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Gemcitabine

Paclitaxel

Pemetrexed

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Albumin-Bound Paclitaxel

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Folate

Vitamin B9

Daily oral rociletinib at 500 mg BID with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Treatment with rociletinib is continuous and each cycle will comprise of 21 days.

Daily oral rociletinib at 625 mg BID with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Treatment with rociletinib is continuous and each cycle will comprise of 21 days.

Pemetrexed

500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle.

Gemcitabine

1250 mg/m2 gemcitabine given intravenously on Day 1 and 8 of each 21-day cycle.

Docetaxel

75 mg/m2 docetaxel (60 mg/m2 for patients residing in East-Asian territories) given intravenously on Day 1 of each 21-day cycle.

or 35 mg/m2 docetaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.

Paclitaxel

80 mg/m2 paclitaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.

Rociletinib

Pemetrexed or gemcitabine or paclitaxel or docetaxel

The purpose of this study is to compare the anti-tumor efficacy of oral single-agent rociletinib, as measured by investigator assessment of the PFS, with that of single-agent cytotoxic chemotherapy in patients with EGFR-mutated, advanced/metastatic NSCLC after failure of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet chemotherapy.

This is a Phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of oral rociletinib at 500 mg BID and 625 mg BID compared with that of single-agent cytotoxic chemotherapy, in patients with previously treated mutant EGFR NSCLC. Eligible patients are those with mutant EGFR NSCLC previously treated with at least 1 EGFR inhibitor and at least 1 line of platinum-containing chemotherapy doublet for advanced/metastatic NSCLC.

After providing informed consent to participate and screening to confirm eligibility, patients will be randomized 1:1:1 to receive either oral rociletinib 500 mg BID, oral rociletinib 625 mg BID, or single-agent cytotoxic chemotherapy (investigator choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel; choice of chemotherapy agent must be specified before randomization).

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

TIGER-3: A Phase 3, Open-label, Multicenter, Randomized Study of Oral Rociletinib (CO-1686) Monotherapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR Non-small Cell Lung Cancer (NSCLC) After Failure of at Least 1 Previous EGFR-directed Tyrosine Kinase Inhibitor (TKI) and Platinum-doublet Chemotherapy

PFS was calculated as 1+ the number of days from the date of randomization to documented radiographic progression as determined by the investigator, or death due to any cause, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of one or more new lesions is also considered progression.

Percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response (OR),is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment was dependent on the achievement of both measurement and confirmation criteria.

DOR in patients with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from date that any of these best responses is first recorded until first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR is at least a 30% decrease in sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response is the best response from start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

OS was calculated as 1+ the number of days from randomization to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.

Blood samples were drawn for PK analysis at 21 ± 3 day intervals for the first 6 months (Day 1 of Cycles 2 to 7 inclusive). The sample could be taken predose or postdose. Plasma concentrations are presented for Rociletinib and 3 metabolites (M460, M502, M544).

Clovis Oncology, Inc.

If a subject experiences the same preferred term (system organ class) multiple times, then the subject will be counted only once for that preferred term (system organ class). Treatment Arm/Groups for subjects who crossed over to Rociletinib from Chemotherapy are included. 1 patient in the Chemotherapy treatment group was not included in the analysis, due to discontinuation of study shortly after randomization and prior to first dose of study drug.

Starting dose of 500 mg. Taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

Rociletinib 500 mg BID

Starting dose of 625 mg. Taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

Rociletinib 625 mg BID

Pemetrexed - 500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle.

Gemcitabine - 1250 mg/m2 gemcitabine given intravenously on Day 1 and 8 of each 21-day cycle.

Paclitaxel - 80 mg/m2 paclitaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.

Docetaxel - 75 mg/m2 docetaxel (60 mg/m2 for patients residing in East-Asian territories) given intravenously on Day 1 of each 21-day cycle.

or 35 mg/m2 docetaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.

Treatment duration until radiographically confirmed disease progression.

Chemotherapy

Patients initially randomized to comparator chemotherapy had the option to cross over to rociletinib following disease progression per RECIST Version 1.1. Rociletinib starting dose of 500 mg taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

Crossover From Chemotherapy to Rociletinib 500 mg BID

Patients initially randomized to comparator chemotherapy had the option to cross over to rociletinib following disease progression per RECIST Version 1.1. Rociletinib starting dose of 625 mg taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression

Crossover From Chemotherapy to Rociletinib 625 mg BID

Starting dose of 500mg. Taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

Starting dose of 625mg. Taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

White

Asian

Non-White, Non-Asian

Race/Ethnicity, Customized

Number of Previous Therapies

Information missing for one patient in the Chemotherapy treatment group.

Time Since Diagnosis of NSCLC

History of CNS Metastases

Due to early study termination, only 149 of 600 planned patients were randomized.

Vi Nguyen

Intent-to-treat: All patients randomized. 1 patient in the Chemotherapy treatment group was not included in the analysis, due to discontinuation of study shortly after randomization and prior to first dose of study drug.

Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)

Percentage of Participants With Confirmed Response

The DOR was measured only in those patients with a confirmed Complete Response (CR) or Partial Response (PR). The overall number of participants analyzed in the "Chemotherapy" arm includes only participants treated with chemotherapy and not patients who crossed over into the rociletinib treatment groups.

Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment

Intent-to-treat: All patients randomized.1 patient in the Roci 500 and 2 patients in the Chemo treatment group were not included in the analysis because their OS data was not collected. 1 additional patient in the Chemo group was not included due to discontinuation from study shortly after randomization and prior to first dose of study drug.

Overall Survival (OS)

M460

M502

M544

A small subset of patients treated with rociletinib (ie, patients randomized to receive rociletinib or who crossed over to receive rociletinib following treatment with single agent cytotoxic chemotherapy). Note: 2 patients in the 625mg treatment group had M502 values at upper limit of quantification (ULOQ) which were set as missing values.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT02322281	Non-small Cell ...	Rociletinib Pemetrexed or g...	18 Years -	Clovis Oncology, Inc.
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	NCT02322281	Non-small Cell ...	Rociletinib Pemetrexed or g...	18 Years -	Clovis Oncology, Inc.
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	NCT02322281	Non-small Cell ...	Rociletinib Pemetrexed or g...	18 Years -	Clovis Oncology, Inc.
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	NCT02322281	Non-small Cell ...	Rociletinib Pemetrexed or g...	18 Years -	Clovis Oncology, Inc.

Spots Global Cancer Trial Database for pemetrexed or gemcitabine or paclitaxel or docetaxel