Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.
Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.
Trastuzumab deruxtecan (TDXD) and datopotamab deruxtecan (Dato-DXd) share the same cytotoxic payload, yet Dato-DXd has a much lower rate of interstitial lung disease (ILD). This indicates the toxicity is driven by the antibody-antigen interaction, not the payload itself.
To manage the common side effect of stomatitis from datopotamab deruxtecan (Dato-DXd), a preemptive strategy is effective. Prescribing steroid mouthwash and advising patients to use ice chips during infusion can reduce the severity and incidence of this toxicity.
Unlike older antibody-drug conjugates (ADCs), newer agents are designed so their chemotherapy payload can diffuse out of the target cell and kill nearby tumor cells that may not even express the target antigen. This "bystander effect" significantly enhances their anti-tumor activity.
When combining sacituzumab govitecan (SASE) and pembrolizumab (IO), it's crucial to differentiate the cause of diarrhea. SASE-induced diarrhea is similar to standard chemotherapy, while IO-induced diarrhea often presents with bloody stools and severe abdominal cramping.
Despite the presence of PIK3CA mutations in some triple-negative breast cancer (TNBC) tumors, Phase III trials with AKT inhibitors have been negative. Currently, there is insufficient evidence to support using PI3K/AKT pathway inhibitors for TNBC in clinical practice.
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.
When efficacy and safety profiles are comparable between ADCs like sacituzumab and datopotamab, the final choice can be guided by patient logistics. Factors include infusion frequency (Day 1 & 8 vs. every 3 weeks) and total time spent at the infusion center.
For patients who previously received immunotherapy (IO), a recurrence more than 12 months after completing treatment makes re-challenging with an IO agent a reasonable option. The likelihood of benefit is lower if the recurrence is within 6-12 months and minimal if under 6 months.
For managing nausea from ADCs like TDXD, a three-drug prophylactic regimen (steroid, 5-HT3 antagonist, NK1 inhibitor) is recommended. For delayed nausea, continuing the 5-HT3 antagonist on days two and three is often effective before needing to add agents like olanzapine.
In trials like ASCENT-4, where over 80% of the control arm received sacituzumab govitecan upon progression, the true overall survival (OS) benefit is obscured. This makes progression-free survival (PFS) a more reliable endpoint for evaluating the drug's first-line efficacy.
Clinical trial data shows that despite specific toxicities, antibody-drug conjugates (ADCs) can be better tolerated overall than standard chemotherapy. For example, trials for both sacituzumab govitecan and dato-DXd reported fewer patients discontinuing treatment in the ADC arm compared to the chemotherapy arm.