Neoadjuvant SHR-A1811 Produces pCRs in Early HER2+ Breast Cancer

Breast Cancer
| Image Credit: © Sebastian Kaulitzki – stock.adobe.com

Although the efficacy of standard-of-care neoadjuvant treatment strategies has been established in the treatment of patients with early-stage HER2-positive breast cancer, neoadjuvant data for the antibody-drug conjugate SHR-A1811 highlight the potential role for the use of this class of agents in this setting, according to Jun-Jie Li, MD.

Findings from the phase 2 FASCINATE-N trial (NCT05582499) presented at the 2024 San Antonio Breast Cancer Symposium (SABCS) demonstrated a pathologic complete response (pCR) rate of 63.2% (95% CI, 53.9%-71.8%) with SHR-A1811 monotherapy (n = 87). Patients treated with SHR-A1811 plus pyrotinib (n = 88) experienced a pCR rate of 62.5% (95% CI, 53.2%-71.1%), and those randomly assigned to PCbHP (nab-paclitaxel [Abraxane], carboplatin, trastuzumab [Herceptin], and pertuzumab [Perjeta]; n = 90) achieved a pCR rate of 64.4% (95% CI, 55.3%-72.8%).

“We found that the 3 [regimens] had a similar efficacy [data],” Li said.

In an interview with OncLive^®, Li provided background on SHR-A1811, explained the rationale for exploring the use of ADCs in the neoadjuvant setting, and detailed the significance of the FASCINATE-N findings.

Li is a surgical oncologist and the associate chief of the breast cancer department at Fudan University Shanghai Cancer Center in China.

OncLive: What is the mechanism of action of SHR-A1811?

Li: SHR-A1811 is a third-generation anti-HER2 ADC. It's composed of trastuzumab, a cleavable linker, and a topoisomerase 1 inhibitor payload. The drug:antibody ratio is 6. Currently, we don't have any results [on] another third-generation ADC in the neoadjuvant treatment of HER2-positive breast cancer.

The whole world is now waiting for [results] from the [phase 3] DESTINY-Breast11 trial [NCT05113251] evaluating [neoadjuvant] fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], but [DESTINY-Breast11] has a bit of different trial design. It's a phase 3 trial, and it's composed of the 3 arms. One arm is evaluating [neoadjuvant] T-DXd for 8 cycles; the second arm B is T-DXd for 4 cycles, followed by 4 cycles of THP [docetaxel, trastuzumab, and pertuzumab]; and the [control] arm is AC [doxorubicin plus cyclophosphamide] followed by THP. [DESTINY-Breast11] is a phase 3 trial to see whether T-DXd is superior to the current standard [neoadjuvant] therapy.

However, FASCINATE-N was a phase 2 trial. We compared [SHR-A1811 with or without pyrotinib] with the PCbHP regimen, [which features] dual anti-HER2 therapy [trastuzumab and pertuzumab] plus chemotherapy [nab-paclitaxel and carboplatin]. According to the literature, PCbHP [is associated with] a higher pCR rate vs AC followed by THP.

What were the efficacy findings that were presented at the 2024 SABCS?

The pCR rate ranged between 60% to 65% [in all 3 arms]; however, I should mention that the standard [neoadjuvant] therapy for HER2-positive breast cancer is quite [efficacious]. Usually, for [patients with] low-risk HER2-positive early-stage breast cancer, we are testing ways to de-escalate treatment. Therefore, in our clinical trial, we tried to enroll patients with higher tumor burden. More than 90% of patients were lymph node positive, and approximately 70% of patients had stage III [disease].

Even with this higher tumor burden, our pCR rate was quite promising. [The pCR rate with single-therapy SHR-A1811 monotherapy was] 63.2%; in patients with hormone receptor [HR]–negative, HER2-positive [disease (n = 47)], the pCR rate was 74.5% [with SHR-A1811 alone], and [in those with] HR-positive, HER2-positive [disease (n = 40)], the pCR rate was 50.0%

What safety findings were observed from this agent?

When compared with the PCbHP, although the proportion of grade 3/4 [treatment-related adverse] effects [TRAEs] was similar, SHR-A1811 monotherapy had lower rates of dose reduction [10.3% vs 13.3%] and drug discontinuation [5.7% vs 16.7%] due to TRAEs. [SHR-A1811 monotherapy was also associated with] lower rates of alopecia, neutropenia, diarrhea, and neuropathy [vs PCbHP].

However, when we combined [SHR-A1811] with [pyrotinib], we had a higher rate of grade 3/4 TRAEs, especially diarrhea.

What are the next steps of research for SHR-A1811?

We have the tumor tissue and blood [samples from enrolled patients] that can all be used in clinical analysis [to assess] the different characteristics, [which could help us identify] different patients with HER2-positive [disease] who may be sensitive to the ADC, PCbHP, both, or neither.

In the future, we could use the ADC as a backbone for select patients if they are sensitive to this kind of [therapy]. Monotherapy may be enough, but if patients are not sensitive [to treatment], we can test why it's not sensitive. We could combine [SHR-A1811] with immune therapy, pertuzumab, or endocrine therapy.

Reference

Li J-J, Wang Z-H, Chen L, et al. HER2-directed antibody-drug conjugate SHR-A1811 in the neoadjuvant treatment of HER2-positive early breast cancer: a prospective, randomized, open-label, phase 2 trial. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract GS1-04.