Although ADC drugs have greatly improved the survival benefits of patients, the duration of their objective response or clinical benefits as a monotherapy is limited due to the emergence of drug resistance mechanisms, as is the case with most cytotoxins. Therefore, in recent years, the preclinical and clinical trials of ADC in combination with other anticancer drugs, including chemotherapy, molecular targeted drugs, and immunotherapy, have been actively studied.
Combining ADCs and chemotherapeutic drugs requires a better understanding of the unique cell cycle interactions and the regulation of surface antigen expression by cytotoxic partners. So far, increasing preclinical and clinical data have shown some success, pointing the way for further drug development.
Cell Cycle Interaction
DNA damaging agents, such as antimetabolic drugs, platinum and topoisomerase inhibitors, which act on the S phase and lead to G2/M phase arrest can be effectively combined with microtubule inhibitors. The best effect is observed in G2 / M phase. This concept has been confirmed by the excellent curative effect of carboplatin combined with mirvetuximab soravtansine (FR α-DM4), anetumab ravtansine (mesothelin-DM4) or luveltamab tazevibulin (FR α-SC239) in an ovarian cancer model.
In early trials, significant response rates were achieved in combination therapy of ADCs of ravtansine and carboplatin or adriamycin for patients with ovarian cancer and platinum-sensitive and drug-resistance, and in combination therapy of ADCs of deruxtecan and capecitabine or cisplatin for patients with gastric and lung cancer.
For hematoma, representative examples include brentuximab vedotin (CD30- MMAE) combined with CHP (cyclophosphamide, doxorubicin and prednisone) in the treatment of CD30+ peripheral T-cell lymphoma, and Polatuzumab vedotin (CD79b-MMAE) combined with rituximab-CHP in the treatment of diffuse large B-cell lymphoma.
Timing Design of Drug Administration
The timing of administration needs to be designed in combination strategy. Tubulin polymerization is a key component of ADC internalization, while DNA damage-induced G 2/M phase arrest may take some time to be sensitized by microtubule interferers.
Wahl et al. have demonstrated this well in colon, lung and breast cancer models where sequential administration of SGN-15 (Lewis Y-doxorubicin) and paclitaxel caused more DNA fragmentation than simultaneous administration.
Regulation of Surface Antigens
Chemotherapy may regulate the expression of ADC-targeted surface antigens. In this regard, gemcitabine has been shown to up-regulate the expression of HER2 in pancreatic cancer cells, while the combination of gemcitabine and T-DM1 enhances efficacy. Intertwined with the above cell cycle interactions, the upregulation of HER2 mainly occurs in the population of G2/M, which is the result of the inhibition of DNA synthesis mediated by gemcitabine.
Therefore, specific chemotherapeutic drugs may be more suitable for combination with ADCs, depending on their ability to increase antigen availability. Whether this finding is applicable to other ADC-chemotherapy combinations requires further research.
Overlapping Toxicity
Targeted chemotherapy is essentially chemotherapy, so improving the efficacy of combination regimen is often hindered by unacceptable toxicity. The main toxicity is driven by the cytotoxic payload. Currently, ADC carries a highly effective payload, and its IC50 is within the range of nM or pM, mainly because less than 2% can reach the target tumor. ADCs with higher DAR and cuttable connectors may cause higher off-target toxicity. This consideration must be carefully considered when designing joint strategies and potential pharmacokinetic (competitive) interactions and iconic payload toxicity.
Although most of the available data on competitive interactions are negligible, some recurring toxicities include peripheral neuropathy of MMAE and DM1 derivatives, eye toxicity of MMAF and DM4, gastrointestinal reactions of DM1 or topoisomerase inhibitors, or hepatotoxicity of Calicheamin derivatives, and almost universal neutropenia and thrombocytopenia. This is illustrated by two phase 2a/b studies of trastuzumab in combination with docetaxel or paclitaxel in the treatment of advanced HER2+ breast cancer, in which more than half of patients needed to reduce their dose or stop using paclitaxel.
Newer and more tumor-selective ADC, such as mirvetuximab soravtansine and datopotamab deruxtecan, have shown milder toxicity characteristics, making them suitable companions for chemotherapy with different mechanisms. In this regard, myelosuppression and peripheral neuropathy caused by mirvetuximab soravtansine exposure were reduced compared to those who participated in the third phase of FORWARD I trial, and their tolerance in combination with carboplatin was equivalent to that of standard nursing chemotherapy.