Third-Line Treatment of HER2-Positive Advanced Breast Cancer: From No Standard to A Pandora’s Box - Episode 3

Experts Discuss Third-line Treatment Options for HER2-Positive Advanced Breast Cancer

“We’ve been spoiled by 2 extraordinary experiences [in this setting]. Both tucatinib and trastuzumab deruxtecan are much better than anything we’ve had since we got pertuzumab for first-line therapy.” —SARA A. HURVITZ, MD, FACP

For what used to be a tumor type with very poor outcomes, HER2-positive advanced breast cancer now has a number of treatment options. In a recent edition of Between the Lines, Sara A. Hurvitz, MD, FACP, and Steven E. Vogl, MD, reviewed treatment standards for patients with advanced disease.1

As Hurvitz, director of the Breast Oncology Program at the David Geffen School of Medicine of the University of California, Los Angeles, explained, “We have 8 FDA-approved, HER2-targeted therapies for metastatic disease, and this review article very nicely takes us through the history of the approvals, what the standard first-line and second-line treatments are, and then dives into all the data relating to [the] third line and beyond.”

Although Hurvitz and Vogl agreed on standards for first- and second-line treatment, they noted that a clear treatment strategy in the third line was still needed. As such, the experts reviewed supporting data for available agents to clarify best use of each in clinical scenarios.

FDA-Approved Regimens in Third-Line Setting

Use of the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) has shown impressive activity in patients pretreated with ado-trastuzumab emtansine (Kadcyla). In the phase 2 DESTINY-Breast01 trial (NCT03248492), investigators reported a median progression-free survival (PFS) of 16.4 months among 184 heavily pretreated patients. Responses were observed in 112 patients (60.9%); the disease control rate was 97.3%.2

“As the authors of the article pointed out, the patients enrolled in the DESTINY-Breast01 study had a median of 6 prior lines of therapy, enormously heavily pretreated patients … we would expect, or get excited to see, an objective response rate [ORR] of 20%,” Hurvitz commented.

These data resulted in the FDA granting accelerated approval to trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive cancer who have received 2 or more prior anti-HER2-based therapies in the metastatic setting.3

Tucatinib (Tukysa) is another agent with proven efficacy when given as third-line treatment for HER2-positive advanced breast cancer. This drug was approved by the FDA for use with trastuzumab and capecitabine (Xeloda) in patients with unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have been pretreated with at least 1 prior anti-HER2–based regimen in the metastatic setting.4 The approval was based on results from the phase 2 HER2CLIMB trial (NCT02614794), in which 612 patients were randomized to receive trastuzumab plus capecitabine with either tucatinib or placebo.5

Patients treated with the tucatinib combination experienced a statistically significant improvement in median PFS (7.8 months vs 5.6 months in the control group; P <.001) and median overall survival (OS; 21.9 months vs 17.4 months, respectively; P = .005). The ORR also favored use of the tucatinib combination when compared with placebo plus trastuzumab/capecitabine (40.6% vs 22.8%, respectively; P < .001).

Notably, patients with untreated brain metastases in the tucatinib group also experienced an improvement in intracranial PFS (10 months vs 4 months in those not given tucatinib; P <.0001), intracranial ORR (47% vs 20%, respectively), and OS (18 months vs 12 months, respectively; P = .005).

“I think tucatinib is the way to go, because it really gets into the brain. It’s a remarkably better treatment—the way it was given with capecitabine and trastuzumab—than anything we’ve had before for brain metastases in HER2-positive breast cancer,” explained Vogl, a medical oncologist at the Montefiore Medical Center in Bronx, New York.

Although the combination of neratinib (Nerlynx) and capecitabine was approved for treating HER2-positive advanced or metastatic breast cancer following 2 or more HER2-directed regimens,6 both Hurvitz and Vogl said they were hesitant to use it because of the toxicity.

Hurvitz explained, “We do think that starting neratinib at a low dose and escalating up slowly may mitigate that adverse effect, but it’s still bad. When you have a drug like tucatinib, of course, I’m going to use that earlier, and I think the authors agreed.”

In the phase 3 NALA trial (NCT01808573), 621 patients with centrally confirmed, HER2-positive metastatic breast cancer who had received at least 2 HER2-directed regimens were randomized to receive either neratinib plus capecitabine (750 mg/m2 twice daily on days 1-14 of 21-day cycles) or lapatinib (Tykerb) plus capecitabine (1000 mg/m2 twice daily on days 1-14 of 21-day cycles). The 12-month PFS rate was higher with use of the neratinib combination (28.8%) than with the lapatinib combination (14.8%), but there was no significant improvement in the 12-month OS rate (72.5% vs 66.7%, respectively; P = .2).7

Grade 3 toxicities were twice as common among the group given neratinib (24%) than among those give lapatinib (13%), despite the lower capecitabine dose used in the neratinib group. The limited clinical benefits plus the high toxicity of neratinib make this agent a less appealing option when compared with other targeted therapies approved by the FDA, according to the NALA investigators.

Alternative Therapeutic Options

The anti-HER2 monoclonal antibody margetuximab-cmkb (Margenza) was approved in December 2020 in combination with chemotherapy to treat patients with metastatic HER2-positive breast cancer who previously received 2 or more prior anti-HER2 therapies, with at least 1 being for metastatic disease.8 The antibody was combined with chemotherapy and compared with trastuzumab therapy in the phase 3 SOPHIA trial (NCT02492711).9

A total of 536 patients with HER2-positive metastatic breast cancer who had received 2 or more lines of therapy were randomized to receive margetuximab or trastuzumab. A statistically significant, yet clinically modest, improvement in investigator-assessed median PFS was noted with use of margetuximab as compared with trastuzumab therapy (5.7 months vs 4.4 months, respectively; P < .001). The ORR also favored the margetuximab arm vs the trastuzumab arm (22% vs 16%, respectively; P < .001).

“Margetuximab was designed to elicit an antibody-drug–mediated cellular cytotoxicity response,” Hurvitz explained. “It appears only to work in patients who have a particular genotype that puts them at a higher risk of not being able to generate that response. Although it’s available to us to use, we don’t have a way to test for that that genotype.”

Lastly, abemaciclib (Verzenio) plus trastuzumab and fulvestrant (Faslodex) was examined in the phase 2 monarcHER trial (NCT02675231), in which 237 pretreated patients with hormone receptor (HR)–positive, HER2-positive advanced breast cancer were randomized to treatment with either the triplet, the doublet of abemaciclib plus trastuzumab, or trastuzumab plus physician’s choice of chemotherapy.10

Significant improvement in PFS was noted in the triplet arm when compared with the chemotherapy arm (8.3 months vs 5.7 months, respectively; P = .05); there was no statistically significant difference between the doublet and chemotherapy arms. The confirmed ORR was also improved in the triplet arm (33%) when compared with the chemotherapy arm (14%).

The triplet provided an intriguing chemotherapy-free option for this cohort of patients. Still, Vogl explained, the study was suboptimally designed due to limited data on the impact on patient response with the addition of abemaciclib to trastuzumab/fulvestrant.

The Future of Third-Line Therapies

“We’ve been spoiled by 2 extraordinary experiences,” explained Vogl when discussing the recent use of these combination therapies. “Both tucatinib and trastuzumab deruxtecan are much better than anything we’ve had since we got pertuzumab [Perjeta] for first-line therapy.”

As promising novel anti-HER2 treatments emerge, the monarcHER investigators suggested, the field will continue to revolutionize, with guidelines beginning to include novel treatment options in the third-line setting and thereafter.

“I think we’re going to see more data relating to [trastuzumab deruxtecan] compared with standard of care in the coming year,” Vogl said. He also suggested that investigators may look to established agents. These include everolimus (Afinitor) given with hormonal and HER2-targeted therapy in the second, third, and fourth lines for palliative treatment of patients with hormone receptor–positive, HER2-positive disease. Vogl commented that although obtaining funding for research involving palliative therapy may present a problem, the efforts will pay off in the end.

Editor’s Note: Interview quotes slightly modified for readability.


  1. Tarantino P, Prat A, Cortes J, Cardoso F, Curigliano G. Third-line treatment of HER2-positive advanced breast cancer: from no standard to a Pandora’s box. Biochim Biophys Acta Rev Cancer. 2021;1875(1):188487. doi:10.1016/j.bbcan.2020.188487
  2. Modi S, Saura C, Yamashita T, et al; Destiny-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
  3. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. New release. United States Food and Drug Administration. December 20, 2019. Accessed September 10, 2021.
  4. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. United States Food and Drug Administration. April 20, 2020. Accessed September 10, 2021.
  5. 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
  6. FDA approves neratinib for metastatic HER2-positive breast cancer. News release. United States Food and Drug Administration. February 26, 2020. Accessed September 10, 2021.
  7. 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
  8. FDA approves margetuximab for metastatic HER2-positive breast cancer. United States Food and Drug Administration. News release. December 17, 2020. Accessed September 16, 2021.
  9. 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. 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932
  10. Tolaney SM, Wardley AM, Zambelli S, et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(6):763-775. doi:10.1016/S1470-2045(20)30112-1

For videos of the discussion, see:

Third-Line Treatment Data for HER2+ Advanced Breast Cancer

HER2+ Advanced Breast Cancer: Selecting Third-Line Therapy