Raul H. Oyola

1000 Background: Pretreated HER2+ MBC lacks a defined standard of care, although T is commonly used. M has similar HER2 binding and antiproliferative effects as T. By contrast, M’s Fc region is engineered to increase affinity for both alleles of the activating Fc receptor (FcR), CD16A, and decrease affinity for the inhibitory FcR, CD32B. The low affinity CD16A-158F allele (~85% of population) has been associated with diminished clinical response to T. In a Phase 1 trial, M demonstrated acceptable safety, anti-tumor activity, and evidence of HER2-specific antibody and T-cell responses. Methods: SOPHIA (NCT02492711), a randomized, open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior Tx for MBC. Pts were randomized 1:1 to M (15 mg/kg IV q3w + C) or T (6 [8 for loading dose] mg/kg IV q3w + C), stratified by met sites (≤2, > 2), lines of Tx for met disease (≤2, > 2), and C choice (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). Primary endpoints are central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Objective response rate (ORR) was a secondary endpoint. 257 PFS events were required to provide 90% power to show PFS superiority at 2-sided α = 0.05. Results: Intent-to-treat analysis (536 pts: M 266; T 270) occurred after 265 PFS events. M prolonged PFS over T (median 5.8 vs 4.9 mo, hazard ratio [HR], 0.76; 95% CI, 0.59–0.98; P= 0.033). Treatment effects were more pronounced in pts with CD16A genotypes containing a 158F allele (median PFS 6.9 vs 5.1 mo, HR, 0.68; 95% CI, 0.52–0.90; P= 0.005). In 524 pts with baseline measurable disease (M 262; T 262), ORR was higher with M (22%; 95% CI, 17.3-27.7%) vs T (16%; 95% CI 11.8-21.0%). Safety profiles were comparable in 529 pts who received study therapy. Grade ≥3 AEs and serious AEs occurred in 138 (52%) and 39 (15%) vs 128 (48%) and 46 (17%) pts on M vs T, respectively. PFS data cutoff: 10/10/18. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improves PFS over T with comparable safety. CD16A genotyping suggests a differential benefit in patients with a 158F allele. OS data are maturing. Clinical trial information: NCT02492711.

Abstract Background: Margetuximab (M), an investigational Fc-engineered, immune-activating, HER2-targeted monoclonal antibody, shares specificity with trastuzumab (T) and is being studied in HER2 overexpressing tumors including MBC. The randomized phase 3 SOPHIA trial (NCT02492711) in pretreated HER2+ MBC demonstrated PFS superiority by blinded analysis of M + chemotherapy over T + chemotherapy. M demonstrated a tolerable safety profile. Here, patient-reported health-related quality of life (HRQOL) is reported. Methods: In SOPHIA, 536 patients with HER2+ MBC and ≥ 2 prior HER2+ directed therapies, including pertuzumab, were randomized 1:1 to M (15mg/kg IV q3w) or T (6 [8 for loading dose] mg/kg IV q 3wk). Each antibody was given with physician’s choice chemotherapy (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). HRQOL was measured at baseline and on D1 of each odd cycle using the Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI) - 16 and EuroQol 5-Dimension 5 level (EQ-5D-5L) questionnaires. Descriptive statistics were performed on NFBSI-16 total score (possible score range: 0 [most symptomatic] - 64 [least symptomatic]), EQ-5D-5L overall score (possible score range: 0 [most symptomatic] - 100 [least symptomatic]), and subscales of each measures. Lower scores reflect a higher impact on HRQOL domains. Changes from baseline in NFBSI-16 total score and in EQ-5D-5L utility score were assessed using mixed model repeated measures analysis (MMRM) with treatment group, stratification factors, time, and treatment group by time interaction as covariates. Each analysis used an unstructured covariance matrix, and least square mean estimates were calculated at each time point. A Cox proportional hazard model was used to assess time to symptom progression, defined as a ≥ 5-point decrease from baseline in NFBSI-16, using the same covariates as in MMRM analyses.Results: HRQOL questionnaire completion rates were comparable between M and T treatment groups. Mean NFBSI-16 total scores and EQ-5D-5L overall scores were similar between treatment arms at baseline and at end of treatment. During cycles 11-17, a greater proportion of patients in the M group reported being bothered by side effects and fatigue “quite a bit” or “very much” on the NFBSI-16. However, adverse event assessments at corresponding time points were largely attributed to concomitant chemotherapy. Also, a smaller proportion of patients on T completed these measures at these times. Overall, least mean square estimates (95% CIs) of change from baseline NFBSI-16 total scores were -1.99 (-3.395, -0.594) in the M group, and -2.13 (-3.794, -0.469) in the T group. A slightly higher proportion of patients in the M group had ≥ 5-point decrease from baseline NFBSI-16 total score compared to those in the T group (M: 105 [39.5%]; T: 100 [37%]). However, this difference was neither prespecified nor statistically significant (Cox model HR: 0.88, 95% CI: 0.672, 1.164; p=0.382). Overall least square mean estimates (95% CIs) of change from baseline in EQ-5D-5L total scores were -0.93 (-4.493, 2.637) in the M group, and -3.93 (-8.253, 0.387) in the T group, suggesting that patients on M had less signs of deterioration compared to the T group; statistical significance testing was not prespecified. Conclusions: Overall, HRQOL domains, including symptoms and functioning, were maintained. Changes from baseline were similar between the 2 treatment groups. Treatment-specific symptoms were consistent with side effects associated with chemotherapy, not antibody study therapy. Findings support similar, acceptable safety profiles demonstrated previously for margetuximab and trastuzumab. Citation Format: Fatima Cardoso, Javier Cortes, William Gradishar, Seock-Ah Im, Mark D. Pegram, Hope S. Rugo, Gail S. Wright, Michelino De Laurentiis, Christelle Levy, Jean-Marc Ferrero, Janine Mansi, Raul Oyola, Francesco Ricci, Erik H. Jakobsen, Beatriz Uziely, Daniel Egle, Aristoteles Giagounidis, Kirstin Williams, Shengyan Hong, Edwin Rock, Giuseppe Curigliano. Health-related quality of life for margetuximab + chemotherapy vs. trastuzumab + chemotherapy in the phase 3 SOPHIA trial of patients with pretreated HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-11.