Serial Biopsies Map Resistance in EGFR-Mutant NSCLC

Key Takeaways

• In a case report, one patient with stage IVB EGFR L858R/TP53 R282W lung adenocarcinoma had a partial response to first-line icotinib lasting 7 months before rebiopsy found acquired EGFR T790M plus MET c.3010C>G annotated as an exon 14-related alteration.
• After the first resistance shift, almonertinib was associated with a 7-month partial response, and after later progression, almonertinib plus savolitinib was associated with an 8-month partial response.
• A later right iliac biopsy showed persistent EGFR L858R, disappearance of EGFR T790M and MET c.3010C>G, and emergence of RET-CCDC6 fusion; subsequent systemic treatment plus local radiotherapy was followed by survival nearing 50 months at January 2026 follow-up.

Each progression event changed the resistance profile in EGFR-mutant metastatic non-small cell lung cancer in a serial re-biopsy case in EGFR-mutant NSCLC that the authors presented as a case report, with a later iliac biopsy showing loss of EGFR T790M and MET c.3010C>G and emergence of RET-CCDC6 fusion. The patient remained alive nearly 50 months from diagnosis at January 2026 follow-up, making this a longitudinal account of resistance switching in one individual rather than a broader estimate of expected outcomes.

In November 2021, a 55-year-old man presented with a 5.7-cm left upper lobe mass and was staged as cT3N3M1c stage IVB lung adenocarcinoma with bone and small liver metastases; brain MRI was negative. Computed tomography-guided biopsy showed poorly differentiated adenocarcinoma, and 425-gene next-generation sequencing identified EGFR L858R and TP53 R282W. Icotinib was selected for economic reasons. First-line therapy was associated with a partial response and 7 months of progression-free survival.

When the primary lesion enlarged in July 2022, lung rebiopsy again showed poorly differentiated adenocarcinoma, and icotinib was briefly escalated to 250 mg three times daily while molecular results were pending. Sequencing then showed persistent EGFR L858R with newly acquired EGFR T790M and MET c.3010C>G annotated as an exon 14-related alteration, after which almonertinib 110 mg once daily produced a 7-month partial response; after renewed progression, almonertinib plus savolitinib 600 mg once daily produced another partial response lasting 8 months. The authors interpreted the MET finding through clinicogenomic context and treatment response, while noting that no RNA assay or functional experiment was reported.

Early in 2024, oligoprogression developed in the right iliac lesion, and biopsy of that site showed persistent EGFR L858R, disappearance of EGFR T790M and MET c.3010C>G, and emergence of RET-CCDC6 fusion. Because selective RET inhibition was initially unaffordable, the patient received four cycles of pemetrexed 500 mg/m2 plus carboplatin AUC 5 every 3 weeks with continued almonertinib, achieving stable disease but developing grade 3 neutropenia and thrombocytopenia that required growth factor support and a brief delay. Selpercatinib 160 mg twice daily was later added, with radiotherapy of 30 Gy in 10 fractions to the right iliac lesion and 50 Gy in 4 fractions to the primary lung lesion; at January 2026 follow-up, disease control was ongoing and survival was nearly 50 months from diagnosis. This case traced clonal evolution under treatment pressure rather than providing comparative evidence or a basis for guideline change.

Clinician Questions

What resistance alterations emerged across serial biopsies in EGFR L858R-mutant metastatic NSCLC in this case?

Baseline tumor genomics in EGFR L858R-mutant metastatic NSCLC showed EGFR L858R and TP53 R282W; lung rebiopsy at first progression identified acquired EGFR T790M plus MET c.3010C>G annotated as an exon 14-related alteration; and biopsy of a newly progressive right iliac metastasis later showed persistent EGFR L858R, loss of EGFR T790M and the MET alteration, and emergence of RET-CCDC6 fusion.

What treatment sequence followed the evolving resistance profile in this EGFR-mutant NSCLC case?

The treatment sequence in this EGFR-mutant NSCLC case was icotinib first, then almonertinib after EGFR T790M and MET c.3010C>G were identified, then almonertinib plus savolitinib after later progression, followed by pemetrexed-carboplatin with continued almonertinib when RET inhibition was initially unaffordable, and later selpercatinib plus almonertinib with local radiotherapy after RET-CCDC6 fusion emerged.

What adverse events were reported during pemetrexed-carboplatin with continued almonertinib in EGFR-mutant NSCLC?

Grade 3 neutropenia and thrombocytopenia were reported during pemetrexed 500 mg/m2 plus carboplatin AUC 5 given with continued almonertinib in EGFR-mutant NSCLC, and these events required growth factor support and a brief treatment delay.

What follow-up outcome was reported after selpercatinib plus almonertinib and local radiotherapy in this EGFR-mutant NSCLC case?

Selpercatinib 160 mg twice daily was added to almonertinib in October 2024 in this EGFR-mutant NSCLC case, radiotherapy delivered 30 Gy in 10 fractions to the right iliac lesion and 50 Gy in 4 fractions to the primary lung lesion, and the patient remained alive nearly 50 months from diagnosis with ongoing disease control at January 2026 follow-up.

Recommended Reading

• For more on EGFR-mutated NSCLC therapy: Novel Strategies for Managing EGFR-mutated mNSCLC: Expert Insights into the Latest Data and Recommendations