TROP2 positive

In the subcutaneous xenograft model using BxPC3 cells, the combined administration of αTROP2-MMAE and an autophagy inhibitor elevated the tumor inhibition rate of αTROP2-MMAE from 71.6 % to 99.0 %, resulting in the eradication of tumors in half of the mice. Collectively, our research demonstrated for the first time the cytoprotective role of autophagy in TROP2-targeted antibody-drug conjugate therapy for pancreatic cancer, providing new perspectives for mechanistic exploration and therapeutic strategies in the treatment of pancreatic cancer.

P3, N=675, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting | Trial primary completion date: May 2030 --> Apr 2028

Moreover, compared to sacituzumab govitecan, hIMB1636-LDP-AE showed more potent antitumor activity and significantly lower myelotoxicity in tumors with moderate Trop2 expression. This study fully revealed the potent antitumor efficacy of hIMB1636-LDP-AE, and also provided a new preparation method for LDM-based ADC, as well as a promising candidate for breast cancer and lung cancer therapeutics.

P3, N=675, Not yet recruiting, AstraZeneca

Following antigen-specific killing, these cells markedly secreted interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), IFN-γ, and Granzyme B compared to non-transduced T cells. This study highlights the therapeutic potential of anti-Trop2 CAR4-T cells in adoptive T cell therapy for BC, offering significant promise for the advancement of BC treatment strategies.

P=N/A, N=26, Completed, Xiang'an Hospital of Xiamen University | Recruiting --> Completed | N=20 --> 26 | Trial completion date: Jan 2024 --> Oct 2023

HuNb-MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer.

The recent approvals and data of pembrolizumab (anti-PD-1 inhibitor) in combination with chemotherapy in advanced-metastatic and early high-risk TNBC, and sacituzumab govitecan (an ADC that targets the tumor cell surface antigen TROP2 coupled with the irinotecan metabolite SN-38) in metastatic TNBC, has shed light on some of the immune and cancer signaling associated with TNBC. This preliminary analysis confirmed that only a limited number of early TNBC highly expressed PD-L1 and that a different immune suppressive landscape for PD-L1± and TROP2± tumors exists. In addition, our data suggest that early TNBC cases lacking PD-L1 might escape immune surveillance by virtue of the upregulation of key alternate signaling. Ongoing efforts investigating the expression of such markers on stroma/epithelial tumor components will help to clarify their biological, clinical, and potential therapeutic role in TNBC.

In addition to their high avidity, these polyclonal anti-sera against truncated Trop2 protein also mediated antibody-dependent cell-mediated cytotoxicity (ADCC). In summary, our comparative analysis demonstrated the utility of truncated Trop2 ECD as a promising candidate to be pursued as an active immunotherapeutic molecule against Trop2-positive cancer cells.

Patients will be randomized 1:1 to receive: Dato-DXd (6.0 mg/kg) + durvalumab (1120 mg) + carboplatin (AUC 5) as IV infusions Q3W for the first 4 cycles, followed by maintenance with Dato-DXd + durvalumab; or histology-specific therapy (non-squamous NSCLC: pembrolizumab [200 mg] + pemetrexed [500 mg/m2] + carboplatin [AUC 5] or cisplatin [75 mg/m2] as IV infusions Q3W for the first 4 cycles followed by maintenance with pembrolizumab pemetrexed; squamous NSCLC: pembrolizumab [200 mg] + paclitaxel [200 mg/m2] + carboplatin [AUC 5 or 6] as IV infusions Q3W for the first 4 cycles followed by maintenance with pembrolizumab). AVANZAR will enroll 1000 patients across 230 sites in Europe, North America, Latin America, Asia and the Middle East. Clinical trial enrollment is ongoing.

More importantly, a murine orthotopic GC model demonstrates that Trop2 antibody modification can significantly promote the accumulation of BP at tumor tissues and strengthen antitumoral activity of phototherapy. Directional conjugation of Trop2 antibody to BP facilitates the BP with superior stability, tumor targeting ability and excellent anti-tumor activity under NIR irradiation without systemic toxicity.

These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.

P1, N=5, Terminated, Bio-Thera Solutions | N=50 --> 5 | Unknown status --> Terminated; Considering that the safety risk will affect the subsequent development, it is decided to terminate the test voluntarily

TROP2 expression and sensitivity to SN38 in MPM cell lines support biomarker-selected clinical exploration of sacituzumab govitecan in patients with MPM.

Here, we demonstrated antigen specific killing of Trop2 overexpressing tumor cells in vitro. Targeted deployment of recombinant immunotoxin to specifically engage and kill Trop2 positive cells is a potential approach for cancer therapeutics. As such, the ability of the rIT to specifically target and kill Trop2 expressing tumors is an important initial finding towards the possibility of antigen-dependent elimination of Trop2 expressing cancer cells.

These results suggest that Dato-DXd may stimulate tumor immunity and sensitize tumors to PD-1/PD-L1 inhibitors. The combination of Dato-DXd and PD-1/PD-L1 blockers could be a valuable therapy for patients with TROP2-positive tumors.

In the heterogeneous Trop2 xenograft model (A431 and SW620), BL-M02D1 exhibited higher tumor inhibition capacity than IMMU-132, indicating that BL-M02D1 possess a more potent bystander effect than IMMU-132.In summary, these studies suggest BL-M02D1, a novel Trop2-targeting ADC, is potentially more efficacious in the treatment of Trop2-expressing carcinomas than IMMU-132. The clinical phase I has been progressing and the available data exhibit excellent efficacy in breast cancer therapy with manageable toxicity.

Metaplastic breast carcinoma could benefit from tailored therapeutic strategies adapted to the phenotypic specificities of histological subtypes.

P3, N=1000, Recruiting, AstraZeneca

The aim of this study was to improve the intratumoral accumulation of an antibody-drug conjugate (ADC) and minimize its off-target toxicity, SKB264, a novel anti-trophoblast antigen 2 (TROP2) ADC that was developed using 2-methylsulfonyl pyrimidine as the linker to conjugate its payload (KL610023), a belotecan-derivative topoisomerase I inhibitor. At the same dose, SKB264's exposure in tumor tissue was 4.6-fold higher than that of IMMU-132. Compared with IMMU-132, the longer half-life of SKB264 had a stronger targeting effect and better antitumor activity, suggesting the better therapeutic potential of SKB264 for treating TROP2-positive tumors.

Our study showed that HGOvCa with positive TROP2 expression had a significant better overall survival as compared to patients with equivocal or negative TROP2 expression. This overall survival benefit may be due to better clinical response. These results indicate that TROP2 may be a prognostic marker for better survival and potential targets for immunotherapy.

No abstract available

Blood-based assessment of TROP2 and HER2 expression is a potential marker for selecting MBC patients likely to respond to anti-TROP2 targeted therapies such as Sacituzumab, or Trastuzumab Deruxtecan has shown to improve survival in mTNBC in the ASCENT trial and DESTINY-04 studies...The development of quantitative, reproducible, and more sensitive immunofluorescence assays is becoming crucial for assigning patients whose disease continually evolves to targeted therapies by increasing clinical trial options. Analysis of the clinical utility of the blood-based cell analysis in guiding patient selection strategies for novel anti-TROP2, HER2, and other targeted therapies treatment in MBC is ongoing.