TIGER-3: Open Label, Multicenter Study of Rociletinib (CO-1686) Mono Therapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR NSCLC Who Have Failed at Least One Previous EGFR-Directed TKI and Platinum-doublet Chemotherapy

Inclusion Criteria: All patients must meet all of the following inclusion criteria:

1. Histologically or cytologically confirmed metastatic or unresectable locally advancedNSCLC with radiological progression on the most recent therapy received

2. Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon 20 insertion

3. Disease progression confirmed by radiological assessment while receiving treatmentwith single agent EGFR-TKI (e.g., erlotinib, gefitinib, afatinib, or dacomitinib) orEGFR-TKI in combination with other targeted therapy (e.g. bevacizumab, immunotherapy)

4. Multiple lines of prior treatment are permitted and there is no specified order oftreatment, but in the course of their treatment history, patients must have receivedand have radiologically documented disease progression following: At least 1 line of prior treatment with a single-agent EGFR-TKI (e.g., erlotinib,gefitinib, afatinib, or dacomitinib) If EGFR-TKI is a component of the most recent treatment line, the washout period forthe EGFR-TKI is a minimum of 3 days before the start of study drug treatment AND A platinum-containing doublet chemotherapy (either progressed during therapy orcompleted at least 4 cycles without progression with subsequent progression after atreatment-free interval or after a maintenance treatment). If cytotoxic chemotherapy is a component of the most recent treatment line, treatmentwith chemotherapy should have been completed at least 14 days prior to start of studytreatment. When an EGFR-TKI is given in combination with platinum-containing doubletchemotherapy, treatment with the EGFR-TKI may continue until at least 3 days beforestart of treatment.

5. Have undergone a biopsy of either primary or metastatic tumor tissue within 60 daysprior to start of treatment and have tissue sent to the central laboratory prior torandomization

6. Measureable disease according to RECIST Version 1.1

7. Life expectancy of at least 3 months

8. ECOG performance status of 0 to 1

9. Age ≥ 18 years (in certain territories, the minimum age requirement may be highere.g., age ≥ 20 years in Japan and Taiwan, age ≥ 21 years in Singapore)

10. Patients should have recovered to National Cancer Institute (NCI) Common TerminologyCriteria for Adverse Events (CTCAE) Grade ≤ 1 from any significantchemotherapy-related toxicities

11. Adequate hematological and biological function

12. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study specific evaluation

Exclusion Criteria: Any of the following criteria will exclude patients from study participation:

1. Any other malignancy associated with a high mortality risk within the next 5 years andfor which the patients may be (but not necessarily) currently receiving treatment Patients with a history of malignancy that has been completely treated, with noevidence of that cancer currently, are permitted to enroll in the trial provided allchemotherapy was completed > 6 months prior and/or bone marrow transplant > 2 yearsprior

2. Known pre-existing interstitial lung disease

3. Tumor small cell transformation by local assessment, irrespective of presence ofT790M+ component

4. Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system (CNS) metastases are only permitted if treated, asymptomatic, and stable (notrequiring steroids for at least 2 weeks prior to randomization and the patient isneurologically stable i.e. free from new symptoms of brain metastases)

5. Patients who are currently receiving treatment with any medications that have thepotential to prolong the QT interval and that treatment cannot be either discontinuedor switched to a different medication (known to have no effect on QT) before startingprotocol-specified treatment (see http://crediblemeds.org/ for a list of QT-prolongingmedications)

6. Prior treatment with rociletinib, or other drugs that target T790M+ mutant EGFR withsparing of WT-EGFR including but not limited to osimertinib, HM61713, and TAS-121

7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine ordocetaxel unless a contraindication with respect to one of these drugs will not affectthe use of any of the others as a comparator to rociletinib

8. Any of the following cardiac abnormalities or history:

9. Clinically significant abnormal 12-lead ECG, QT interval corrected usingFridericia's method (QTCF) > 450 msec

10. Inability to measure QT interval on ECG

11. Personal or family history of long QT syndrome

12. Implantable pacemaker or implantable cardioverter defibrillator

13. Resting bradycardia < 55 beats/min

14. Non-study related surgical procedures ≤ 7 days prior to randomization. In all cases,the patient must be sufficiently recovered and stable before treatment administration

15. Females who are pregnant or breastfeeding

16. Refusal to use adequate contraception for fertile patients (females and males) whileon treatment and for 6 months after the last dose of study treatment (rociletinib andchemotherapy irrespective of single cytotoxic agent used)

17. Presence of any serious or unstable concomitant systemic disorder incompatible withthe clinical study (e.g., substance abuse, uncontrolled intercurrent illness includinguncontrolled diabetes, active infection, arterial thrombosis, and symptomaticpulmonary embolism)

18. Any other reason the investigator considers the patient should not participate in thestudy

19. Treatment with live vaccines initiated less than 4 weeks prior to randomization