ADCs: The New Frontier in Cancer Treatment

Antibody-drug conjugates (ADCs) are an innovative class of cancer treatments that combine the precision of monoclonal antibodies with the cell-killing potency of chemotherapy drugs, connected via a chemical linker. This advanced approach allows ADCs to selectively target and destroy cancer cells while sparing healthy tissues, which enhances the therapeutic index of cytotoxic agents.¹ Key examples include tisotumab vedotin-tftv (Tivdak; Pfizer, Genmab) which targets tissue factor (TF) in cervical cancer (CC), and fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo, AstraZeneca) which targets human epidermal growth factor receptor 2 (HER2) in various solid tumors. Their development highlights the critical integration of nonclinical safety, pharmacology, and advanced pharmacokinetics (PK) and pharmacodynamics (PD) modeling to effectively create transformative solutions in cancer therapy.²

Despite advances in preventive measures such as vaccination and early detection through screening, cervical cancer remains a significant health concern. Image Credit: © Jo Panuwat D - stock.adobe.com

Tisotumab Vedotin and Fam-Trastuzumab Deruxtecan in Action

ADCs are structured with 3 main components: a monoclonal antibody, a chemical linker, and a cytotoxic drug. The monoclonal antibody specifically targets antigens on cancer cells, ensuring that the cytotoxic drug, once released by the cleavable linker inside the cancer cell, directly kills these cells while minimizing damage to healthy tissues. This targeted approach offers several benefits over traditional chemotherapy, including reduced off-target effects and a better safety profile. Leading ADCs in cancer treatment include tisotumab vedotin (targeting TF in CC), and fam-trastuzumab deruxtecan (targeting HER2-positive tumors). These advancements in ADC technology are indicative of their potential to improve treatment outcomes and patient quality of life significantly.³

Battling Cervical Cancer With ADCs

Recurrent or metastatic CC, now treated with ADCs, is a particularly aggressive and challenging form of cancer, marked by the return or spread of cancer cells beyond the cervix after initial treatment. Despite advances in preventive measures such as vaccination and early detection through screening, CC remains a significant health concern. In 2023, an estimated 13,960 new cases of invasive CC were diagnosed in the United States, with approximately 4,310 deaths attributed to the disease. Metastatic CC has a poor prognosis, with a 5-year survival rate of less than 20%. Up to 15% of patients present with metastatic disease at diagnosis, and among those treated at earlier stages, up to 61% may experience disease recurrence. This highlights the urgent need for effective treatment options that can extend survival and improve the quality of life for affected patients.⁴

The Science Behind Tisotumab Vedotin

TIVDAK was developed by Pfizer and Genmab and has undergone clinical evaluation, leading to its FDA approval. The clinical trials, innovaTV 204 (NCT03438396) and innovaTV 301 (NCT04697628), demonstrated the efficacy of the drug in treating recurrent or metastatic CC. Tisotumab vedotin functions by targeting TF on cancer cells, using a monoclonal antibody linked to the cytotoxic agent Monomethyl auristatin E (MMAE). This mechanism allows tisotumab vedotin to bind to TF-expressing cancer cells, leading to the internalization of the ADC and release of MMAE, which disrupts the microtubule network of the cancer cells, causing cell death.⁴

Clinical Success of Tisotumab Vedotin

The clinical impact of tisotumab vedotin has been significant, with the innovaTV 301 study showing a 30% reduction in the risk of death compared with chemotherapy, as evidenced by a hazard ratio of 0.70. The study's results revealed a median overall survival (OS) of 11.5 months for tisotumab vedotin-treated patients versus 9.5 months for those receiving chemotherapy. The safety profile of tisotumab vedotin includes common adverse reactions such as decreased hemoglobin, peripheral neuropathy, and conjunctival reactions. Severe adverse reactions include ocular toxicity, peripheral neuropathy, hemorrhage, and pneumonitis, which require careful monitoring and management.⁴

The Targeting of ADCs

Tisotumab vedotin's approval highlights the advantages of ADCs over traditional chemotherapy, including improved target specificity and reduced systemic toxicity. The accelerated approval by the FDA was initially granted based on tumor response and durability of response, with full approval following the positive results from the phase 3 innovaTV 301 trial. This is indicative of the potential of ADCs, such as tisotumab vedotin, to offer new hope for patients with limited treatment options, providing a crucial advancement in the fight against recurrent or metastatic CC. The US Prescribing Information for tisotumab vedotin includes a boxed warning for ocular toxicity and highlights the importance of adhering to premedication and eye care protocols to mitigate these risks.^4,5

Innovations in Precision Medicine

The advances in ADC technology represent a significant leap towards precision medicine, focusing on designing ADCs that bind directly to cancer cells with high specificity. This technology is part of a broader shift towards personalized treatment options, aiming to improve patient outcomes by tailoring therapies to individual patient profiles. Some clinical trials and case studies involving ADCs, including tisotumab vedotin, have shown promising results, reinforcing the potential of these therapies in extending survival and enhancing the quality of life for cancer patients. However, challenges such as managing the unique toxicities associated with ADCs; including ocular toxicity, peripheral neuropathy, hemorrhage, pneumonitis, and severe cutaneous adverse reactions; and understanding resistance mechanisms remain. These challenges are being addressed through continuous research and development, aiming to further refine ADCs' efficacy and safety.^4,5

The Future of ADCs in Oncology

Expert opinions on the future of ADCs in oncology suggest that these therapies will continue to transform cancer treatment by offering more targeted and effective options with fewer side effects. ADCs represent a promising new class of treatment with less toxicity than standard chemotherapy and excellent response rates. Future research will likely focus on identifying new targets and biomarkers, improving ADC design, and exploring combination therapies to enhance their efficacy and minimize resistance. The continued exploration of target antigens and ADCs is critical to finding new ways to treat recurrent, platinum-resistant disease that presents differently in each patient.⁶

Fam-Trastuzumab Deruxtecan: a Tumor-Agnostic Breakthrough

The promise of precision medicine is evident in the development of ADCs, such as fam-trastuzumab deruxtecan, which has shown clinically meaningful responses across various tumor types. Fam-trastuzumab deruxtecan's approval as a tumor-agnostic HER2-directed therapy marks a significant advancement, allowing for broader application in treating HER2-positive cancers. This shift towards precision medicine aims to provide personalized treatment options that can improve patient outcomes and quality of life. Ongoing clinical trials and studies will continue to explore the full potential of ADCs, addressing challenges such as resistance and adverse effects to ensure their optimal use in oncology.⁷

Tisotumab Vedotin Versus Fam-Trastuzumab Deruxtecan

Comparing tisotumab vedotin and fam-trastuzumab deruxtecan highlights the versatility and impact of ADCs in oncology. Tisotumab vedotin targets TF in CC, offering a new treatment option for patients with recurrent or metastatic disease, while fam-trastuzumab deruxtecan targets HER2-positive tumors across various cancer types, demonstrating significant efficacy in hard-to-treat cancers. Both ADCs exemplify the advancements in targeted cancer therapy, focusing on improving specificity and reducing systemic toxicity. As research progresses, these ADCs will continue to set new standards in cancer treatment, providing hope for patients with limited options.^4,7

The Next Generation of Cancer Treatments

Puja Sapra, senior vice president of biologics engineering & oncology targeted delivery at AstraZeneca, emphasizes the company's ambition to redefine cancer treatment with highly targeted ADCs and radioconjugates. These advanced therapies aim to deliver powerful payloads directly into cancer cells, minimizing off-target effects and improving patient outcomes. AstraZeneca’s capabilities and proprietary discovery platforms are at the forefront of developing these novel therapies, which promise to offer more effective and personalized treatment options for cancer patients.⁸

The Importance of ADCs

The importance of ADCs in the fight against cancer cannot be overstated. Their ability to target cancer cells with precision while minimizing damage to healthy tissues represents a significant advancement in oncology. Continued innovation and research in this field are crucial to further enhancing the efficacy and safety of ADCs, addressing challenges such as drug resistance, and expanding their applicability to various cancer types. The future of ADCs in oncology is bright, and sustained efforts in research and development will be essential to realize their full potential in improving patient outcomes and quality of life.

References

1. Liao MZ, Leipold DD, Chen SC, et al. Translational PK/PD framework for antibody-drug conjugates to inform drug discovery and development. Xenobiotica. May 13, doi:10.1080/00498254.2024.2351044

2. Tolcher AW, Calvo E, Maitland ML, et al. 28LBA A phase 1 study of PF-06647020, an antibody-drug conjugate targeting PTK7, in patients with advanced solid tumors. European Journal of Cancer. 2015. doi:10.1016/s0959-8049(16)31946-3

3. Shastry M, Gupta A, Sarat Chandarlapaty, et al. Rise of Antibody-Drug Conjugates: The Present and Future. 2023. doi:10.1200/edbk_390094

4. FDA grants full approval for TIVDAK® to treat recurrent or metastatic cervical cancer | Pfizer. April 29, 2024. https://www.pfizer.com/news/press-release/press-release-detail/fda-grants-full-approval-tivdakr-treat-recurrent-or

5. Pfizer Highlights Progress in Accelerating Breakthrough Cancer Medicines at ASCO 2024 Annual Meeting. Pfizer. April 29, 2024. Accessed June 27, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-highlights-progress-accelerating-breakthrough-cancer

6. The Future of Ovarian Cancer Treatment with Antibody-Drug Conjugates (ADCs). moffitt. December 15, 2023. Accessed June 27, 2024 https://www.moffitt.org/for-healthcare-professionals/clinical-perspectives/clinical-perspectives-story-archive/the-future-of-ovarian-cancer-treatment-with-antibody-drug-conjugates-adcs/#:~:text=The%20Future%20of%20ADCs&text=The%20continued%20exploration%20of%20target

7. Kemp A. Enhertu approved in the US as first tumour-agnostic HER2-directed therapy for previously treated patients with metastatic HER2-positive solid tumours. Astrazeneca. April 6, 2024. Accessed June 27, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/enhertu-approved-in-the-us-as-first-tumour-agnostic-her2-directed-therapy-for-previously-treated-patients-with-metastatic-her2-positive-solid-tumours.html#:~:text=AstraZeneca%20and%20Daiichi%20Sankyo's%20Enhertu%20(trastuzumab%20deruxtecan)%20has%20been%20approved,no%20satisfactory%20alternative%20treatment%20options

8. Sapra P. Engineering novel cancer treatments: ADCs and radioconjugates. Astrazeneca. October 18, 2023. Accessed June 27, 2024 https://www.astrazeneca.com/what-science-