Antibody–drug conjugates (ADCs) are driving a multi-billion-dollar dealmaking frenzy. Over 20 years since the first ADC was approved, the approach — using antibodies’ specificity for targeted delivery of potent cytotoxic drugs — is coming of age. 

In 2023, the market size of ADCs exceeded $10 billion for the first time, marking a significant milestone. Enhertu is on track to surpass Kadcyla and become the leading ADC drug in terms of sales. Kadcyla, with sales of $2.22 billion, holds a strong position as the second-highest selling ADC. Adcetris, Trodelvy, and Padcev, each with sales surpassing $1 billion.

Table 1. Sales of ADCs in 2023

Enhertu

Enhertu, succeeding Kadcyla, continues to excel in treating HER2-positive solid tumors, addressing HER2-positive gastric cancer, HER2-low expression breast cancer, and HER2-positive non-small cell lung cancer previously untargeted by Kadcyla. This advancement has elevated the standard of care for HER2-targeted therapies. Expanding treatment possibilities has also driven significant growth in annual sales, propelling Enhertu to become a "blockbuster" drug within three years of commercialization. In 2023, with the groundbreaking approval for HER2-low expression breast cancer, Enhertu's annual sales doubled from $1.238 billion to $2.556 billion. At the beginning of this year, AstraZeneca and Daiichi Sankyo once again sought FDA approval to expand Enhertu's indications to include HER2-positive solid tumors, anticipating further market success in the future.

In October 2023, AstraZeneca/Daiichi Sankyo released encouraging findings from the DESTINY-PanTumor02 trial of Enhertu. Across the entire study group, Enhertu achieved an objective response rate (ORR) of 37.1%, with a median duration of response (DOR) of 11.3 months, a median progression-free survival (PFS) of 6.9 months, and a median overall survival (OS) of 13.4 months. These results reaffirm Enhertu's potential as a broad-spectrum cancer therapy for previously treated patients with HER2-expressing solid tumors (Figure 1).

Figure 1. Results of DESTINY-PanTumor02

In 2024, several highly anticipated top-line results for Enhertu are expected, including outcomes from Phase 3 trials such as DESTINY-Breast06 for the initial treatment of HR+/HER2-low expression breast cancer, DESTINY-Breast09 for first-line therapy of HER2+ breast cancer, and DESTINY-Gastric06 for third-line treatment of HER2+ gastric cancer, among others (Figure 2).

Figure 2. Clinical trials of Enhertu

Kadcyla

Kadcyla (ado-trastuzumab emtansine) is the first approved HER2-targeted ADC jointly developed by Roche and ImmunoGen. It combines the microtubule inhibitor DM1 with the HER2 antibody trastuzumab through a non-cleavable linker. Launched in the United States in February 2013, Kadcyla has witnessed consistent annual sales growth as the pioneering HER2 ADC product in the market. In 2022, its global sales reached 1.89 billion Swiss francs (approximately 2.136 billion US dollars), with a 4% increase in 2023 to 1.966 billion Swiss francs (approximately 2.222 billion US dollars). This growth slowdown is primarily attributed to competition from biosimilars and Enhertu.

Adcetris

Adcetris is an anti-CD30 antibody conjugated via a protease-cleavable linker to the potent anti-microtubule agent monomethyl auristatin E (MMAE), originally developed by Seagen (later acquired by Pfizer). In 2009, Takeda Pharmaceutical and Seagen reached an agreement granting Takeda commercialization rights for Adcetris in countries outside the United States and Canada.

It was approved by the FDA in August 2011 for the treatment of Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). In 2021, Adcetris was approved by the European Union as a first-line treatment for CD30-expressing sALCL, becoming the world's first ADC approved for first-line treatment.

Trodelvy

Trodelvy was originally developed by Immunomedics as an ADC targeting Trop-2. It combines the Trop-2 antibody sacituzumab with the active metabolite SN-38 of the DNA topoisomerase I inhibitor irinotecan through a cleavable linker. In September 2020, Gilead Sciences acquired Immunomedics for $21 billion, thereby obtaining Trodelvy.

Trodelvy received accelerated FDA approval in April 2020 and was fully approved for second-line or later treatment of metastatic triple-negative breast cancer (mTNBC) patients by the FDA one year later, making it the first ADC drug approved by the FDA for the treatment of TNBC. Subsequently, Trodelvy was also approved for the treatment of urothelial carcinoma and HR+/HER2- locally advanced or metastatic breast cancer indications.
Trodelvy  has incorporated monodispersed polyethylene glycol (PEG) chains into its linker. 

With the approval of new indications, Trodelvy's sales have been increasing year by year. Its first full year of sales after market launch was $380 million, reaching global sales of $681 million in 2022. In 2023, Trodelvy's sales surpassed $1 billion for the first time, with a year-on-year growth of 56% to $1.063 billion, placing it among the blockbuster drugs (Figure 3).

Figure 3. Sales of Trodelvy

However, Trodelvy faces fierce competition in the market. On one hand, two rival products, Datopotamab deruxtecan and SKB264, have recently applied for market approval. On the other hand, frontline treatments for TNBC like pembrolizumab and atezolizumab show significant efficacy, narrowing Trodelvy's role as a second-line treatment option. As a result, Gilead is also investigating the use of this drug in frontline treatment settings.

Padcev

Padcev (enfortumab vedotin) is the first approved ADC targeting Nectin-4, jointly developed by Seagen and Astellas. It was initially granted accelerated FDA approval in December 2019 and subsequently received full FDA approval in July 2021 for the treatment of urothelial carcinoma.

In addition to monotherapy, Padcev has also been studied in combination with Keytruda in clinical trials. In October 2023, positive results were reported from the Phase 3 EV-302 trial evaluating Padcev in combination with Keytruda in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC) patients. Compared to platinum-containing chemotherapy, the EV-302 study met both primary endpoints of overall survival (OS) and progression-free survival (PFS). The median OS for the combination therapy was 31.5 months, while for chemotherapy it was 16.1 months, indicating a 53% reduction in the risk of death for patients in the combination therapy group compared to the chemotherapy group. The median PFS for the combination therapy was 12.5 months, while for chemotherapy it was 6.3 months, representing a 55% reduction in the risk of cancer progression or death for patients in the combination therapy group compared to the chemotherapy group.

Figure 4. EV-302 OS

Based on this, on December 15, 2023, Astellas and Pfizer announced FDA approval of Padcev in combination with Keytruda for the treatment of adult patients with la/mUC. This combination therapy is the first approved alternative to platinum-containing chemotherapy, which is currently the first-line standard of care for la/mUC treatment.

Polivy

Polivy (polatuzumab vedotin) is the world's first approved ADC targeting CD79b, developed by Roche. It combines the cytotoxic agent MMAE with the CD79 antibody polatuzumab via a cleavable linker. It was approved for marketing in the United States in June 2019 for the treatment of diffuse large B-cell lymphoma (DLBCL).

In April 2023, the FDA approved Polivy in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) in adult patients with previously untreated DLBCL with an International Prognostic Index (IPI) score of 2 or greater. This combination is the first FDA-approved therapy in nearly 20 years for the first-line treatment of DLBCL.

This approval is based on pivotal data from POLARIX POLARIX trial, which demonstrated a statistically significant and clinically meaningful improvement in PFS compared to R-CHOP. The risk of disease progression, relapse or death was reduced by 27% with Polivy plus R-CHP compared with R-CHOP.

Thanks to the approval of this first-line combination therapy, Polivy's sales increased by 108% to 837 million Swiss francs (946 million US dollars) in 2023 (Figure 5).

Figure 5. Sales of Polivy

Summary

ADC has emerged as one of the most dynamic research areas in recent years. Last year, Pfizer's $43 billion acquisition of Seagen, Merck's $22 billion cooperation agreement with Daiichi Sankyo, and AbbVie's $11 billion acquisition of Immunogen all underscore the intense activity within the ADC sector.

In 2023, the total sales of ADC drugs exceeded $10 billion, with Enhertu and Kadcyla leading the global ADC wave, both surpassing $2 billion in sales.

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References:
1.FY2023 Q3 Financial Results Presentation
2.https://assets.roche.com/f/176343/x/e7f2bce770/01022024_mr_fy_roche2023_en.pdf
3. Roche 2023 results Basel, 1 February 2024
4. Gilead Sciences Announces Fourth Quarter and Full Year 2023 Financial Results
5. https://s28.q4cdn.com/781576035/files/doc_financials/2023/q4/Q4-2023-PFE-Earnings-Release.pdf
6. https://www.gsk.com/media/10928/fy-2023-results-announcement.pdf
7. Hope S Rugo, Aditya Bardia, Frederik Marmé, Javier Cortés, Peter Schmid, Delphine Loirat, Olivier Trédan, Eva Ciruelos, Florence Dalenc, Patricia Gómez Pardo, Komal L Jhaveri, Rosemary Delaney, Theresa Valdez, Hao Wang, Monica Motwani, Oh Kyu Yoon, Wendy Verret, Sara M Tolaney, Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial, Lancet 2023; 402: 1423–33
8. KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) Reduced Risk of Death by More Than Half Versus Chemotherapy in Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

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