The NAOTRACT trial is pioneering the use of Tumor-Infiltrating Lymphocytes (TILs) as a predictive biomarker. Patients with high TILs receive a less intensive, anthracycline-free neoadjuvant regimen, potentially sparing them from toxicity while maintaining efficacy, representing a major step toward personalized immunotherapy.

For elderly patients with locally advanced cancer who are not candidates for surgery, an ADC with an every-three-week schedule, like datopotamab, can provide an excellent balance of efficacy and tolerability. This approach can achieve local disease control and maintain quality of life, with dose and schedule modifications further improving safety.

For patients with lung metastases and symptoms like shortness of breath, choosing an ADC becomes complex. The primary concern is the inability to distinguish between disease progression and drug-induced interstitial lung disease (ILD), a known risk with certain ADCs. This diagnostic ambiguity can lead clinicians to favor ADCs with a lower ILD risk profile.

The Begonia trial showed an ~80% response rate by combining an ADC (Dato-DXD) with immunotherapy (Durvalumab) in first-line metastatic TNBC patients, 87% of whom were PD-L1 negative. This suggests ADCs, through immunogenic cell death, may create an immune-responsive environment, expanding IO benefit beyond the traditional biomarker.

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.

While TROP2-ADCs are currently approved for later-line lung cancer treatment, active clinical trials are already evaluating them as a potential replacement for traditional chemotherapy in the first-line setting. This represents a significant strategic ambition to shift the entire treatment paradigm for newly diagnosed patients with both non-small cell and small cell lung cancer.

For de novo metastatic, PD-L1 positive TNBC patients with a BRCA mutation, experts prefer an ADC with immunotherapy over a PARP inhibitor. This choice is driven by the potential for longer-lasting responses with the ADC/IO combination, even though PARP inhibitors directly target the underlying genetic mutation.

As multiple effective Antibody-Drug Conjugates (ADCs) become available, the primary clinical challenge is no longer *if* they work, but *how* to use them best. Key unanswered questions involve optimal sequencing, dosing for treatment versus maintenance, and overall length of therapy, mirroring issues already seen in breast cancer.

Clinical trial data suggests immunotherapy's timing is crucial in early-stage TNBC. Given with chemotherapy before surgery (neoadjuvant), it improves outcomes. However, when given alone after surgery (adjuvant), the IMPASSION 030 trial showed no benefit and was halted for futility, indicating pre-surgical tumor priming is essential.