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Clinical Trial
. 2023 Jan 10;41(2):198-205.
doi: 10.1200/JCO.21.02937. Epub 2022 Nov 4.

Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial

Hope S Rugo  1 , Seock-Ah Im  2 , Fatima Cardoso  3 , Javier Cortes  4   5 , Giuseppe Curigliano  6 , Antonino Musolino  7   8   9 , Mark D Pegram  10 , Thomas Bachelot  11 , Gail S Wright  12 , Cristina Saura  13 , Santiago Escrivá-de-Romaní  13 , Michelino De Laurentiis  14 , Gary N Schwartz  15 , Timothy J Pluard  16 , Francesco Ricci  17 , William R Gwin 3rd  18 , Christelle Levy  19 , Ursa Brown-Glaberman  20 , Jean-Marc Ferrero  21 , Maaike de Boer  22 , Sung-Bae Kim  23 , Katarína Petráková  24 , Denise A Yardley  25 , Orit Freedman  26 , Erik H Jakobsen  27 , Einav Nili Gal-Yam  28 , Rinat Yerushalmi  29 , Peter A Fasching  30 , Peter A Kaufman  31 , Emily J Ashley  32 , Raul Perez-Olle  32   33 , Shengyan Hong  32 , Minori Koshiji Rosales  32   33 , William J Gradishar  34 ; SOPHIA Study Group
Affiliations
Clinical Trial

Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial

Hope S Rugo et al. J Clin Oncol. .

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2-positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2-positive breast cancer with different CD16A allelic variants are warranted.

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Conflict of interest statement

Shengyan Hong

Employment: MacroGenics

Stock and Other Ownership Interests: MacroGenics

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
(A) Final OS in the ITT population and (B-E) planned prespecifieda exploratory OS analysis, per CD16A genotypeb by treatment group, June 14, 2021, cutoff. (A) Kaplan-Meier estimates of OS in the ITT population (n = 536). Kaplan-Meier estimates of OS by treatment group in (B) CD16A-158F carriers (FF or FV; n = 437; 86%), (C) CD16A-158FF homozygotes (n = 192; 38%), (D) CD16A-158FV heterozygotes (n = 245; 48%), and (E) CD16A-158VV homozygotes (n = 69; 14%). aNon–α-allocated analysis. bA total of 506 of 536 ITT patients genotyped (94%). HR, hazard ratio; ITT, intention-to-treat; NA, not available (because cannot be calculated); OS, overall survival.
FIG 2.
FIG 2.
Planned prespecifieda exploratory OS subgroup analyses (cutoff, June 14, 2021)b. Median OS, HRs, and 95% CIs are shown by subgroup. aNon-α-allocated analysis. bA total of 506 of 536 ITT patients genotyped (94%). cCD32B-232TT not included in the forest plot because n = 9 is too small (five on margetuximab and four on trastuzumab) to make the analysis meaningful. HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IHC, immunohistochemistry; ISH, in situ hybridization; OS, overall survival.
FIG A1.
FIG A1.
SOPHIA study design. CBA, central blinded analysis; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
FIG A2.
FIG A2.
CONSORT diagram. All randomly assigned patients were included in the intention-to-treat population; randomly assigned patients who received at least one dose of study treatment were included in the safety population. Reasons for withdrawals are shown. aA patient may have more than one reason for screening failure. AE, adverse event; PD, progressive disease; tx, treatment.
FIG A3.
FIG A3.
PFS assessed by the investigator in the intention-to-treat population (cutoff, June 14, 2021; n = 536). HR, hazard ratio; PFS, progression-free survival.
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