Emerging data indicates that Tarlatamab, a DLL3-targeted therapy, has inferior performance in small cell lung cancer (SCLC) that transformed from EGFR-mutant NSCLC compared to its efficacy in de novo SCLC. This suggests the biological context of transformation impacts treatment response, a critical nuance for this new therapy.

The success of early CAR-T cell therapies was partly luck. Future therapies face a high bar, as an ideal target must meet three criteria: 1) be abundant on cancer cells, 2) be indispensable for the cancer's survival, and 3) be dispensable for the patient's healthy tissues to avoid lethal toxicity.

In ambiguous cases, immunohistochemistry showing the loss of the RB1 protein is a powerful indicator of a poorly differentiated neuroendocrine carcinoma (NEC). This helps distinguish NECs from high-grade neuroendocrine tumors or adenocarcinomas with neuroendocrine features, a critical distinction for prognosis and treatment.

After standard immunotherapy biomarkers like PD-L1 and TMB proved ineffective in SCLC, the field shifted to a more direct approach. Novel therapies like the bispecific antibody tarlatumab target surface proteins such as DLL3, physically bridging immune cells to cancer cells without relying on predictive biomarkers.

Companies like VIR are making progress with masked T-cell engagers that limit systemic toxicity like cytokine release syndrome (CRS). This approach, which concentrates efficacy at the tumor site, could be the key to unlocking the broad potential of T-cell engagers beyond hematologic malignancies into the much larger solid tumor market.

Despite widespread use in oncology, immunotherapy has limited efficacy in extrapulmonary NEC. Real-world data for combination CTLA-4 and PD-1 inhibitors show response rates around 15%, with sustained responses in less than 10% of patients. This highlights the urgent need for novel therapeutic approaches beyond checkpoint inhibition.

Contrary to common belief, HER2 can be expressed or amplified in prostate cancer, particularly in subtypes with neuroendocrine features. This creates a rare but actionable target, with reported complete responses to HER2-directed therapies like TDXD, highlighting the need for broader genomic testing.

Many promising solid tumor antigens (e.g., PSMA, HER2) are also on normal tissues, making them too toxic for T-cell engagers. By using masks that are cleaved only in the tumor microenvironment, these "dirty" targets become viable, dramatically expanding the therapeutic landscape for solid cancers.

To combat immunosuppressive "cold" tumors, new trispecific antibodies are emerging. Unlike standard T-cell engagers that only provide the primary CD3 activation signal, these drugs also deliver the crucial co-stimulatory signal (e.g., via CD28), ensuring full T-cell activation in microenvironments where this second signal is naturally absent.