In recent years, a variety of immune checkpoint inhibitors (IO) have shown a prospective therapeutic effect, such as PD-1 inhibitor, PD-L1 inhibitor and CTLA-4 inhibitor. However, the problem is gradually emerging with the increasing real data, that is, the complete remission rate of most solid tumor patients treated with immune checkpoint inhibitors is less than 30%. Thus, it will bring greater clinical and commercial value to improve the response rate of IO and prolong the response time.
With the maturity of ADC technology, the combined scheme of IO and ADC is showing a therapeutic potential. Many studies have shown that cytotoxic drugs carried by ADC, such as microtubule inhibitor and topoisomerase inhibitor, can directly activate and promote the maturation of dendritic cells. It means that ADC may have an immune activation function, with a synergy with IO. At the same time, immune checkpoint inhibitor can also enhance the activity of ADC. In 2016, CTLA-4 inhibitor was found to enhance the lethality of ADC to breast cancer in the mouse model by Gerber H-P et al.
And more and more evidences suggest that immune checkpoint inhibitor combined with chemotherapy will produce the effect of 1+1>2. Thus, it will produce a better therapeutic effect to combine ADC with IO. At present, immune checkpoint inhibitor combined with ADC is being favored by major pharmaceutical companies.
Keytruda (PD-1) + Padcev (Nectin-4 ADC): urothelial carcinoma
On April 3, 2023, Padcev combined with anti-PD-1 monoclonal antibody Keytruda (Pembrolizumab) used as the first-line treatment for patients with urothelial carcinoma who are not suitable for cisplatin-based chemotherapy was approved by FDA acceleratedly, which has become the first approved PD-1+ADC therapy.
Padcev is an ADC targeting Nectin-4 developed by Seagen/Astellas Pharma Inc. Nectin-4, a cell adhesion molecule, is a Type I transmembrane protein encoded by Nectin family NECTIN4, which is highly expressed in urothelial carcinoma and plays a key role in the occurrence, invasion and metastasis of tumor. Padcev is composed of a Nectin-4-targeted fully humanized monoclonal antibody and MMAE. Padcev binds to cells expressing Nectin-4, then internalizes and releases the antitumor drug MMAE into cells, causing the cell cycle arrest and apoptosis. In 2019, Padcev was approved for treating the patients with locally advanced or metastatic urothelial carcinoma by FDA.
The approval of Keytruda + Padcev for the indication as the first-line treatment for urothelial carcinoma is based on an EV-103 research, in which for the Keytruda combined with Padcev, the ORR is 68%, CR is 12% and PR is 55% in the combined efficacy analysis of dose increasing cohort, cohort A and cohort K (n=121). DOR of dose increasing cohort and cohort A is 22.1 months (Range: from 1.0+ to 46.3+ months), but that of cohort K has not been reached (Range: from 1.2+ to 24.1+ months).
At present, the efficacy of Padcev combined with anti-PD-1/L1 monoclonal antibody as a neoadjuvant therapy or adjuvant therapy for bladder cancer is being explored, so as to push Padcev combined with PD-1/L1 into the early treatment stage.
Keytruda + Dato-DXd (TROP2 ADC): NSCLC
Dato-DXd (DS-1062), an ADC targeting TROP2, is composed of a humanized anti-TROP2 monoclonal antibody coupled to DNA topoisomerase I inhibitor through a stable cleavable linker based on tetrapeptide. TROP2 (Trophoblast Cell-Surface Antigen) is a transmembrane glycoprotein, which is overexpressed in many solid tumors.
Dato-DXd is designed and developed by using Daiichi Sankyo's DXd-ADC patented technology platform, which uses DXd, a DNA topoisomerase I inhibitor, with a high activity, which can kill nearby cancer cells through bystander effect, a short half-life and a little toxic and side effect. In addition, Dato-DXd optimizes the coupling method and selectively adjusts the DAR to 4, further improving the safety.
At last year's WCLC, researcher announced the therapeutic effect of Dato-DXd combined with Keytruda in the treatment of locally adva...
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