Phase 1/2 Study of the Safety and Efficacy of Rociletinib in Combination With Trametinib in Patients With mEGFR-positive Advanced or Metastatic Non-small Cell Lung Cancer

Inclusion Criteria:

* Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation
* Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with EGFR activating mutation (excluding exon 20 insertion); measurable disease per RECIST 1.1
* Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI
* Patient willingness to undergo tumor biopsy at baseline and on treatment (optional for Phase 1; mandatory for Phase 2)
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1; life expectancy at least 3 months
* Adequate hematological and biological function; LVEF ≥50%

Exclusion Criteria:

* Documented evidence in tumor of exon 20 insertion, small cell transformation, or MET amplification
* Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroids within 2 weeks)
* Known preexisting interstitial lung disease or pneumonitis
* Concurrent use of QT-prolonging medication
* Uncontrolled diabetes (HA1C \> 10%) despite optional therapy
* Cardiac abnormalities:

  * Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) \>450 ms
  * Inability to measure QT interval on ECG
  * Personal or family history of long QT syndrome
  * Implantable pacemaker or implantable cardioverter defibrillator
  * Resting bradycardia \< 55 beats/min
* Inability to swallow oral study treatment or any gastrointestinal disease or condition that would preclude adequate absorption of study treatment
* Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse; uncontrolled intercurrent illness including active infection; arterial thrombosis; unstable respiratory, hepatic, renal or cardiac disease; and other active malignancy)
* Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 16 weeks after the last dose of study treatment
* Any contraindication, allergy, or hypersensitivity to rociletinib, trametinib, or excipients