The purpose of this study is to assess whether dacomitinib after osimertinib is effective in participants with metastatic EGR-mutant lung cancers.

Inclusion Criteria:

• Written informed consent

• Advanced biopsy-proven metastatic non-small cell lung cancer

• Somatic activating mutation in EGFR in a tumor biopsy or plasma cfDNA liquid biopsy

• Prior treatment with osimertinib with response followed by disease progression

• No prior first or second generation EGFR inhibitor treatment (gefitinib, afatinib, erlotinib)

• Archival tissue available from a tumor biopsy done after disease progression on osimertinib or willing to undergo a tumor biopsy or liquid biopsy after disease progression on osimertinib prior to study initiation

• Measurable (RECIST 1.1) indicator lesion not previously irradiated

• Karnofsky performance status (KPS) >/= 70%

• Age >/= 18 years old

• Ability to swallow oral medication

• Adequate organ function

  • AST, ALT </= 3 x ULN
  • Total bilirubin </= 1.5x ULN
  • Creatinine </= 1.5x ULN OR calculated creatinine clearance >/= 60ml/min
  • Absolute neutrophil count (ANC) >/= 1000 cells/mm3
  • Hemoglobin>/=8.0 g/dL
  • Platelets >/=75,000/mm3

Exclusion Criteria:

• Pregnant or lactating women
• Any radiotherapy within 1 week of starting treatment on protocol.
• Any major surgery within 1 weeks of starting treatment on protocol.
• Any evidence of active clinically significant interstitial lung disease
• Continue to have unresolved > grade 1 toxicity from any previous treatment Treatment
• Patients with a known mechanism of resistance to osimertinib that will clearly not respond to dacomitinib therapy (i.e. known MET amplification, ALK fusion, RET fusion).
• Symptomatic brain metastases or leptomeningeal disease requiring escalating doses of steroids

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.