A 40-year-old male with
EML4-ALK
(E6:A20) fusion variant 3 and previously unreported
PLEKHA7-ALK
(P3:A20) fusion in lung adenocarcinoma exhibited resistance to alectinib and chemotherapy. Subsequent next-generation sequencing (NGS) from the plasma specimen revealed the co-existing mutation in the
KEAP1
gene, which may represent an intrinsic resistance to ALK-TKI. Furthermore, the presence of double fusion
PLEKHA7-ALK
(P3:A20) may also have played a critical role in the resistance to alectinib.
KEAP1
mutation (p.E244K) was also founded in this patient which may lead to resistance to standard chemotherapy. The patient was then treated with brigatinib, which effectively halted the rapid progression. Unfortunately, the patient deceased to uncontrollable, rapidly progressing pleural effusion and pulmonary embolism, resulting in an overall survival of 9 months. This represents the rare case of NSCLC with a double fusion of
EML4-ALK
and
PLEKHA7-ALK
, exhibiting resistance to alectinib and chemotherapy. Our case suggests that the double fusion of
EML4-ALK
and
PLEKHA7-ALK
and co-existing
KEAP1
mutation may serve as an adverse prognostic factor. Additionally, brigatinib may offer a potential treatment option for lung adenocarcinoma patients with
PLEKHA7-ALK
(P3:A20) fusion.