At ESMO 2024, TROP2-targeting antibody-drug conjugates (ADCs) are generating significant buzz as emerging therapies across various cancer types, including non-small cell lung cancer (NSCLC), endometrial cancer, ovarian cancer, and cervical cancer among others. As of now, the only established TROP2-targeting ADC in the market is  Gilead Sciences’ (acquired through Immunomedics’ acquisition) TRODELVY (sacituzumab govitecan). Approved for metastatic triple-negative breast cancer (TNBC) and urothelial carcinoma, it has paved the way for TROP2 ADCs, offering significant survival benefits, especially in heavily pretreated patients. New entrants in the TROP2 ADC space are gaining attention, with several pharmaceutical companies like AstraZeneca/Daiichi Sankyo, Merck/Kelun biotech, Shanghai Escugen Biotechnology, and others unveiling data of their respective ADCs, featuring improved payloads and linker technology aimed at enhancing efficacy while minimizing toxicity.

This year's conference highlights TROP2 ADCs as a game-changing approach, particularly for patients who have become resistant to standard therapies. As the field of TROP2-targeting ADCs continues to evolve, TRODELVY is likely to face increasing competition from AstraZeneca and Daiichi’s datopotamab deruxtecan, Merck’s Sacituzumab Tirumotecan, and Shanghai Escugen Biotechnology’s ESG401, offering new hope for patients with TROP2-expressing cancers who have limited options.

Unveiling the latest in TROP-targeting ADC space

• Abstract Number – 1312P
• Abstract Type – Poster session
• Indication - Non-small cell lung cancer (NSCLC)

Title:  AstraZeneca’s and Daiichi’s Dato-DXd Emerges as a Game-Changer in Advanced Non-squamous NSCLC with Brain Metastases at ESMO 2024: Insights from the Phase III TROPION-Lung01 study

Executive Summary: Dato-DXd's performance in the TROPION-Lung01 trial offers improved outcomes compared to docetaxel. Its future approval could shift treatment paradigms in the second-and third-line settings, especially as competition with other TROP2-ADCs, like TRODELVY, intensifies.

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NSCLC accounts for approximately 85% of lung cancer cases, with a significant portion of patients developing brain metastases as their disease progresses. As per DelveInsight, the total number of incident cases of NSCLC in the 7MM was approximately 531,800 in 2023. The competitive landscape for NSQ NSCLC, particularly in patients with brain metastases, is dominated by immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) targeting driver mutations (e.g., EGFR, ALK). However, for patients without actionable mutations or those who progress on ICIs, treatment options become more limited, with docetaxel often being the standard chemotherapy option. 

The advent of immunotherapy and targeted therapies has changed the treatment paradigm, but for those with brain metastases, occurring in up to 30-40% of advanced NSCLC patients, the therapeutic efficacy remains suboptimal, necessitating novel treatment approaches. The Phase III TROPION-Lung01 study, presented at ESMO 2024, highlights the potential of datopotamab deruxtecan (Dato-DXd), a TROP2-ADC in advanced non-squamous NSCLC, particularly in patients with brain metastases. 

In May 2024, the company reported results from TROPION-Lung01 trial, demonstrates datopotamab deruxtecan as the only investigational therapy to show a clinically meaningful survival improvement in patients with previously treated nonsquamous NSCLC versus docetaxel, which has long been unsurpassed in this post-targeted treatment and post-immunotherapy setting. These results reinforce the potential for datopotamab deruxtecan to replace conventional chemotherapy in this late-line setting and underscore our confidence in ongoing trials evaluating this therapy in first-line lung cancer. AstraZeneca and Daiichi Sankyo are all set to present this data at the ESMO 2024. Moreover, based on these results, recently in February 2024, the BLA for datopotamab deruxtecan in this patient segment has been accepted in the US, with an assigned PDUFA action date for its regulatory decision during the fourth quarter of 2024. Dato-DXd’s superior performance in brain metastases could position it as a leading option for second and third-line treatment in patients with advanced NSCLC. 

• Abstract Number – 716MO
• Abstract Type – Mini oral session
• Indication - Recurrent or Metastatic Cervical Cancer

Title: Data from phase II trial of Merck’s sacituzumab tirumotecan in combination with pembrolizumab to offer fresh hope for recurrent cervical cancer at ESMO 2024

Executive Summary: At ESMO 2024, Sacituzumab Tirumotecan (sac-TMT), an innovative TROP2-targeting ADC is drawing significant attention for its potential in treating recurrent or metastatic cervical cancer.

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Cervical cancer remains a major global health challenge, with approximately 14,000 incident cases in 2023, in the US. While early-stage cervical cancer can often be treated with surgery, radiation, or chemoradiation, patients with recurrent or metastatic disease have fewer effective options, creating a significant unmet need. Standard therapies like bevacizumab combined with chemotherapy, and more recently, pembrolizumab for PD-L1 positive patients, have shown modest survival benefits. 

Merck in collaboration with Kelun biotech, is conducting a Phase II trial, evaluating its next-generation TROP-2 ADC, Sacituzumab Tirumotecan (sac-TMT) in combination with pembrolizumab in patients with recurrent or metastatic cervical cancer. Unlike earlier ADCs, sac-TMT incorporates an optimized payload and linker technology aimed at enhancing drug delivery to tumors while minimizing off-target toxicity. The company is geared up to present data from this trial at the ESMO 2024, providing new hope for patients with limited options, with the added benefit of targeting TROP2. Until now, TIVDAK is the first and only ADC approved in cervical cancer.

Top Abstracts for TROP2 targeted ADCs