INTRODUCTION: NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase 
gene (ALK) rearrangements and EGFR or KRAS mutations co-occur very rarely. 
Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly 
understood.
METHODS: Outcomes of patients with metastatic NSCLC de novo co-alterations of 
ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and 
sequencing (EGFR/KRAS) from six Swiss centers were analyzed.
RESULTS: A total of 14 patients with adenocarcinoma were identified. Five 
patients had ALK/EGFR co-alterations and nine had ALK/KRAS co-alterations. Six 
of seven patients with ALK/KRAS co-alterations (86%) were primary refractory to 
crizotinib. One patient has had ongoing disease stabilization for 26 months. Of 
the patients with ALK/EGFR co-alterations, one immediately progressed after 
receiving crizotinib for 1.3 months and two had a partial response for 5.7 and 
7.3 months, respectively. Three of four patients with ALK/EGFR co-alterations 
treated with an EGFR TKI achieved one or more responses in different lines of 
therapy: four patients had a partial response, three with afatinib and one with 
osimertinib. One patient achieved a complete remission with osimertinib, and one 
patient was primary refractory to erlotinib. Median PFS during treatment with a 
first EGFR TKI was 5.8 months (range 3.0-6.9 months).
CONCLUSIONS: De novo concurrent ALK/KRAS co-alterations were associated with 
resistance to ALK TKI treatment in seven out of eight patients. In patients with 
ALK/EGFR co-alterations, outcomes with ALK and EGFR TKIs seem inferior to what 
would be expected in patients with either alteration alone, but further studies 
are needed to clarify which patients with ALK/EGFR co-alterations may still 
benefit from the respective TKI.