Tucatinib Triplet Takes Up Residence in Third-Line Metastatic HER2+ Breast Cancer

Elisavet Paplomata, MD, discusses the lack of standard third-line regimens for patients with metastatic HER2-positive breast cancer, especially for those with brain metastases.

There is no standard third-line regimen for patients with metastatic HER2-positive breast cancer, especially for those with brain metastases, according to Elisavet Paplomata, MD. However, there are a handful of agents that could be poised as potential third-line standards of care in the space.

Tucatinib (Tukysa) could be 1 such drug, according to Paplomata. The agent was evaluated in the phase 2 HER2CLIMB study in combination with trastuzumab (Herceptin) and capecitabine in patients with previously treated HER2-positive metastatic breast cancer and brain metastases.

Results showed that in the experimental arm, the risk of death was reduced by 34% with tucatinib versus trastuzumab and capecitabine alone.1 Updated results featuring a subset of patients with brain metastases were presented during the 2020 ASCO Virtual Scientific Program and showed a 68% reduction in the risk of central nervous system progression-free survival (CNS-PFS) in the triplet arm (HR, 0.32; 95% CI, 0.22-0.48; P < .00001) at 1 year.2

In April 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for patients with unresectable, locally advanced or metastatic HER2-positive breast cancer based on findings from HER2CLIMB. The approval includes patients with brain metastases, who have had at least 1 prior anti-HER2–based regimen in the metastatic setting.

“For patients who have progressed on second-line [ado-trastuzumab emtansine (T-DM1; Kadcyla)], tucatinib plus trastuzumab and capecitabine is a great regimen in the third-line [setting],” said Paplomata. “We do have a high level of evidence [indicating] good toxicity for those who have used tucatinib. [Those who] participated in the HER2CLIMB study know that the drug was very well tolerated.”

Additional agents that could be positioned for use in the third-line setting include fam-trastuzumab deruxtecan-nxki (Enhertu) and neratinib (Nerlynx), which received regulatory approvals in December 2019 and February 2020, respectively.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer (IPC) webinar on Breast Cancer, Paplomata, an assistant professor at the University of Wisconsin School of Medicine and Public Health, and an oncologist at the University of Wisconsin Carbone Cancer Center, discussed the current third-line treatment landscape for patients with metastatic HER2-positive breast cancer.

OncLive®: How can we optimize the advances that have been made in metastatic HER2-positive breast cancer in the clinic?

Paplomata: It’s an exciting time for breast oncologists. We’ve had 3 drugs approved in the past year based on findings from the HER2CLIMB, DESTINY-Breast01, and NALA trials. HER2-positive metastatic breast cancer has become a chronic disease and that’s great for our patients. Of course, we want to do better when it comes to systemic therapy, and also for CNS disease. When it comes to third-line therapy and beyond, we have several good options to choose from. For each individual patient we take care of, we need to look at the level of evidence, toxicities, OS data, CNS activity, whether the patient has CNS disease or not, as well as prior therapies. Tucatinib, trastuzumab, capecitabine; trastuzumab deruxtecan; and neratinib [Nerlynx]/capecitabine are all reasonable regimens to use. We can use them sequentially based on the prior regimens and toxicities [experienced by] the patient.

Most of our patients with metastatic HER2-positive breast cancer will receive trastuzumab, pertuzumab [Perjeta], and a taxane based on the CLEOPATRA study, followed by T-DM1 based on the EMELIA study. However, there is no standard of care in the third-line [setting].

What distinguishes the HER2CLIMB study from other trials that have been done in the metastatic setting?

The HER2CLIMB study was a randomized double-blind, international study. Patients were randomized 2:1 to tucatinib plus trastuzumab and capecitabine versus placebo plus trastuzumab and capecitabine. Patients had HER2-positive metastatic disease that was centrally confirmed, and all patients were required to have had prior [exposure to] trastuzumab, pertuzumab, and T-DM1. [These patients] essentially progressed on the first- and second-line treatments I mentioned earlier. All patients were required to have a brain MRI at baseline.

What is different about the HER2CLIMB study is that patients with active brain metastases, including new, untreated, or previously treated and progressing brain metastases, were enrolled. About half of the patients in the study had brain metastases and about half had active brain metastases. Most of the studies [in this space] enroll patients with [stable] brain metastases. There really was an unmet need for this patient population with HER2-positive metastatic disease because almost half develop metastatic disease in the brain, which can be difficult to control locally with systemic therapy.

HER2CLIMB did meet its primary end point and showed some impressive data. [The triplet] reduced the risk of progression or death by about half, it almost doubled the objective response rate [ORR], and when we specifically looked at patients with brain metastases, it also improved the CNS-PFS and overall survival [OS]. These data were presented separately at the 2020 ASCO Virtual Scientific Program by Nancy U. Lin, MD, of Dana-Farber Cancer Institute, and were published in the Journal of Clinical Oncology at the same time. [The HER2CLIMB regimen] doubled the intracranial ORR and was well tolerated. Quality of life [QoL] data were presented during the 2020 ESMO Virtual Congress; the QoL was the same between the 2 arms. [These were] very impressive data with a high level of evidence supporting tucatinib in the third-line [setting].

How are you applying these data to your own practice?

[The agent] is very well tolerated. About 80% of patients in the tucatinib arm did experience diarrhea, but that was well managed with anti-diarrheal medications. No diarrhea prophylaxis was required. Some patients developed elevated liver function tests but, again, that was well managed with dose interruptions and reductions. With the data we have, tucatinib plus trastuzumab and capecitabine is a good regimen in the third-line [setting]. I would prefer it specifically for patients with brain metastases.

Could you speak to the data supporting the use of trastuzumab deruxtecan in heavily pretreated patients?

The DESTINY-Breast01 study, [utilizing] trastuzumab deruxtecan, has also shown very impressive data. It is an antibody-drug conjugate using a topoisomerase 1 payload, which is very potent and is also membrane permeable; it can also cause a bystander effect. The DESTINY-Breast01 study used a dose of 5.4 mg/kg and enrolled 184 patients. That was a single arm, open-label study. The drug is given intravenously every 3 weeks and [yielded] impressive response rates; the ORR was 61%. These were heavily pretreated patients; the median prior lines of therapy was 6. The OS has not yet been reached, so we will await those results. [These were] impressive data, even though this is a single-arm study.

This also is a great regimen that could play a role in the third-line [setting] and beyond. Toxicity can be an issue with trastuzumab deruxtecan. Twenty-five cases of interstitial lung disease [ILD] were reported, of which 4 were fatal, which led to a black box warning. Whenever there’s any suspicion of pneumonitis or ILD, the drug needs to be stopped and steroids [should be] started. Having seen that this study enrolled patients who had 6 prior lines of treatment, it may be reasonable to use [this agent] in the later-line setting. Again, we’re awaiting more data, but [these are] definitely very impressive data from the DESTINY-Breast01 study.

What is your advice with regard to managing ILD in those who receive this agent?

You have to look out for it [and include a] review of systems and exams. Of course, with any suspicion of ILD, the drug needs to be held and steroids need to be started. Our recommendation is that if a patient develops grade 1 [ILD], which is essentially symptomatic and probably found incidentally in scans, stop the drug and start steroids. If the patient goes back to grade 0 you can resume the drug, but for anything from grade 2 and beyond, the black box warning recommends stopping the drug. As clinicians, we have to keep our eyes and ears open and make sure we hold the drug and use steroids aggressively if we suspect ILD.

The current recommendation is not to screen patients up front with pulmonary function tests. For patients who might have a history of lung disease, I would be more cautious to use the drug. DESTINY-Breast01 did not include patients who had prior ILD; we would not enroll or treat patients with prior ILD with trastuzumab deruxtecan. When it comes to choosing patients for this regimen, a patient with CNS disease will probably [respond] best to a TKI as opposed to [an ADC]. DESTINY-Breast01 did enroll patients with a history of brain metastases, but not active brain metastases, [as in the] HER2CLIMB study.

What should we know about margetuximab?

Margetuximab was evaluated in the SOPHIA study. This is another new agent and the data were presented during the 2020 ASCO Virtual Scientific Program and at the 2019 San Antonio Breast Cancer Symposium by Hope Rugo, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. The drug showed modest activity and we are still awaiting OS data. The drug has not been approved yet but there may be a subset of patients in which [the agent] works better. We’re still waiting for more data before we [bring the agent] into practice.

Where does neratinib fit into the landscape?

Neratinib is a TKI [that] irreversibly binds HER2, so it is slightly different in that way from lapatinib [Tykerb]. Neratinib is already approved based on findings from the ExteNET trial for use as an adjuvant therapy in patients with HER2-positive breast cancer who completed adjuvant trastuzumab.

The NALA study included patients with metastatic disease and [those with] centrally-confirmed HER2-positive breast cancer. Patients had 2 or more prior lines of therapy. The study randomized patients to neratinib or capecitabine and all patients were required to take prophylactic loperamide for cycle 1 versus lapatinib and capecitabine. The primary end point of PFS was met, with an improvement of 2.2 months between the 2 arms favoring neratinib. OS did favor neratinib, but it was not statistically different. There was some delay in CNS events with neratinib, which is very encouraging because patients with HER2-positive metastatic breast cancer do develop brain metastases.

The authors did present the data on diarrhea toxicity; the discontinuation of the drug due to diarrhea was 2.3% and 2.6% in the investigational and control arms, respectively, which is relatively low. No new safety signals were reported. Essentially, the outcome of the NALA trial was that neratinib was better than lapatinib. It is definitely a reasonable regimen to use in patients with HER2-positive metastatic breast cancer.

Could the coronavirus disease 2019 [COVID-19] affect the progress that has been made in this space?

The COVID-19 [crisis] has been hard on everyone, including our patients, but patient care never stops. It’s exciting that we have made these advances in the past year, despite COVID-19 and everything [else that is going on]. The fight continues to treat patients with cancer.


  1. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Eng J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
  2. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005