Purpose: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This first-in-human phase I study evaluated the safety/tolerability, pharmacokinetics, preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to patients with HER2-positive metastatic breast cancer (MBC). Patients and Methods: Female patients with HER2-positive MBC who had progressed on prior anti HER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (once weekly), 10 mg/kg (once weekly), 20 mg/kg (once every 2 weeks), or 30 mg/kg (once every 3 weeks). Dose escalation was guided by a “3+3” dose escalation rule followed by dose expansion. Results: Sixty-three patients were enrolled. The most common treatment-related adverse events (TRAE) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). Only 4 patients reported grade 3 TRAEs. Results from exposure-response analysis supported the selection of the recommended phase II doses at 20 mg/kg once every 2 weeks or 30 mg/kg once every 3 weeks, which had objective response rates (ORR) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% confidence interval: 4.2–8.3) in 57 patients. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no co-amplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and median PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). Conclusions: KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.

Background: Ovarian function suppression is being widely utilized as endocrine therapy to reduce estrogen release in premenopausal breast cancer patients and was achieved either by medical treatment with bilateral oophorectomy, irradiation, or the Gonadotropin releasing hormone (GnRH) agonist. This study aimed to examine whether GnRHa differed from ovarian ablation on depression, sexual dysfunction and quality of life.Methods: The premenopausal breast cancer patients who received ovarian function suppression were enrolled from seven hospital between June 2019 and June 2020. Our independent variable was the type of ovarian suppression, categorized as Ovarian Ablation (OA cohort, n=174) and medical GnRH agonist (GnRHa cohort, n=389). The self-administered questionnaire (OFS-Q5) was developed and used in this study aimed to assess the depression (PHQ-9), sexual dysfunction (FSFI) and quality of life (EORTC QLQ-BR23).Results: In this cross-sectional study, 563 patients with ovarian function suppression completed surveys were collected. The mean sum score of the PHQ-9 tend to be slight decrease in GnRHa cohort than that in ovarian ablation (OA) cohort (11.4 ±5.7 vs. 12.8 ±5.8, OR=1.910, P=0.079). Patients with major depression (PHQ-9≧15) was indicated significantly fewer in GnRHa cohort (31.1% vs 40.2%, P=0.025). The more surprising correlation is less patients with sexual dysfunction (61.5%, FSFI< 23) in OA cohort, a remarkable increase in GnRHa cohort (72.2%, P = 0.011). The ratio of sexual dysfunction remained lower for ovarian ablation women in long-term ovarian suppression (duration of ovarian suppression > 2 years: OA vs GnRHa, OR=1.555, P=0.037). No significantly difference for most subscales of QLQ-BR23 between two cohorts was evident.Conclusions: Our current investigation demonstrate here for the first time that medical GnRHa resulted in favour depression, worse sexual function than those with ovarian ablation, with similar quality of life. This new understanding should help to improve and alleviate adverse effect in patients with diverse ovarian function suppression.

e13061 Background: Fulvestrant, a selective estrogen receptor (ER) down-regulator, is a standard of care for first-line treatment in hormone receptor-positive (HR+) advanced breast cancer. This study is to assess the safety profile and effectiveness of fulvestrant 500mg as the first-line endocrine therapy of post-menopausal women with HR+ locally advanced or metastatic breast cancer. Methods: The study is an open-label, multicentre, prospective, observational study in China. Chinese patients receiving fulvestrant 500mg as the first endocrine agent after relapse according to investigator’s clinical practice were enrolled. Primary variable is the frequency and severity of adverse events (AEs). Secondary variables were objective response rate (ORR), clinical benefit rate (CBR), progress free survival (PFS) and overall survival (OS). Predictive effects of endocrine resistance, chemotherapy for advanced disease and adjuvant endocrine therapy on the effectiveness were prespecified as exploratory variables. Results: From November 2017 to December 2020, 461 patients were enrolled by 29 Chinese centers. Median age was 56 years and the ECOG score was: 0, 165 (35.8%); 1, 281 (60.9%); 2, 12 (2.6%); and 3, 3 (0.7%). 20 (4.3%) patients had the Kaplan-Feinstein index ≥2. Majority (77.0%) of the patients were ER+ and PgR+, and 190 (41.2%) had visceral metastasis. In total, 91 (19.7%) patients were primary endocrine resistant, 202 (43.8%) were secondary endocrine resistant and 123 (26.7%) were endocrine-therapy naïve. 147 (31.9%) patients received previous chemotherapy for advanced disease, while 101 (21.9%) patients had anti-estrogen drugs as adjuvant therapy. 54 (11.7%) patients had concurrent CDK4/6 inhibitors. After a median follow-up of 26.8 months (IQR 18.7-38.2), median PFS was 13.0 months (95% CI 9.8-16.4) and median OS was 41.2 months (95% CI 37.3-NE). ORR was 11.3% (95% CI 8.2-15.1) and CBR was 60.6% (95%CI 55.2-65.8). Patients with endocrine-therapy naïve tumor, no previous chemotherapy for advanced disease and adjuvant anti-estrogen treatment had a longer PFS of first-line fulvestrant 500mg. 67 (14.5%) patients had at least one AE, with 1 (0.2%) patient withdrawing because of AEs. Drug-related serious AEs (SAEs) were rare, occurring in 2 (0.4%) patients. No patient died as a result of a drug-related AE. Neutropenia, increased ALT/AST, and anemia were the most commonly reported AEs in this study. Conclusions: This is the first prospective real-world study confirming that fulvestrant 500mg is a well-tolerated treatment option in unselected ABC in China. In the real clinical practice, fulvestrant 500mg can achieve the consistent anti-tumor activity as in clinical trials. Patients with endocrine-therapy naïve status and no prior chemotherapy tend to have a longer control time. Clinical trial information: NCT02909361 .

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