Antibody drug conjugates (ADCs), as a new type of drugs, conjugate monoclonal antibodies, which are responsible for specifically recognizing antigens on the surface of cancer cells, with cytotoxic chemotherapeutic drugs through specific linkers to exert great tumor-killing effects. Currently, 15 ADC drugs, represented by trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd, DS-8201), have been approved and marketed worldwide, which have significantly changed the treatment landscape of malignant tumors.
Although ADC agents have significantly improved the survival benefit for patients, however, the duration of objective response or clinical benefit produced by ADCs as monotherapies is limited due to the emergence of resistance mechanisms. Therefore, in recent years, ADCs are being actively investigated in preclinical and clinical trials in combination with other anticancer agents, including chemotherapy, molecularly targeted agents, and immunotherapy (Figure 1).
Figure 1. Rationale for antibody–drug conjugate (ADC)-based combination therapies. Source: reference 
A. ADC combined with chemotherapy: upregulates tumor cell surface antigens, results in cell cycle arrestOR inhibiting DNA repair.
B. ADC combined with targeted drugs: the synergistic use of ADC and targeted drugs can lead to the simultaneous arrest of multiple oncogenic pathways or double blockade of a specific pathway, thus inhibiting downstream signaling more effectively.
C. ADC combined with antiangiogenic agents: normalization of the tumor vascular system can be restored, contributing to a higher rate of ADC delivery within the tumor.
D. ADC combined with immunotherapy: ADCs with cytotoxic payloads can favor immunosurveillance over immunotolerance through different mechanisms, including macrophage reprogramming, T memory generation, dendritic and T cell activation, and increase of programmed death ligand (PD-L)1 expression. In addition, ADCs can be designed to target specific elements of the tumor microenvironment (TME), such as fibroblasts.
Overall Superiority of ADC Combination Therapy Over ADC Monotherapy
A study by J.F. Antrás in Trends in Cancer tallied the results of 16 randomized clinical trials and showed that the efficacy of ADC combination therapies in terms of progression-free survival (PFS), relapse-free survival (RFS), event-free survival (EFS), and/or overall survival (OS) had a smaller hazard ratio (HR) overall, compared to treatment alone.
Figure 2. Forest plot showcasing clinical outcomes from randomized clinical trials testing ADC-based combinations. Source: Trends in Cancer
ADC Combination Therapies in Development
The most compelling combination agents for ADCs are those that provide additive or synergistic effects on tumor cells or their microenvironment without unacceptable superimposed toxicity. Figure 3 summarizes the combination regimens that have been studied in clinical trials or are currently under investigation. Among these, combination with immunotherapy is currently an important area of exploration for ADC combination therapies. Combination strategies of immunotherapy and ADCs have recently entered clinical trials. Although preclinical data and results from early clinical studies suggest enhanced antitumor activity, there is a need for sustained clinical outcomes to support this. There is growing evidence that ADCs may increase the efficacy of immunotherapeutic agents.
Figure 3. ADC-based combinations that have been published or are in development. Source: reference 
Currently, ADC in combination with immunotherapy is mainly focused ADC with PD1/L1 and CTLA4, while the uses of ADCs with other immunotherapy such as CAR-T, lysovirus, and TCR-T are rare and need to be explored urgently.
Figure 4. ADC in combination with PD1/L1 and CTLA4
On April 3, 2023, Merck and Seagen announced that the FDA granted accelerated approval for Keytruda (PD1 monoclonal antibody) in combination with Padcev (Nectin-4 ADC) for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who are not eligible for cisplatin-containing chemotherapy. This marks the first time an anti-PD-1 therapy has been approved in combination with ADC in these patients.
This approval is based on the dose-escalation cohort, Cohort A and Cohort K of the KEYNOTE-869 (EV-103) study. The objective response rate (ORR) for the combination of Keytruda + Padcev was 68% (95% CI: 58.7-76.0), with complete response (CR) and partial response (PR) rates of 12% and 55%, respectively. The median duration of response (DOR) was 22.1 months (range: 1.0+ to 46.3+ months) for the dose-escalation cohort + Cohort A, and Cohort K had not yet reached DOR (range: 1.2 to 24.1+ months).
In addition, multiple ADCs targeting HER2, such as Kadcyla® (Trastuzumab emtansine), ENHERTU® (Trastuzumab Deruxtecan), and RC48 (Disitamab vedotin), have been tested both in combination with ICIs, both in vitro and in vivo, confirming synergistic activity with enhanced homing and activation of immune effectors.
In the KATE2 study the efficacy of Kadcyla® in combination with Atezolizumab versus Kadcyla® in combination with placebo was compared in pre-treated HER2+ breast cancer patients. The combination failed to improve progression-free survival (8.2 vs 6.2 months, P=0.33), suggesting that the addition of an ICIs to HER2-targeted therapy may only be beneficial in the PD-L1-positive population. Despite the disappointing results observed in this randomized trial, clinical exploration in multiple tumors is ongoing.
Furthermore, preclinical evidence indicate that combination therapies may restore immune sensitivity. For example, the AXL-specific ADC Enapotamab vedotin was tested in combination with an anti-PD-1 antibody in a patient model of ICI-refractory melanoma and non-small-cell lung cancer (NSCLC), in which the ADC potentiated ICI activity and led to pro-inflammatory changes in the TME by inducing T-cell infiltration and enhancing antigen presentation.
ADCs given as single agents have demonstrated antitumor activity and have been approved in a variety of solid and hematological tumors. Extensive efforts are currently underway by both academic and biopharmaceutical sectors to develop next-generation ADCs by identifying new targets and enhancing their pharmacologic effects, as well as combination therapies based on current ADC drugs.
However, the limited success of ADC combination strategies to date may be related to nonspecific expression of the target leading to adverse reactions in normal tissues, overlapping toxicities, and emerging resistance mechanisms. Therefore, a deep understanding of the pharmacology of ADCs and the associated predictive biomarker combinations is needed for preclinical evaluation in well-characterized patient-derived xenograft models in order to select the most promising ADC-based combinations.
 Fuentes-Antrás J, Genta S, Vijenthira A, Siu LL. Antibody-drug conjugates: in search of partners of choice. Trends Cancer. 2023;9(4):339-354. doi:10.1016/j.trecan.2023.01.003
 Drago, J.Z., Modi, S. & Chandarlapaty, S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol 18, 327–344 (2021). https://doi.org/10.1038/s41571-021-00470-8
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