The first-line standard of care for patients with HER2-postive metastatic breast cancer has long been held by the combination of pertuzumab (Perjeta), trastuzumab (Herceptin), and a taxane established with the publication of data from the CLEOPATRA trial (NCT00567190).

“This regimen has really landed very solidly in that space and has yet to be dethroned and for a good worthwhile reason,” Virginia F. Borges, MD, said in a recent 

. Final results from the CLEOPATRA trial demonstrated significant improvement in overall survival (OS), at 56.5 months with the pertuzumab combination compared with 40.8 months in the placebo combination group.

 “Fast forward to 2022, [and] the only thing I’ve incorporated into my practice around those original data is some flexibility on what my choice of taxane might be,” Borges said. Despite the long-held success in the frontline, most patients eventually experience disease progression, and the demand for effective second- and third-line options for patients with HER2-positive, metastatic disease have recently undergone a shake-up. “It’s wonderful how the metastatic setting has become a little bit of an embarrassment of riches in comparison with where we were a decade or 2 ago,” Borges said. 

Joining Borges, a panel of breast cancer experts discussed the recent updates to the second-line setting with the incorporation of fam-trastuzumab deruxtecan-nxki (Enhertu), as well as the successes and challenges seen in the third- and later-line arena for these patients.

In patients who fail to respond to first-line therapy, the preferred second-line treatment for HER2-positive metastatic breast cancer is to use the antibody-drug conjugate (ADC), trastuzumab deruxtecan based on findings from the DESTINYBreast03 trial (NCT03529110).

 “I think most, if not all of us, would agree that trastuzumab deruxtecan is really the current standard of care in that second-line space for these patients,” Maryam Lustberg, MD, MPH, said. 

The phase 3, open-label trial evaluated the safety and efficacy of trastuzumab deruxtecan compared with the reigning standard-of-care ado-trastuzumab emtansine (Kadcyla; T-DM1) in 524 patients who had disease progression following treatment with trastuzumab and/or taxane therapy.

 Updated findings presented at the 2022 San Antonio Breast Cancer Symposium (SABCS) and published in the 

 supported the sustained progression-free survival (PFS) benefit of the regimen from the original publication and demonstrated an OS advantage with trastuzumab deruxtecan.

The primary end point of median PFS was 28.8 months (95% CI, 22.4-37.9) in the trastuzumab deruxtecan arm (n = 261) vs 6.8 months (95% CI, 5.6-8.2) in the T-DM1 arm (n = 263). The HR for disease progression or death was 0.33 (95% CI, 0.26-0.43; 

 < .0010). The 12-month PFS rates were 75.2% (95% CI, 69.3%-80.2%) and 33.9% (95% CI, 27.7%-40.2%), respectively, with 24-month PFS rates of 53.7% (95% CI, 46.8%-60.1%) and 26.4% (95% CI, 20.5%-32.6%), respectively.

The median OS was not reached in either the trastuzumab deruxtecan arm (95% CI, 40.5-not estimable [NE]) or the T-DM1 arm (95% CI, 34.0NE), with a reported 36% reduction in the risk of death with trastuzumab deruxtecan (HR, 0.64; 95% CI, 0.47-0.87; P = .0037).

 The 12- and 24-month OS rates with trastuzumab deruxtecan were 94.1% (95% CI, 90.4%-96.4%) and 77.4% (95% CI, 71.7%-82.1%), respectively, compared with 86.0% (95% CI, 81.1%-89.8%) and 69.9% (95% CI, 63.7%-75.2%) in the T-DM1 arm.

“We had been concerned that with trastuzumab deruxtecan the responses might be short lived [based on data] from the later-line trials, but these are very durable responses,” Debu Tripathy, MD, said. “Now the concern, of course, is how long patients are going to be on this [agent]. How long are they going to tolerate [it]? Those are things we’re going to need to sort out as time goes on. What is the natural history post trastuzumab deruxtecan? But so far, the most important step is that patients are doing well and going a long time without progression. This is really a tour de force, [and] the big questions are more about understanding why it is effective. Is it the payload? Is it something about the design of the [ADC] in terms of how it’s internalized?” 

Another key concern for Tripathy is staying on top of the associated toxicities, something he affirms has gotten better with awareness. “The key challenge here is to make sure we stay on top of the toxicities, particularly the very concerning risk of interstitial lung disease [ILD], which thankfully we’ve seen that with awareness and monitoring, rates are very low in the more recent trials, but it does still occur.” 

The rate of ILD did see an increase from the original publication to the updated data (10.5% to 15.2%), but investigators noted that this was a result of increased treatment duration and follow-up.

 Moderator Joyce A. O’Shaughnessy, MD, said that most ILD occurs in the first year but some reports came at 2 years. “We have to always be vigilant,” she said. “I’m interested in what my colleagues are doing. One of the things I’ve been hearing is that they’ve been getting CT scans every 6 weeks, or even more likely 9 weeks because we can get those covered. Even if [the patient] doesn’t have lung metastases, they’ve been getting CT scans every 9 weeks.” Borges agreed saying that her decision point is 6 weeks, because “we can’t afford to miss this.” 

O’Shaughnessy added that the way to avoidgrade 4 and grade 5 toxicity is “don’t treat through symptoms. Pay careful attention, but if symptoms [develop], we’ve got to stop and then evaluate [and] treat [them]. And at least based on what we have right now, we don’t have any data that say with symptoms we can go back.” Other key safety data from the study are reflected in the Table.

Treatment guidelines now reflect the use of the HER2CLIMB regimen (NCT02614794) which includes tucatinib (Tukysa), trastuzumab, and capecitabine or T-DM1.1 “What I’m using for third line is usually the HER2CLIMB regimen,” Tripathy said. The final OS analysis of the HER2CLIMB trial showed that at a median follow-up of 29.6 months, the median OS with the addition of tucatinib was 24.7 months vs 19.2 months for trastuzumab and capecitabine alone (HR, 0.73; 95% CI, 0.59-0.90; P = .004).

 The 12-month OS rates were 51% and 40%, respectively. 

The triplet also showed efficacy among patients with active and stable brain metastases. The median OS was 21.6 months (95% CI, 18.1-28.5) vs 12.5 months (95% CI, 11.2-16.9), respectively (HR, 0.60; 95% CI, 0.44-0.81).

 “Over half the patients [who] were enrolled had brain metastases, which was allowed,” Tripathy said. “And half of those patients actually had active brain metastases or untreated brain metastases. This is important because we all know that in later lines of therapy, brain metastases become common and we sometimes find many [tumors] amenable for gamma knife, and we would like to avoid whole brain radiation….that benefit now has been maintained on follow-up analysis, and I see it as an important adjunct, particularly for patients with brain metastases. That’s our preferred go-to regimen after trastuzumab deruxtecan.”

Tripathy noted that he then turns to T-DM1 or other investigational agents. “I’m using [T-DM1] pretty far out. Sometimes I’ll use it in fourth line, [but] I tend to use the tyrosine kinase inhibitors [TKIs], capecitabine, neratinib [Nerlynx], or even margetuximab-cmkb [Margenza]. It’s really hard with all these regimens to know which is the best one to use. Some of my colleagues tend to use TDM-1 more than I do, and I’ve seen responses and maintenance of disease control with it as well.” 

O’Shaughnessy agreed, noting that she uses T-DM1 in the third line almost consistently. “Back in the old days, when patients progressed on first line with trastuzumab/pertuzumab, they’d go onto capecitabine/lapatinib [Tykerb]. That’s what we had,” she said. She also added that after T-DM1 became available, patients proceeded onto T-DM1. “That’s where I saw multiyear benefits. I remember I went back to the charts [to see] what was common about these exceptional responders, and it was interesting. The antecedent therapy to the T-DM1 had been a TKI. And there’s some preclinical evidence that [shows] when you get the TKI and you’re squeezing the tyrosine kinase, HER2 levels can be upregulated by the cell, which is of course when T-DM1 really works. When there’s enough HER2, it can get internalized because after trastuzumab/pertuzumab, you get downregulation. Interestingly, we’re seeing a lot of data now that with trastuzumab deruxtecan, upon progression, you see downregulation. This probably isn’t the best time to come in with T-DM1, we’re speculating, because we don’t have data. [And] you want it to work; it’s such a well-tolerated agent. I’d love to give it after the [HER2CLIMB regimen], but real-world evidence would be awesome in this space.”

Emerging therapies are playing a larger role in HER2-positive disease including novel therapies such as zanidatamab, ARX788, and GLSI-100. 

Zanidatamab is a bispecific antibody that uses biparatopic binding so that each antibody molecule can bind to 2 different HER2 receptors.

 In a single-arm phase 2 trial the agent was assessed among 45 patients in combination with palbociclib plus fulvestrant. The median number of prior HER2 therapies in the metastatic setting was 3 (range, 1-9). Among patients with measurable disease at baseline and postbaseline assessment (n = 36), the confirmed objective response rate was 33% (95% CI, 18.6%51.0%). The confirmed best overall response included a complete response in 1 patient (3%), partial response in 11 patients (33%), and stable disease in 21 patients (58%). The disease control rate was 92% (95% CI, 77.5%-98.2%). The primary end point of PFS at 6 months was NE at the interim analysis.

“Zanidatamab is a very interesting drug. It binds to epitopes and these are involved in not only enhanced binding, but it brings about more clustering and receptor internalization. Which of those phenotypes gave it its activity isn’t clear,” Tripathy said. He added that activity has been seen across tumor types that are HER2 positive. 

Another ADC is ARX788, which is a HER2specific monoclonal antibody that is conjugated with the tubulin inhibitor Amberstatin269.8 Early results from the ongoing phase 2 ACEBreast-03 trial (NCT04829604) in 7 patients with HER2-positive metastatic breast cancer revealed a confirmed ORR of 57.1% 

Lastly, GLSI-100 comprises GP2, an amino acid peptide vaccine of the HER2/ neu protein and granulocyte-macrophage colony-stimulating factor (GM-CSF).

 GLSI100 is under investigation in the ongoing FLAMINGO-01 trial (NCT05232916), which is a double-blind, randomized, phase 3 study that will evaluate the effects of GLSI-100 on survival following 1 year of trastuzumab therapy.

Tripathy highlighted that several peptide vaccines have been evaluated over the past 15 to 20 years but have elicited inadequate immune responses. “The question is: Are these [immune] responses sufficient to bring about a clinical difference? So far, we haven’t seen that…large, well-done randomized trials in the right setting, maybe with minimal residual disease burden, are what’s needed. That’s what we hope to see with some of these trials, including the FLAMINGO-01.”

Future directions for the field will also have a focus on resistance and will pay close attention to biologic changes with the ADCs. “We’re into this realm of [ADCs, and] it brings up a novel set of questions for us to begin wondering about the known [and] unknowns, if you will,” Borges said. “In the setting of sequential chemotherapy, we try to avoid drugs that have similar mechanisms of action for the cross-resistance that has been described for a very long time. In the HER2 space, we know there are mechanisms by which those drugs can be outsmarted by the cancers. Now we’re marrying the 2 situations: we have targeted therapies that need the HER2 to work but then we also have molecules that are linked to these ADCs. Which is more important? The answer might be both: the target vs the companion drug. At least in this case, we can see that going from one HER2targeted ADC to another HER2-targeted ADC, there’s reason to feel very convinced that it’s a great idea as opposed to avoiding that plan. How will that look as we move forward with ADCs that target similar things but have different linkers? It is a whole new field to explore to keep the resistance scientists in business.”

NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 1.2023. Accessed February 1, 2023. https://www.nccn. org/professionals/physician_gls/pdf/breast.pdf 

Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513 

Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):11431154. doi:10.1056/NEJMoa2115022 

Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY- Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5 

Hurvitz S, Hegg R, Chung Wei-Pang, et al. GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of the randomized, phase 3 study DESTINY-Breast03. Presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. 

Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005 

Escriba-de-Romani S, Alba E, Rodriguez-Lescure A, et al. Treatment of HER2-positive (HER2+) hormone-receptor positive (HR+) metastatic breast cancer (mBC) with the novel combination of zanidatamab, palbociclib, and fulvestrant. Poster presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

Hurvitz S, Kalinsky K, Gansu V, et al. ACE-Breast-03: efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1. Poster presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. 

Patel S, Thompson J, Patel M, et al. A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01. J Clin Oncol. 2022;40(suppl16):TPS1110. doi:10.1200/JCO.2022.40.16_suppl.TPS1110 

Phase 3 study to evaluate the efficacy and safety of HER2/Neu peptide GLSI-100 (GP2 + GM-CSF) in HER2/Neu positive subjects (FLAMINGO-01). ClinicalTrials.gov. Updated February 28, 2023. Accessed February 28, 2023. https://www.clinicaltrials.gov/ct2/ show/NCT05232916

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