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New drug research is the first to know
Written by: Su Xuhan
About 20% of breast cancer patients have human epidermal growth factor receptor-2 (HER2) overexpression. Patients with HER2 overexpression/amplification tend to have a worse prognosis and higher mortality compared with HER2-negative cases [1]. In recent years, HER2-targeted therapy has significantly improved the prognosis of patients with HER2-positive breast cancer.
Among the various types of HER2-targeted therapies, antibody-drug conjugates (ADCs) have developed rapidly, and three drugs have been approved: trastuzumab (T-DM1), trastuzumab (T-DXd), and vedicitumab (RC48). FS-1502 is a next-generation site-directed conjugated cleavage ADC consisting of a cleavable β-glucuronate linker, the trastuzumab biosimilar HLX45-mAb, and a microtubule inhibitor auristatin methyl F (MMAF). Preclinical data show that FS-1502 has significant HER2 targeting and potent antitumor activity[2].
Recently, the journal Nature communications, the top international medical journal, published the results of a phase Ia/Ib study on FS-1502 conducted by the team of academician Xu Binghe from the Cancer Hospital of the Chinese Academy of Medical Sciences. In this article, we summarize the highlights of the research for readers' reference.
Figure 1 Research cover (source: official website)
Study design
The study is a multicenter, open-label, single-arm, Phase 1a/1b clinical trial consisting of two phases: dose escalation (Phase 1a) and dose expansion (Phase 1b).
- The Phase 1a trial was designed to evaluate the safety and tolerability of FS-1502 in patients with HER2-expressing advanced solid tumors, with the primary outcomes being dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D).
- The Phase 1b trial was designed to evaluate the efficacy and safety of FS-1502 in patients with HER2-positive metastatic breast cancer who have received at least two prior lines of therapy and failed anti-HER2 therapy, with objective response rate (ORR) as the primary outcome measure and disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS) as secondary outcomes.
Findings:
A total of 150 patients were treated with FS-1502, including 85 and 65 patients enrolled in Phase 1a and Phase 1b, respectively, with a median follow-up of 5.8 months. The treatment plan and duration of treatment received by the patients are shown in Figure 2.
Fig.2 Treatment plan design
Throughout the study, the median age of patients was 52.0 years (range 27-76 years), with the majority of patients being female (n=146, 97.3%). Among them, 145 patients (96.7%) were diagnosed with breast cancer; Two patients (1.3%) had lung cancer, and one case (0.7%) had ampullary cancer, submandibular gland malignancy, and gastric cancer, respectively. Among breast cancer patients, 112 (77.2%) were HER2-positive, and 32 (22.1%) had tumors expressing low levels of HER2. Among non-breast cancer patients, 2 (40%) had HER2 IHC 2+ and 3 (60%) had HER2 IHC 3+. The most common sites of metastases were lymph nodes (60.7%), lung (54.0%), bone (42.0%), and liver (42.0%); Eleven patients (7.3%) had brain metastases. Among all dose groups, patients with ≥ 3 metastases accounted for 59.3% (n=89). Almost all HER2-positive patients treated with RP2D (99%) had visceral metastases.
Of all enrolled patients, 88.7% had received a median of 3 lines of prior therapy, compared with 93.3% of patients in the RP2D dose group who had received ≥ 2 lines of prior therapy. All patients with HER2-positive breast cancer had received anti-HER2 therapy, with trastuzumab (n=107, 95.5%), pyrotinib (n=75, 67.0%), and pertuzumab (n=38, 33.9%). A small number of patients had been treated with T-DM1 (n=6, 5.4%). As of the data cut-off date, a total of 97 patients (64.7%) discontinued treatment, mainly due to disease progression (n=77, 79.4%). The baseline characteristics of specific patients are shown in Table 1.
Table 1 Baseline characteristics of patients
Safety and tolerability
- Drug-related treatment-related adverse events (TEAEs) occurred in 146 of 150 patients (97.3%). The most common drug-related TEAEs are elevated aspartate aminotransferase (AST), hypokalemia, and alanine aminotransferase (ALT).
- Grade 3 drug-related TEAEs ≥ 3 were developed in 34.0% of the patients, the most common of which were hypokalemia and thrombocytopenia; Serious adverse events (SAEs) related to the study drug were reported in 9.3% of patients, with the most common event being thrombocytopenia.
- 30.7% and 24.7% of patients discontinued or reduced therapeutic dose due to TEAEs, and no decreased left ventricular ejection fraction (LVEF) or serious gastrointestinal adverse reactions were observed in the study.
- In addition, 55.3% of patients developed drug-related ocular TEAEs, and 2.7% of patients had grade 3 drug-related ocular TEAEs, including 2 cases of dry eye syndrome, 1 case of blurred vision, and 1 case of dry eye syndrome. However, the investigators emphasize that all ocular TEAEs are reversible and can be restored to grade ≤1 with ocular lubricants, topical antibiotics, and anti-inflammatory agents.
Table 2 Summary of adverse events
Antitumor activity
- Objective remission was observed in the dose group of 1.0 mg/kg Q4W and above;
- Of the 67 HER2-positive breast cancer patients treated with an RP2D of 2.3 mg/kg, 2 (3.0%) had a complete response (CR) and 34 (50.7%) had a partial response (PR).
- The optimal ORR was 53.7% (95% CI 41.1%-66.0%), the DCR was 88.1% (95% CI 77.8%-94.7%), the median PFS was 15.5 months (95% CI 4.6 months-not reached), and the median DoR and OS were not reached.
Fig.3 Anti-tumor activity of FS-1502 at 2.3 mg/kg based on the efficacy analysis set (A. Duration of treatment, B. Optimal percent change from baseline in the sum of diameters of target lesions, C. PFS)
In conclusion, the above results suggest that FS-1502 has good tolerability and anti-tumor activity in patients with HER2-positive advanced breast cancer. However, due to the open-label, single-arm design of the study and the small sample size, the conclusions drawn are still validated by randomized controlled studies with larger sample sizes.
FS-1502 is currently in Phase II clinical trials in various HER2-positive solid tumor indications, including lung, gastric and colorectal cancer. In addition, a randomized controlled phase III trial comparing FS-1502 with T-DM1 in HER2-positive, unresectable locally advanced/metastatic breast cancer is underway. At present, there are hundreds of ADC drugs in different stages of development, and it is believed that the new generation of ADC drugs will greatly enhance the efficiency and attenuation of drugs, and provide more and better treatment options for cancer patients.
参考文献：[1] Chia S, Norris B, Speers C, et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol. 2008; 26(35):5697-5704. doi:10.1200/JCO.2007.15.8659
[2] Rathi C, Collins J, Struemper H, Opalinska J, Jewell RC, Ferron-Brady G. Population pharmacokinetics of belantamab mafodotin, a BCMA-targeting agent in patients with relapsed/refractory multiple myeloma. CPT Pharmacometrics Syst Pharmacol. 2021; 10(8):851-863.
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