New Options Mark Major Strides in Treating HER2+ Metastatic Breast Cancer

Oncology Live®Vol. 21/No. 18
Volume 21
Issue 18

A panel of breast cancer experts discuss a variety of new and emerging agents to treat patients with advanced or metastatic HER2-positive breast cancer with disease progression following treatment with at least 1 anti-HER2 therapy.

Hope S. Rugo, MD, FASCO

Despite the improved outcomes seen with HER2-targeted therapies in patients with breast cancer in both the early and advanced settings, almost all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy because of de novo or acquired resistance.1,2 This has prompted efforts to improve anti-HER2 treatment strategies, and several new agents recently have been approved by the FDA. As the armamentarium of novel therapies expands, so does the need for an understanding of safety and efficacy in patients, especially those with brain metastases.

During an OncLive Peer Exchange®, a panel of breast cancer experts discussed a variety of new and emerging agents to treat patients with advanced or metastatic HER2-positive breast cancer with disease progression following treatment with at least 1 anti-HER2 therapy, including the recent approvals of a new antibody-drug conjugate, several novel tyrosine kinase inhibitors (TKIs), and a new anti-HER2 antibody. “The HER2-positive space is really the most exciting space right now in terms of what we can do or will be able to do in the clinic very soon to offer yet more life-prolonging therapies [to our patients],” Priyanka Sharma, MD, said.

Trastuzumab Deruxtecan

Fam-trastuzumab deruxtecan-nxki (Enhertu) is an antibody-drug conjugate that has shown remarkable results in treating unresectable or metastatic HER2-positive breast cancer. “The payload with this drug is a TOPO1 [type I topoisomerase] inhibitor, and there is a high drug-to-antibody ratio. There is also some bystander effect with it easily crossing the cell membrane. It has a relatively short half-life, so the thought is that it can get to neighboring cells but doesn’t hang around for very long,” Claudine J. Isaacs, MD, said.

On December 20, 2019, based on data from the phase 2 DESTINY-Breast01 trial (NCT03248492), the FDA granted accelerated approval to trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive breast cancer who received at least 2 prior anti-HER2–based regimens in the metastatic setting.3 The study reported an objective response rate (ORR) of 60.3%, which was particularly remarkable because patients in the study were heavily pretreated, with a median of 6 prior treatments (range, 2-27), including trastuzumab (Herceptin; 100%), ado-trastuzumab emtansine (T-DM1/Kadcyla; 100%), pertuzumab (Perjeta; 66%), and other HER2-targeted regimens (54%).4,5 Additionally, ORRs were consistent across subgroups, including those who received at least 3 previous regimens (59%) and those who were previously treated with pertuzumab (64%). The disease control rate was 97%, with only 5 of 184 patients not showing stable disease or better on their first postbaseline scan.4

“There were very few patients who progressed. Most patients had a response, but 61% had an actual objective response, and if you think about the median number of prior therapies, that was very impressive,” Isaacs said.

The most common adverse effects (AEs), which were observed in 20% or more of patients, included nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, and neutropenia.5 “The adverse effect that we need to think about most, and that was the most concerning, is interstitial lung disease [ILD]. Any grade was about 13.5%, but there were just over 2.0% of patients who had fatal ILD with this drug, which is obviously a very concerning adverse effect,” Isaacs said. Because of this finding, the prescribing information includes a boxed warning advising health care providers of the risk of ILD and pneumonitis, noting that patients need to be carefully monitored for any signs or symptoms of these complications, including cough, dyspnea, fever, and other new or worsening respiratory symptoms.5

“It seemed like, if the drug was continued when you had just abnormalities on x-ray, that could progress very rapidly,” Isaacs said. Although there are no contraindications to using trastuzumab deruxtecan, because of its potential to affect the lungs, Isaacs emphasized that its use needs to be carefully considered in patients with preexisting lung disease, particularly while the world is still grappling with the coronavirus disease 2019 (COVID-19) pandemic. Despite this AE, she noted that it is an exciting drug “whose results showed the most phenomenal waterfall plot that many [clinicians] have seen in a trial.”

Newly Approved and Emerging TKIs

Several TKIs, including neratinib (Nerlynx), tucatinib (Tukysa), and pyrotinib, have recently shown benefit in clinical trials when used in combination with capecitabine. Of these, neratinib and tucatinib were recently approved by the FDA based on their clinical trial data.6,7 Both are indicated in adult patients with previously treated advanced or metastatic HER2-positive breast cancer, with neratinib approved for use after failure of at least 2 anti-HER2–based regimens and tucatinib approved for use after failure of at least 1 anti-HER2–based regimen. Notably, the indication for tucatinib includes patients with brain metastases (Table).8,9

Table. Prescribing Information for Recent Tyrosine Kinase Inhibitor Approvals for HER2-Positive Breast Cancer8,9


Neratinib was approved based on the phase 3 NALA trial (NCT01808573), which randomly assigned patients with stage IV HER2-positive breast cancer previously treated with at least 2 prior HER2-directed regimens in the metastatic setting to neratinib plus capecitabine (n = 307) or lapatinib plus capecitabine (n = 314).6,10 The risk of disease progression or death was reduced by 24% in the neratinib arm, with 6- and 12-month progression-free survival (PFS) rates of 47.2% and 28.8% versus 37.8% and 14.8%, respectively. The 6-month overall survival (OS) rate was 90.2% in the neratinib arm versus 87.5% in the lapatinib arm, and the 12-month OS rates were 72.5% versus 66.7% in these arms, respectively.10 “It was noted that a smaller proportion of patients needed intervention for CNS [central nervous system] disease on the neratinib arm compared to lapatinib arm, [but the investigators] did not [include] any data in terms of responses in the brain,” Sharma said.

Treatment-emergent AEs were similar between arms; however, grade 3 diarrhea was significantly more common in the neratinib arm than the lapatinib arm (24.4% vs 12.5%), despite antidiarrhea prophylaxis. “This has been one of the limiting factors in terms of utilization of this drug,” Sharma said.


Tucatinib was approved based on data from the phase 2 HER2CLIMB trial (NCT02614794), which randomly assigned 612 patients with locally advanced or metastatic HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1 2:1 to tucatinib, capecitabine, and trastuzumab (n = 410) or to placebo, capecitabine, and trastuzumab (n = 202).7 The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the placebo arm (HR, 0.54; 95% CI, 0.42-0.71; P < .00001). The confirmed overall response rate for patients with measurable disease was 40.6% and 22.8% in the tucatinib and placebo arms, respectively (P = .00008). Most importantly, tucatinib showed a survival benefit. “There was about a 4.5-month prolongation in OS for the group of women who got the tucatinib on top of the capecitabine and the trastuzumab,” Isaacs said. Further, a median OS of 21.9 months in the tucatinib arm compared with 17.4 months in the placebo arm was observed.7

Isaacs emphasized that HER2CLIMB included a large proportion of patients with brain metastases, with just under half having CNS involvement (n = 291), and that these patients also derived benefit from the addition of tucatinib. The median PFS was 7.6 months for tucatinib-treated patients compared with 5.4 months in patients treated with placebo (HR, 0.48; 95% CI, 0.34-0.69; P < .00001).9

“The fact that that benefit is there and it’s an overall survival benefit not limited to patients with brain metastases, but really, at least in the third line, anybody with that higher-exposure HER2-positive disease, I lean toward using tucatinib,” said Tiffany A. Traina, MD. As for the future of the agent, Traina added that it would be wonderful to see a time when tucatinib may find utility in the ability to minimize the development of brain metastases.

Panelist John Fox, MD, MHA, concurred, adding that the HER2CLIMB data were reminiscent of the efficacy of osimertinib (Tagrisso) in patients with EGFR-mutant non–small cell lung cancer. “Osimertinib not only treated brain metastases but also reduced the likelihood of development of them and was subsequently approved as a first-line therapy,” Fox said. “We’ll see if tucatinib makes that same progression from third-line to earlier line therapies.”


Pyrotinib has been examined in a phase 3 study (NCT02973737) in China, which randomly assigned patients with HER2-positive metastatic breast cancer previously treated with taxanes and trastuzumab 2:1 to pyrotinib plus capecitabine (n = 185) or placebo plus capecitabine (n = 94).11 The median PFS was 11.1 months in the pyrotinib arm and 4.1 months in the placebo plus capecitabine arm.

“The pyrotinib trial has this huge PFS benefit, more than what we’ve seen with other oral tyrosine kinase inhibitors, and also a benefit in patients with brain metastases,” moderator Hope S. Rugo, MD, FASCO, said. “The key with that trial is that some of the patients hadn’t received trastuzumab so they were a relatively treatment-naïve group of patients who didn’t have access to other therapies.” When the trial was conducted, said Sharma, pertuzumab was not approved in China and the approval of T-DM1 was recent.

Pyrotinib also showed benefit in the phase 3 PHOEBE trial (NCT03080805), which was presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.12

The trial randomly assigned 267 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes and/or anthracyclines 1:1 to receive pyrotinib plus capecitabine (n = 134) or lapatinib plus capecitabine (n = 133). The median PFS was 12.5 months in the pyrotinib arm versus 6.8 months in the lapatinib arm (HR, 0.39; 95% CI, 0.27-0.56; P < .0001). Pyrotinib also showed benefit over lapatinib in ORR (67.2% vs 51.5%), clinical benefit rate (73.1% vs 59.1%), and median duration of response (11.1 vs 7.0 months). The most common grade 3 or higher AEs with pyrotinib included diarrhea (30.6%) and hand-foot syndrome (16.4%).12


Margetuximab is an innovative immune-enhancing monoclonal antibody that has shown good clinical activity in the ongoing phase 3 SOPHIA study (NCT02492711).13 “This [drug] was designed to try to increase the binding for the low-affinity activating Fc gamma receptor, which is CD16A, and decrease affinity for the inhibitory Fc gamma receptor,” said Rugo, who is part of the SOPHIA Study Group. This mechanism of action enhances innate immunity and potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.13

The SOPHIA study randomly assigned patients with progression of HER2-positive metastatic breast cancer after at least 2 lines of anti-HER2 therapy, including pertuzumab, and 1 to 3 lines of therapy for HER2-positive metastatic breast cancer 1:1 to margetuximab or trastuzumab, both given with investigator’s choice of chemotherapy (ie, capecitabine, eribulin, gemcitabine, vinorelbine).13 Patients in the margetuximab arm had a longer median PFS than those in the trastuzumab arm (5.8 vs 4.9 months; HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more pronounced in patients with CD16A genotypes containing a 158F allele, with this subset of margetuximab-treated patients having a median PFS of 6.9 months. Margetuximab also showed a trend toward OS benefit.

“[These] are very interesting data, but it’s difficult to understand exactly how [margetuximab is] going to play a role in terms of all of these other therapies. It still may play a role in the later-line setting. There is a lot of interest in setting the antibody specifically in patients who have the F allele, which is a large majority of patients, so it’ll be interesting,” Rugo said.

Margetuximab is currently being reviewed by the FDA for the treatment of patients with pretreated metastatic HER2-positive breast cancer in combination with chemotherapy.14 The Prescription Drug User Fee Act decision date is set for December 18, 2020.


1. Callahan R, Hurvitz S. Human epidermal growth factor receptor-2-positive breast cancer: current management of early, advanced, and recurrent disease. Curr Opin Obstet Gynecol. 2011;23(1):37-43. doi:10.1097/gco.0b013e3283414e87

2. Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11:1758835919833519. doi:10.1177/1758835919833519

3. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer News release. FDA. December 20, 2019. Accessed August 12, 2020.

4. Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: a phase 2, multicenter, open-label study (DESTINY-Breast01). Cancer Res. 2019;80(suppl 4):GS1-03. doi:10.1158/1538-7445.SABCS19-GS1-03

5. Enhertu. Prescribing information. Daiichi Sankyo Inc; 2019. Accessed August 24, 2020. 

6. FDA approves neratinib for metastatic HER2-positive breast cancer. News release. FDA. February 25, 2020. Accessed August 12, 2020.

7. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. FDA. April 17, 2020. Accessed August 12, 2020.

8. Nerlynx. Prescribing information. Puma Biotechnology Inc; 2020. Accessed August 24, 2020.

9. Tukysa. Prescribing information. Seattle Genetics Inc; 2020. Accessed August 24, 2020.

10. Saura C, Oliveira M, Feng YH, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37(suppl 15):1002. doi:10.1200/JCO.2019.37.15_suppl.1002

11. Jiang Z, Yan M, Hu X, et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: a randomized phase III study. J Clin Oncol. 2019;37(suppl 15):1001. doi:10.1200/JCO.2019.37.15_suppl.1001

12. Xu B, Yan M, Ma F, et al; The PHOEBE Group. Pyrotinib or lapatinib plus capecitabine for HER2+ metastatic breast cancer (PHOEBE): a randomized phase III trial. J Clin Oncol. 2020;38(suppl 15):1003. doi:10.1200/JCO.2020.38.15_suppl.1003

13. Rugo HS, Im S-A, Cardoso F, et al; SOPHIA Study Group. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Cancer Res. 2019;80(suppl 4):GS1-02. doi:10.1158/1538-7445.SABCS19-GS1-02

14. MacroGenics provides update on FDA review of margetuximab for HER2-positive metastatic breast cancer. News release. MacroGenics Inc. May 28, 2020. Accessed August 14, 2020.

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