MacroGenics : JAMA Oncology - Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer - A Phase 3 Randomized Clinical Trial

Research

JAMA Oncology | Original Investigation

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer A Phase 3 Randomized Clinical Trial

Hope S. Rugo, MD; Seock-Ah Im, MD, PhD; Fatima Cardoso, MD; Javier Cortés, MD, PhD; Giuseppe Curigliano, MD, PhD;

Antonino Musolino, MD, PhD, MSc; Mark D. Pegram, MD; Gail S. Wright, MD; Cristina Saura, MD, PhD; Santiago Escrivá-de-Romaní, MD; Michelino De Laurentiis, MD, PhD; Christelle Levy, MD; Ursa Brown-Glaberman, MD; Jean-Marc Ferrero, MD; Maaike de Boer, MD, PhD; Sung-Bae Kim, MD, PhD; Katarína Petráková, MD, PhD; Denise A. Yardley, MD; Orit Freedman, MD, MSc; Erik H. Jakobsen, MD; Bella Kaufman, MD; Rinat Yerushalmi, MD; Peter A. Fasching, MD; Jeffrey L. Nordstrom, PhD; Ezio Bonvini, MD; Scott Koenig, MD, PhD; Sutton Edlich, MS, PA; Shengyan Hong, PhD; Edwin P. Rock, MD, PhD; William J. Gradishar, MD; for the SOPHIA Study Group

IMPORTANCE ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation.

OBJECTIVE To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC.

DESIGN, SETTING, AND PARTICIPANTS The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019.

INTERVENTIONS Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice.

MAIN OUTCOMES AND MEASURES Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis.

RESULTS Atotalof536patientswererandomizedtoreceivemargetuximab(n = 266)ortrastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced.

Allbut1patienthadreceivedpriorpertuzumab,and489(91.2%)hadreceivedpriorado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98;P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95%CI,4.2-5.6]months;October10,2018).Afterthesecondplannedinterimanalysisof270deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13;P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86;P< .001; median,

5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab:22%vs16%(P = .06;October10,2018),and25%vs14%(P< .001;September10,2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable.

CONCLUSIONS AND RELEVANCE In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021.

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02492711

JAMA Oncol. doi:10.1001/jamaoncol.2020.7932

Published online January 22, 2021.

Visual Abstract

Supplemental content

Author Affiliations: Author affiliations are listed at the end of this article.

Group Information: The SOPHIA Study Group members appear at the end of the article.

Corresponding Author: Hope S. Rugo, MD, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, 1825 Fourth St, 3rd Floor, PO Box 1710, San Francisco, CA 94158 ([e-mail]).

E1

Downloaded From: https://jamanetwork.com/ on 01/24/2021

Research Original Investigation

Efficacy of Margetuximab vs Trastuzumab in Pretreated ERBB2-Positive Advanced Breast Cancer

• ddition of ERBB2 (formerly HER2)-targeting monoclo- nal antibodies to chemotherapy improves progression-
  free survival (PFS) and overall survival (OS) in pa-

tients with ERBB2-positive advanced breast cancer (ABC).1-4 Generally, patients with ERBB2-positive metastatic breast cancer (BC) receive multiple lines of therapy, yet with rare excep- tions, ERBB2-positive metastatic BC remains incurable.5,6

Margetuximab is a chimeric, Fc-engineered, immune- activating anti-ERBB2 immunoglobulin G1 (IgG1) monoclo- nal antibody that shares epitope specificity and Fc- independent antiproliferative effects with trastuzumab. Fc engineering of margetuximab alters 5 amino acids from wild- type IgG1 to increase affinity for activating Fcγ receptor (FcγR) CD16A (FcγRIIIa) and to decrease affinity for inhibitory FcγR CD32B (FcγRIIb).6,7 These effects are proposed to increase activation of innate and adaptive anti-ERBB2 immune re- sponses, relative to trastuzumab.

Three FcγRs (CD16A, CD32A, and CD32B) expressed on immune effector cells regulate cellular activation by antibodies.8 CD16A can trigger antibody-dependent cellular cytotoxicity (ADCC) by innate immune cells.9,10 Two CD16A polymorphisms at amino acid 158 bind IgG1 with higher (valine [V]) or lower (phenylalanine [F]) affinity.11 Clinical benefit of therapeutic antibodies, including trastuzumab,11-15 appears greater for patients with the high-affinity VV genotype compared with the lower-affinity FV and FF genotypes (CD16A-158F carri- ers), although not all studies observed this effect.16,17 Nota- bly, most people (approximately 85%) are CD16A-158F allele carriers.11,12 A key feature of margetuximab's engineered Fc domain is increased binding to all CD16A-158 V/F variants, relative to wild-type IgG1.

In a phase 1 study18 of margetuximab monotherapy in 66 patients with pretreated ERBB2-positive carcinomas, 4 of 24 (17%) evaluable patients with ABC had a confirmed partial re- sponse. Three patients continued margetuximab mono- therapy for 4 or more years.19 Here we report initial results of a phase 3 randomized clinical trial of margetuximab vs trastuzumab, each combined with single-agent chemo- therapy, in pretreated patients with ERBB2-positive ABC. In addition, we present an exploratory analysis of PFS and OS by FcγR genotype.

Methods

Study Design and Participants

This international, randomized, open-label, phase 3 study (SOPHIA; MacroGenics study protocol No. CP-MGAH22-04) enrolled patients at 166 centers in 17 countries. Eligible patients were aged 18 years or older with confirmed ERBB2-positive ABC by local or optional central testing of the most recent biopsy, following 2013 American Society of Clinical Oncology testing recommendations.20 Patients must have had progressive disease after 2 or more lines of prior ERBB2-targeted therapy, including pertuzumab, and 1 to 3 lines of nonhormonal meta- static BC therapy. Prior brain metastases were allowed if treated and stable. Trial conduct was in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. An in-

Key Points

Question Does margetuximab plus chemotherapy prolong progression-free survival and/or overall survival of patients with pretreated ERBB2-positive advanced breast cancer, relative to trastuzumab plus chemotherapy?

Findings In the SOPHIA phase 3 randomized clinical trial of 536 patients with pretreated ERBB2-positive advanced breast cancer, margetuximab plus chemotherapy generated a statistically significant 24% relative risk reduction in the hazard of progression vs trastuzumab plus chemotherapy. After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab, and final analysis of OS will be reported subsequently.

Meaning This trial demonstrates a head-to-head advantage of margetuximab (an Fc-engineeredERBB2-targeted antibody) compared with trastuzumab in a pretreated ERBB2-positive advanced breast cancer population.

dependent ethics committee approved the protocol at each participating site. All patients provided written informed consent. The trial protocol and statistical analysis plan are available online (Supplement 1). This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Randomization and Masking

Investigators chose 1 of 4 chemotherapies (capecitabine, er- ibulin, gemcitabine, or vinorelbine) for each eligible patient before 1:1 randomization by a permuted-blocks procedure. Stratification factors were metastatic sites (≤2, >2), lines of therapy for metastatic disease (≤2, >2), and chemotherapy choice. The trial was open label for patients and investigators but sponsor blinded with central blinded analysis (CBA) of PFS to prevent observer bias.

Procedures

Margetuximab was given intravenously at 15 mg/kg over 120 minutes on day 1 of each 21-day cycle. Trastuzumab was given intravenously at 6 mg/kg (over 30-90 minutes) on day 1 of each 21-day cycle after a loading dose of 8 mg/kg (over 90 min- utes). Capecitabine was given orally at 1000 mg/m2 twice daily for 14 days followed by 7 days off. Eribulin, gemcitabine, and vinorelbine were given intravenously before antibody infusion at 1.4 mg/m2, 1000 mg/m2, and 25 to 30 mg/m2, respec- tively, on days 1 and 8 of each cycle. Margetuximab premedi- cation was recommended, if not already given with chemotherapy: standard doses of acetaminophen or ibupro- fen, diphenhydramine, ranitidine, and dexamethasone, or equivalents. Disease assessment was performed at baseline, every 6 weeks for the first 24 weeks of therapy, and then every 12 weeks until disease progression, adverse event (AE) necessitating discontinuation, consent withdrawal, or death. Safety was assessed at each visit, including AEs from study therapy initiation through the end-of-treatment visit, or 28 days after last administration of the study drug. Investigators assessed both event severity, using Common Terminology Criteria for Adverse Events, version 4.03, and causality. Left ventricular ejection fraction (LVEF) was monitored every 6 weeks

E2

JAMA Oncology Published online January 22, 2021

jamaoncology.com

Downloaded From: https://jamanetwork.com/ on 01/24/2021

Efficacy of Margetuximab vs Trastuzumab in Pretreated ERBB2-Positive Advanced Breast Cancer

Original Investigation Research

for 24 weeks and then every 12 weeks thereafter. Optional CD16A, CD32A, and CD32B genotyping was performed by poly- merase chain reaction amplification of blood DNA, followed by DNA sequencing.

Outcomes

Primary end points were PFS by CBA, with the α entirely allocated to PFS, and OS. The PFS was defined as time from randomization to disease progression or death from any cause. Secondary end points included investigator-assessed PFS and CBA-assessed objective response rate (ORR). The PFS and ORR were assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Additional end points included safety, clinical benefit rate (CBR; ORR plus stable disease lasting at least 6 months), investigator-assessed ORR, response duration, an- tidrug antibodies, and exploratory evaluation of FcγR allelic variation on efficacy.

Statistical Analysis

For 90% power to detect median PFS improvement from 4 to

• months (hazard ratio [HR], 0.67) at a 2-sided .05 signifi- cance level, 257 PFS events were needed. Primary PFS by CBA occurred after 257 PFS events or all patients were random- ized, whichever occurred last. The OS was time from random- ization to death from any cause and was to be assessed only if PFS was positive. For 80% power to detect a median OS im- provement from 12 to 16 months (HR, 0.75) at a 2-sided .05 sig- nificance level, 385 OS events were needed. Three OS analy- ses were planned: first interim coincident with primary PFS analysis, second interim after 270 deaths, and final analysis after 385 events. All α was allocated to PFS, tested at a 2-sided
  .05 significance level. If PFS passed the test, then OS would be tested at the same significance level of 2-sided .05. The O'Brien-Fleming type Lan-DeMetsα-spending function was applied for α allocation to each interim OS analysis.
  The PFS and OS were assessed in the randomized, intention- to-treat population. Patients were censored at the last tumor assessment date for PFS and at the last time known to be alive for OS. The ORR and CBR were assessed in randomized patients with baseline measurable disease (response-evaluable popula- tion). For ORR analysis, if a patient's response was missing, the patient was classified as not available. Safety and antidrug an- tibodies were assessed in randomized patients after any study treatment (safety population).
  Kaplan-Meier methods were used to estimate median PFS, OS, and 95% CIs for each treatment group. The stratified log- rank test was used to compare time-to-event end points be- tween groups. A stratified Cox proportional hazards model, with treatment as the only covariate, was used to estimate PFS and OS HRs and 95% CIs.
  Prespecified PFS and OS subgroup analyses included che- motherapy choice, metastatic sites, lines of prior metastatic therapy, prior ado-trastuzumab emtansine use, hormone re- ceptor status, ERBB2 status, Eastern Cooperative Oncology Group performance status, region, age, and race, as well as FCGR3A (FcγRIIIa/CD16A), FCGR2A (FcγRIIa/CD32A), and FCGR2B (FcγRIIb/CD32B) genotype. The HRs and 95% CIs for PFS in each subgroup were assessed using an unstratified Cox

proportional hazards model with treatment as the only covar- iate.

If the primary PFS and OS were each positive, then secondary PFS and ORR end points were to be tested using the Hochberg step-up procedure for multiplicity adjustment. Investigator-assessed PFS was analyzed using the same methods as the primary PFS end point. The ORR was compared between groups by the stratified Mantel-Haenszel test. Data were analyzed from February 2019 to October 2019. Analyses were performed using SAS, version 9.4 (SAS Institute).

Results

Study Population

From July 2015 through October 2018, a total of 536 patients were enrolled at 166 centers in 17 countries and randomized to receive margetuximab plus chemotherapy (margetuximab group, n = 266) or trastuzumab plus chemotherapy (trastuzumab group, n = 270; Figure 1). The median age was

56 (27-86) years (55.0 [29-83] years for patients in the mar- getuximab group and 56.0 [27-86] years in the trastuzumab group); 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. In- vestigator-selected chemotherapy choices were vinorelbine (n = 191, 35.6%), capecitabine (n = 143, 26.7%), eribulin (n = 136, 25.4%), and gemcitabine (n = 66, 12.3%). Patients received a median of 6 cycles of margetuximab vs 5 cycles of trastuzumab.

Baseline characteristics were balanced across groups (Table 1). All patients had received prior trastuzumab; all but 1 had received prior pertuzumab, and 489 (91.2%) had re- ceived prior ado-trastuzumab emtansine. One-third of pa- tients in both groups received 3 or more prior therapies for metastatic BC (margetuximab, 92 of 266 [34.6%]; vs trastuzumab, 87 of 270 [32.2%]).

Efficacy

Primary PFS analysis was triggered by last randomization (October 10, 2018), after 265 PFS events. On that date, 79 (30%) vs 58 (22%) patients remained on margetuximab vs trastuzumab, respectively, including 13 (5%) and 5 (2%) remaining exclusively on margetuximab vs trastuzumab. Mar- getuximab plus chemotherapy prolonged centrally assessed PFS (HR, 0.76; 95% CI, 0.59-0.98;P = .03; median PFS, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; Figure 2A), with a 24% PFS relative risk reduction over trastuzumab plus chemotherapy, meeting the primary end point of the study. The test of proportional hazards assumption indicated that the proportional hazards assumption was not violated. Investigator-assessed PFS based on 337 events was also greater with margetuximab than with trastuzumab (HR, 0.70; 95% CI, 0.56-0.87;P = .001; median, 5.6 vs 4.2 months; Figure 2B), with a 30% PFS relative risk reduction over trastuzumab. Coincident with the second interim OS analy- sis, updated investigator-assessed PFS based on 430 PFS events showed increased statistical significance in favor of margetux- imab with a similar HR (HR, 0.71; 95% CI, 0.58-0.86;P< .001; median, 5.7 vs 4.4 months; Figure 2C).

jamaoncology.com

JAMA Oncology Published online January 22, 2021

E3

Downloaded From: https://jamanetwork.com/ on 01/24/2021

Research Original Investigation

Efficacy of Margetuximab vs Trastuzumab in Pretreated ERBB2-Positive Advanced Breast Cancer

Figure 1. Patient Flow/Patient Disposition

763 Patients assessed for eligibility

227 Ineligiblea

115	Not meeting all inclusion criteria
68	Met at least 1 exclusion criterion
39	Other reasons
21	Declined to participate

536 Randomized

266 Randomized to margetuximab + chemotherapy	270 Randomized to trastuzumab + chemotherapy
98	Margetuximab+vinorelbine (36.1%)	95	Trastuzumab+vinorelbine (35.2%)
71	Margetuximab+capecitabine (26.7%)	72	Trastuzumab+capecitabine (26.7%)
66	Margetuximab+eribulin (24.8%)	70	Trastuzumab+eribulin (25.9%)
33	Margetuximab+gemcitabine (12.4%)	33	Trastuzumab+gemcitabine (12.2%)

264	Received allocated intervention	265	Received allocated intervention
2	Did not receive allocated intervention	5	Did not receive allocated intervention
	1 Withdrew consent		3	Withdrew consent
	1 Physician decision		1	Patient discontinued tx
			1	Patient did not receive tx before the data
				cutoff date

All randomized patients were included in the intention-to-treat population; randomized patients who received at least 1 dose of study treatment were included in the safety population; randomized patients with baseline measurable disease were included in the RE population.

AE indicates adverse event;

PD, progressive disease; RE, response evaluable; tx, treatment.

2 Lost to follow-up

185 Discontinued treatment

157 PD

8 AE

7 Physician decision

6 Withdrew consent

3 Patient discontinued tx

2 Death

2 Other

79 Treatment ongoingb,c

1. Included in intention-to-treat analysisd

1. Safety populatione

1. RE populationb,f

207 Discontinued treatment 172 PD

9 AE

5 Physician decision

10 Withdrew consent

5 Patient discontinued tx

3 Death

3 Other

58 Treatment ongoingb,c

1. Included in intention-to-treat analysisd

1. Safety populatione

1. RE populationb,f

• A patient may have more than 1 reason for screening failure.

• As of the October 10, 2018, cutoff.

• As of the April 10, 2019, cutoff, 37 patients remained on margetuximab therapy vs 20 on trastuzumab therapy.

• As of the October 10, 2018, cutoff and the September 10, 2019, cutoff.

• As of the April 10, 2019, cutoff.

• As of the September 10, 2019, cutoff, there were 266 margetuximab-treated patients and 270 trastuzumab-treated patients in the RE population.

The OS analysis after 270 deaths (70% of 385 final required events) occurred on September 10, 2019, after 131 (49.2%) and 139 (51.5%) OS events in the margetuximab and trastuzumab groups, respectively. Median OS was 21.6 months with margetuximab and 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13;P = .33; Figure 3). The stopping threshold was not reached; final OS analysis will occur after 385 deaths (anticipated in 2021).

Among 524 response-evaluable patients, margetuximab recipients had higher blinded ORR (22% vs 16%; P = .06) and CBR (37% vs 25%; P = .003) than trastuzumab recipients (eTable 1 in Supplement 2). These rates were similar at the Sep- tember 2019 cutoff when investigator-assessed ORR and CBR were 25% vs 14% (P< .001) and 48% vs 36% ( P = .003), respectively (eTable 1 in Supplement 2). Median response duration was similar between treatment groups: 6.1 vs 6.0 months (October 10, 2018, CBA) and 6.9 vs 7.0 months (September 10, 2019, investigator assessed).

Prespecified exploratory subgroup analyses of primary PFS (October 10, 2018, cutoff) and second interim OS (September 10, 2019, cutoff) by CD16A genotype are shown in eFigures 1 and 2 in Supplement 2, respectively. Genotyping was available for 506 patients (94%). Study groups were in Hardy- Weinberg equilibrium for all 3 FCGR genotypes (eTable 2 in

Supplement 2). Baseline characteristics of patients assigned to margetuximab vs trastuzumab by FcγR genotype are shown in eTable 3 in Supplement 2. The interim OS per treatment group by CD16A genotype is shown in eFigure 3 in Supplement 2. Efficacy outcomes by CD32A and CD32B are shown in eFigure 4 and eFigure 5 in Supplement 2.

Safety

As of April 10, 2019, which provided 6 additional months of safety follow-up after the primary PFS analysis, the safety population included 264 margetuximab and 266 trastuzumab recipients. Common AEs (≥20% of patients), regardless of cau- sality, included fatigue, nausea, diarrhea, and neutropenia in both groups (Table 2), as well as vomiting (margetuximab group) and anemia (trastuzumab group). Grade 3 or greater AEs in at least 5% of patients included neutropenia and anemia in both groups, as well as fatigue in the margetuximab group and febrile neutropenia in the trastuzumab group. Discontinuations owing to AEs were similar (margetuximab, 8 of 266 [3.0%]; trastuzumab, 7 of 270 [2.6%]; eTable 4 in Supplement 2). Adverse events leading to death were reported in 5 patients (margetuximab, n = 3 [1.1%]; trastuzumab, n = 2 [0.8%]; eTable 4 in Supplement 2); none were considered treatment related.

E4

JAMA Oncology Published online January 22, 2021

jamaoncology.com

Downloaded From: https://jamanetwork.com/ on 01/24/2021