Osimertinib (Tagrisso) has a strong foothold as first-line therapy for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), but resistance to the third-generation EGFR tyrosine kinase inhibitor is a major stumbling block.
“Understanding osimertinib resistance mechanisms and currently available treatment options are essential to selecting optimal second-line therapy for patients whose disease progresses during front-line osimertinib,” advised Zofia Piotrowska, MD, of Massachusetts General Hospital in Boston, and colleagues.
In a review article, Piotrowska’s group offered an “evidence-based, algorithmic approach to the evaluation and management of post-osimertinib progression,” including the following key points:
- Slow, asymptomatic progression often does not require an immediate change in treatment, and many patients can safely continue osimertinib beyond initial radiographic progression
- Add-on locally ablative therapy to osimertinib is an option for patients with oligoprogression
- MET alterations, EGFR C797X, small-cell lung cancer transformation, and oncogene fusions are the most common mechanisms of osimertinib resistance
- “For patients with an EGFR mutation whose disease progresses on osimertinib and who move to second-line chemotherapy, the role of combination chemoimmunotherapy is not well understood,” and, as a result it is possible that “both a PD-L1 inhibitor and antiangiogenesis agent are required to improve on chemotherapy for patients with EGFR-positive disease”
- Metastasis to the central nervous system (CNS) is common in these patients (about 20% of the FLAURA trial population had CNS metastases at presentation), and “osimertinib’s strong CNS penetration has likely contributed to the drug’s success”