A new meta-analysis indicates that combining antibody-drug conjugates (ADCs) with immune checkpoint inhibitors (ICIs) shows promise in cancer treatment, yielding a pooled objective response rate (ORR) of 58% across various cancer types. The study, encompassing 12 clinical trials and 584 patients, highlights the potential of this combination therapy while also noting the importance of patient selection and biomarker analysis.
Efficacy and Safety of ADC Plus ICI
The meta-analysis revealed a significant difference in favor of the efficacy of combination therapy, with an ORR of 58% (95%CI 46%, 70%). Acceptable adverse events (AEs), primarily related to the skin and digestive system, were observed. These findings suggest that the combination of ADCs and ICIs can provide meaningful clinical benefits without unacceptable toxicity.
However, the study also points out that not all patients benefit equally from this combination. Some late-stage clinical trials have not shown effectiveness when compared with conventional chemotherapy drugs. For example, the KATE-2 study showed no significant progression-free survival (PFS) difference between trastuzumab emtansine (T-DM1) and T-DM1 plus atezolizumab in HER2-positive breast cancer patients according to intention to treat (ITT). Nevertheless, survival benefits were observed in the PD-L1-positive subgroup, with a median PFS of 8.5 vs 4.1 months (HR 0.60 95%CI 0.32–1.11).
Subgroup Differences and Biomarker Importance
Further analysis suggested that the improvement in patients with combination therapy may show subgroup-level differences, correlating with information on histologic subtype and regimens. Notably, classical Hodgkin lymphoma (cHL) benefited most from combinations, followed by urothelial carcinoma (UC), primary mediastinal B-cell lymphoma (PMBL), breast cancer (BC), non-small cell lung cancer (NSCLC), and several advanced solid tumors. This may be related to the drug target, as tumors with high expression of targeted antigen showed better effect when treated with ADC or ICI.
CD30 and PD-L1 are consistently overexpressed in patients with HL, while human epidermal growth factor 2 (HER2) is highly expressed in multiple solid tumors. HER2-positive oncogenesis was more likely to be correlated to higher PD-L1 and immunogenicity, suggesting that HER2-high tumors may benefit more from ADC + ICI therapy. These results emphasize the importance of immunohistochemical and pathological examinations in clinical settings. Acquiring the level and type of targeted antigen may allow cancer patients, especially those with hematologic malignancy, to derive significant clinical efficacy.
Regimen-Specific Analysis
When comparing different regimens, brentuximab vedotin (BV) combined with nivolumab or pembrolizumab seemed to provide more ORR benefits than other arms, potentially due to heterogeneity caused by tumor types. However, the study could not conclude which combination was better, given that both pembrolizumab and nivolumab target PD-1 inhibitors and the totality of efficacy data was not uniformly reported. Efficacy data also suggested that enfortumab vedotin (EV) plus pembrolizumab could benefit UC patients more compared with sacituzumab govitecan (SG) plus pembrolizumab, but these data should be interpreted cautiously due to differences in baseline characteristics.
Safety Considerations and Adverse Events
The meta-analysis identified immune-related adverse events (irAEs) mainly involving digestive and skin problems, with no severe AEs spotted. The toxicity of ADC therapy is mainly related to the cytotoxic drugs carried, while the toxicity of ICI may have a delayed onset and prolonged duration. The study observed a significantly increased risk or progression in ICI-treated patients with hypoalbuminemia. However, the irAEs identified were mainly digestive and skin problems, and no significant additive toxicity was spotted.
To mitigate potential toxicities, the study suggests advanced assessment for patients’ physical condition, the use of variable ADC formats, appropriate dosing strategies, and comprehensive surveillance during medication. Personalized treatment plans based on individual patient responses rather than standardized dosing may also improve overall treatment outcomes.
Future Directions
Future prospective clinical trials should validate the value of combination strategies in negative-gene-expression patients and in advanced or metastatic cancer patients who may have developed resistance to monotherapy. Detailed stratification of patients with specific antigen levels may be needed in clinical trials to meet the requirements of personalized treatment. Further studies that investigate the mechanism of resistance of ADC and ICI monotherapy may also help promote the development of new subtypes.
