The COMPEL study provides the first formal data supporting the common practice of continuing osimertinib when adding chemotherapy after disease progression. This is a significant finding as previous studies with older-generation TKIs showed this strategy was not helpful, highlighting osimertinib's unique CNS-protective benefits.

The COMPEL study showed a near doubling of progression-free survival by continuing osimertinib with chemotherapy after first-line progression. This contradicts findings with first-generation TKIs (like gefitinib) and establishes "TKI continuation" as a new standard of care.

The LAURA trial shows a favorable overall survival trend for osimertinib consolidation even though 80% of placebo patients received osimertinib upon progression. This high crossover rate makes the persistent trend highly significant, suggesting a strong benefit to earlier TKI administration.

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.

Due to a 10-11 month overall survival benefit shown in the FLORA two regimen, leading oncologists now consider osimertinib plus chemotherapy the standard first-line treatment for metastatic EGFR-mutant NSCLC. Monotherapy is reserved only for patients who cannot tolerate or refuse chemotherapy.

Contrary to expectations from metastatic disease trials like FLAURA2, the NeoAdura study showed that combining chemotherapy with neoadjuvant osimertinib did not yield a better major pathologic response (MPR) than osimertinib alone for resectable EGFR-mutant lung cancer, questioning the role of upfront chemo in this setting.

Despite initial benefits, fewer than 10% of EGFR-mutated NSCLC patients on osimertinib monotherapy survive five years. A significant portion (25-40%) never even receive a second-line treatment, highlighting the limitations of this once-standard approach.

The COMPEL trial provides strong evidence for a "treat through progression" strategy. For patients progressing on osimertinib monotherapy, continuing the TKI while adding chemotherapy significantly reduces the probability of CNS progression, highlighting its role as a CNS protectant even when systemic efficacy is waning.

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.