Summary of Immune Checkpoint Inhibitor Combined with ADC

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 advanced or metastatic NSCLC. The result shows that the remission rate of Dato-DXd+Keytruda is 37%; and the remission rate of Dato-DXd + Keytruda + platinum chemotherapy is 41%. As the first and second-line treatment, the DCR of Dato-DXd + Keytruda or Dato-DXd + Keytruda + platinum chemotherapy reaches 84%, among which the effect is better when it is used as the first-line treatment, in which DCR of Dato-DXd + Keytruda and Dato-DXd + Keytruda + platinum chemotherapy is 100% and 90%. 

Keytruda + SKB264 (TROP2 ADC): many advanced solid tumors

SKB264, an innovative ADC targeting TROP2 developed by Kelun Biotech, adopts proprietary toxin-linker strategy (that is Kthiol design strategy) and realizes the optimal balance between security and effectiveness of ADC through combining the novel irreversible antibody coupling technology, pH sensitive toxin release mechanism and uniform loading the moderately active toxin (novel topoisomerase I inhibitor) of DAR 7.4.

On June 16, Kelun Biotech announced that the Phase II clinical research of SKB264 combined with Keytruda, developed by both Kelun Biotech and MSD, for the treatment of patients with various advanced solid tumors, had been approved for clinical trials by the European Medicines Agency (EMA).

In addition, there are many Phase II clinical researches of SKB264 combined with Keytruda or anti-PD-L1 monoclonal antibody KL-A167 under way at present.

Keytruda + Tivdak (TF ADC): cervical cancer

Tivdak is an ADC targeting TF developed by Seagen. TF is a cell surface protein with a high expression on many solid tumors including cervical cancer, which is related to tumor growth, angiogenesis, metastasis and poor prognosis.

The safety and efficacy of Tivdak combined with Keytruda on the treatment for cervical cancer were evaluated by innovaTV 205 research. The research showed that 33 patients with recurrent or metastatic cervical cancer have received Tivdak+Keytruda as the first-line treatment. When the median follow-up time is 18.8 months, the ORR of 32 evaluable patients is 40.6%, with a CR of 15.6% and a PR of 25%. Among the cervical cancer patients who have received Tivdak+Keytruda as the second or third-line treatment, when the median follow-up time is 15.0 months, the ORR of 34 evaluable patients is 38.2%.

Keytruda + LV (Ladiratuzumab vedotin, LIV-1 ADC): triple negative breast cancer

Ladiratuzumab vedotin (LV) is an ADC targeting LIV-1 developed by Seagen. It is linked by LIV-1-targeted monoclonal antibody and MMAE through the linker which can be cleaved by protease. LV binds to LIV-1 on cancer cells, and will release MMAE into target cells once internalized. LIV-1 is high expressed in a variety of tumors, including breast cancer (93%), melanoma (82%), prostate cancer (72%), etc.

In the Phase I clinical trial of Keytruda + LV in the treatment for patients with locally advanced or metastatic triple negative breast cancer, ORR of the patients with metastatic triple negative breast cancer receiving treatment is 35%, and the tumor focus of most patients (> 90%) has been reduced to some extent. 

At present, a Phase II clinical research of Keytruda combined with LV in the treatment of triple negative breast cancer and other solid tumors is in progress.

Imfinzi (PD-L1) + DS-8201 (HER2 ADC): triple negative breast cancer

DS-8201 (Enhertu), a HER2 ADC jointly developed by Daiichi Sankyo and AstraZeneca, is a kind of ADC that is familiar to the industry. Imfinzi (durvalumab) is an anti-PD-L1 inhibitor developed by AstraZeneca. In the Phase Ib/II research named as BEGONIA, there were 58 patients with locally advanced or metastatic triple negative breast cancer who have received the combination therapy of Imfinzi+DS-8201 as of July 2022, among which 28 patients are still under the treatment, with a median follow-up time of 13.4 months. The result shows that ORR of all the patients is 56.9%, including 1 patient of complete remission, and the median PFS is 12.6 months. The incidence of III/IV adverse events is 43.1%, which is mainly blood toxicity.

Generally speaking, immune checkpoint inhibitors represented by anti-PD-1/PD-L1 have played an important role in anti-tumor therapy. Combined treatment has become the main strategy due to the limited efficacy of single-drug. ADC targeting tumor cells can deliver toxin molecules that can induce the death of immunogenic cells, trigger congenital and adaptive immune responses and infiltrate lots of T cells into the tumor to improve the effect of immunotherapy. The clinical trial data of many cancer types have shown that anti-PD-1 monoclonal antibody combined with ADC shows a good curative effect, and the potential synergy between them can overcome the drug resistance when they are used alone. At present, many related clinical trials are still in progress, which are hoped to achieve positive results at an early stage and benefit more tumor patients.

Reference:

1. Datopotamab deruxtecan-based combinations show promising clinical activity in patients with advanced non-small cell lung cancer

2. https://www.astrazeneca.com/media-centre/press-releases/2022/datopotamab-deruxtecan-based-combinations-show-promising-clinical-activity-in-patients.html.

3. Datopotamab Deruxtecan (Dato-DXd) Plus Pembrolizumab and Platinum-Based Chemotherapy in Advanced NSCLC.

4. Seagen and Genmab Announce FDA Accelerated Approval for TIVDAK™ (tisotumab vedotin-tftv) in Previously Treated Recurrent or Metastatic Cervical Cancer.