Outcomes in Patients With Lung Adenocarcinoma With Transformation to Small Cell Lung Cancer After EGFR Tyrosine Kinase Inhibitors Resistance: A Systematic Review and Pooled Analysis

Abstract

BackgroundLung adenocarcinoma can transform into small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. Approximately 3% to 10% of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) could transform to SCLC. This phenomenon has been described in several case reports and small patient series. However, the characteristics and treatment outcomes of this population have not been comprehensively reported, and their clinical course is poorly characterized.MethodsWe performed a systematic review of the published literature to summarize the clinical and pathological features and prognosis of the reported cases and analyzed the demographics, disease features, and outcomes.ResultsA total of 72 patients (50 females and 22 males) initially diagnosed with lung adenocarcinoma were included. EGFR mutations included 19-deletion (75%), L858R (22%), and G719X (3%). All patients received EGFR-TKIs before SCLC transformation. The median time from diagnosis to transformation was 20.5 months (95% CI, 15.45 to 26.55 months). Of the 67 patients with post-translational gene test results, 58 maintained their EGFR mutation, and only 1 of 18 with prior T790M positivity retained T790M mutation. After the pathological transformation, both conventional chemotherapy regimen and chemotherapy combined targeted therapy yielded high response rates. The disease control rate of first-line therapy after transformation was 76%, while the objective response rate was 48%. The median overall survival (OS) since diagnosis was 27 months (95% CI, 22.90 to 31.10 months), whereas median OS since SCLC transformation was 8.5 months (95% CI, 5.50 to 11.60 months).ConclusionThe prognosis of transformed SCLC is worse than primary SCLC. The response rate to conventional chemotherapy was high. However, the progression-free survival and OS after transformation were short and the prognosis was poor with first-line therapies. New therapies are needed in the management of transformed SCLC.

Etoposide/platinum plus anlotinib for patients with transformed small-cell lung cancer from EGFR-mutant lung adenocarcinoma after EGFR-TKI resistance: A retrospective and observational study

“…Additionally, PIK3CA mutation was found in 20% of the patients, and BRAF mutation occurred in 10% of the patients, suggesting the molecular heterogeneity of transformation from LUAD to SCLC. Finally, the interval time from EGFR-TKI treatment to histological transformation was 20.1 months, which is consistent with previous reports of 17.8-22.7 months (Marcoux et al 2019;Xu et al 2021;Yu et al 2022).…”

Sequential small cell transformation and T790M mutation in an epidermal growth factor‐mutant lung adenocarcinoma: A rare occurrence with significant management implications

“…A recent systematic review analysis by Xu et al described 72 patients; mostly non‐smoking Asian females with lung adenocarcinomas and small cell transformation post‐EGFR TKI therapy 19 . The most common EGFR mutation in this cohort was exon 19‐deletion, followed by L858R and G719X mutations.…”

“…By contrast, the original adenocarcinoma clone acquired T790M mutation and flourished uncontrollably in the absence of targeted therapy against it. The index case also supports the use of newer regimens that combine the standard chemotherapy and third-generation TKIs for the management of such cases, as the administration of such a regimen may have prevented the subsequent proliferation of the original adenocarcinoma clone.A recent systematic review analysis by Xu et al described 72 patients; mostly non-smoking Asian females with lung adenocarcinomas and small cell transformation post-EGFR TKI therapy 19. The most common EGFR mutation in this cohort was exon 19-deletion, followed by L858R and G719X mutations.…”

“…Most patients had received first-line TKI and maintained their baseline EGFR mutation after transformation. Xu et al observed that only a few of these cases demonstrated new mutations on sequential genetic analysis, as in the index case 11,[19][20][21][22][23][24].…”

Double-dose icotinib may induce the emergence of the EGFR exon 20 T790M mutation in non-small cell lung cancer patients harboring EGFR-sensitive mutation

“…Among patients with the acquired EGFR T790M mutation, osimertinib, an irreversible EGFR-TKI selective for both EGFR-sensitive mutations and T790M resistance mutations, has emerged as a standard treatment choice, with an objective response rate (ORR) of 61% and a progression-free survival (PFS) time of 12.3 months ( 7 , 8 ). However, there are still approximately 50% of patients who developed resistance to EGFR-TKIs treatment, the mechanism of which remains unknown ( 9 ). Although systematic therapy with cytotoxic agents has been suggested as standard therapy for those patients without the T790M mutation, confined efficacy accompanied with related adverse events significantly limited its application, especially for patients with poor performance status.…”