Urothelial carcinoma (UC) is a common urological neoplasm, the most common type of bladder cancer (approximately 90%), and can also be found in the renal pelvis, ureter, and urethra. There are approximately 549,000 new cases and 200,000 deaths from bladder cancer worldwide each year. For a long time, for patients with inoperable metastatic urothelial carcinoma (mUC), the first-line treatment is still based on platinum-based chemotherapy, but with the decline of platinum sensitivity or drug resistance, it will eventually lead to tumor recurrence and disease progression. Patients have limited treatment options after failure of platinum-based chemotherapy. Therefore, it is urgent to explore new drugs with high efficiency and safety.
The birth of immune checkpoint inhibitors represented by PD-1/L1 inhibitors is a milestone event in the history of tumor treatment, and has achieved good curative effects in various tumor treatments. Antibody-drug conjugates (ADC), as another hot spot in the research and development of new anti-tumor drugs, plays an important role in tumor treatment. If ADC and PD-1 inhibitors are used in combination, what kind of sparks will be created?
On April 3, 2023, the FDA granted accelerated approval for the PD-1 inhibitors Keytruda (pembrolizumab) in combination with Nectin-4 ADC drug Padcev (enfortumab vedotin-ejfv) for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who are not suitable for cisplatin-based chemotherapy. This is the first combination therapy of a PD-1 antibody and ADC approved for this indication.
Padcev is an ADC drug targeting Nectin-4 developed by Seagen/Astellas. Nectin-4 is a cell adhesion molecule and a type I transmembrane protein encoded by Nectin family Nectin-4. It is mainly expressed in embryonic and placental tissues, and its expression decreases significantly in adults. Studies have found that Nectin-4 is highly expressed in urothelial carcinoma and plays a key role in tumorigenesis, invasion and metastasis, and is a new important target of ADC.
Padcev is composed of a fully human monoclonal antibody against Nectin-4 linked to monomethyl auristatin E (MMAE). Padcev binds to cells expressing Nectin-4 and subsequently internalizes and releases the antineoplastic drug MMAE into the cells, leading to cell cycle arrest and apoptosis. In 2019, Padcev was approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma, becoming the first ADC drug approved for the treatment of urothelial carcinoma.
Mechanism of Action of PD-1 Combined With ADC
According to the difference in response efficiency to immune checkpoint inhibitors and based on the infiltration of T cells, some studies have divided the tumor immune microenvironment into three different phenotypes. These are the immune-desert type, the immune-excluded type, and the immune-inflamed type, the first two of which are also known as "cold tumors" and the last as "hot tumors." In short, a cold tumor is a tumor with few immune cells and is difficult to penetrate, and a hot tumor is a tumor infiltrated by many immune cells such as anti-tumor T lymphocytes.
The core difference between hot and cold tumors is whether immunotherapy represented by PD-1 inhibitors is effective. This is determined by the mechanism of action of PD-1 inhibitors. Researchers have found that tumor cells highly express PD-L1 protein and induce immune cells such as T cells to highly express PD-1. When PD-1 and PD-L1 combine, it will inhibit the function of T lymphocytes, thereby enabling tumor cells to achieve immune escape.
Immune checkpoint inhibitors represented by PD-1 inhibitors can block the combination of PD-1 and PD-L1, relieve the inhibition of tumor cells on T cells, and reactivate the immune mechanism to recognize and kill tumor cells. Despite the promise of this therapy, however, immune checkpoint inhibitors are less effective against cold tumors because there are fewer immune cells in their vicinity, ultimately leading to insufficient response rates.
Therefore, turning cold tumors into hot tumors has become the key to breaking through such refractory tumors. In previous studies, researchers have found that immunostimulatory antibody conjugates (ISACs) consisting of antibody + linker + agonist has the potential to turn cold tumors into hot tumors, although the previous efficacy data of ISAC is limited, but it is a potential therapy.
In addition to ISAC, a number of companies have deployed PD-1 inhibitors combined with ADC drugs in order to improve the effect of immunotherapy. From a mechanistic point of view, PD-1 inhibitor combined with ADC can relieve the inhibitory state of T cells through immune checkpoint inhibitors on the one hand, and realize the killing of tumor cells through ADC drugs carrying cytotoxic payload on the other hand. The success of Keytruda combined with Padcev first-line uroepithelial cancer is undoubtedly an affirmation of this combination therapy, from the trend of research and development, PD-1 combined ADC is expected to gradually replace the existing standard therapy.
Antibody–drug conjugates (ADCs) are a promising cancer treatment. Although PD-1/L1 drugs have shown extensive efficacy in tumor treatment, their tumor treatment response rate is only 20-30% on average. In order to improve the response rate, more and more pharmaceutical companies began to explore the combination of drugs with ADC.
Potential Drugs of PD-1 Combined With ADC
Merck: Cooperates With Some ADC Pharmaceutical Companies
Keytruda (commonly known as K drug) is a PD-1 monoclonal antibody developed by Merck, which can block the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby activating T lymphocytes and exerting anti-tumor effects. Since it was approved by the FDA for the treatment of advanced melanoma in 2015, Keytruda has been approved for use in more than 80 countries, covering more than 12 indications of 9 tumor types, including melanoma, non-small cell lung cancer, head and neck cancer , Hodgkin's lymphoma, bladder cancer, cervical cancer, etc.
Merck is a leader in the PD-1 market. In 2022, Keytruda's annual sales were $20.937 billion, an increase of 22%, ranking first in PD-1, second only to Humira ($21.237 billion). With the continuous expansion of indications, it is expected that Keytruda will soon surpass Humira and become the new king of medicine. How to consolidate the status of K drug "potential new drug king"? The combined ADC could be an important move for Merck.
This combination therapy of Keytruda and Padcev is approved for the first-line treatment of uroepithelial carcinoma, but Merck's ambitious layout is far more than that. In 2022, Merck and Kelun Biotech have completed three collaborations and successively obtained Kelun Biotech's Trop2 ADC, Claudin 18.2 ADC and seven preclinical ADC projects at a potential price of $11.8 billion, demonstrating Merck's high preference for ADC drugs. As early as 2020, Merck acquired VelosBio for $2.75 billion, optimistic about VelosBio's ROR1 ADC drug potential, this ROR1 ADC drug has also been promoted to clinical phase III.
In addition, Merck has spared no effort in the exploration of PD-1 combined ADCs. As early as 2021, it reached a cooperation agreement with Gilead to jointly promote K drugs and Trodelvy (Trop2 ADC) for the first-line treatment of triple-negative breast cancer. Trodelvy is composed of a humanized IgG1 antibody targeting the TROP-2 antigen conjugated to SN-38, an active metabolite of the chemotherapy drug irinotecan. Trodelvy targets TROP-2 and delivers the anticancer agent SN-38 to kill cancer cells.
In December 2022, Keytruda combined with AstraZeneca/Daiichi Sankyo's Trop2 ADC - DS-1062, to target low-expression non-small cell lung cancer with PD-L1. Results from a Phase Ib study of the combination therapy, TROPION-Lung02, were reported at last year's World Conference on Lung Cancer, and data showed that DS-1062 combined with Keytruda had an ORR of 37% in previously untreated and pretreated patients with advanced NSCLC, rising to 41% when platinum-based chemotherapy was added. As a first-line treatment, DS-1062+Keytruda has a disease control rate (DCR) of 100%.
RemeGen: Disitamab Vedotin + Toripalimab
RemeGen is a leader in domestic ADC drugs. Disitamab Vedotin (HER2 ADC) were approved for marketing in 2021. It is a new humanized anti-HER2 ADC drug independently developed by RemeGen. It has successively won two indications for HER2-positive gastric cancer and HER2-positive urothelial cancer. For the combination therapy of PD-1 and ADC, RemeGen is exploring multiple indications for Disitamab Vedotin combined with Shanghai Junshi Biosciences Co., Ltd. 's Toripalimab.
Preliminary results showed that the combination of Disitamab Vedotin and Toripalimab achieved a response rate of 75%, including 3 cases with CR (complete response) and DCR of 95%. ORR reached 80% in patients treated with mUC, and even 100% in patients with high HER2 expression (ICH 3+).
In terms of safety, the combination of Disitamab Vedotin and Toripalimab was well tolerated and no dose-limiting toxicity (DLT) was observed. The results of this study confirm that Disitamab Vedotin combined immunotherapy may be a leader in the field of combination therapy for urothelial carcinoma.
Kelun-Biotech: SKB264(TROP2-ADC) + KL-A167(PD-L1 monoclonal antibody)
Kelun-Biotech is a rising star in the ADC field. SKB264 is a TROP2-targeting ADC drug developed by Kelun-Biotech. It combines a humanized monoclonal antibody targeting TROP2 with a novel topoisomerase I inhibitor to target tumor cells to deliver toxin molecules that can induce immunogenic cell death (ICD), triggering an immune system response. It provides theoretical support for ADC drugs combined with PD-1/PD-L1 immune checkpoint inhibitors. KL-A167 is an innovative recombinant humanized monoclonal antibody against PD-L1 developed by Kelun-Biotech. The Phase II clinical trial of the two combined with or without platinum in patients with advanced NSCLC was approved by the NMPA in March last year and is currently underway.
Hengrui Medicine: SHR-A1811(HER2 ADC) + SHR-1701(PD-L1/TGF-β fusion protein)
Hengrui Medicine, as a leading domestic innovative drug company, took the lead in exploring the combination of "ADC+dual antibodies". On October 21, 2022, Hengrui Medicine's SHR-A1811 combined with SHR-1701 in the treatment of HER2-positive advanced gastric cancer was approved for clinical trials. SHR-A1811 is a HER2-targeting ADC drug that can induce cell cycle arrest and apoptosis by binding to HER2-expressing tumor cells and endocytosis, releasing toxins in tumor cells. SHR-1701 is a PD-L1/TGF-β bifunctional fusion protein, which can promote the activation of effector T cells, but also effectively improve the immune regulation in the tumor microenvironment, and ultimately effectively promote the immune system to kill tumor cells.
With the launch of Keytruda combined with Padcev for the first-line treatment of mUC, the combination therapy of PD-1 inhibitors and ADC officially debuted. Who will be the next medicine king? It is still difficult to make a decision. However, the continuous expansion of drug indications through combination therapy may be the key to rising sales of innovative tumor drugs. Looking at the domestic market, RemeGen, Kelun-Biotech, Hengrui Medicine, Junshi Bio, etc. have taken the lead in entering this combination therapy market.
Huateng Pharma, as a world-leading supplier of PEG derivatives and CDMO for APIs and intermediates, is dedicated to being your most reliable partner to provide chemical synthesis and high-quality PEG linkers for ADC drugs. We are committed to promoting the progress of your ADC discovery and development projects.
.FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination With Padcev® (enfortumab vedotin-ejfv) for First-Line Treatment of Certain Patients With Locally Advanced or Metastatic Urothelial Cancer.