TIGER-1: Safety and Efficacy Study of Rociletinib (CO-1686) or Erlotinib in Patients With EGFR-mutant/Metastatic NSCLC Who Have Not Had Any Previous EGFR Directed Therapy

The purpose of this study is to compare the safety and anti-tumor effect of rociletinib with erlotinib in patients whose tumors have specific EGFR mutations and who have not previously received any treatment for advanced/metastatic EGFR mutated NSCLC. This study is a 'Randomized' Study. This means that upon entering the study, patients will be randomly assigned to be dosed with either rociletinib twice a day or erlotinib once a day. Patients will continue to take either rociletinib or erlotinib until it is no longer beneficial.

This is a randomized, Phase 2/3 study of rociletinib versus erlotinib as a first-line treatment for patients with EGFR-mutant advanced/metastatic NSCLC whose tumors have EGFR-activating mutations. The study will consist of Phase 2 and Phase 3 parts which will use the same enrollment criteria and treatment assignment principles. Patients will be randomized 1:1 to erlotinib or rociletinib. The Phase 2 part is an open-label study. In the Phase 3 part, the sponsor will be blinded to the efficacy and safety results. The study will consist of a screening phase to establish study eligibility (including tumor genotype) and document baseline measurements, a treatment phase, in which patients will receive either rociletinib BID (twice a day) or erlotinib QD (once daily) to ascertain safety and efficacy until protocol-defined disease progression, and a follow-up phase, to monitor survival status and subsequent NSCLC cancer therapy. In the Phase 2 part only, patients initially randomized to erlotinib may be eligible to participate in an optional crossover phase to receive rociletinib if they demonstrate the T790M resistance mutation after radiographic progression on erlotinib treatment among other eligibility requirements. Patients eligible for this study must have EGFR-mutated NSCLC who have not been treated with an EGFR-directed therapy.Treatment with rociletinib or erlotinib is continuous. Each 28 day period of treatment will represent one cycle, with dosing initiated on Cycle 1 Day 1 (C1 D1).

Eligibility Criteria:
Inclusion Criteria:

1. Histologically or cytologically confirmed metastatic or unresectable locally advanced/metastatic NSCLC
2. Documented evidence of a tumor with activating EGFR mutations by local testing. Patients with exon 20 insertions are not eligible with the exception of patients with documented evidence of the exon 20 insertion A763_Y764insFQEA in the EGFR gene
3. Have undergone a biopsy or surgical resection of either primary or metastatic tumor tissue within 60 days of the first day of study treatment, C1D1, and have tissue available to send to sponsor laboratories or are able to undergo a biopsy during screening and provide tissue to sponsor laboratories
4. Measureable disease according to RECIST Version 1.1
5. Life expectancy of at least 3 months
6. ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 1
7. Minimum age 18 years (in certain territories, the minimum age requirement may be higher (e.g. 20 years in Japan and Taiwan)
8. Adequate hematological and biological function, confirmed by defined laboratory values
9. Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study-specific evaluation

Exclusion Criteria:

1. Documented evidence of an exon 20 insertion activating mutation other than A763_Y764insFQEA in the EGFR gene
2. Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant chemotherapy is permitted if at least 6 months has elapsed between the end of chemotherapy and randomization
3. Active second malignancy; i.e., patient known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment
4. Patients with a history of malignancy that has been completely treated, and currently with no evidence of that cancer, are permitted to enroll in the trial provided all chemotherapy was completed \> 6 months prior and/or bone marrow transplant \> 2 years prior to first day of study treatment
5. Known pre-existing interstitial lung disease
6. Brain metastases
7. Treatment with prohibited medications less than or equal to 14 days prior to first day of study treatment
8. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval if that treatment cannot be either discontinued or switched to a different medication prior to administration of study drug
9. Prior treatment with EGFR TKIs (e.g. erlotinib, gefitinib, neratinib, afatinib, AZD9291, or dacomitinib), rociletinib or other drugs that target mutant EGFR
10. Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) \> 450 ms
11. Inability to measure QT interval on ECG
12. Personal or family history of long QT syndrome
13. Implantable pacemaker or implantable cardioverter defibrillator
14. Resting bradycardia \< 55 beats/min
15. Non-study related surgical procedures less than or equal to 7 days prior to administration of study drug. In all cases, the patient must be sufficiently recovered and stable before treatment administration.
16. Females who are pregnant or breastfeeding
17. Refusal to use adequate contraception for fertile patients (females and males) for 12 weeks after the last dose of rociletinib and 2 weeks after the last dose of erlotinib
18. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study
19. Any other reason the investigator considers the patient should not participate in the study