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Release date:2023/3/9 9:57:31

Gastric cancer is one of the most common gastrointestinal malignancies worldwide, of which approximately 12-20% of gastric cancer patients have HER2 overexpression or gene amplification [1]. More than a decade ago, the seminal ToGA study led to routine use of the monoclonal antibody trastuzumab in conjunction to platinum-fluoropyridimine first-line chemotherapy for HER2-positive gastric cancers as standard-of-care. [2] However, since the progression of first-line anti-HER2 therapy, second-line and subsequent anti-HER2 therapy did not show significant benefits until the emergence of the DESTINY-Gastric01 study, since then ADC drugs have been in full swing in the field of HER2-targeted gastric cancer.

Antibody-Drug Conjugate (ADC) for Gastric Cancer

Antibody-Drug Conjugates (ADCs) are composed of monoclonal antibodies covalently bound to cytotoxic drugs via linkers, combining both targeting and cytotoxic effects, and are known as magic bullets. After intravenous administration, ADCs enter circulation, After intravenous administration, ADCs enter circulation, distribute to tumor tissues and bind to the tumor surface antigen. The antigen then undergoes endocytosis to internalize the ADC into tumor cells, where it is transported to lysosomes to release the payload. The released toxic payloads can induce apoptosis through DNA damage or microtubule inhibition and can kill surrounding cancer cells through the bystander effect. 

ADC-MOA

Figure. Mechanism of action of ADC

The rise of ADCs has brought new opportunities for HER2-positive gastric cancer. T-DXd was the first ADC approved for the third- or later-line treatment for HER2-positive gastric cancer with an objective response rate (ORR) of up to 51.3% and overall survival (OS) of up to 12.5 months. In addition, RC48 was also approved for third-line treatment of gastric cancer in China. Based on the good foundation of third-line treatment, ADC entered into second-line treatment, and the first second-line study for HER2-positive gastric cancer, DESTINY-Gastric02, is rapidly underway and offers new hope for patients.

ADC-for-GC

Table. Antibody-Drug Conjugate (ADC) for gastric cancer

Appoeved ADCs for Gastric Cancer

Trastuzumab deruxtecan

Trastuzumab deruxtecan (DS-8201 or T-Dxd) consists of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The antibody moiety of T-DXd blocks HER2 homo-heterodimerization and blocks the activation of downstream signaling pathways, thereby blocking tumor cell growth, proliferation, differentiation and migration. The cytotoxic payload DXd is 10 times more potent against tumors than the active metabolite of irinotecan (SN-38) and is not cross-resistant to conventional chemotherapeutic agents. The linker is a hydrophilic tetrapeptide linker, whose hydrophilic properties ensure the stability of the drug structure in the blood circulation and reduce toxic side effects. Inside the tumor cells, the linker is specifically cleaved by lysosomal enzymes to release the payload. After tumor cell apoptosis, the payload passes through the cell membrane, thus producing a "bystander effect" on surrounding tumor cells.

Structure-of-T-DXd

Figure. Structure of T-DXd. 

In the randomized, phase II trial DESTINY-Gastric01, T-DXd demonstrated a significantly higher objective response rate (51.3%) and a longer overall survival (12.5 months) in patients with pretreated HER2-positive advanced gastric cancer (AGC).[3] Based on the results of this study, T-DXd was approved for third- or later-line treatment for HER2-positive advanced gastric cancer in Japan in September 2020, making it the first ADC approved in HER2-positive advanced gastric cancer worldwide; and in January 2021, the FDA approved T-DXd for second- or later-line treatment for HER2-positive advanced gastric cancer.

In the single-arm, phase II trial of T-DXd, DESTINY-Gastric02 (NCT04014075), demonstrated a confirmed objective response rate (cORR) of 41.8%, mPFS of 5.6 months and mOS of 12.1 months. [4] Based on the results of the DESTINY-Gastric01 and DESTINY-Gastric02 studies, T-DXd was approved by the EMA second- or later-line treatment for HER2-positive advanced gastric cancer.

Disitamab Vedotin (RC-48)

Disitamab Vedotin (RC48) contains the novel humanized anti-HER2 antibody (hertuzumab) conjugated to monomethyl auristatin E (MMAE) via a cleavable linker.

molecular-structure-of-RC48

Figure. The molecular structure of RC48. 

In the phase I clinical trial (NCT02881190), RC48 showed good antitumor activity in solid tumors, including HER2-positive gastric cancer, with an ORR of 21% and a DCR of 49.1% [5]. In the single-arm phase II C008 study (NCT03556345), RC48 achieved an ORR of 24.8%, mPFS of 4.1 months, and mOS of 7.9 months in patients with HER2-positive advanced gastric cancer who had previously received second-line therapy and beyond [6].

Based on these results, RC48 was granted conditional marketing by the Chinese National Medical Products Administration (NMPA) in 2021 for the treatment of patients with HER2-positive locally advanced or metastatic gastric cancer or adenocarcinoma of the gastroesophageal junction who have received at least 2 systemic treatments. A randomized, multicenter, open-label Phase III clinical trial (NCT04714190) is currently underway to confirm the efficacy of RC-48 versus standard therapy in extending survival in patients with HER2-positive advanced gastric cancer.

Clinical Trails of ADCs for Gastric Cancer

Trastuzumab emtansine (T-DM1)

Trastuzumab emtansine (T-DM1) consists of a humanized anti-HER2 monoclonal antibody (trastuzumab), a non-cleavable thioether linker and the microtubulin inhibitor DM1.

TDM1

Figure. Structure of T-DM1

In the multicenter phase II/III clinical study GATSBY [7], T-DM1 failed to improve median overall survival (mOS: 7.9 months vs. 8.6 months, P=0.86) and median progression-free survival (mPFS: 2.7 months vs. 2.9 months, P=0.31) over paclitaxel in patients with HER2-positive metastatic gastric cancer after failure of first-line therapy. In addition, primary and acquired resistance to T-DM1 was observed in preclinical models of gastric cancer, and the use of T-DM1 in gastric cancer remains to be explored.

SYD985

SYD985 (trastuzumab duocarmazine) comprises of trastuzumab covalently bound to a linker drug containing the DNA-alkylating agent duocarmycin. SYD985 showed promising preclinical anti-tumor activity in solid tumor cell lines with varying HER2 expression, including those derived from gastric cancers. First-in-human assessment was conducted in patients with breast, gastric, urothelial and endometrial cancer with at least HER2 IHC expression of 1+. The non-breast cancer expansion cohort included 16 gastric adenocarcinoma patients. Of these, 1 patient had a partial response (ORR: 6%) and a median PFS was 3.2 months (95% CI 1.6–5.3 months) [51]. The safety, pharmacokinetics and efficacy of SYD985 is next assessed in combination with niraparib, a PARP inhibitor, in HER2-expressing advanced solid tumours (NCT04235101).

SYD985-formula

Figure. Structure of SYD985

ARX788

ARX788 is comprised of a humanized HER2 targeting mAb conjugated to a cytotoxic tubulin inhibitor, Amberstatin (AS269).

ARX-788

Figure. Structure of ARX788

At the annual meeting of the Chinese Society of Clinical Oncology (CSCO) in 2021, results from a phase Ib clinical study of ARX788 for HER2-positive advanced gastric cancer were published [8]. The results showed that ARX788 was well tolerated in patients with HER2-positive advanced gastric adenocarcinoma. 28 patients (93.3%) experienced at least one drug-related adverse event (TRAE) and were mostly classified as grade 1 to 2 TRAEs. 4 patients (13.3%) experienced ≥grade 3 TRAEs, including ocular adverse events, interstitial lung disease (ILD), anemia, and elevated glutamyl transferase levels. Meanwhile, ARX788 showed a more favorable antitumor effect, including a confirmed objective response rate (cORR) of 37.9% and a median duration of response (DOR) of 8.4 months. The median progression-free survival (mPFS) and overall survival (OS) were 4.1 months and 10.7 months, respectively.

In summary, with the continuous development and improvement of ADC clinical studies, more and more ADCs are continuously joining the army of anti-HER2 therapy for gastric cancer. In the future, we look forward to the publication of more clinical study data in this war against HER2-positive gastric cancer.

References:
[1]  Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Annals of Oncology. Sep 2008; 19 (9): 1523-1529
[2] Bang YJ,Van Cutsem E,Feyereislova A,et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer(ToGA):a phase 3,open-label,randomised controlled trial.Lancet.2010 Aug 28;376(9742):687-97.
[3] Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020;382(25):2419-2430.
[4] Van Cutsem E, di Bartolomeo M, Smyth E, et al. Primary analysis of a phase 2 single-arm trial of trastuzumab deruxtecan (T-DXd) in Western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) Cancer who progressed on or after a trastuzumab-containing regimen. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA55
[5] Xu Y, Wang Y, Gong J, et al. Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer. 2021;24(4):913-925. doi:10.1007/s10120-021-01168-7
[6] Peng Z, Liu T, Wei J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study. Cancer Commun (Lond). 2021;41(11):1173-1182. doi:10.1002/cac2.12214
[7] Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomized, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640-653.
[8] Yang Zhang, Miao-Zhen Qiu, Ju-Feng Wang, et al. Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma. 2022, Cell Reports Medicine 3, 100814 November 15, 2022. https://doi.org/10.1016/j.xcrm.2022.100814

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