Stage IVA EGFR-mutant lung adenocarcinoma: clonal evolution, chemoimmunotherapy response, osimertinib rechallenge, and death after progression

What happened, in summary

This 68-year-old man with a smoking history of more than 20 years was evaluated in September 2021 for cough and progressive shortness of breath. PET imaging showed a right upper-lobe lung mass, and biopsy of a right supraclavicular lymph node confirmed poorly differentiated lung adenocarcinoma. Staging was cT4N3M1a, Stage IVA. Initial molecular testing found compound EGFR mutations, L747S and L858R, with TP53 Q192*. He started osimertinib 80 mg daily in September 2021. After 1 month, CT showed stable disease with clear tumor shrinkage and his cough and dyspnea improved, but progression occurred after about 3 months. Repeat biopsy showed the original EGFR mutations had disappeared and a different clone had emerged, with MET amplification, TP53 R249S, high tumor mutational burden, and PD-L1 TPS 80%. In January 2022, he started pembrolizumab with pemetrexed and carboplatin, then changed to pemetrexed plus pembrolizumab because of nausea and vomiting. This produced a durable partial response lasting about 23 months. In February 2023, progression occurred again, and the EGFR L747S/L858R mutations reappeared, making osimertinib rechallenge reasonable. He restarted osimertinib in March 2023 and again had partial response and symptom improvement. Later progression led to pemetrexed, bevacizumab, and pembrolizumab, followed by another osimertinib rechallenge and then pemetrexed plus osimertinib in March 2025. After developing infection from treatment-related myelosuppression, he died on 30 April 2025. The case highlights why repeated biopsies and molecular testing were central: each new progression reflected a changing dominant clone, which directly shaped the next treatment choice. Despite several temporary responses, the final progression and treatment-related infection determined the outcome.