HER2- and TROP2-antibody-drug conjugates in small cell lung cancer cell lines and 3D culture: Efficacy and role of target expression

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by robust responsiveness to frontline chemotherapy and immunotherapy followed by rapid resistance and poor survival. Recently, cell-surface targeting drugs, such as T-cell engagers (tarlatamab) and antibody-drug conjugates (ADCs), have demonstrated significant responses in relapsed SCLC patients. Paradoxically, the efficacy of TROP2-ADCs and HER2-ADCs both have failed to correlate with the level of target expression in both SCLC and breast cancer patients, yielding difficulty in predicting the patient population which would receive benefit from these treatments. Treatment efficacy across a range of expression may be due to tumor heterogeneity and the delivery of the payload to a cell presenting the target resulting in a bystander effect on cells with low or no expression. SCLC cell lines and dissociated PDX tumors were evaluated for development of spheroids, which better mimic a solid tumor than 2D cell culture. The growth of these spheroids and PDX organoids were evaluated following treatment with HER2-ADC (trastuzumab deruxtecan), TROP2-ADC (sacituzumab govitecan), tarlatamab, activated T-cells, and combinations of these. Effect of complete siRNA knockdown of the surface target on the efficacy of targeted ADCs was also determined. HER2- and TROP2-ADCs slowed growth of the spheroids as compared to the control. Additionally, the combination of TROP2-ADC, tarlatamab, and T-cells caused contraction of the spheroids. Notably, the tarlatamab and T-cells arm demonstrated what is likely a pseudo-progression sometimes seen in patients as T-cells infiltrate and begin to kill tumor cells. Knockdown of ERBB2 and TACSTD2 demonstrated no demonstrable difference in ADC sensitivity. In conclusion, HER2- and TROP2-ADCs demonstrated efficacy in these models and may be used in combinatorial approaches in the future. Additionally, co-cultured cell line spheroids could provide a better model of tumor heterogeneity. Lastly, HER2- and TROP2- levels are not predictive biomarkers for ADC sensitivity, suggesting that other biomarkers should be explored to identify responsive patient populations.