an indication that CNS metastases were reduced in the neratinib arm, however still about a quarter of patients developed moderate to severe diarrhea with this drug in spite of the lower dose of capecitabine and the use of loperamide,” explained Hurvitz. “And this is a big limiting factor in the use of this agent.”

Another TKI discussed was tucatinib, which was approved in combination with trastuzumab and capecitabine to treat patients who received 1 or more previous HER2-targeted therapy.6 In the phase 2 HER2CLIMB trial (NCT02614794), patients who had received prior treatment with trastuzumab, pertuzumab, and T-DM1 (n = 612) were randomized 2:1 to either tucatinib or placebo plus trastuzumab and capecitabine.

At the first report in December 2019, the PFS rate at 1 year was 33.1% for patients in the tucatinib group compared with 12.3% for patients in the placebo group (HR, 0.54; 95% CI, 0.42-0.71; P <.001). More, the OS rate measured at 2 years was 44.9% for the tucatinib group versus 26.6% for the placebo group (HR, 0.66; 95% CI, 0.50-0.88; P = .005). Median OS was 21.9 months and 17.4 months for the tucatinib and placebo groups, respectively (HR, 0.66; 95% CI, 0.50-0.88; P = .005).7

Finally, margetuximab in combination with chemotherapy was approved in December 2020 to treat patients with HER2-positive breast cancer who received 2 or more prior anti-HER2 regimens. This combination was analyzed in the phase 3 SOPHIA trial (NCT02492711), which compared this combination to trastuzumab plus chemotherapy.

Median PFS was recorded at 5.8 months for the margetuximab combination compared with 4.9 months for the trastuzumab combination (HR, 0.76; 95% CI, 0.59-0.98; P = .033).8

“We have 4 new third-line approvals, we have a possible expanded indication for abemaciclib [Ibrance], and multiple ongoing clinical trials for novel agents,” concluded Hurvitz.


1. Hurvitz S. Novel Therapies for HER2+ Metastatic Breast Cancer. Presented at: 38th Annual Miami Breast Cancer Conference. March 4-7, 2021.

2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. FDA. December 20, 2019. Accessed March 5, 2021. https://bit.ly/2tzcabv

3. 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. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster PD3-06. https://bit.ly/3m7rDoV

4. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. February 25, 2020. Accessed March 5, 2021. https://bit.ly/38eD3Dc

5. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. 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. 2020;38(27):3138-3149. doi: 10.1200/JCO.20.00147

6. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. April 17, 2020. Accessed March 5, 2021. https://bit.ly/38az36v

7. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi: 10.1056/NEJMoa1914609

8. FDA approves mergetuximab for metastatic HER2-positive breast cancer. FDA. December 16, 2020. Accessed March 5, 2021. https://bit.ly/3qkZOLR