title: EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis.
abstract: OBJECTIVE
  PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients.
  
  
  METHODS
  We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes (TIL) were evaluated by IHC.
  
  
  RESULTS
  Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI-resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8(+) TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens.
  
  
  CONCLUSIONS
  NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585-93. ©2016 AACRSee related commentary by Gettinger and Politi, p. 4539.
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. jgainor@partners.org mminokenudson@partners.org.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Piotrowska
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Tiffany G
authors.initials: TG
authors.lastname: Huynh
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Linnea
authors.initials: L
authors.lastname: Fulton
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Schultz
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Emily
authors.initials: E
authors.lastname: Howe
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Farago
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Subba
authors.initials: S
authors.lastname: Digumarthy
authors.affiliation: Catalan Institute of Oncology, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Moran
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Hata
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Yagi
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. jgainor@partners.org mminokenudson@partners.org.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014057:Tomography, X-Ray Computed; D014178:Translocation, Genetic; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases