Joyce A. O'Shaughnessy, MD, chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center of Texas Oncology, as well as the 2016 Giant of Cancer Care

 in Community Outreach, discusses the utility of tucatinib (Tukysa) in HER2-positive breast cancer with brain metastases.

An update on the phase 2 HER2CLIMB trial was presented during the 

. In this trial, the selective HER2-targeted TKI tucatinib was added to capecitabine plus trastuzumab (Herceptin) versus capecitabine, trastuzumab, and placebo, says O’Shaughnessy. The update focused specifically on patients who had brain metastases. A total of 174 patients had active brain metastases that were either untreated or treated and progressing.

Results showed that the addition of tucatinib improved progression-free survival (PFS) in the brain metastases themselves, says O'Shaughnessy. Tucatinib not only improved overall PFS, including all of the systemic, metastatic disease, but also substantially reduced progression in the central nervous system; the agent showed powerful penetration and activity in the brain, adds O'Shaughnessy. Importantly, tucatinib also improved the survival of patients with brain metastases compared with those who did not receive the TKI.

These data cemented the importance of tucatinib for use in patients with HER2-positive metastatic breast cancer who have brain metastases, even if they are progressing and active or they have not been treated previously. This allows patients to be spared from radiation therapy for a while, concludes O’Shaughnessy.

Videos

Joyce A. O'Shaughnessy, MD, discusses the utility of tucatinib in HER2-positive breast cancer with brain metastases.

Dr. O’Shaughnessy on the Utility of Tucatinib in the HER2+ Breast Cancer Brain Metastases

Erika P. Hamilton, MD, director of the Breast Cancer and Gynecologic Cancer Research Program and principal investigator at the Sarah Cannon Research Institute, discusses the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-low breast cancer.

There are a lot of data on the use of trastuzumab deruxtecan in HER2-low–expressing breast cancers, says Hamilton. This is impressive because it is not the first time the field has looked at this antibody-drug conjugate (ADC) in HER2-low disease, according to Hamilton.

A few years ago, at a San Antonio Breast Cancer Symposium, data were presented in this space, although they were negative. This speaks to the unique mechanism of action of the ADC; it is a unique molecule that can be very effective, says Hamilton. In patients with HER2-low breast cancer, trastuzumab deruxtecan has a bystander effect; even if a small amount of trastuzumab deruxtecan binds, it can kill neighboring cells that may not have much HER2 expression at all, explains Hamilton. Impressive response rates have been reported with this agent in the HER2-low space.

Notably, the minority of patients are HER2-overexpressing, meaning they're 3+ or amplified; more patients that are 1+ or 2+ and FISH negative, says Hamilton. As such, it will be exciting to see how many patients may be reached with this approach in the future, concludes Hamilton.

Erika P. Hamilton, MD, discusses the efficacy of fam-trastuzumab deruxtecan-nxki in HER2-low breast cancer.

Dr. Hamilton on the Efficacy of Trastuzumab Deruxtecan in HER2-Low Breast Cancer

Novel antibody-drug conjugates (ADCs) introduce promising options for the management of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, management of drug-related toxicities and optimal sequencing of HER2-targeted therapies remains an ongoing challenge, according to stakeholders who participated in a recent 

As of 2016, approximately 3.5 million women were living with a breast cancer diagnosis in the United States, and the number of new cases of breast cancer in 2019 represented approximately 15.2% of all new cancer diagnoses. Based on data from 2014 to 2016, approximately 1 in 8 women will be diagnosed with breast cancer in their lifetime, with the largest proportion of diagnoses occurring in women between the ages of 55 and 64 years.

HER2-positive breast cancer accounts for approximately 15% of all breast cancers.

 HER2 is a member of the ERBB family, which comprises 4 plasma membrane-bound receptor tyrosine kinases (HER1, HER2, HER3, and HER4).

 Overexpression of HER2 is identified by evaluating samples of either the primary tumor or metastatic tissue with immunohistochemistry (IHC) or fluorescent in situ hybridization (ISH). Testing guideline updates released in 2018 by the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) define HER2-positive as an IHC score of 3+, which involves strong staining of the entire membrane circumference of more than 10% of tumor cells.

 Tumor specimens with an IHC score of 2+ with weak to moderate complete membrane staining in more than 10% of tumor cells are considered HER2-equivocal and require reflex testing with fluorescent ISH to clarify HER2 status. Specimens with very slight, incomplete membrane staining in more than 10% of tumor cells (IHC score 1+) or those with no observable staining (IHC score 0) are considered HER2-negative.

 Another term, HER2-low, recently emerged to describe breast cancer with an IHC score of 1+ or 2+ with a negative fluorescent or chromogenic ISH assay. More than 50% of breast cancers may be HER2-low; those with low HER2 expression and no ERBB2 amplification may experience benefit from HER2-targeted therapies.

HER2 positivity was historically associated with high rates of recurrence and poor survival, but the availability of trastuzumab and other HER2-targeted therapies has substantially improved outcomes.

 According to a recent analysis, the estimated 5-year survival rates are 83% for hormone receptor-negative, HER2-positive breast cancer and 89% for hormone receptor-positive, HER2-positive breast cancer. “Before we had targeted agents against HER2, particularly in the curative setting, it used to be among our most virulent and rapidly fatal of breast cancers,” said session moderator 

, of Baylor University Medical Center in Dallas, Texas. “[HER2 amplification] is a very, very powerful growth and survival signal. It leads to a lot of therapy resistance right across the board.”

Although O’Shaughnessy noted that recurrence rates for HER2-positive disease are decreasing, she estimated more than half of patients who need first-line treatment for metastatic HER2-positive breast cancer have de novo metastatic disease, which emphasizes the continued need for further metastatic therapies. In addition, central nervous system (CNS) metastases are relatively common in HER2-positive breast cancer and were identified by the stakeholders as 1 of the challenges in management of their patients. Up to 50% of patients with HER2-positive advanced breast cancer develop CNS metastases in their lifetime.

, of Sarah Cannon Research Institute in Nashville, Tennessee, noted that it is important to identify patients in the neoadjuvant or adjuvant setting who are at higher risk for CNS relapse and most likely to benefit from early escalation of therapy.

Several targeted therapies are approved for HER2-positive breast cancer in the adjuvant and metastatic setting, including trastuzumab, pertuzumab, lapatinib, ado-trastuzumab emtansine (T-DM1), and neratinib.

 An additional treatment option, the kinase inhibitor tucatinib, was approved in April 2020 and is indicated in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, after receiving 1 or more HER2-targeted regimens in the metastatic setting.

 This approval was based on data from the phase 3, randomized, controlled HER2CLIMB trial, which had results that showed that the progression-free survival at 1 year among adult patients with HER2-positive breast cancer (N = 612) was significantly better with tucatinib, trastuzumab, and capecitabine than with placebo, trastuzumab, and capecitabine (33.1%; vs 12.3%; HR, 0.54; 95% CI, 0.42–0.71; 

 <.001) and risk for disease progression or death was 52% lower in those with CNS metastases who received the tucatinib combination (HR, 0.48; 95% CI, 0.34–0.69; 

Although the arrival of tucatinib has helped with managing CNS metastasis in HER2-positive breast cancer, 

, of Levine Cancer Institute, Atrium Health in Charlotte, North Carolina, predicted that managing these patients will remain an ongoing challenge because they are living longer.

ADCs offer a targeted approach to HER2-positive breast cancer treatment, and have also shown promise for patients with heavily pretreated disease, CNS metastases, or HER2-low expressing breast cancer.

 ADCs consist of a recombinant monoclonal antibody molecularly bound to a cytotoxic drug (known as the drug payload) with a synthetic linker, and they combine the antibody’s high specificity for a target with the chemotherapy drug’s cytotoxicity.

 HER2-targeted ADCs bind to HER2 on the cancer cell surface and are internalized by the cell, after which the cytotoxic drug component is released intracellularly and exerts its antitumor effect. ADCs may also be designed to stimulate the release of drug from the target cell into the extracellular space, which kills surrounding and bystander cells that may or may not express the target antigen (ie, a bystander effect). This may also occur if the cytotoxic drug is released after binding to the antigen and before internalization.

The ADC trastuzumab emtansine (T-DM1) was approved in 2013 and is indicated for treatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination, and for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.14 T-DM1 is composed of trastuzumab linked with the chemotherapy agent DM1. This agent derives from maytansine, a plant isolate that binds tubulin and blocks microtubule assembly by hindering polymerization and enhancing depolymerization. Although the activity of maytansine is extremely potent, dose-limiting toxicities halted clinical development in early trials.

 T-DM1 resolves these toxicity limitations through a nonreducible thioether linker that prevents chemotherapy release into circulation once the linker breaks down in the tumor cell. These linkers may have minimal cytotoxicity on bystander cells. T-DM1 must be internalized by the target cell for degradation of the antibody and subsequent release of the drug to occur, and the cleaved drug product is unable to enter surrounding cells because its positively charged lysine moiety is unable to penetrate the cell membrane.

 Results from a preclinical study demonstrated that thioether linkers have lower toxicity and better potency than disulfide linkers and induce dose-dependent cell death in HER2-overexpressing breast cancer cells (SK-BR-3 and BT-474) through apoptotic and cell lysis mechanisms.

The high efficacy and relatively good tolerability of T-DM1 have helped to establish it as a common second-line therapy for HER2-positive metastatic breast cancer.

 The phase 3 EMILIA trial randomized patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane to receive T-DM1 (n = 495) or lapatinib plus capecitabine (n = 496); primary endpoints were progression-free survival (assessed by independent review), overall survival, and safety. T-DM1 was associated with significantly longer median progression-free survival (9.6 months vs 6.4 months; HR for death from any cause, 0.65; 95% CI, 0.55–0.77; 

 <.001) and overall survival at the second interim analysis (30.9 months vs 25.1 months; HR for death from any cause, 0.68; CI, 0.55–0.85; 

 The T-DM1 group also had a significantly higher objective response rate than the lapatinib plus capecitabine group (43.6% vs 30.8%; 

 <.001) and lower rate of grade 3 or higher adverse events (AEs) (40.8% vs 57.0%).

The most commonly reported grade 3 or 4 AEs in the T-DM1 group were thrombocytopenia (12.9%) and elevations in serum aspartate aminotransferase and alanine aminotransferase (4.3% and 2.9%, respectively). For the majority of patients, onset of grade 3 or 4 thrombocytopenia occurred during the first 2 cycles of T-DM1, and most were able to continue treatment with dose modifications. Serious AEs were reported for 88 patients (18.0%) in the lapatinib-capecitabine group and 76 patients (15.5%) in the T-DM1 group.

Regarding treatment in the adjuvant setting for patients with HER2-positive early breast cancer, T-DM1 showed positive results in the phase 3 KATHERINE trial, which randomized patients to receive adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) with the primary endpoint of invasive disease-free survival. Invasive disease-free survival at 3 years was significantly better in the T-DM1 group than in the trastuzumab group (88.3% vs 77.0%; HR 0.05; 95% CI 0.39–0.64; 

 <.001). T-DM1 was generally well-tolerated in this trial, with decreased platelet counts (5.7%) and hypertension (2.0%) as the most common grade 3 or higher events. Serious AEs were reported in 94 patients (12.7%) in the T-DM1 group and 58 patients (8.1%) in the trastuzumab group.

Although survival data have not been published yet, O’Shaughnessy said that the data from the KATHERINE trial highlighted T-DM1 as an effective, safe option in the adjuvant setting. “This is a well-tolerated, feasible regimen that we’re all very, very familiar with, and it’s an important standard of care, particularly in the curative setting,” she said.

The efficacy of T-DM1 is thought to be greater in breast cancers with high and homogeneous expression of HER2, as suggested by results of a randomized phase 2 trial that compared first-line T-DM1 to trastuzumab plus docetaxel in patients with locally advanced or metastatic HER2-positive breast cancer (N = 137). In the trial, the improvements in risk for disease progression with T-DM1 were greater in patients with HER2 messenger RNA (mRNA) expression equal to or more than the median (HR, 0.3; 95% CI, 0.18–0.85) than in those with HER2 mRNA expression below the median (HR, 0.85; 95% CI, 0.44-1.67). Within the T-DM1 treatment arm, patients with HER2 mRNA expression equal to or greater than the median had numerically longer progression-free survival than those with HER2 mRNA expression less than the median (not reached versus 10.6 months).

Trastuzumab deruxtecan (DS-8201a) is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti—HER2-based regimens in the metastatic setting.

 The ADC is composed of a humanized anti-HER2 antibody (trastuzumab), enzymatically cleavable tetrapeptide linker, and novel topoisomerase I inhibitor payload (DXd), which is a derivative of exatecan (DX-8951). The tetrapeptide linker, glycynglycyn-phenylalanyn-glycyn (GGFG), is decomposed by cathepsins B and L and other lysosomal enzymes that are strongly expressed inside the tumor cells.

 Trastuzumab deruxtecan has a higher drug-to-antibody ratio (DAR) than other ADCs, with approximately 8 molecules of DXd homogeneously conjugated to 1 trastuzumab molecule versus 2 to 4 drug molecules conjugated to the antibody molecule in other ADCs (3.5 drug molecules in T-DM1). Although a higher DAR (6 to 8) has been known to contribute to ADC instability and higher clearance, which leads to reduced efficacy and greater toxicity, the drug linker system of trastuzumab deruxtecan offers high stability in plasma and strong antitumor activity that relies on its high DAR. Unlike ADCs with a lower DAR (3.4), trastuzumab demonstrated antitumor activity in HER2-low models.

 In addition to having a higher DAR, trastuzumab deruxtecan has a DXd payload with a higher cell membrane permeability than that of T-DM1; this was shown to contribute to a bystander effect in an in vitro coculture of HER2-positive and -negative cells and an in vivo mouse model with tumors heterogeneous for HER2 expression.

An open-label, dose-escalation, and dose expansion phase I trial evaluated safety and preliminary activity of trastuzumab deruxtecan in patients with HER2-positive, advanced- stage breast cancer previously treated with T-DM1. Analysis of the 115 patients treated with at least 1 dose of trastuzumab deruxtecan at the recommended doses for expansion showed an objective response rate of 59.5%. The most common grade 3 or higher treatment-emergent AEs were anemia (17%) and decreased neutrophil (14%), white blood cell (9%), and platelet (8%) counts, and 9 cases of interstitial lung disease or pneumonitis required discontinuation of treatment.

The 2-part, open-label, phase 2 DESTINY-Breast01 trial enrolled patients with HER2-positive metastatic breast cancer who had been treated previously with T-DM1 (N = 184). Part 1 of the trial consisted of pharmacokinetics and dose-finding stages, and part 2 evaluated the efficacy and safety in patients treated with the recommended dose. Part 2 included a cohort of patients who had experienced tumor progression with T-DM1 and a cohort of patients who had discontinued T-DM1 due to toxicity and additional reasons other than progressive disease. The confirmed response rate (by independent central review) was 60.9% among patients who received the recommended dose of 5.4 mg/kg (95% CI, 53.4–68.0), and the median duration of response was 14.8 months (95% CI, 12.7–not reached). The onset of response was relatively quick (median 1.6 months). Patients received a median of 6 prior cancer therapies and the confirmed response rate was 61.1% among the cohort who had tumor progression during or after receipt of T-DM1. This suggests the agent has strong activity even when HER2 is downregulated by prior targeted therapies, according to O’Shaughnessy. “It really speaks to the noncross-resistant nature of the deruxtecan and the ability of this agent to really bind and kill cells, even with the low level of HER2 expression,” she said. Some clinicians may also use trastuzumab deruxtecan in patients with a large disease burden or severe diseaserelated symptoms, according to O’Shaughnessy. 

Trastuzumab deruxtecan may also have efficacy in patients with a history of CNS metastases, according to a subgroup analysis of 24 patients with baseline CNS metastases from the DESTINY-Breast01 trial. The overall response rate was 58.3% (95% CI, 36.6–77.9), including 1 patient who had a 55% regression of a metastatic brain lesion, and the median progression-free survival was 18.1 months (95% CI, 6.7-18.1). At a median follow-up of 11.1 months, 33% of patients with CNS metastases (8/24) and 26% of the overall population (48/184) experienced disease progression before the cutoff  date. However, only 4 of the 48 patients with progressive disease (including 2 of 8 patients with CNS metastases at baseline) had a CNS progression.

In the DESTINY-Breast01 trial, 57.1% of the patients who received the recommended dose had a grade 3 or higher AE. Decreased neutrophil count (20.7%) was the most common; however, the risk for drug-induced lung complications was of particular concern to the stakeholders, with 11 patients discontinuing trastuzumab deruxtecan due to pneumonitis and 5 discontinuing due to interstitial lung disease. Of the 25 reported deaths, 18 occurred during the survival follow-up period (the 47 days after end of treatment), and 2 of these were caused by situations related to interstitial lung disease, which had started during treatment.

An analysis of 7 ongoing studies across multiple tumor types of 665 patients who received at least 1 dose of trastuzumab deruxtecan showed that 66 cases of interstitial lung disease were reported, and 13 of these were grade 3 or higher. Five patients with interstitial lung disease had a fatal outcome, and 4 of these deaths were identified as related to trastuzumab deruxtecan. Of the 665 patients, 289 were from the DS9201-A-J101 study, whose results showed that higher doses and Japanese origin may increase the probability of developing interstitial lung disease after adjustment for baseline factors, such as age, previous radiotherapy to the chest, number of previous anticancer therapies, lung metastases, and HER2 status. The study authors concluded that patients with suspected interstitial lung disease should be diagnosed early with imaging, laboratory testing, and meeting with a pulmonologist. These patients should also discontinue trastuzumab deruxtecan and, in moderate to severe cases, receive steroids.

The interchange faculty agreed that increased awareness among clinicians and early identification of drug-related lung issues is critical. “I am pretty convinced that if we catch this pneumonitis in a grade 1 or a grade 2, we can reverse it, but a lot of times it’s just not caught that early,” said Hamilton. “I think if you do get somebody with a grade 3 pneumonitis, it’s just beyond the point of return.”

, of Virginia Cancer Specialists in Arlington, Virginia, also said that differentiating drugmediated pneumonitis from pulmonary disease related to the breast cancer itself has been challenging in her experience. She added that having a low threshold to give patients a break from the drug and/or start steroids is important for proactive management.

Currently in development, SYD985 is an ADC composed of trastuzumab linked to the duocarmycin prodrug seco-duocarmycin-hydroxybenzamide-azaindole orseco-DUBA via a cleavable linker. The trastuzumab moiety binds to HER2 on the cell surface of the tumor, which activates endocytosis and subsequent cleaving of the linker inside the tumor cell by proteases at the valine-citrulline dipeptide and release of duocarmycin (the active moiety). Binding of duocarmycin to the minor groove of DNA followed by alkylation of adenine at the N3 position induces tumor cell death, and the trastuzumab moiety also causes antibody-dependent cell-mediated cytotoxicity in tumor cells with overexpression of HER2.28

An in vitro analysis showed that HER2 3+ and 2+ human cancer cell lines (SK-BR-2 and AK-OV-3, respectively) were sensitive to seco-DUBA, the cytotoxic component of SYD985.

 Additionally, a bystander effect has been reported for SYD985, with killing effects observed in HER2-low and negligible cells, and the cytotoxicity of SYD985 was 7 and 54 times more effective than T-DM1 for HER2/neu 3+ and HER2/neu 1+ cells, respectively (

Results from a phase 1 expansion cohorts study (NCT02277717) (N = 99) on SYD985 showed an overall response rate of 33% and a median progression-free survival of 9.4 months in patients with HER2-positive breast cancer (n = 50), most of whom had received 3 or more prior HER2-targeting regimens (including T-DM1) for locally advanced or metastatic disease. SYD985 was considered to have a favorable tolerability profile, with fatigue, dry eyes, conjunctivitis, and increased lacrimation as the most common AEs. The most common grade 3 or higher AEs included neutropenia (6%) and conjunctivitis (4%).

The efficacy and safety profile of SYD985 is also currently being reviewed in the phase 3, randomized, active-controlled TULIP trial (NCT03262935)(estimated enrollment = 345). The study launched in 2017 and is randomly assigning SYD985 or physician’s choice of treatment (2:1) to patients with HER2-positive advanced or metastatic breast cancer who had disease progression during or after 2 or more HER2-targeting treatment regimens in the locally advanced or metastatic disease setting. The estimated date of study completion is May 2021.

The antitumor activity of trastuzumab deruxtecan and SYD985 in HER2-low expressing breast cancer may confer an advantage over T-DM1 in this subgroup of patients. An analysis of 54 patients with HER2-low expressing advanced breast cancer from the DESTINY-Breast01 trial showed an objective response rate, confirmed by independent central review, of 37.0%, with a median duration of response of 10.4 months, median progression-free survival of 11.1 months, and median overall survival of 29.4 months (95% CI, 12.9–29.4). These findings prompted the initiation of a phase 3 randomized trial (DESTINY-Breast04; NCT03734029), which will compare the efficacy and safety of trastuzumab deruxtecan with physician’s choice of treatment (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel) in patients with HER2-low expressing, unresectable, and/or metastatic breast cancer.

In the phase 1 expansion cohorts study (NCT02277717) previously mentioned, SYD985 also showed efficacy in patients with heavily pretreated HER2-low metastatic breast cancer. The overall response rates were 27% among patients with hormone receptor-positive disease and 40% among those with triple-negative breast cancer.

According to the stakeholders, these ADCs could fill an important niche role in the treatment of HER2-low breast cancer if these findings are confirmed in ongoing and future phase 3 randomized trials. “It will be a compelling initiative to have an ADC available for this population and to figure out where to sequence it relative to how we currently treat these patients,” said Tan. “I would imagine [these therapies would be administered after] they’ve progressed on endocrine therapy [when] trying to figure out which potential cytotoxic therapy to use.”

, of Reginal Cancer Care Associates in Englishtown, New Jersey, added that using 1 of the new HER2-directed ADCs after hormone therapy may help address the upregulation of HER2 expression that can occur as a resistance mechanism to hormone therapy. However, 

, of Tennessee Oncology in Nashville, Tennessee, emphasized improving identification of patients with HER-low expressing breast cancer will also be necessary for determining whether a patient with low expression of HER2 could benefit from HER2-directed therapies. “I would imagine so many of our notes say ER/PR positive, HER2-negative, and they don’t specify HER2 2+, FISH-negative or HER2 1+,” he said. Identifying these patients is an “extra roadblock that is different than anything else in breast cancer” because clinicians are familiar with HER2-positive so typically think within that framework.

XMT-1522 and ARX788 are 2 of the newest HER2-targeting ADCs currently in early-phase clinical trials for HER2-positive breast and other cancers. XMT-1522 is composed of a novel human IgG1 anti-HER2 monoclonal antibody with Auristatin F-hydroxypropylamide (AF-HPA) as the cytotoxic payload, and a biodegradable polymer conjugation platform is used to achieve an average DAR of 12 AF-HPA molecules to 1 HER2 antibody.

 Initial results from an ongoing phase 1 doseescalation trial (NCT02952729) that included patients with HER2-positive breast, lung, or gastric cancer (N = 19) showed that intravenous administration of XMT-1522 every 3 weeks is generally well-tolerated, with no dose-limiting toxicities or serious AEs attributed to the drug. Disease control (1 partial response and 4 stable disease) was achieved in 5 of 6 patients who received doses of 16 mg/m

, including those who had previously progressed on T-DM1.

ARX788 is composed of a HER2-targeted antibody site-specifically conjugated to Amberstatin269, a cytotoxic tubulin inhibitor.

 An ongoing 2-part, phase 1 study (NCT03255070) is evaluating ARX788 infused every 3 weeks or every 4 weeks in 6 sequential dose escalation cohorts to determine the recommended phase 2 dose in patients with advanced HER2-positive breast or gastric cancer (estimated enrollment = 60).

Practical Considerations of New Data in HER2+ Breast Cancer 

According to the 2020 NCCN guidelines, the preferred regimen for systemic treatment for recurrent or metastatic HER2-positive breast cancer is pertuzumab, trastuzumab, and docetaxel or paclitaxel; other multiple other recommended combinations include HER2-targeted therapy with or without cytotoxic agents.

The stakeholders discussed how patient factors affect their decision-making in the selection and sequencing of therapies for HER2-positive breast cancer. Clinicians generally use the CLEOPATRA regimen (pertuzumab combined with trastuzumab and docetaxel) in the first-line setting. Hamilton said that for most patients without CNS metastasis, she uses T-DM1 in the second-line setting. For those with CNS metastasis, she usually uses tucatinib plus capecitabine followed by trastuzumab deruxtecan if the patients have normal liver function tests and low to moderate disease burden, and uses trastuzumab deruxtecan if the patients have a large disease burden, including pulmonary symptoms. She noted the difficulty of choosing between the tucatinib regimen and trastuzumab deruxtecan for those with CNS metastasis. “I definitely am very impressed with the duration of response and the response rate with trastuzumab deruxtecan, but I also temper that with knowing that they had a median of 6 prior lines, so they were really a more heavily pretreated patient population than the tucatinib patients,” she said.

Tan said that she generally prefers to give T-DM1 in the second-line setting and has just begun to incorporate trastuzumab deruxtecan as a third-line treatment in her practice. For patients with brain metastases, she previously used a tyrosine kinase inhibitor such as lapatinib; however, with the compelling tucatinib data, she now prefers a trastuzumabcapecitabine-tucatinib regimen for this patient population. She added that the recent approval of tucatinib introduces the question of whether to obtain an MRI of the brain in patients who are asymptomatic. “With the availability of [tucatinib], I am now thinking that if I can get it approved, it might be worthwhile to screen and get that MRI of the brain at the point they’re progressing…to then help me decide [whether] to use the tucatinib in that setting,” said Tan. Schleicher added that clinicians need to communicate to payors about the importance of brain MRI in asymptomatic patients as it relates to selection of systemic therapy. “Imaging is really part of the utilization management strategy, and brain MRI in the asymptomatic breast cancer patient is one of the targets,” said Schleicher. “We might have trouble doing that routinely depending on how much of our practice is in that space.”

Denduluri said that she generally prefers T-DM1 in the second-line setting and may also consider this therapy for patients with an isolated brain metastasis, although she would discuss treatment options with the patient and consider the trastuzumab, capecitabine, and tucatinib regimen as well. For patients with several brain metastases, she would consider the trastuzumab, capecitabine, and tucatinib regimen instead of subjecting them to whole-brain radiation. Although she said that use of trastuzumab deruxtecan in the third-line setting is “compelling,” the transition from T-DM1 in terms of tolerability can come as a “shock” to many patients in her experience. “I would probably use the tucatinib, cape[citabine] and tucatinib independent of brain mets if they progress on T-DM1 before I would DS-8201, knowing that DS-8201 is so active in a heavily pretreated population,” she said.

At the end of the interchange, the stakeholders concluded that new ADCs, particularly trastuzumab deruxtecan and SYD985, could address unmet needs in HER2-positive breast cancer, such as HER2-low expressing disease and CNS metastases. They identified improvement in education about the drug-associated toxicities and further studies about potential roles for ADCs in other settings, such as the adjuvant setting, will be key steps moving forward. 

1. SEER cancer stat facts: female breast cancer. National Cancer Institute. Bethesda, MD. March 17, 2020. Accessed July 10, 2020. https://seer.cancer.gov/statfacts/html/breast.html

2. Breast cancer facts & figures 2019-2020. American Cancer Society. Accessed July 10, 2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancerfacts-and-figures-2019-2020.pdf

3. Schramm A, De Gregorio N, Widschwendter P, Fink V, Huober J. Targeted therapies in HER2-positive breast cancer - a systematic review. 

. 2015;10(3):173–178. doi:10.1159/000431029

4. Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline focused update. 

. 2018;36(20):2105-2122. doi:10.1200/JCO.2018.77.8738

5. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. 

. 2020;38(17):1951-1962. doi:10.1200/JCO.19.02488

6. Pestalozzi BC, Holmes E, de Azambuja E, et al. CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01). 

. 2013;14(3):244-248. doi:10.1016/S1470-2045(13)70017-2

7. Meric-Bernstam F, Johnson AM, Dumbrava EEI, et al. Advances in HER2-targeted therapy: novel agents and opportunities beyond breast and gastric cancer. 

. 2019;25(7):2033-2041. doi:10.1158/1078-0432.CCR-18-2275

8. Tukysa. Prescribing information. Seattle Genetics; 2020. Accessed July 16, 2020. https://seagendocs.com/TUKYSA_Full_Ltr_Master.pdf

9. 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. Published correction appears in 

10. Saura C, Thistlethwaite F, Banerji U, et al. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. 

. 2018;36(supp 15):1014-1014. doi:10.1200/JCO.2018.36.15_suppl.1014

11. Modi S, Park H, Murthy RK, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. 

. 2020;38(17):1887-1896. doi:10.1200/JCO.19.02318

12. Jerusalem G, Park YH, Yamashita T, et al. CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Presented at: 2020 ESMO breast cancer virtual meeting; May 23–24, 2020. Abstract 138O.

13. Rinnerthaler G, Gampenrieder SP, Greil R. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer. Int J Mol Sci. 2019;20(5):1115. Published March 5, 2019. doi:10.3390/ijms20051115 Kadclya. Prescribing information. Genetech; 2019. Accessed July 16, 2020. https://www.gene.com/download/pdf/kadcyla_prescribing.pdf

15. Kovtun YV, Audette CA, Ye Y, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. 

. 2006;66(6):3214-3221. doi:10.1158/0008-5472.CAN-05-3973

16. Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. 

. 2006;66(8):4426–4433. doi:10.1158/0008-5472.CAN-05-448

17. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. 

. 2008;68(22):9280-9290. doi:10.1158/0008-5472.CAN-08-1776

18. NCCN. Breast cancer. Version 5.2020. Published July 15, 2020. Accessed July 20, 2020. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

19. Verma S, Miles D, Gianni L. Trastuzumab emtansine for HER2-positive advanced breast cancer. 

. 2012;367:1783-1791. doi:10.1056/NEJMoa1209124

20. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. 

. 2019;380(7):617. doi:10.1056/NEJMoa1814017

21. Perez EA, Hurvitz SA, Amler LC, et al. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. 

22. Enhertu. Prescribing information. Daiichi Sankyo; 2019. Accessed July 18, 2020. https://dsi.com/prescribing-information-portlet/getPIContent?productName= Enhertu&inline=true

23. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A novel HER2-Targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. 

. 2016;22(20):5097–5108. doi:10.1158/1078-0432.CCR-15-2822

24. Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. 

. 2016;107(7):1039–1046. doi:10.1111/cas.12966

25. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. 

. 2019;20(6):816-826. doi:10.1016/S1470-2045(19)30097-X. Published correction appears in 

l. 2019;(6):e293. doi:10.1016/S1470-2045(19)30292-X

26. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610–621. doi:10.1056/NEJMoa1914510

27. Powell CA, Camidge DR, Gemma A, et al. Characterization, monitoring, and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload. Poster presented at San Antonio Breast Cancer Symposium; December 4–8, 2018; Poster #P6-17-06.

28. ADC Review. SYD985 ([vic-] trastuzumab duocarmazine) drug description. Accessed July 13, 2020. https://www.adcreview.com/syd985-drug-description/

29. Elgersma RC, Coumans RGE, Huijbregts T. Design, synthesis, and evaluation of linker-duocarmycin payloads: toward selection of HER2-targeting antibody-drug conjugate SYD985. 

. 2015;12(6):1813-35. doi:10.1021/mp500781a

30. Menderes G, Bonazzoli E, Bellone S, et al. SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/Neu expression. 

. 2017;23(19):5836-5845. doi:10.1158/1078-0432.CCR-16-2862

31. SYD985 vs. physician’s choice in participants with HER2-positive locally advanced or metastatic breast cancer (TULIP). Clinicaltrials.gov. Updated April 2, 2020. Accessed July 20, 2020. https://clinicaltrials.gov/ct2/show/NCT03262935

32. Yurkovetskiy A, Gumerov D, Ter-Ovanesyan E, et al. Non-clinical pharmacokinetics of XMT-1522, a HER2 targeting auristatin-based antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; April 1-5, 2017; Washington, DC. Philadelphia (PA):AACR; Cancer Res. 2017;77(supple 13):abstract nr 48. doi:10.1158/1538-7445.AM2017-48

33. Hamilton EP, Barve MA, Bardia A, et al. Phase 1 dose escalation of XMT-1522, a novel HER2-targetingantibody-drug conjugate (ADC), in patients (pts) with HER2-expressing breast, lung and gastric tumors. 

. 2018;36(suppl 15):2546-2546. doi:10.1200/JCO.2018.36.15_suppl.2546

34. ARX788 HER2 ADC—oncology. Fact Sheet. Ambrx. Accessed July 13, 2020 ambrx. com/pipeline/arx788-aher2-adc-oncology

35. A dose-escalation study of ARX788, IV administered in subjects with advanced cancers with HER2 expression. Updated June 4, 2020. Accessed July 20, 2020. https://clinicaltrials.gov/ct2/show/NCT03255070?term=NCT03255070&draw=2&rank=1#studydesc

Articles

Novel antibody-drug conjugates introduce promising options for the management of patients with HER2-positive breast cancer; however, management of drug-related toxicities and optimal sequencing of HER2-targeted therapies remains an ongoing challenge.

Antibody-Drug Conjugates in HER2+ Breast Cancer | Supplements and Featured Publications

Dr. O’Shaughnessy on the Utility of Tucatinib in the HER2+ Breast Cancer Brain Metastases

Dr. Hamilton on the Efficacy of Trastuzumab Deruxtecan in HER2-Low Breast Cancer

Antibody-Drug Conjugates in HER2-Positive Breast Cancer