Sertaly (trastuzumab botidotin)

P1, N=120, Active, not recruiting, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

Furthermore, we present updated clinical trial data for published HER2-targeted agents and explore ongoing clinical trials examining combinatorial therapies and next-generation HER2-targeted agents such as zongertinib, A166, ARX788, SHRA1811, and others. Given the rapid evolution in this field, our review offers a timely and comprehensive synthesis of the current state and future directions for HER2-altered NSCLC.

P3, N=365, Active, not recruiting, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

P1, N=120, Recruiting, Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Jun 2023 --> Jun 2025

P1/2, N=49, Completed, Klus Pharma Inc. | Active, not recruiting --> Completed

For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.

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.

Median age was 53.5 years (range 26-71), 58 pts (100%) had prior HER2-targeted therapy with the median lines of 4, including 100% received trastuzumab ± pertuzumab, 94.8% received anti-HER2 TKIs, and 20.7% received anti-HER2 ADCs in the metastatic setting. The previously demonstrated preliminary clinical benefit of A166-ADC was maintained with no new safety signals, which demonstrated manageable toxicity and encouraging anti-tumor activity in heavily pretreated HER2-positive metastatic breast cancer patients.

P1, N=120, Recruiting, Sichuan Kelun Pharmaceutical Research Institute Co., Ltd.

A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.

P1/2, N=49, Active, not recruiting, Klus Pharma Inc. | Recruiting --> Active, not recruiting | N=82 --> 49