When Gefitinib Stops Working: — Resistance and What Comes Next

T790M is a change in the EGFR gene at a specific position that alters the shape of the protein so that first-generation drugs like gefitinib can no longer bind to it effectively. NCCN and ESMO identify it as the most commonly found cause of acquired resistance to first-generation EGFR inhibitors. It develops inside the tumour over time in response to treatment pressure — it is not something you were born with. Knowing it is present is clinically important because a specific drug class exists to overcome it.

A liquid biopsy — a blood draw that looks for fragments of tumour DNA — can detect T790M without repeat surgery or a needle into the tumour in many cases. NCCN guidelines include liquid biopsy as an accepted initial test for acquired resistance. However, if the blood result is negative or inconclusive, a tissue biopsy is still recommended, because a negative blood result does not rule out the mutation. Your oncologist will advise which approach is right given your situation.

This occurs in a proportion of patients. When the resistance mechanism cannot be identified despite testing, the decision moves to your overall fitness, your cancer type, and your oncologist's assessment of similar presentations. Platinum-based chemotherapy remains the most established next line in this situation according to NCCN guidance. Enrolling in a clinical trial is also worth discussing at this point, because some trials specifically recruit patients where the resistance pattern is unclear or uncommon.

Chemotherapy after an EGFR inhibitor achieves disease control in a proportion of patients, though response rates vary between individuals and the evidence continues to mature. NCCN and ESMO both include platinum-based doublet regimens in their guidance for patients who have progressed on an EGFR inhibitor. Your oncologist will explain what the evidence suggests for your specific situation — whether the aim is shrinking the disease, controlling its growth, or managing symptoms.

Yes, and this is one of the more important moments to raise it. Several trials are specifically designed for patients who have progressed on a first-generation EGFR inhibitor, including trials of drug combinations, newer targeted agents, and strategies for patients with uncommon or unidentified resistance patterns. Your oncologist can tell you whether any currently open trials match your resistance profile. If none are available locally, a referral to a centre with a broader trials programme is a reasonable request.

In a small proportion of patients, cancers that became resistant to a first-generation EGFR inhibitor may show some renewed sensitivity after a period off the drug, particularly following treatment with a drug from a later generation. The evidence on this is not yet mature enough for rechallenge to be a standard recommendation. Whether it might be considered for you would depend on your specific resistance mechanism, what other treatments you have received, and your oncologist's overall assessment.