It is incredible to reflect upon the scientific advances in the treatment of HER2-positive breast cancer over the past 23 years. Once considered the worst subtype of breast cancer, HER2-positive disease is now associated with the best long-term outcomes in this age of targeted treatments. With a total of eight U.S. Food and Drug Administration (FDA)-approved HER2-directed therapies for advanced disease, four in just the past ~18 months, clinicians and patients now have a number of tools available from which to choose. Though level 1 evidence clearly dictates the current gold standard in the first- and second-line settings (taxane/trastuzumab/pertuzumab and ado-trastuzumab emtansine, respectively), we now have multiple options available after the second line, with no data to guide optimal sequencing.
Clinicians are tasked to select among these treatments, balancing the therapeutic index of a given regimen against each patient’s unique clinical situation, taking into account location of metastases, disease burden, prior therapies, comorbidities, and personal goals. Though clinicians undoubtedly cheer with the approval of each new agent—as this is great news for our patients—celebration almost certainly comes with a bit of confusion, if not dread, as one begins to wonder where to fit the new therapy in the complex algorithm of already-approved regimens.
Sara A. Hurvitz, MD, FACP
Shiliang Zhang, MD
This is the complex clinical backdrop leading up to the approval of the most recent HER2-targeted agent on December 16, 2020. The FDA approval of margetuximab-cmkb in combination with chemotherapy for third-line therapy in metastatic HER2-positive breast cancer was based on data from the phase III SOPHIA trial, reviewed in this issue of The ASCO Post. In this study, a modest, yet statistically significant, improvement in median progression-free-survival was observed when comparing margetuximab plus chemotherapy with trastuzumab plus chemotherapy (5.8 months vs 4.9 months, hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.52–0.90, P = .005), thus meeting its prespecified endpoint.1
The Science Behind the Novel Molecule
The rationale supporting the development of margetuximab and the novelty of this agent are notable and worthwhile to consider. Preclinical data and retrospective analyses of clinical trials have indicated that benefit from the original HER2-targeted monoclonal antibody, trastuzumab, may be stronger in patients whose immune effector cells (natural killer and dendritic cells) are better able to tightly bind the Fc (tail) portion of antibodies at their Fc receptors.2 The binding affinity for activating Fc receptors is determined primarily by genetic polymorphisms in the gene for CD16A, such that patients carrying an F allele have weaker binding of their immune effector cells to antibodies and seem to be less able to generate an antibody-dependent cellular cytotoxic response. Margetuximab is a novel anti-HER2 IgG1 monoclonal antibody similar to trastuzumab, but it has an engineered Fc portion to increase affinity for the activating Fcγ receptor (CD16A) and to decrease affinity for the inhibitory Fcγ receptor (CD32B), thereby increasing antibody-dependent cellular cytotoxic response.
The SOPHIA study nicely validates the science behind this molecule. Though the improvement in progression-free survival in the intent-to-treat population was small, exploratory subgroup analysis confirms that the progression-free survival benefits of margetuximab are restricted to carriers of the CD16A-158F allele (6.9 vs 5.1 months, HR = 0.68, P = .005). Of note, the proportion of patients confirmed to be F carriers was not trivial, comprising 86% of those enrolled in this trial. Conversely, patients with a “VV” genotype did not appear to benefit from margetuximab (HR = 1.78, P = .110). Similarly, although overall survival was no different in the treatment arms in the intent-to-treat population, a prespecified analysis of survival in F carriers indicated a promising, but not statistically significant, 4.3-month improvement with margetuximab (23.7 vs 19.4 months, HR = 0.79, P = .087). Of note, margetuximab was well tolerated, with toxicity comparable to that of trastuzumab, with the exception of infusion-related reactions, which occurred more frequently with margetuximab (13.3% vs 3.4%).
Once considered the worst subtype of breast cancer, HER2-positive disease is now associated with the best long-term outcomes in this age of targeted treatments.— Sara A. Hurvitz, MD, FACP, and Shiliang Zhang, MD
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Abundance of Riches
The FDA’s approval of margetuximab marks the fourth novel drug for HER2-positive advanced breast cancers approved in the past 2 years. As previously mentioned, the recent approvals of fam-trastuzumab deruxtecan-nxki (T-DXd; December 20, 2019), neratinib with capecitabine (February 25, 2020), and tucatinib in combination with trastuzumab and chemotherapy (April 17, 2020), on top of trastuzumab- and lapatinib-based therapies, have led to an abundance of options in the third-line setting and beyond.
Though no specific guidelines are in place for the sequencing of third-line therapies, T-DXd is a front-runner in light of phenomenal efficacy data from the single-arm, 184-patient phase II DESTINY-Breast01 trial. A remarkable objective response rate of more than 60% and a median progression-free survival in excess of 19 months in an extremely heavily pretreated population (median of six prior lines of therapy) led to its accelerated approval.3 However, T-DXd is associated with significant toxicities, including life-threatening interstitial lung disease (2.7% grade 5) in addition to less severe but still bothersome nausea, alopecia, cytopenias, and fatigue. Moreover, a phase III trial comparing T-DXd with the standard of care has not yet been reported.
Another recently approved regimen worth noting is tucatinib in combination with trastuzumab and capecitabine. The phase III placebo-controlled HER2CLIMB trial demonstrated significant improvements in progression-free survival (7.8 months vs 5.6 months, P < .001) and overall survival (21.9 months vs 17.4 months, P = .005) in patients with fairly heavily pretreated disease.4 Its activity in those with active or stable brain metastases is both unique and impressive. Of note, these data led to its approval in the second-line setting and beyond, despite the fact that HER2CLIMB enrolled patients primarily in the third-line setting and beyond.
The safety of this combination regimen is reasonable, with rates of grade ≥ 3 diarrhea of approximately 13%, 4% higher than in the control arm. Though no direct comparison of treatments exists, the severity of diarrhea appears favorable compared with its tyrosine kinase inhibitor predecessor, neratinib, which was associated with double the amount of grade ≥ 3 diarrhea compared with its control arm.
A Nuanced Choice in Clinical Practice
In the shadow of such impressive outcomes from the DESTINY-Breast01 and the HER2CLIMB trials, the results from the SOPHIA trial are unlikely to establish margetuximab as the preferred third-line agent for the average patient with HER2-positive advanced breast cancer. Perhaps if these same results were reported 2 years earlier, prior to the approvals of T-DXd or tucatinib in combination with trastuzumab and capecitabine, margetuximab, with its favorable therapeutic index, may have been a favored third-line therapy. Instead, in this age of multiple FDA-approved third-line therapies, the decision to reach for margetuximab may be more nuanced and may depend on the accessibility and timeliness of testing for CD16A polymorphisms.
The decision to reach for margetuximab may be more nuanced and may depend on the accessibility and timeliness of testing for CD16A polymorphisms.— Sara A. Hurvitz, MD, FACP, and Shiliang Zhang, MD
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In carriers of the CD16A-158F allele, the use of margetuximab may be justified, given its favorable side-effect profile and its more pronounced progression-free survival and overall survival benefits in this particular subset of patients. For patients with the CD16A-158VV genotype, where no benefit with this agent has been proven, there is far less impetus to choose a new and costly agent, especially as the availability of relatively affordable trastuzumab biosimilars continues to increase.
As we gain more data on the efficacy of margetuximab with further reports from the SOPHIA trial and emerging data testing it in a less pretreated population, margetuximab may find new roles in clinical practice. The phase II MARGOT trial is currently comparing margetuximab in combination with pertuzumab and paclitaxel with trastuzumab in combination with pertuzumab and paclitaxel in the neoadjuvant setting for patients with stage II to III HER2-positive breast cancer. The study is estimated to complete data collection for its primary outcome of pathologic complete response in July 2024. Margetuximab in the neoadjuvant setting may elicit better immune response and demonstrate more significant improvements, especially when paired with pertuzumab, which has been shown to increase antibody-dependent cellular cytotoxic response in combination with trastuzumab and may thus demonstrate the same with margetuximab.5
As novel therapies continue down the pipeline and as further data emerge for already FDA-approved therapies in new settings, the possibility for a cure—or at least prolonged durable remissions—for those with HER2-positive metastatic breast cancer may become a more common reality. Though the impressive science and positive trial results supporting the approval of margetuximab may be overshadowed by an overabundance of options, the hope is that future trials will help identify optimal ways to use and sequence this agent among the others.
Dr. Hurvitz is the Director of the Breast Cancer Clinical Trials Program in the Division of Hematology-Oncology at the David Geffen School of Medicine at UCLA. Dr. Zhang works in the Division of Hematology-Oncology in the David Geffen School of Medicine at UCLA.
Editor’s Note: The four-letter suffix “cmkb” after the core name “margetuximab” in the title and first mention here is in accordance with the FDA’s guidance on nonproprietary naming of biologic products. The suffix itself is devoid of meaning and exists to distinguish between biologic originators, related biologics, and biosimilars. The intent of this naming convention is to increase pharmacovigilance and prevent prescriptions of related biologics and biosimilars where interchangeability has not been proven.
DISCLOSURE: Dr. Hurvitz has an immediate family member who holds stock or other ownership interests in Ideal Implant and ROMTech; has received institutional research funding from Ambrx, Amgen, Arvinas, Bayer, BioMarin, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Immunomedics, Lilly, MacroGenics, Merrimack, Novartis, OBI Pharma, Pfizer, Phoenix Molecular Designs, Pieris, Puma Biotechnology, Radius, Samumed, Sanofi, Seattle Genetics, and Zymeworks; has been reimbursed for travel, accommodations, or other expenses by Lilly; and has stock options from NKMax. Dr. Zhang reported no conflicts of interest.
REFERENCES
1. Rugo HS, Im SA, Cardoso F, et al: Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: A phase 3 randomized clinical trial. JAMA Oncol. January 22, 2021 (early release online).
2. Nordstrom JL, Gorlatov S, Zhang 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 13:R123, 2011.
3. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.
4. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-609, 2020.
5. Diessner J, Bruttel V, Becker K, et al: Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells. Am J Cancer Res 3:211-220, 2013.
