title: Clinical Outcome of ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs).
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. Electronic address: sabine.schmid@kssg.ch.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmid
authors.affiliation: Department of Oncology, Cantonal Hospital Lucerne, Lucerne, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gautschi
authors.affiliation: Department of Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Sacha
authors.initials: S
authors.lastname: Rothschild
authors.affiliation: Department of Oncology, Cantonal Hospital Grisons, Chur, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.affiliation: Oncology Institute of Southern Switzerland, Regional Hospital San Giovanni, Bellinzona, Switzerland.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Froesch
authors.affiliation: Swiss Group for Clinical Cancer Research, Berne, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Klingbiel
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichegger
authors.affiliation: Institute of Pathology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.affiliation: Institute of Pathology, Cantonal Hospital Lucerne, Lucerne, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Früh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D000077716:Afatinib; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ALK/EGFR; ALK/KRAS; Co-alteration; NSCLC; Outcome; TKI treatment