Editor’s Note: With its remarkable therapeutic efficacy, DS-8201 has dramatically reshaped the treatment landscape for patients with advanced breast cancer. In HER2-positive advanced breast cancer, DS-8201 has firmly established its role as the standard second-line therapy and is also expected to move into the first-line setting in the near future.
However, for patients who have developed resistance after receiving DS-8201 (as well as other ADCs such as T-DM1), there are currently no approved and effective treatment options. This has created a major unmet clinical need. Current exploratory strategies include switching to ADCs targeting other antigens, or using HER2 ADCs with different payloads, but these novel agents remain in early clinical stages and lack clear breakthrough results.
At the 2025 ESMO Annual Congress, data from the Phase I clinical trial of the novel ADC SMP-656 (Abstract No. 552P) were presented. This study enrolled patients resistant to prior ADC therapies. Results showed that among HER2 ADC–resistant breast cancer patients treated with SMP-656, all experienced tumor shrinkage, and all patients resistant to DS-8201 achieved partial responses (PRs), suggesting the drug’s strong clinical potential.
Tumor Outlook invited Prof. Jian Zhang, principal investigator of the SMP-656 Phase I trial at Fudan University Shanghai Cancer Center, to discuss the efficacy and safety of SMP-656.
Study Overview
Study Background
SMP-656 is a novel antibody–drug conjugate (ADC) composed of a humanized anti-HER2 antibody linked via a unique cleavable linker to the payload eribulin, with a drug-to-antibody ratio (DAR) of 4.
In preclinical models resistant to HER2 ADCs (T-DM1 and DS-8201), SMP-656 demonstrated potent antitumor activity. Given the unmet clinical need among HER2 ADC–resistant patients, a Phase I clinical study was initiated to evaluate the safety and efficacy of SMP-656 in HER2-expressing solid tumors. The study primarily enrolled patients who had progressed after prior ADC therapy.
Study Design
The first part of the trial adopted a “3+3” dose-escalation design, with dose levels of 0.5, 1.0, 1.5, 2.0, and 2.5 mg/kg, administered once every three weeks (Q3W).
Patients with HER2-expressing or HER2-mutant locally advanced or metastatic solid tumors who were refractory to or intolerant of standard therapies were enrolled.
The primary endpoints were safety, dose-limiting toxicity (DLT), and determination of the recommended Phase II dose (RP2D). Secondary endpoints included efficacy and pharmacokinetics (PK).
Study Results
As of July 23, 2025, a total of 30 patients with HER2-expressing or HER2-mutant solid tumors were enrolled. The mean age was 50.9 ± 9.67 years, including 28 females.
Tumor types: 25 breast cancers, 2 non–small cell lung cancers, and 1 each of gastric, colorectal, and endometrial cancer. Prior ADC treatment: 21 patients (70%) had previously received ADC therapy.
Safety
Among the 30 patients, 29 (96.7%) experienced at least one treatment-emergent adverse event (TEAE). Seven patients (23.3%) experienced grade ≥3 TEAEs. No adverse events led to treatment discontinuation. No cases of interstitial lung disease (ILD) occurred.
In terms of hepatic or hematologic toxicity—commonly seen with eribulin—no adverse events requiring special attention were observed.
Common TEAEs (≥20%) included hypertriglyceridemia, thrombocytopenia, hypercholesterolemia, elevated AST, elevated ALT, peripheral neuropathy, anemia, hypokalemia, hyponatremia, and leukopenia.
Efficacy
Efficacy was assessed in 28 patients.
Among HER2-positive breast cancer patients who had not received prior ADC therapy, the objective response rate (ORR) was 100% (4/4).
In ADC-pretreated patients:
- At RP2D or higher doses, patients with prior DS-8201 treatment achieved an ORR of 100% (3/3).
- Patients previously treated with non–DS-8201 ADCs or multiple ADCs containing both topoisomerase I inhibitors and microtubule inhibitors achieved an ORR of 33%, with a disease control rate (DCR) of 100%.
Strong antitumor activity was observed in both HER2-high and HER2-low ADC-pretreated breast cancer patients.
Efficacy in ADC-Resistant Breast Cancer Patients
- 9 ADC-pretreated breast cancer patients were evaluable.
Among them:
- 3 patients previously treated only with DS-8201 achieved partial responses (PRs, ORR = 100%).
- 6 patients previously treated with non–DS-8201 ADCs or multiple ADCs achieved:
- 2 partial responses (ORR = 33%)
- 4 stable disease (SD)
- All 6 patients experienced tumor shrinkage (DCR = 100%).
Study Conclusions
SMP-656 demonstrated favorable tolerability and encouraging efficacy among breast cancer patients previously treated with ADCs. Further development of SMP-656 for HER2 ADC–pretreated breast cancer is planned.
Investigator’s Remarks
SMP-656 is a HER2-targeted antibody–drug conjugate (ADC) that innovatively employs the novel payload eribulin, with a drug-to-antibody ratio (DAR) of 4, conjugated via a hydrophilic and stable cleavable linker.
In preclinical studies, SMP-656 demonstrated potent antitumor activity across multiple models, especially in DS-8201–resistant breast and gastric cancers.
In the ongoing Phase I clinical study, significant efficacy signals have been observed—not only in HER2-positive breast cancer patients without prior ADC treatment (all of whom achieved objective responses), but also in those who had developed resistance after previous ADCs (including DS-8201 or multiple ADCs). All ADC-resistant patients experienced tumor shrinkage, and notably, all patients who had developed resistance after DS-8201 treatment achieved partial responses (PRs).
“I believe the unique mechanism of eribulin may be key to SMP-656’s ability to overcome resistance to prior HER2 ADCs,” said Prof. Jian Zhang. “Eribulin not only inhibits microtubule dynamics but also modulates the tumor microenvironment. This dual mechanism may make it particularly effective in overcoming resistance, providing strong scientific rationale for its continued clinical development.”
“The Phase I clinical study of SMP-656 is nearing completion, and subsequent studies are now in preparation.”
Prof. Jian Zhang
Chief Physician, Department of Medical Oncology Doctoral Supervisor Executive Director, Phase I Clinical Trials Unit Fudan University Shanghai Cancer Center
