The control arms (chemotherapy alone) in two major, independent trials, Mariposa 2 and Harmony, both yielded an identical median progression-free survival of 4.4 months. This consistency across studies validates the data and strengthens the conclusion that chemotherapy alone is a poor benchmark post-TKI failure.

If gastroesophageal cancer does not respond to first-line zolbetuximab, experts advise against continuing it with a new chemo backbone. This is based on tumor heterogeneity and parallels with a negative trial of continuing trastuzumab past progression in HER2+ disease.

The NeoADURA trial demonstrates that adding osimertinib in the neoadjuvant setting for EGFR-mutated NSCLC results in a 'humongous benefit' in major pathological response and nodal downstaging compared to chemotherapy alone, significantly improving surgical outcomes.

The FLORA two study's overall survival benefit was so compelling that clinicians should now default to osimertinib plus chemotherapy for most first-line EGFR-mutant NSCLC patients, only opting out for specific reasons like comorbidities or patient preference.

When EGFR+ NSCLC transforms to small cell, clinicians often continue the TKI osimertinib alongside chemotherapy. This practice is largely based on expert consensus and the rationale of suppressing any remaining EGFR-driven clones, rather than on definitive clinical trial data showing a clear benefit.

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.

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.

A sobering finding from the LAURA trial was its control arm. EGFR-mutant patients receiving standard "curative-intent" chemoradiation alone had extremely high and rapid relapse rates (PFS ~6 months), highlighting the inadequacy of this standard and underscoring the necessity of adding consolidation osimertinib.

Clinicians advise against continuing targeted agents like zolbituximab or trastuzumab after disease progression in gastroesophageal cancer. The biological heterogeneity of this cancer type means that if a targeted therapy isn't working, it's unlikely to provide benefit with a different chemotherapy backbone.