anvatabart opadotin (JNJ-0683)

P1, N=106, Completed, Ambrx, Inc. | Active, not recruiting --> Completed

P2, N=36, Not yet recruiting, Laura Huppert, MD, BA

P2, N=71, Recruiting, Ambrx, Inc.

P1, N=106, Active, not recruiting, Ambrx, Inc.

If recently progressed on T-DXd or trastuzumab emtansine (T-DM1), a new biopsy for HER2 status is required. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients.

P2, N=71, Recruiting, Ambrx, Inc. | Active, not recruiting --> Recruiting | N=31 --> 71 | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Jun 2024 --> Jun 2025

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.

In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. The median duration of response is 8.4 (95% CI: 2.1-18.9) months. ARX788 is well tolerated and has promising anti-tumor activity in patients with HER2-positive advanced gastric adenocarcinoma (ChinaDrugTrials.org.cn: CTR20190639).

P1, N=106, Active, not recruiting, Ambrx, Inc. | Recruiting --> Active, not recruiting | N=190 --> 106 | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Aug 2022 --> May 2023

ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T- DM1, T-DXd, and/or tucatinib-containing regimens...5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD)... In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%). ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1.

P2, N=31, Active, not recruiting, Ambrx, Inc. | Recruiting --> Active, not recruiting | N=220 --> 31

P2, N=220, Recruiting, Ambrx, Inc. | Trial completion date: Feb 2025 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Jun 2024

P2, N=30, Recruiting, Shengjing Hospital | Not yet recruiting --> Recruiting

The first patient enrolled in 07-Feb-2022 under protocol version 2. The study is currently recruiting patients.

P2/3, N=150, Recruiting, Caigang Liu

P2, N=0, Withdrawn, Ambrx, Inc. | N=250 --> 0 | Trial completion date: Jan 2025 --> Apr 2022 | Initiation date: Mar 2022 --> Nov 2021 | Recruiting --> Withdrawn | Trial primary completion date: Oct 2024 --> Apr 2022

P2, N=54, Recruiting, Fudan University | Not yet recruiting --> Recruiting

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.

P2, N=250, Recruiting, Ambrx, Inc. | Not yet recruiting --> Recruiting | Initiation date: Oct 2021 --> Mar 2022 | Trial primary completion date: Nov 2023 --> Oct 2024

At the 1.5 mg/kg dose level, ARX788 had robust anti-tumor activity in patients whose disease was resistant/refractory to other HER2 targeted therapies and was generally well tolerated with low systemic toxicity. Table 1 Summary of ACE-Breast-01 Confirmed ORR in patients whose disease is resistant or refractory to prior HER2 treatment (trastuzumab, ADCs, TKIs, and bispecific antibodies) at ARX788 1.5 mg/kg Q3W *All patients (29/29) received prior trastuzumab-containing regimens.**One patient who received prior pertuzumab also achieved confirmed PR.

The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information.

P2, N=250, Not yet recruiting, Ambrx, Inc.

P1, N=190, Recruiting, Ambrx, Inc. | Trial primary completion date: Mar 2022 --> Aug 2022

P2, N=250, Not yet recruiting, Ambrx, Inc.

P2, N=54, Not yet recruiting, Fudan University

P2, N=32, Recruiting, Fudan University

P2, N=30, Not yet recruiting, Shengjing Hospital

P2, N=200, Recruiting, Ambrx, Inc. | Not yet recruiting --> Recruiting | Trial completion date: Nov 2024 --> Feb 2025

ARX788 was well tolerated with promising antitumor activity in patients with HER2-positive advanced gastric and GEJ adenocarcinoma.

ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies . High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs.

P2, N=200, Not yet recruiting, Ambrx, Inc.

P1, N=190, Recruiting, Ambrx, Inc. | N=60 --> 190 | Trial completion date: Aug 2021 --> Mar 2023 | Trial primary completion date: Jun 2021 --> Mar 2022

The second interim analysis will be performed when 2/3 of the IRC assessed PFS events have occurred, in which early superiority will be declared if the P-value crossed the O’Brien Fleming boundary, and sample size will be recalculated if the conditional power is promising but below 80%. Global phase II/III trial of ARX788 to include sites in US and other regions is under planning.

Metabolism studies demonstrated pAF-AS269 was the sole major metabolite of ARX788, with no evidence for the release of free drug often observed in conventional ADCs and responsible for adverse side effects. Furthermore, ARX788 demonstrated a favorable safety profile in monkeys with a Highest Non-Severely Toxic Dose (HNSTD) of 10 mg/kg, which was well above the efficacious dose level observed in preclinical tumor models, thus supporting clinical development of ARX788.

P1, N=60, Recruiting, Ambrx, Inc. | Trial completion date: Aug 2020 --> Aug 2021 | Trial primary completion date: Aug 2020 --> Jun 2021

ARX788 was well tolerated in heavily-pretreated patients with HER2-positive metastatic breast cancer without evidence of Grade 3 or greater pneumonitis. Encouraging overall response rate was observed in 1.3 mg/kg Q3W cohort. Considering the predicted benefit/risk profile, 1.3 mg/kg Q3W is the recommended dose for further development of ARX788 in HER2-positive breast cancer.