Metastatic HER2+ Breast Cancer Treatment Must Move to Personalized Approach

The optimal sequence of therapies for patients with metastatic HER2-positive breast cancer must be an individualized one, and should be dependent on the presence and/or level of central nervous system (CNS) disease, according to Ian E. Krop, MD, PhD, in a presentation during the 19th Annual International Congress on the Future of Breast Cancer® East, a virtual program by Physician Education Resource® (PER®).¹

“We have 3 approved drugs [in the third-line and beyond setting], and a fourth that may be approved soon,” explained Krop, an associate professor of medicine with Harvard Medical School; associate chief, Division of Breast Oncology with Susan F. Smith Center for Women's Cancers; and a medical oncologist and clinical research director with the Breast Oncology Center at Dana-Farber Cancer Institute, during the presentation. “How do we sequence these in clinical practice? I don’t think we can use a once-size-fits-all approach like we used to previously; we have to tailor this to the particular patient population.”

The 4 agents garnering excitement in the HER2-positive breast cancer space include tucatinib (Tukysa), neratinib (Nerlynx), fam-trastuzumab deruxtecan-nxki (Enhertu), and the investigational agent margetuximab. Taking the clinical data from the HER2CLIMB, NALA, DESTINY-Breast01, and SOPHIA trials, respectively, into consideration, Krop proposed appropriate following sequences for patients with and without CNS metastases.

Frontline treatment should begin with trastuzumab (Herceptin) and pertuzumab (Perjeta) plus taxane chemotherapy, followed by ado-trastuzumab emtansine (T-DM1; Kadcyla) in the second-line setting. For patients with no or minor CNS disease, Krop recommended third-line trastuzumab deruxtecan, fourth-line tucatinib combined with trastuzumab/capecitabine (Xeloda), and fifth-line trastuzumab/chemotherapy or, if approved, margetuximab/chemotherapy for patients with low affinity FcR genotype.

In patients with significant CNS disease, optimal third-, fourth-, and fifth-line treatments would be tucatinib/trastuzumab plus chemotherapy, trastuzumab deruxtecan, and trastuzumab/chemotherapy or margetuximab/chemotherapy for patients with low affinity FcR genotype.

The recent additions add variety to the third-line and beyond setting in HER2-positive breast, which prior to December 2019 had limited therapeutic options beyond trastuzumab plus chemotherapy.

Tucatinib

The potent and selective small molecule HER2 TKI tucatinib was approved by the FDA in April 2020 for use in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti-HER2-based regimen in the metastatic setting.

The approval is based on data from the phase II HER2CLIMB trial, which showed that the tucatinib regimen reduced the risk of death by 34% compared with trastuzumab and capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.^2,3

In the international, double-blind, placebo-controlled study, 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab, and T-DM1were randomized 2:1 to receive trastuzumab and capecitabine combined with either tucatinib (n = 410) or placebo (n = 202). Patients were permitted to have previously treated stable brain metastases, untreated brain metastases not requiring immediate local therapy, or previously treated progressing brain metastases not needing immediate local therapy.

“One of the unique features of this trial was that it allowed patients not only with stable brain metastases, but those who had untreated or progressive brain metastases, leveraging the activity of this drug in the brain,” said Krop.

Results showed that the median overall survival (OS) was 21.9 months (95% CI,18.3-31.0) with the tucatinib triplet compared with 17.4 months (95% CI, 13.6-19.9) with trastuzumab and capecitabine alone (HR, 0.66; 95% CI, 0.50-0.88; P = .0048). The 1- and 2-year OS rates were 76% versus 62% and 45% versus 27% in the tucatinib and control arms, respectively, and the OS benefit was upheld across all prespecified subgroups.

The addition of the small molecule TKI tucatinib also led to a 46% reduction in the risk of disease progression or death compared with trastuzumab and capecitabine alone, with a median progression-free survival (PFS) of 7.8 months (95% CI, 7.5-9.6) versus 5.6 months (95% CI, 4.2-7.1), respectively (HR, 0.54; 95% CI, 0.42-0.71; P <.00001). The 6-month and 1-year PFS rates were 63% versus 46% and 33% versus 12%, respectively.

Notably, the tucatinib regimen reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69; P <.00001) in patients with brain metastases at baseline. The median progression-free survival (PFS) in this subpopulation was 7.6 months with tucatinib versus 5.4 months in the control arm. The 1-year PFS rates were 25% versus 0%, respectively.

Subgroup analysis also indicated an OS benefit with tucatinib in those with active brain metastases, with a median OS of 20.7 months and 11.6 months, respectively (HR, 0.49, 95% CI, 0.30-0.80; P = .004). The 1-year OS rates were 71.7% versus 41.1%, respectively. Investigators also measured intracranial response rate (ORR-IC) in patients with active brain metastases and measurable intracranial lesions at baseline. With tucatinib, the complete response (CR) rate was 5.5% versus 5.0% with trastuzumab/capecitabine; the partial response (PR) rate was 41.8% versus 15.0%, respectively.

Moreover, the stable disease (SD) rate was 43.6% versus 80.0% with the addition of tucatinib versus trastuzumab/capecitabine, respectively. The duration of intracranial response was also longer with tucatinib, at 6.8 months versus 3.0 months, respectively.

The PFS benefit was also upheld in patients with isolated CNS progression who continued with assigned study treatment. The median time from randomization to second progression or death was 15.9 months and 9.7 months for the addition of tucatinib and trastuzumab/capecitabine alone, respectively (HR, 0.292; 95% CI, 0.11-0.77; P = .009). The median time from first CNS progression to second progression or death was 7.6 months with tucatinib and 3.1 months with trastuzumab/capecitabine (HR, 0.332; 95% CI, 0.13-0.85; P = .02).

The most common adverse effects (AEs) occurring in 20% or more of patients on tucatinib, included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, vomiting, stomatitis, decreased appetite, headache, aspartate transaminase, and alanine transaminase. Additionally, tucatinib’s HER2 selectivity leads to decreased potential for EGFR-related toxicities compared with dual TKIs, Krop explained.

Neratinib

Neratinib is a low–molecular weight, irreversible, pan-HER TKI against ErbB1/2/4. While potent, its most significant toxicity is grade 3/4 diarrhea.⁴

In February 2020, the FDA approved a supplemental new drug application for neratinib in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more prior anti—HER2-based regimens in the metastatic setting.

The approval was based on findings from the international, open-label, phase 3 NALA trial, which enrolled 621 patients with metastatic breast cancer and centrally confirmed HER2-positive disease.

Results showed that the combination reduced the risk of disease progression or death by 24% compared with lapatinib (Tykerb) plus capecitabine (HR, 0.76; 95% CI, 0.63-0.93; log-rank P value = .0059).⁵ Moreover, the median OS was 24.0 months for neratinib plus capecitabine compared with 22.2 months with lapatinib/capecitabine (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The OS benefit was upheld across most prespecified subgroups, except for patients of North America (HR, 1.06; 95% CI, 0.71-1.58; P = .313).

The time to intervention for CNS metastases was also improved with neratinib, with an overall cumulative incidence of 22.8% versus 29.2% with lapatinib/capecitabine (P = .043).

The phase 2 TBCRC 022 trial evaluated neratinib plus capecitabine in 49 patients with HER2-positive breast cancer and brain metastases. In a cohort of patients who did not receive prior lapatinib (n = 37), the CNS ORR was 49% and the median PFS was 5.5 months.⁶

Regarding the safety profile in the NALA trial, as previously mentioned, diarrhea was the most frequent treatment-emergent AE for patients on neratinib/capecitabine (all-grade, 83%; grade 3/4, 24%). In the lapatinib/capecitabine arm, diarrhea was all-grade in 66% and grade 3/4 in 13% of patients.

“It’s important to note that the rate of patients having to discontinue therapy for treatment-emergent adverse events was pretty low, only about 11%, and this is consistent with our usual observation in the clinic, which is that if you get patients through the first couple cycles of neratinib, it is usually a manageable regimen," Krop said.

Due to its toxicity profile, and that its efficacy doesn’t appear to be as pronounced as tucatinib—although Krop stressed that the 2 agents have not been compared head to head—he proposed the use of third-line tucatinib versus neratinib in this patient population.

“What I would really like to know is whether neratinib works after patients progress after tucatinib-based treatment,” Krop said. “We don’t have that data yet, but I think it is something definitely worth exploring.”

Trastuzumab Deruxtecan

Trastuzumab deruxtecan is a novel antibody-drug conjugate (ADC) designed to deliver an optimal antitumor effect. It is composed of 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, a topoisomerase I inhibitor payload with an exatecan derivative, and a tetrapeptide-based cleavable linker.

The agent is also known to have a high potency of payload, a high drug to antibody ratio, a payload with short systemic half-life, a stable linker-payload, tumor-selective cleavable linker, and a membrane-permeable payload—the last of which can attack neighboring cells.

“This bystander effect, as we call it, potentially allows this drug to kill cancer cells that are heterogenous for HER2 expression, and hopefully that would mean it would have more uniform activity than drugs that are only active in highly HER2-positive homogenous cancers,” Krop explained.

Initial results from the phase 2 DESTINY-Breast01 trial led to the 2019 regulatory approval of the drug for the treatment of patients with metastatic HER2-positive breast cancer who have received at least 2 prior anti–HER2-based regimens in the metastatic setting.

In the open-label, international, multicenter phase 2 registration study, investigators enrolled 184 patients with HER2-positive breast cancer who were heavily pretreated, including with T-DM1 and other HER2-targeted treatments.

Data showed an objective response rate (ORR), which was the primary end point, of 60.9%, along with a 6.0% CR rate, 54.9% PR rate, and a 36.4% SD rate. The disease control rate was 97.3%, and 76.1% of patients had a clinical benefit rate of 76.1%. The duration of response was 14.8 months.^7,8

Moreover, at a median follow-up of 11.1 months (range, 0.7-19.9), the median progression-free survival (PFS) of 16.4 months, and the median OS was not reached. In patients with stable brain metastases, the ORR was 58.3% and the median PFS was 18.1 months.

Krop pointed out that the ADC had clinical activity across all lines of therapy, with ORRs of 76.7%, 62.5%, 53.8%, 64.3%, and 55.3% in the second-, third-, fourth-, fifth-, and sixth-line and beyond settings.

Sites of progression were similar across all patients, as well as the CNS subgroup; 4 of 48 patients had progression in the CNS.

An AE of special interest in the study was interstitial lung disease (ILD), which occurred in 13.6% of patients (n = 25). The median time to investigator-reported onset was 193 days (range, 42-535 days), and 17 of 20 patients who had grade 2 or higher ILD received corticosteroids. Seven patients recovered, 2 were recovering, 12 had outcomes that were either unknown or not followed until resolution; 4 patients died. Of the 4 fatal cases from ILD, the onset was in the range of 63 to 148 days, 3 patients received steroids as part of their treatment, and death occurred 9 to 60 days after diagnosis.

For ILD management, Krop recommended physicians monitor for symptoms, and as soon as ILD is suspected, trastuzumab deruxtecan should be held and steroids should be initiated.

Margetuximab

Margetuximab, a novel HER2-positive antibody with Fc engineering that alters Fc receptor affinities, has the same affinity for HER2 as trastuzumab. The agent was designed to increase IgG1 Fc affinity for the activating Fc gamma receptor CD16A and decrease affinity for the inhibitory Fc gamma receptor CD32B; its Fc engineering enhances both innate and adaptive immunity. Early data demonstrated that margetuximab would be most superior to trastuzumab in patients with low affinity Fc receptor (FF or FV).⁹

The agent most recently was evaluated in the phase 3 SOPHIA trial. Data from a prespecified second interim OS analysis showed that at a median follow-up of 15.6 months, the median OS in the intent-to-treat (ITT) population was 21.6 months (95% CI, 18.86-24.05) with margetuximab plus chemotherapy compared with 19.8 months (95% CI, 17.54-22.28) with trastuzumab plus chemotherapy (HR, 0.89; 95% CI, 0.69-1.13; P = .326).¹⁰

The investigator-assessed PFS showed a 29% reduction in risk of disease progression or death. The median PFS was 5.7 months (95% CI, 5.22-6.97) with margetuximab arm versus 4.4 months (95% CI, 4.14-5.45) with trastuzumab (HR, 0.71; 95% CI, 0.58-0.86; P = .0006).

In a prespecified exploratory OS analysis in patients who were CD16A-185 F allele carriers, the median OS was 23.7 months in the margetuximab arm versus 19.4 months in the trastuzumab arm (HR, 0.79; 95% CI, 0.61-1.04; P = .087).

The safety profile was comparable to that trastuzumab/chemotherapy.

In December 2019, a biologics license application was submitted to the FDA for margetuximab for use in combination with chemotherapy as a treatment for patients with metastatic HER2-positive breast cancer.

“The bottom line is, all of us in clinic still see patients with HER2-positive metastatic breast cancer, and we need to figure out optimal ways of managing it,” Krop concluded. “Fortunately, we do have a number of new therapies that have just been approved, so it is a worth a discussion of how we can integrate these new treatments into this paradigm."

References

1. Krop I. Prioritizing therapeutic options for HER2+ advanced breast cancer. Presented at: 19th Annual International Congress on the Future of Breast Cancer East; July 17-18; 2020; Virtual.
2. Murthy R, Loi S, Okines A, et al. Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-01.
3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609
4. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8):1301-1307. doi:10.1200/JCO.2009.25.8707
5. Saura C, Oliveira M, Feng Y-H, 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; abstr 1002) doi: 10.1200/JCO.2019.37.15_suppl.1002
6. Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2–positive breast cancer and brain metastases. J Clin Oncol. 2019;37(13):1081-1089. doi: 10.1200/JCO.18.01511
7. 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). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract GS1-03.
8. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Eng J Med. 2020;382:610-621. doi:10.1056/NEJMoa1914510
9. Nordstrom JL, Gorlatov S, Xhang W, et al. Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties. Breast Cancer Res. 2011;13(6):R123. doi:10.1186/bcr3069
10. Rugo HS, Im S-A, Cardoso F, et al. 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. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-02.