BAT8001

Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors.Table 1. Subgroup analyses of ORRNo. of prior treatment lines in metastatic setting in all pts (N=250)HER2 positive BC (N=108)HER2-low BC (N=77)Other tumor types (N=65)≤381.8% (45/55)58.7% (27/46)36.7% (18/49)>381.1% (43/53)51.6% (16/31)31.3% (5/16)Prior anti-HER2 therapies in pts with BC (N=185)*HER2 positive BC (N=108)HER2-low BC (N=77)All BC (N=185)Any82.2% (88/107, 73.7-89.0)68.8% (11/16, 41.3-89.0)80.5% (99/123, 72.4-87.1)Trastuzumab81.9% (86/105, 73.2-88.7)75.0% (9/12, 42.8-94.5)81.2% (95/117, 72.9-87.8)Pertuzumab83.0% (39/47, 69.2-92.4)100% (5/5, 47.8-100)84.6% (44/52, 71.9-93.1)Pyrotinib86.9% (53/61, 75.8-94.1)71.4% (5/7, 29.0-96.3)85.3% (58/68, 74.6-92.7)Lapatinib80.0% (28/35, 63.1-91.6)100% (1/1, 2.5-100)80.6% (29/36, 64.0-91.8)T-DM182.4% (14/17, 56.6-96.2)100% (3/3, 29.2-100)85.0% (17/20, 62.1-96.8)Other HER2-ADC (except T-DM1)**60.0% (9/15, 32.3-83.7)50.0% (2/4, 6.8-93.2)57.9% (11/19, 33.5-79.8)ORR in pts with tumor types other than BC (N=65)HER2 IHC3+ or IHC2+/ISH+ (N=36)HER2 IHC2+/ISH- or IHC1+ or unknown (N=29)All other tumor types (N=65)% (n/N)38.9% (14/36)31.0% (9/29)35.4% (23/65)ORR was shown as % (n/N, 95% CI) or % (n/N).

Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026 and zanidatamab) and the anti-HER3 monoclonal antibodies; for both classes, clinical trials are ongoing...In the early setting, the first large, randomized, phase III trial testing the addition of an ICI (atezolizumab) to neoadjuvant dual-anti HER2 blockade and chemotherapy was negative [10]...In the phase Ib B-PRECISE-01 study (NCT03767335) the PI3 K inhibitor izorlisib (MEN1611) was tested in combination with trastuzumab ± fulvestrant in patients with HER2-positive/PIK3CA mutated metastatic breast cancer, showing a manageable safety profile with encouraging anti-tumor activity in heavily pre-treated patients (34.1% of partial responses, 2.4% complete response, 56.1% stable disease)...Thus, due to the close crosstalk between ER and HER2 receptor pathways, the simultaneous blockade of both signaling pathways represents a promising approach to prevent the onset of mechanisms of resistance. Large evidence supports the combination of endocrine and anti-HER2 therapies (often as maintenance treatment), while new strategies with novel agents (including novel SERDs, and CDK4/6i) are currently being investigated.

BAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

Patients and methods In this open-label, phase 1 trial, we recruited 29 patients aged 18 years or older with HER2-positive advanced or recurrent breast cancer who had been previously treated with trastuzumab and/or lapatinib plus cytotoxic agents. Conclusions BAT8001 was safe, tolerable and the preliminary activity seems promising in patients with HER2-positive advanced or recurrent breast cancer. The results suggest that BAT8001 has the potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer.