RE:RE:RE:RE:ONCY pelareorep as a potential bispecific or ADC payload.Despite their antibody-directed homing, ADcs come with their share of toxicities obligating appropriate patient selection and vigilant monitoring while on treatment. As more ADCs are included in the treatment armamentarium, mechanisms of resistance need to be studied and understood for optimal sequencing. Modifying the payload to use immune-stimulating agents or combination therapies with immunotherapy and other effective targeted therapies may further extend the utility of these agents in the treatment of solid tumors.
The advent of ADCs for the treatment of metastatic cancers over the past decade has significantly improved outcomes across different solid tumors. Nevertheless, patients on these therapies eventually experience disease progression, likely because of resistance.
Resistance may be related to the components of ADCs including altered target cell surface expression or gene mutation, upregulation of drug efflux transporters to offset payload toxicity, changes in trafficking of the ADC and internalization rates, or simple payload resistance.
However, the multifaceted mechanism of action of ADCs also includes the engagement of immune effector cells with the goal of eliciting antitumor immunity. Harnessing the power of the immune system to ADC development and generating molecules that target immune cells and other components of the TME are already underway.
Data from ADC + monotherapy CPI randomized trials of T-DM1/placebo + atezolizumab in HER2+ MBC (KATE-2) and the phase 1 trial of T-DXd with nivolumab did not show significant improvement in efficacy with the combination over HER2-ADC alone, which is consistent with our understanding of CPI monotherapy versus combination of pelareorep + CPI that has proven to be synergistic.
Consequently, a combination of pelareorep + CPI +/- ADC as either a first line (ADC+ pelareorep + CPI) or second line (pelareorep + CPI) treatment is an increasingly forthcoming option as the next generation of cancer therapies.
https://ascopubs.org/doi/full/10.1200/EDBK_390094