In the Keynote 522 trial for early-stage TNBC, adding pembrolizumab to chemotherapy resulted in only a modest improvement in pathological complete response (pCR). Surprisingly, this small initial gain translated into much more robust and significant long-term improvements in event-free and overall survival.

The TROPION-PanTumor01 study showed that patients who progressed on the TROP2-ADC sacituzumab govitecan still achieved responses to a second TROP2-ADC, Dato-DXD. This suggests that targeting the same antigen with a different payload can overcome initial resistance, informing future treatment sequencing.

In metastatic breast cancer, approximately one-third of patients are unable to proceed to a second line of therapy due to disease progression or declining performance status. This high attrition rate argues for using the most effective agents, such as ADCs, in the first-line setting.

A decade ago, metastatic triple-negative breast cancer (mTNBC) had a median survival of about one year. Today, the duration of response to modern antibody-drug conjugates (ADCs) in the first-line setting can be longer than what the entire overall survival used to be, highlighting a massive therapeutic advancement.

The long-standing platinum doublet backbone for frontline SCLC may soon be challenged. The high efficacy of novel agents like antibody-drug conjugates and bispecific antibodies in later lines is prompting trials that consider moving them into the first-line setting, a strategy previously considered "unthinkable."

With two newly approved, effective ADCs (Sacituzumab govitecan and Datopotamab deruxtecan) for first-line PD-L1 negative TNBC, clinicians face a state of "equipoise." Lacking head-to-head data, treatment selection hinges on physician experience and patient factors like side effect tolerance and schedule, not superior efficacy.

A significant portion of patients (30-50%) with metastatic triple-negative breast cancer do not survive to receive second-line treatment. This high attrition rate underscores the critical importance of administering the most effective therapy—offering the best PFS and response rate—in the first-line setting to maximize patient outcomes.

The SURE-01 trial's data suggests non-luminal subtypes and low TOP1 expression are linked to better outcomes with sacituzumab govitecan. This finding points toward a future where molecular profiling, not just treatment ineligibility, could guide personalized neoadjuvant therapy selection for patients.

Oncologists view datopotamab deruxtecan and sacituzumab govitecan as similarly effective for first-line TNBC. The choice is driven by side effect profiles: stomatitis/ILD with Dato versus alopecia/GI toxicity with SG, and logistics like infusion frequency.