Compared to standard chemotherapy, ADC (antibody-drug conjugate) improves the therapeutic index, and its activity in patients with selective tumors makes it a potential partner for targeted drugs. Joint strategies can be conceived to overcome therapeutic drug resistance and tumor heterogeneity, leading to stronger inhibition of oncogene-dependent signaling pathways, increased availability of surface antigens, sensitization of tumors with low antigen expression, regulation of the TME (tumor microenvironment), and use of synthetic killing. Although existing clinical data mainly involve T-DM1 and HER2 targeting strategies, these experiences can be applied to other ADC.
Use of ADCs Instead of Chemotherapy
Currently, some studies have attempted to use ADCs instead of standard chemotherapeutic drugs as a companion to targeted drugs, However, the results have not been satisfactory. Clinical trials such as KAITLIN, KRISTINE, and MARIANNE were based on the preclinical synergistic antitumor activity of T-DM1 combined with pertuzumab, but in the new adjuvant and metastatic environment, this combination was not more effective than paclitaxel, trastuzumab and pertuzumab, especially in patients with low HER2 expression or high HER2 heterogeneity. Similarly, the efficacy of anetumab ravtansine combined with bevacizumab in the treatment of ovarian cancer was not as good as paclitaxel.
Although current results are not satisfactory, they do not necessarily imply that the next generation of ADC and combined targeting drugs will also fail.
Tyrosine Kinase Inhibitors (TKIs)
Dual-target blockade of TKI may provide greater selectivity and potential improvement in therapeutic index. In the TEAL study, the combination of T-DM1, pan-HER2 inhibitors Lapatinib, and nab-paclitaxel produced a better response to neoadjuvant therapy in patients with HER2+ breast cancer than standard paclitaxel, trastuzumab, and pertuzumab. This effect was amplified in HR positive subgroups.
Tucatinib, a more selective HER2 TKI, achieved a 47% ORR in advanced patients after previous treatment with paclitaxel and trastuzumab when used in combination with T-DM1. These results have stimulated the ongoing phase III trial of T-DM1 or T-DXd combined with tucatinib (HER2CLIMB-02 and HER2CLIMB-04).
Targeted ADC Resistance
Increasing evidence supports targeting known ADC resistance mechanism. For example, since the malignant transformation of breast epithelial cells by HER2 depends on cyclin D1 and T-DM1, the inhibitor of CDK4 hand 6 has been used in combination with T-DM1 in patients with HER2 drug resistance, with moderate efficacy and acceptable toxicity.
Another key cell cycle regulator, PLK1, has recently been identified as an up-regulated target in acquired and primary T-DM1 models, and its inhibition by volasertib leads to T-DM1 sensitization.
ADC may also be an effective companion in regulating the mechanism of drug resistance of targeted drugs. For example, in the EGFR mutated non-small cell lung cancer model, the combined use of EGFR TKIs osimertinib and T-DM1 can produce an additive anti-tumor effect, where T-DM1 can delay or overcome osimertinib drug resistance.
Regulation of Surface Antigens
Some TKIs have been shown to regulate the availability of surface antigens, potentially inducing stronger ADC activity and sensitizing tumors with low antigen expression. Examples include up-regulation of AXL and sensitization to enapotamab vedotin (AXL-MMAE) in melanoma cell lines exposed to BRAF/MEK inhibitors.
HER2-TKIs lapatinib, neratinib, tucatinib and poziotinib have also been shown to increase the efficacy of T-DM1. However, the mechanism is still unclear.
Anti-angiogenesis
Anti-angiogenic drugs may promote the penetration and exposure of ADC to tumor cells. An excellent effect has been described in preclinical models of ovarian cancer with the combination of anetumab ravtansine or mirvetuximab soravtansine and bevacizumab. A recent phase 1b clinical trial studied the combination of mirvetuximab soravtansine and bevacizumab, achieving a 39% ORR in ovarian cancer patients who had undergone a large number of pretreatments, platinum resistance, and elevated FR α. This exceeds the benchmark value of the AURELIA test (27%).
DNA Damage Reaction Reagent
Combining drugs that target the DNA damage response (DDR) with ADCs carrying DNA damage agents to synthesize lethality could be a promising strategy for treating tumors with genomic instability. Combining DDR drugs with chemotherapy has traditionally been hindered by intolerable toxicity. Although the combination of topotecan or irinotecan with olaparib or veliparib can cause higher toxicity and side effects, the excellent activity and tolerance of the new generation of ADC carrying topoisomerase I inhibitor payloads make them more suitable as joint partners.
Sacituzumab govitecan (TROP2-SN38) combined with olaparib or talazoparib produced a synergistic anti-tumor effect in vivo and in vitro without obvious bone marrow toxicity. Several clinical trials are ongoing to explore this strategy, including niraparib and trastuzumab duocarmazine,talazoparib and sacituzumab govitecan, as well as olaparib and trastuzumab deruxtecan.
Since the synthesis and killing of poly (adenosine diphosphate ribose polymerase) (PARP) inhibitors depends largely on the inhibition of PARP1, while PARP2 is mainly involved in the dynamic balance of the blood system, selective PARP1 inhibitors will be the main choice for combination therapy. This concept is being tested with trastuzumab deruxtecan and datopotamab deruxtecan in the 1amp Phase 2 PETRA trial.
In addition to PARP inhibition, the increased selectivity of ADCs for chemotherapy will undoubtedly expand the range of DDR drugs that can be bound. For example, a joint trial of ATR inhibitors berzosertib and saituzumab govitecan (NCT04826341) is under way.