Purpose The epidermal growth factor receptor (EGFR) gene mutation is the most common genetic mutation in non-small cell lung cancer (NSCLC). The most frequent EGFR mutations are exon 19 deletion and exon 21 L858R mutation, which together account for approximately 75%~80% of all EGFR mutations. Results from multiple phase Ⅲ clinical trials consistently demonstrate that NSCLC patients harboring sensitive EGFR mutations have a high response rate to EGFR tyrosine kinase inhibitors (TKIs) and a significantly prolonged progression-free survival (PFS). However, about 10% of EGFR mutations are uncommon or rare mutations. As most of these were excluded from clinical trials, evidence for the efficacy of EGFR-TKIs in uncommon mutations is limited to small retrospective cohort studies. For some rare mutations, there are only a few case reports, lacking evidence-based medical data, which may lead to some patients missing the opportunity for EGFR-TKIs treatment in clinical practice. This study reports the clinical characteristics and efficacy of EGFR-TKIs in 11 patients diagnosed between 2016 and 2025 with the rare EGFR L833V/H835L compound mutation. A literature review and pooled analysis were also conducted to provide reference for the clinical management of such patients.

Methods Cases of NSCLC diagnosed between 2016 and 2025, with genetic testing confirming the presence of the rare EGFR L833V/H835L compound mutation, were collected. Detailed data including pathological type, gender, smoking status, metastatic sites, genetic status, treatment regimens, and survival outcomes were gathered for all patients. One long-term survivor was selected for detailed presentation. All available medical records from diagnosis to the present were collected for this case. Genetic testing was performed at each disease progression to elucidate resistance mechanisms and guide subsequent therapy. Additionally, a PubMed search identified 15 published cases of L833V/H835L mutation. A pooled analysis of all cases was performed. All analyses were performed using the statistical software package R-4.4.1 (http://www.R-project.org, The R Foundation).

Results A total of 11 NSCLC patients with the EGFR exon 21 L833V/H835L compound mutation were collected between 2016 and 2025. The median age was 51 years; 7 were female; 10 were non-smokers; 10 were diagnosed with adenocarcinoma and 1 with sarcomatoid carcinoma. As of the follow-up cutoff date (October 15, 2025), 6 patients had died, and 5 were still receiving targeted therapy. Bone and brain metastases were the most common metastatic sites. Among the 11 patients, 8 received EGFR-TKI therapy, demonstrating an overall response rate (ORR) of 75% and a disease control rate (DCR) of 100%. Six patients received second-generation EGFR-TKIs, and two received third-generation EGFR-TKIs. Two patients achieved long-term survival exceeding 60 months. This report details one long-term survivor with the EGFR L833V/H835L compound mutation for whom comprehensive data and clear resistance mechanisms were available. This patient was diagnosed with advanced lung adenocarcinoma via pleural effusion cytopathology, with genetic testing revealing the EGFR exon 21 L833V/H835L compound mutation. First-line treatment with afatinib resulted in a partial response (PR) with a PFS of 13.4 months. Upon progression, plasma EGFR testing (ddPCR) identified an acquired T790M mutation. Second-line treatment with osimertinib yielded a PR with a PFS of 53.8 months. Subsequent progression led to next-generation sequencing (NGS) testing of pleural effusion, which identified a concurrent BRAF V600E mutation as the new resistance mechanism. The patient was then treated with a third-line regimen of almonertinib combined with dabrafenib and trametinib, achieving stable disease (SD), symptomatic improvement, and a treatment duration of 10.7+ months to date. The overall survival (OS) for this patient was 81.9+ months. The literature search identified 15 published cases of NSCLC with the EGFR exon 21 L833V/H835L compound mutation. The pooled analysis (n=26, including current study) showed a median age of 58 years (range: 36~89), with 25 cases of adenocarcinoma and 1 case of sarcomatoid carcinoma. Most patients were non-smokers (n=18) and 13 were female. Among them, 18 patients received first-line EGFR-TKIs, and therapeutic effects of varying degrees were observed with first-, second-, and third-generation EGFR-TKIs. The median PFS was 15 months, 12 months, and 19 months, respectively, with no statistically significant difference(P=0.73).

Conclusion The EGFR L833V/H835L compound mutation is rare in advanced NSCLC. This small-sample, single-center retrospective study suggests its clinical characteristics are similar to those of classic EGFR TKI-sensitive mutations, typically occurring in female, non-smoking patients with adenocarcinoma, with bone and brain being the most common metastatic sites. Most patients showed relative sensitivity to EGFR-TKIs. The case reported herein demonstrated significant long-term survival benefit from EGFR-TKI therapy, and the acquired resistance mechanisms were similar to those seen with classic sensitizing mutations. Given the rarity of this compound mutation, large-scale clinical trials are not feasible. This report is a retrospective analysis with a small sample size. Although it is retrospective and thus provides relatively low-level evidence, it may still offer some reference value for clinical decision-making.