Overview of clinical trials of TROP-2 ADC drugs

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Overview of clinical trials of TROP-2 ADC drugs

Overview of clinical trials of TROP-2 ADC drugs.

Human trophoblast cell surface glycoprotein antigen (TROP-2), also known as tumor-associated calcium signal transducer 2 (TACSTD2), is the protein product of the TACSTD2 gene and is a type I cell surface glycoprotein that is highly expressed in human cancers.

Because TROP-2 is widely expressed in a variety of solid tumors, it has become an emerging hot target for ADC research and development.

Currently, 28 clinical trials related to TROP-2 ADC drugs are registered on clinicaltrials.

Since Trop-2 is also expressed in normal tissues, the toxicity of anti-Trop-2 ADCs is a very important issue. However, from the existing preclinical data and most ongoing clinical trials, the dose-limiting toxicity of Trop-2 ADC is closely related to the payload, and seems to have nothing to do with the targeted antigen.

Research on DS-1062a in Triple Negative Breast Cancer (NCT 03401385)

Datopotamab deruxtecan (DS-1062a) is an ADC targeting TROP2 antibody conjugated to DXd. ROPION-PanTumor01 is a phase 1 clinical trial for TNBC. In 21 evaluable patients who received datopotamab deruxtecan, it was blinded According to independent central evaluation, the initial objective response rate (ORR) was 43%.

As of the data cutoff on January 8, 2021, 5 patients had confirmed complete or partial remission (CR/PR), and another 4 had CR/PR awaiting confirmation. The disease control rate (DCR) reached 95%. In the TNBC cohort, the observed safety of datopotamab deruxtecan is consistent with the safety previously reported in the non-small cell lung cancer (NSCLC) cohort of this trial.

Trodelvy’s Phase I/II Study in Epithelial Cancer (NCT01631552)

Sacituzumab govitecan (Trodelvy) is an ADC targeting Trop-2 antibody coupled to SN-38. The first phase of the clinical trial tested the safety and tolerability of IMMU-32 on 13 different epithelial tumors in 25 patients. The study included patients with different tumor types, including breast cancer, colorectal cancer, endometrial cancer, small cell lung cancer and non-small cell lung cancer.

At the end of the study, 2 patients had a partial response (PR), 16 patients were in stable condition (SD), and 6 of them survived for more than 15-20 months. In this study, there were no treatment-related grade 4 toxicities, and grade 3 toxicities were limited to diarrhea (n=1), fatigue (n=3), and neutropenia (n=2). The results showed that IMMU-132 is generally a well-tolerated therapeutic drug.

The results of the second phase of research on different types of tumors are as follows:

Trodelvy Phase II Study in Patients with Breast Cancer

The results showed that of 69 patients, 2 patients had a complete response and 19 patients had a partial response. The clinical benefit rate of this group (defined in this study as complete remission + partial remission + stable disease ≥ 6 months) was 46%. The median remission period was 8.9 months, the median overall survival period was 16.6 months, and the median progression-free survival period was 6.0 months. Adverse events ≥ grade 3 included anemia (14%), diarrhea (13%), leukopenia (16%), and neutropenia (39%).

Trodelvy Phase I/II Study in Patients with Urothelial Carcinoma

3 out of 6 patients had clinically significant response, progression-free survival period was 6.7-8.2 months, and overall survival period was 7.5 months+ to 11.4 months+. Two of the 6 patients experienced grade 3 adverse reactions (low back pain and bacteremia), and no grade 4 adverse reactions were observed.

Trodelvy’s Phase II Study in NSCLC Patients

Among 54 patients with metastatic NSCLC, the clinical benefit rate (defined in this study as complete remission + partial remission + stable disease) ≥ 4 months) was 43%. In addition, the median duration of response to treatment was 6 months, the median overall survival was 9.5 months, and the median progression-free survival was 5.2 months.

Regarding toxicity, adverse reactions of grade ≥3 include diarrhea (7%), fatigue (6%), neutropenia (4%), nausea (7%), and neutropenia (28%).

Trodelvy in the Phase II study of SCLC patients

In another study of patients with metastatic small cell lung cancer, 60% of patients showed tumor shrinkage compared with baseline CT, and the clinical benefit rate was 34% (this study was defined as complete remission + partial remission + stable disease ≥ 4 month). The median overall survival was 7.5 months, and the median progression-free survival was 3.7 months.

Regarding toxicity, adverse reactions of grade ≥3 include anemia (6%), diarrhea (9%), fatigue (13%), and neutropenia (34%).

Phase II study of Trodelvy in urothelial carcinoma (NCT03547973)

TROPHY is a single-arm, international multi-center phase II clinical study. The study recruited 112 patients with locally advanced or metastatic UC who had been treated with platinum-based chemotherapy and PD-1 or PD-L1 inhibitors.

The results of the study showed that the ORR of 112 curatively assessable patients was 27.7%, of which 5.4% achieved CR and 22.3% achieved PR. The median duration of response (mDoR) was 7.2 months (95%CI: 4.7-8.6). The most common adverse reactions (incidence> 25%) include neutropenia, nausea, diarrhea, fatigue, hair loss, anemia, vomiting, constipation, loss of appetite, skin rash, and abdominal pain.

Trodelvy’s Phase III Study in Triple Negative Breast Cancer (NCT 02574455)

ASCENT is an international, open-label phase III clinical study that enrolled 529 patients with relapsed and refractory metastatic triple-negative breast cancer who had previously received at least 2 types of chemotherapy (including paclitaxel).

The median PFS in the treatment group was 5.6 months (4.3 to 6.3), and the chemotherapy control group was 1.7 months (1.5 to 2.6). The Trodelvy treatment group could reduce the risk of disease progression by 59%. In terms of secondary endpoints, Trodelvy significantly improved the patient’s OS (12.1 vs 6.7 months), the risk of death was reduced by 52%, the ORR of the treatment group was 35% (82/235), and the chemotherapy control group was only 5% (11/233).

In terms of safety, compared with the control group, treatment-related adverse events above grade 3 mainly include neutropenia (51% vs 33%), diarrhea (10% vs 1%), and leukopenia (10% vs 5%) ), anemia (8% vs 5%), and neutropenic fever (6% vs 2%).

Study of PF-06664178 in patients with advanced solid tumors (NCT02122146)

PF-06664178 is an ADC of Trop-2 targeting antibody coupled to Aur0101 (an auristatin microtubule inhibitor), and clinical development has now been terminated. In the phase 1 clinical study that has been carried out, 31 patients with metastatic solid tumors received an increasing dose (0.15-4.8 mg/kg) of PF-0664178. Among the 31 cases, 11 cases were in stable condition, and there was no complete or partial response.

Regarding toxicity, 33% of patients had dose-limiting toxicity at a dose of 3.6 mg/kg, and the toxicity was grade 4 neutropenia and grade 3 mucosal inflammation. At a dose of 4.2 mg/kg, 1/1 (100%) patients had dose-limiting toxicity, grade 3 macular papules. At a dose of 4.8 mg/kg, 4 out of 8 patients (50%) developed dose-limiting toxicities, including grade 4 febrile neutropenia, grade 4 toxic epidermal necrolysis, grade 4 dehydration, and 3 Grade rash.

Overview of clinical trials of TROP-2 ADC drugs

(source:internet, reference only)

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