Meeting NewsPerspective

Margetuximab improves PFS in HER2-positive metastatic breast cancer

Hope S. Rugo, MD
Hope S. Rugo

CHICAGO — The combination of margetuximab and chemotherapy prolonged PFS compared with trastuzumab-chemotherapy among patients with HER2-metastatic breast cancer progressing after treatment with trastuzumab, pertuzumab and chemotherapy, according to results of the phase 3 SOPHIA trial presented at ASCO Annual Meeting.

First-line treatment for HER2-metastatic breast cancer typically consists of trastuzumab (Herceptin, Genentech) plus pertuzumab (Perjeta, Genentech), followed by ado-trastuzumab emtansine (Kadcyla, Genentech).

“However, after [these] therapies, there is no recognized standard of care and subsequent therapies are poorly defined,” Hope S. Rugo, MD, clinical professor in the department of medicine (hematology/oncology) and director of the Breast Oncology Clinical Trials Program at University of California, San Francisco, said during her presentation. “In general, we use sequential chemotherapy with either trastuzumab or lapatinib [Tykerb, Novartis], and continued anti-HER2 therapy is generally preferred in combination with chemotherapy.”

Margetuximab (MacroGenics) is a novel Fc-engineered HER2-targeted antibody designed to activate immune responses, Rugo said. The Fc portion of the agent is engineered to have enhanced affinity for binding to both the low-affinity F and high-affinity V alleles for activating Fc receptor CD16A, as well as decreased affinity for the inhibitory Fc receptor CD32B.

“Controversy exists about the role of CD16A polymorphisms on the efficacy of trastuzumab,” Rugo said. “Two retrospective studies of HER2-positive metastatic breast cancer and early breast cancer suggest that those who carry the lower-affinity CD16A F allele have a lower PFS and overall response with trastuzumab compared with those homozygous for the higher-affinity V allele. In contrast, two other retrospective studies showed no association between Fc receptor genotypes and outcome with adjuvant trastuzumab in early breast cancer.

“Our hypothesis was that margetuximab would show a greater benefit in patients carrying the lower-affinity CD16A F allele, due to the increased affinity of margetuximab for this allele over trastuzumab,” she added.

This marks the first prospective analysis of the impact of Fc receptor genotype on the efficacy of an anti-HER2 antibody.

CD16A genotypes include VV, which occurs in about 15% of the population; FV, seen in about 40% to 45%; and FF, which occurs in about 40%.

A prior phase 1 trial of margetuximab monotherapy showed four confirmed responses in 24 evaluable patients with metastatic breast cancer. Three patients have remained on treatment with margetuximab at 4 to 6 years. Also, serial analyses of peripheral blood mononuclear cells showed 94% of patients had enhanced HER2-specific T-cell responses and enhanced antibody responses after margetuximab monotherapy.

Based on those data, Rugo and colleagues compared margetuximab with trastuzumab in the randomized, open-label SOPHIA trial, which included 536 patients with HER2-positive metastatic breast cancer who previously received pertuzumab and one to three lines of prior therapy.

Researchers randomly assigned patients — stratified according to two or fewer vs. more than two metastatic sites, two or fewer vs. more than two prior lines of treatment, and chemotherapy choice — 1:1 to receive 15 mg/kg IV margetuximab every 3 weeks with chemotherapy (n = 266; median age, 55 years; 100% women) or 6 mg/kg IV trastuzumab every 3 weeks, following an 8-mg/kg loading dose, with chemotherapy (n = 270; median age, 56 years; 98.9% women). Chemotherapy options included standard-dose capecitabine, eribulin (Halaven, Eisai), gemcitabine or vinorelbine.

All patients previously received trastuzumab and pertuzumab, and most (margetuximab group, 91%; trastuzumab group, 92%) had received ado-trastuzumab emtansine. About one-third of patients in each group had received more than two prior lines of therapy for metastatic disease.

Central blinded PFS and OS — assessed sequentially using the stratified log-rank test — served as the study’s primary endpoints. Objective response rate served as a secondary endpoint, and evaluation of the effect of the Fc receptor alleles on the efficacy of margetuximab served as a preplanned exploratory secondary endpoint.

Researchers conducted the PFS analysis in the intent-to-treat population after 265 PFS events.

Results showed median PFS of 5.8 months (95% CI, 5.52-6.97) in the margetuximab group and 4.9 months (95% CI, 4.17-5.59) in the trastuzumab group. Thus, margetuximab appeared associated with a 24% reduction in risk for progression (HR = 0.76; 95% CI, 0.59-0.98).

Margetuximab also conferred a 30% risk reduction for disease progression by investigator assessment (median, 5.6 months vs. 4.2 months; HR = 0.7; 95% CI, 0.56-0.87).

Subgroup analyses showed margetuximab benefit persisted regardless of chemotherapy received, number of metastatic sites, hormone receptor status and age.

The benefit of margetuximab appeared more pronounced in 437 low-affinity CD16A F allele carriers, including FV or FF (median PFS, 6.9 months vs. 5.1 months; HR = 0.68; 95% CI, 0.52-0.9). Patients homozygous for the V allele did not appear to benefit (n = 69; median PFS, 4.8 months vs. 5.6 months; HR = 1.78; 95% CI, 0.87-3.62).

“This is the first prospective analysis of CD16A genotype as a predictor of efficacy from anti-HER2 therapy,” Rugo said.

Researchers conducted an interim OS analysis for the intent-to-treat population and CD16A F allele carriers after 158 deaths occurred.

In the intent-to-treat population, median OS was 18.9 months with margetuximab compared with 17.2 months with trastuzumab, which was not a significant difference (HR = 0.95; 95% CI, 0.69-1.31). Among patients carrying at least one F allele, median OS was 23.6 months with margetuximab vs. 16.9 months with trastuzumab (HR = 0.82; 95% CI, 0.58-1.17).

These data, with only 41% of the deaths needed for the final OS analysis, did not meet the stopping boundary. A second OS analysis will occur after 270 deaths, and final OS analysis is planned after 385 deaths.

ORR was 22.1% in the margetuximab group, with seven complete responses and 51 partial response, compared with 16% in the trastuzumab group, with four complete and 38 partial responses.

Clinical benefit rate — which also included stable disease for more than 6 months — was significantly higher in the margetuximab group (36.6% vs. 24.8%; P = .003).
group died of an adverse event.

Three percent of patients assigned margetuximab and 2.6% assigned trastuzumab discontinued treatment due to an adverse event.

The most common adverse events included fatigue (any grade: margetuximab, 39% vs. trastuzumab, 34.7%), nausea (any grade: 30.7% vs. 31.7%), neutropenia (any grade: 27.7% vs. 19.2%, grade 3, 19.3% vs. 11.3%), and diarrhea (any grade: 22.3% vs. 23.4%).

Adverse events of interest included any-grade infusion-related reaction in 12.9% of patients assigned margetuximab vs. 3.8% with trastuzumab, and any-grade left ventricular dysfunction in 2.3% of patients assigned margetuximab vs. 2.6% assigned trastuzumab.

The next milestone for this study will be a second interim OS analysis, expected later this year, Rugo said. – by Alexandra Todak

Reference:

Rugo HS, et al. Abstract 1000. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Rugo reports research funding to her institution from Daiichi Sankyo, Eisai, Eli Lilly, Genentech, Immunomedics, MacroGenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer and Seattle Genetics, and travel expenses from Amgen, Mylan, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Roche/Genentech and Sanofi. Please see the abstract for all other authors’ relevant financial disclosures.

Hope S. Rugo, MD
Hope S. Rugo

CHICAGO — The combination of margetuximab and chemotherapy prolonged PFS compared with trastuzumab-chemotherapy among patients with HER2-metastatic breast cancer progressing after treatment with trastuzumab, pertuzumab and chemotherapy, according to results of the phase 3 SOPHIA trial presented at ASCO Annual Meeting.

First-line treatment for HER2-metastatic breast cancer typically consists of trastuzumab (Herceptin, Genentech) plus pertuzumab (Perjeta, Genentech), followed by ado-trastuzumab emtansine (Kadcyla, Genentech).

“However, after [these] therapies, there is no recognized standard of care and subsequent therapies are poorly defined,” Hope S. Rugo, MD, clinical professor in the department of medicine (hematology/oncology) and director of the Breast Oncology Clinical Trials Program at University of California, San Francisco, said during her presentation. “In general, we use sequential chemotherapy with either trastuzumab or lapatinib [Tykerb, Novartis], and continued anti-HER2 therapy is generally preferred in combination with chemotherapy.”

Margetuximab (MacroGenics) is a novel Fc-engineered HER2-targeted antibody designed to activate immune responses, Rugo said. The Fc portion of the agent is engineered to have enhanced affinity for binding to both the low-affinity F and high-affinity V alleles for activating Fc receptor CD16A, as well as decreased affinity for the inhibitory Fc receptor CD32B.

“Controversy exists about the role of CD16A polymorphisms on the efficacy of trastuzumab,” Rugo said. “Two retrospective studies of HER2-positive metastatic breast cancer and early breast cancer suggest that those who carry the lower-affinity CD16A F allele have a lower PFS and overall response with trastuzumab compared with those homozygous for the higher-affinity V allele. In contrast, two other retrospective studies showed no association between Fc receptor genotypes and outcome with adjuvant trastuzumab in early breast cancer.

“Our hypothesis was that margetuximab would show a greater benefit in patients carrying the lower-affinity CD16A F allele, due to the increased affinity of margetuximab for this allele over trastuzumab,” she added.

This marks the first prospective analysis of the impact of Fc receptor genotype on the efficacy of an anti-HER2 antibody.

CD16A genotypes include VV, which occurs in about 15% of the population; FV, seen in about 40% to 45%; and FF, which occurs in about 40%.

A prior phase 1 trial of margetuximab monotherapy showed four confirmed responses in 24 evaluable patients with metastatic breast cancer. Three patients have remained on treatment with margetuximab at 4 to 6 years. Also, serial analyses of peripheral blood mononuclear cells showed 94% of patients had enhanced HER2-specific T-cell responses and enhanced antibody responses after margetuximab monotherapy.

PAGE BREAK

Based on those data, Rugo and colleagues compared margetuximab with trastuzumab in the randomized, open-label SOPHIA trial, which included 536 patients with HER2-positive metastatic breast cancer who previously received pertuzumab and one to three lines of prior therapy.

Researchers randomly assigned patients — stratified according to two or fewer vs. more than two metastatic sites, two or fewer vs. more than two prior lines of treatment, and chemotherapy choice — 1:1 to receive 15 mg/kg IV margetuximab every 3 weeks with chemotherapy (n = 266; median age, 55 years; 100% women) or 6 mg/kg IV trastuzumab every 3 weeks, following an 8-mg/kg loading dose, with chemotherapy (n = 270; median age, 56 years; 98.9% women). Chemotherapy options included standard-dose capecitabine, eribulin (Halaven, Eisai), gemcitabine or vinorelbine.

All patients previously received trastuzumab and pertuzumab, and most (margetuximab group, 91%; trastuzumab group, 92%) had received ado-trastuzumab emtansine. About one-third of patients in each group had received more than two prior lines of therapy for metastatic disease.

Central blinded PFS and OS — assessed sequentially using the stratified log-rank test — served as the study’s primary endpoints. Objective response rate served as a secondary endpoint, and evaluation of the effect of the Fc receptor alleles on the efficacy of margetuximab served as a preplanned exploratory secondary endpoint.

Researchers conducted the PFS analysis in the intent-to-treat population after 265 PFS events.

Results showed median PFS of 5.8 months (95% CI, 5.52-6.97) in the margetuximab group and 4.9 months (95% CI, 4.17-5.59) in the trastuzumab group. Thus, margetuximab appeared associated with a 24% reduction in risk for progression (HR = 0.76; 95% CI, 0.59-0.98).

Margetuximab also conferred a 30% risk reduction for disease progression by investigator assessment (median, 5.6 months vs. 4.2 months; HR = 0.7; 95% CI, 0.56-0.87).

Subgroup analyses showed margetuximab benefit persisted regardless of chemotherapy received, number of metastatic sites, hormone receptor status and age.

The benefit of margetuximab appeared more pronounced in 437 low-affinity CD16A F allele carriers, including FV or FF (median PFS, 6.9 months vs. 5.1 months; HR = 0.68; 95% CI, 0.52-0.9). Patients homozygous for the V allele did not appear to benefit (n = 69; median PFS, 4.8 months vs. 5.6 months; HR = 1.78; 95% CI, 0.87-3.62).

“This is the first prospective analysis of CD16A genotype as a predictor of efficacy from anti-HER2 therapy,” Rugo said.

Researchers conducted an interim OS analysis for the intent-to-treat population and CD16A F allele carriers after 158 deaths occurred.

PAGE BREAK

In the intent-to-treat population, median OS was 18.9 months with margetuximab compared with 17.2 months with trastuzumab, which was not a significant difference (HR = 0.95; 95% CI, 0.69-1.31). Among patients carrying at least one F allele, median OS was 23.6 months with margetuximab vs. 16.9 months with trastuzumab (HR = 0.82; 95% CI, 0.58-1.17).

These data, with only 41% of the deaths needed for the final OS analysis, did not meet the stopping boundary. A second OS analysis will occur after 270 deaths, and final OS analysis is planned after 385 deaths.

ORR was 22.1% in the margetuximab group, with seven complete responses and 51 partial response, compared with 16% in the trastuzumab group, with four complete and 38 partial responses.

Clinical benefit rate — which also included stable disease for more than 6 months — was significantly higher in the margetuximab group (36.6% vs. 24.8%; P = .003).
group died of an adverse event.

Three percent of patients assigned margetuximab and 2.6% assigned trastuzumab discontinued treatment due to an adverse event.

The most common adverse events included fatigue (any grade: margetuximab, 39% vs. trastuzumab, 34.7%), nausea (any grade: 30.7% vs. 31.7%), neutropenia (any grade: 27.7% vs. 19.2%, grade 3, 19.3% vs. 11.3%), and diarrhea (any grade: 22.3% vs. 23.4%).

Adverse events of interest included any-grade infusion-related reaction in 12.9% of patients assigned margetuximab vs. 3.8% with trastuzumab, and any-grade left ventricular dysfunction in 2.3% of patients assigned margetuximab vs. 2.6% assigned trastuzumab.

The next milestone for this study will be a second interim OS analysis, expected later this year, Rugo said. – by Alexandra Todak

Reference:

Rugo HS, et al. Abstract 1000. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Rugo reports research funding to her institution from Daiichi Sankyo, Eisai, Eli Lilly, Genentech, Immunomedics, MacroGenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer and Seattle Genetics, and travel expenses from Amgen, Mylan, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Roche/Genentech and Sanofi. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective

    Adam Brufsky
    Adam Brufsky
    Azadeh Nasrazadani
    Azadeh Nasrazadani

    HER2-positive breast cancer portends a more aggressive course than the higher-incident hormone receptor-positive, HER2-negative variety of disease. Although outcomes are poorer, HER2 has served as an effective target for drug development since the 1990s.

    Classically, the backbones of treatment have relied largely on trastuzumab, a humanized monoclonal antibody targeting the extracellular domain of HER2. Initial trials incorporating trastuzumab for patients with HER2-positive disease demonstrated a delay in time to progression when added to chemotherapy in the metastatic setting, which was met with great excitement. More recent advances have come through the CLEOPATRA and KATHERINE trials, which have better defined clinical practice patterns. 

    However, HER2-positive breast cancer frequently recurs — inevitably in the metastatic setting. Beyond combination treatment with trastuzumab and pertuzumab, followed by ado-trastuzumab emtansine, guidelines are lacking.

    The SOPHIA trial evaluated the role of margetuximab in HER2-positive metastatic breast cancer previously treated with standard-of-care HER2-directed therapies. Although margetuximab and trastuzumab bind the same epitope of HER2, margetuximab has cleverly been bioengineered to have an enhanced effect on antibody-dependent cell-mediated cytotoxicity, or ADCC. This effect is attributed to enhanced affinity for both low-affinity, F, and high-affinity, V, alleles, for the activating Fcγ CD16A receptor.

    The primary analysis, reported at ASCO, revealed statistically significant improvement in PFS with margetuximab compared with trastuzumab, with more appreciable differences in patients harboring low-affinity F alleles. Clinically, however, these differences translate to a meager 1 to 2 months at best.

    Margetuximab nonetheless was found to be consistently superior to trastuzumab in this setting across all subgroups, with the exception of patients homozygous for high-affinity VV alleles. Overall, considering otherwise similar toxicities between the groups, the statistically superior clinical benefit rate of margetuximab supports serious consideration of its institution as the next line of therapy beyond currently accepted standard-of-care regimens. These data, however, do not support a convincing role for routine genotype analysis for patient selection purposes.

    As the data mature, we wait to see whether these differences will extend to OS. Regardless, SOPHIA directs us to advance beyond HER2-centered approaches.

    References:

    Baselga J, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1113216.

    Carr JA, et al. Arch Surg. 2000;135:1469-1474.

    Carter P, et al. Proc Natl Acad Sci U S A. 1992;doi:10.1073/pnas.89.10.4285.

    Nordstrom JL, et al. Breast Cancer Res. 2011;doi:10.1186/bcr3069.

    Slamon DJ, et al. N Engl J Med. 2001;doi:10.1056/NEJM200103153441101.

    von Minckwitz G, et al. N Engl J Med. 2019; doi:10.1056/NEJMoa1814017.

    Adam Brufsky, MD, PhD

    HemOnc Today Editorial Board Member

    University of Pittsburgh School of Medicine

    Disclosure: Brufsky reports consultant roles with Eli Lilly, Novartis, Pfizer, Puma and Roche.

    Azadeh Nasrazadani, MD, PhD

    University of Pittsburgh School of Medicine

    Disclosure: Nasrazadani reported no relevant financial disclosures.

    See more from ASCO Annual Meeting