FS-1502 Is Safe and Displays Antitumor Activity in Metastatic HER2+ Breast Cancer


Key Takeaways

  • FS-1502 demonstrated promising antitumor activity and was well tolerated in HER2-expressing metastatic breast cancer.
  • The recommended phase 2 dose was determined to be 2.3 mg/kg every three weeks.
Breast Cancer

Breast Cancer

The HER2-directed antibody-drug conjugate (ADC) FS-1502 was well tolerated and generated early signals of antitumor activity in patients with metastatic HER2-expressing breast cancer, according to findings from a first-in-human, multicenter, single-arm, dose-escalation and -expansion phase 1a/b trial (NCT03944499) published in Nature Communications.1

At a data cutoff of December 24, 2022, and a median follow-up of 5.8 months, 1 dose-limiting toxicity (DLT) each was reported at doses of 3.0 mg/kg and 3.5 mg/kg. The maximum tolerated dose (MTD) was not reached (NR), and the recommended phase 2 dose (RP2D) was determined to be 2.3 mg/kg once every 3 weeks.

Among patients with HER2-positive breast cancer who received the RP2D (n = 67), the overall response rate (ORR) was 53.7% (95% CI, 41.1%-66.0%) comprised of a 3.0% complete response rate and a 50.7% partial response (PR) rate (including 7 PRs pending confirmation).

“FS-1502 was well tolerated and demonstrated promising antitumor activity in patients with HER2-positive advanced breast cancer,” lead study author Qiao Li, MD, of the Department of Medical Oncology in the State Key Laboratory at the National Cancer Center/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, and coauthors, wrote in the paper.

In preclinical in vitro studies, FS-1502 demonstrated more potent target-dependent toxicity and cell cycle arrest vs ado-trastuzumab emtansine (T-DM1; Kadcyla).2

This phase 1 trial enrolled adult patients with HER2-expressing advanced malignant solid tumors who had progressed on standard therapy, could not receive standard therapy, or had no standard therapy available.1 Patients in the phase 1b portion needed to have histologically or cytologically confirmed HER2-positive breast cancer who experienced disease progression on prior HER2-directed therapy and received 2 or more prior lines of therapy for advanced breast cancer.1

The phase 1a portion assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of FS-1502 in patients with HER2-expressing advanced solid tumors. The phase 1b portion investigated the efficacy and safety of the agent in patients with locally advanced or metastatic HER2-positive breast cancer.

The primary end points for the phase 1a portion were DLTs and determining the MTD and RP2D. Secondary end points included safety end points other than DLTs, ORR, progression-free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), and pharmacokinetics. ORR served as the primary end point for the phase 1b portion, and secondary end points included safety, PFS, OS, DOR, CBR, and pharmacokinetics.

Between November 11, 2019, and December 13, 2022, this trial enrolled 150 patients with HER2-expressing breast cancer (n = 145) and other HER2-expressing solid tumors (lung cancer, n = 2; ampullary cancer, n = 1; submandibular gland malignant tumor, n = 1; gastric cancer, n = 1) across 9 sites in China. Patients received doses of FS-1502 ranging from 0.1 mg/kg every 4 weeks to 3.5 mg/kg every 3 weeks. In total, 85 patients were enrolled in the phase 1a portion, and 65 patients were enrolled in the phase 1b portion.

In the entire study population, the median age was 52.0 years (range, 27-76), and most patients were female (97.3%). Among the patients with breast cancer, 77.2% has HER2-positive disease, and 22.1% had HER2-low disease. Among the patients with other cancers, 2 had HER2 2+ disease by immunohistochemistry (IHC), and 3 had HER2 3+ disease by IHC. The most common sites of metastases included the lymph nodes (60.7%), lung (54.0%), bone (42.0%), and liver (42.0%). Furthermore, 7.3% of patients had brain metastases, and 59.3% of patients across all dose groups had at least 3 metastatic sites. Of the patients with HER2-positive disease who received the RP2D, 99% had visceral metastases.

Among the entire population, patients had received a median of 3.0 prior lines of therapy (range, 1-16). All patients with HER2-positive breast cancer had received prior HER2-directed therapy, including trastuzumab (Herceptin; 95.5%), pyrotinib (67.0%), and pertuzumab (Perjeta; 33.9%). Additionally, 5.4% of patients had received prior treatment with T-DM1.

At data cutoff, 64.7% of patients had discontinued treatment, mostly due to disease progression (79.4%).

Among the 2 DLTs observed in the dose-escalation portion, 1 was a grade 2 decrease in creatinine clearance at the 3.0 mg/kg dose level, and the other was grade 3 thrombocytopenia with subcutaneous hemorrhage at the 3.5 mg/kg dose level.

In the overall population, drug-related treatment-emergent adverse effects (TEAEs) were reported in 97.3% of patients, the most common of which were increased aspartate aminotransferase (66.7%), hypokalemia (51.3%), and increased alanine aminotransferase (44.0%). Thirty-four percent of patients had grade 3 or higher drug-related TEAEs, the most common of which were hypokalemia (15.3%) and decreased platelet counts (8.0%). Serious AEs related to FS-1502 were reported in 9.3% of patients, the most common being decreased platelet counts (2.7%). Investigators observed no severe gastrointestinal AEs nor left ventricular ejection fraction decreases.

In the overall population, TEAEs led to drug interruption and dose reduction in 30.7% and 24.7% of patients, respectively. The most common TEAEs leading to drug interruption or dose reduction were hypokalemia (9.3%), proteinuria (8.7%), and weight loss (8.7%). Four patients had TEAEs leading to death: bacterial pneumonia (n = 1), hemoptysis (in 1 patient with an invasive cancer lesion in a main bronchus), and pneumonitis (in 2 patients with poor baseline lung function, including 1 who received several prior rounds of chest radiotherapy for chest lesions and 1 with diffused metastatic lesions in 2 lungs).

Among all patients with grade 3 or higher hypokalemia, blood potassium levels returned to normal or grade 1 after intravenous or oral potassium supplementation. Of the 12 patients who had grade 3 or higher decreased platelet counts, none needed drug discontinuations, and no bleeding AEs occurred except for subcutaneous bleeding in 1 patient who received FS-1502 at 3.5 mg/kg, continued treatment after dose reduction, and experienced no further bleeding. All patients with grade 3 or higher decreased platelet counts recovered after platelet receptor agonist or thrombopoietin treatment.

In total, 55.3% of patients had ocular drug-related TEAEs, most of which were grade 1/2. The most frequently observed drug-related ocular TEAEs were dry eye (24.0%), keratitis (18.0%), and dry eye syndrome (11.3%). Four patients had grade 3 ocular drug-related TEAEs: dry eye (n = 2), blurred vision (n = 1), and dry eye syndrome (n = 1). All these patients received FS-1502 at 2.3 mg/kg every 3 weeks. All observed ocular TEAEs were reversible. The grade 3 toxicities decreased to grade 1 or lower through supportive measures including ocular lubricant; a topical antibiotic and anti-inflammatory agent; and other corneal epithelial recovery interventions.

Objective responses were observed starting at dose levels of 1.0 mg/kg every 4 weeks. The ORR was 48.4% in patients with HER2-positive breast cancer across all these dose levels.

Among the patients with HER2-positive breast cancer who received the RP2D, 34.3% had stable disease (SD) by data cutoff, resulting in a disease control rate of 88.1% (95% CI, 77.8%-94.7%). The median time to response was 2.7 months (95% CI, 1.2-NR), and the median DOR was NR. The median PFS was 15.5 months (95% CI, 4.6-NR). OS data were not mature at data cutoff.

Of 15 efficacy-evaluable patients with HER2-low breast cancer who received the RP2D, 4 achieved a PR, and 5 had a best response of SD. Among the patients other HER2 expressing tumors , 2 patients—1 each with ampullary and lung cancer—had a PR, and the remaining 3 patients had a best response of SD.

“FS-1502 showed higher ORR in patients with HER2-positive than in those with HER2-low breast cancer, [which] may be related to the hydrophobicity and low bystander cell penetration of the payload effect of MMAF,” the authors noted.

An ad hoc, exploratory, retrospective analysis was performed for patients with HER2-positive breast cancer who received the RP2D and had hormone receptor (HR)–positive or HR-negative disease. In these 2 groups, the respective ORRs were 67.6% (95% CI, 49.5%-82.6%) and 40.6% (95% CI, 23.7%-59.4%).

“The ad hoc analysis of this study showed a higher ORR in [patients with] HR-positive [breast cancer] than [patients with] HR-negative [disease,” the authors explained. “The mechanism behind this is not clear. Crosstalk between the HER2 and HR signaling pathways might be one reason.”

Among patients with HER2-positive breast cancer who received the RP2D and had target lesions in the liver, lungs, and lymph nodes, the ORRs were 67.9% (95% CI, 47.7%-84.1%), 39.1% (95% CI, 19.7%-61.5%) and 55.6% (95% CI, 35.3%-74.5%), respectively. In patients with ECOG performance statuses of 0 (n = 31) and 1 (n = 36), the respective ORRs were 64.5% (95% CI, 45.4%-80.8%) and 44.4% (95% CI, 27.9%-61.9%). In patients at least 65 years of age and younger than 65 years of age, the respective ORRs were 37.5% (95% CI, 8.5%-75.5%) and 55.9% (95% CI, 42.4%-68.8%). ORRs were similar between subgroups regarding prior pertuzumab use, number of prior treatment regimens (excluding hormone therapy), and Ki-67 index.

A pharmacokinetic analysis of serum concentrations showed that FS-1502 exposure increased with increasing doses and that the ADC has time-dependent clearance and nonlinear pharmacokinetics. Investigators observed similar pharmacokinetic profiles between the total antibody and the ADC, although exposure and concentration levels were slightly higher for the antibody than the ADC.

At the pharmacokinetics data cutoff of July 30, 2022, among 81 evaluable patients, 5 had detectable anti-drug antibodies (ADAs), 3 of whom were ADA positive at baseline. The magnitude and incidence of immunogenicity in these patients were low.

The authors note that this study’s limitations include its open-label, single-arm nature, which limits definitive conclusions regarding efficacy compared with those that can be drawn from randomized, blinded studies. Additionally, because of safety considerations, the initial dose levels of FS-1502 were low, which may have limited the efficacy of the ADC in initial cohorts. Furthermore, this study allowed for the use of retrospective HER2 status reports; as such, HER2 expression levels at the time of study treatment may have been different than reported for some patients. The authors emphasized that this trial is ongoing and that changes in the efficacy and safety findings may be seen after longer follow-up.

“Further randomized controlled studies with a larger sample size will be needed to confirm the efficacy and safety of FS-1502 in HER2-positive breast cancer,” the authors concluded.

A randomized, controlled, phase 3 trial (NCT05755048) is ongoing to compare FS-1502 with T-DM1 in patients with HER2-positive advanced breast cancer.


  1. Li Q, Cheng Y, Tong Z, et al. HER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial. Nat Commun. 2024;15(1):5158. doi:10.1038/s41467-024-48798-w
  2. Shin SH, Park YH, Park SS, et al. An elaborate new linker system significantly enhances the efficacy of an HER2-antibody-drug conjugate against refractory HER2-positive cancers. Adv Sci (Weinh). 2021;8(23):e2102414. doi:10.1002/advs.202102414
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