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.

Subgroup analyses of menin inhibitor trials reveal a key difference for treatment sequencing. Patients with prior venetoclax exposure showed lower response rates to Revumenitib. In contrast, early data for Ziftomenib suggests prior venetoclax use did not negatively impact its efficacy.

The Mariposa study showed an overall survival benefit for first-line amivantamab. However, since very few patients in the control arm received subsequent amivantamab, the benefit may simply demonstrate the drug's effectiveness at *any* point, not necessarily that it must be used first-line.

In ROS1-positive NSCLC, starting with older TKIs before newer agents like Repotrectinib dramatically worsens outcomes. Median overall survival has not been reached after 5 years for TKI-naive patients but drops to just 25 months for those pre-treated with another TKI. This starkly quantifies the critical importance of using the most effective treatment first.

The new treatment paradigm for HER2-positive lung cancer will likely involve sequencing a TKI like zongertinib first, followed by an antibody-drug conjugate (ADC). Early data suggests that the efficacy of TKIs is significantly reduced when used after an ADC, making the TKI-first approach critical for maximizing patient outcomes.

A significant clinical challenge is the sequencing of antibody-drug conjugates (ADCs). Retrospective data from large databases indicates that using a second TROP2-targeted ADC after a first one provides very limited efficacy, highlighting an urgent need for prospective trials to define optimal sequencing strategies and overcome resistance.

Unlike immunotherapy, neoadjuvant osimertinib yields poor pathologic complete response (pCR) rates. However, it significantly improves major pathologic response (MPR) and survival, suggesting pCR may be the wrong efficacy endpoint for cytostatic EGFR TKIs, which have a different mechanism of action than immunotherapy.

For patients with actionable mutations like EGFR or ALK, targeted therapy is the priority, regardless of PD-L1 score. Starting immunotherapy first in these patients can significantly increase the risk of developing severe pneumonitis (ILD) when they later switch to targeted therapy like osimertinib.

For N2+ EGFR-mutant NSCLC, clinicians now face a choice. Combining neoadjuvant osimertinib with chemotherapy is potent and gets treatment done upfront, but osimertinib monotherapy is better tolerated, reducing the risk of toxicity that could prevent a patient from reaching their planned surgery.