Osimertinib, also known as AZD9291, is a third-generation small molecule tyrosine kinase inhibitor (TKI) that has shown great promise in the treatment of non-small cell lung cancer (NSCLC). Specifically, it has been approved by the FDA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy.
The EGFR gene is commonly mutated in NSCLC, leading to the activation of signaling pathways that promote tumor growth and survival. While first-generation EGFR TKIs, such as gefitinib and erlotinib, showed significant clinical benefit in patients with EGFR-mutated NSCLC, many patients eventually developed resistance to these drugs. This resistance is often due to the emergence of the T790M mutation, which confers resistance to first-generation TKIs, but remains sensitive to osimertinib.Osimertinib selectively targets mutated forms of EGFR, including the T790M mutation, while sparing wild-type EGFR, which reduces toxicity compared to earlier EGFR TKIs. In clinical trials, osimertinib has shown high response rates in patients with the T790M mutation, with a median duration of response of 12.4 months.
In addition to its efficacy against the T790M mutation, osimertinib has also demonstrated activity against the EGFR C797S mutation, which is another mechanism of resistance to EGFR TKIs. Early preclinical data suggest that osimertinib could also have activity against other oncogenic drivers in NSCLC, such as the ALK and ROS1 rearrangements.
Osimertinib is administered orally, once daily, at a dose of 80 mg. Common side effects include diarrhea, rash, and nail toxicity, but these are generally manageable and rarely lead to treatment discontinuation.
Overall, osimertinib represents an exciting development in the treatment of EGFR-mutated NSCLC, particularly for patients with the T790M mutation who have limited treatment options. Ongoing research is investigating osimertinib in combination with other agents, as well as in earlier lines of therapy, which could further expand its utility in the management of lung cancer.
