RADIANT: A Study of Erlotinib (Tarceva) After Surgery With or Without Adjuvant Chemotherapy in Non-Small Cell Lung Carcinoma (NSCLC) Patients Who Have Epidermal Growth Factor Receptor (EGFR) Positive Tumors

• Sponsor: OSI Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00373425
• Collaborator: (none)
• Enrollment: 1,252
• Locations: 295
• Arms: 2
• Duration (Months): 93
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a study to evaluate the effectiveness of erlotinib compared with a placebo sugar pill following complete surgical removal of the tumor with or without chemotherapy after surgery in Stage IB-IIIA NSCLC patients.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer	Drug: Erlotinib; Drug: Placebo	Phase 3

Detailed Description

After the initiation of the study, the sponsor became aware of an error in the drug dispensing module of the interactive voice response such that most patients who were randomized prior to 07 November 2007 were dispensed the incorrect study drug at least once. Since the integrity of the data from these patients was seriously compromised, these patients were considered unevaluable for the protocol-specified analyses. These participants are referred to as the breached protocol cohort (BPC) and those still on study treatment at the time of the breach were offered the option of receiving open-label erlotinib for up to 2 years (including posttreatment and long-term follow-up assessments), not receiving open-label erlotinib but remaining in the study for posttreatment and long-term follow-up assessment, or withdrawing consent from treatment and further assessments. Participants who had discontinued study treatment prior to the breach were not offered open-label erlotinib and remained in long-term follow-up. Data from the BPC participants were analyzed separately and were not included in the assessments of primary or secondary endpoints in the randomized cohort and were not considered part of the primary analyses.The sample size for the randomized cohort was not changed due to the BPC and the data from RC and BPC were analyzed separately.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1252 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Single-agent Tarceva® (Erlotinib) Following Complete Tumor Resection With or Without Adjuvant Chemotherapy in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma Who Have EGFR-positive Tumors
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Erlotinib Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Drug: Erlotinib; 150 mg tablet; Other Names: OSI-774 Tarceva
Placebo Comparator: Placebo Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Drug: Placebo; Placebo tablet

Outcome Measures

Primary Outcome Measures

1. Disease Free Survival (DFS) [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).]

   DFS is the time from the date of randomization until the first day non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

2. Disease Free Survival (DFS) [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cutoff date of 11 June 2014 (maximum time on follow-up was 78 months).]

   DFS is the time from the date of randomization until the first day that non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

Secondary Outcome Measures

1. Overall Survival (OS) [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).]

   Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

2. Overall Survival (OS) [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).]

   Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

3. Disease-free Survival in Participants With EGFR Mutation - Positive Tumors [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).]

   Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

4. Disease-free Survival in Participants With EGFR Mutation - Positive Tumors [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).]

   Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

5. Overall Survival in Participants With EGFR Mutation - Positive Tumors [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months)]

   Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

6. Overall Survival in Participants With EGFR Mutation - Positive Tumors [Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months)]

   Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

7. Number of Participants With Adverse Events (AEs) [From the date of first dose of study drug until 30 days after the last dose. The median time on treatment was 11.9 months for erlotinib and 21.9 months for placebo. Data are based off the 11 June 2014 data cut-off date.]

   An AE was defined as any untoward medical occurrence in a study participant and did not necessarily have a causal relationship with study treatment. An AE was considered serious if it resulted in death, a life-threatening situation, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant, other important medical events, or is on the Astellas Always Serious List. A drug-related AE was any AE with at least a possible relationship to study treatment as assessed by the investigator. Severity was graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0, where Grade 1=Mild AE; Grade=2 Moderate AE; Grade 3=Severe AE; Grade 4=Life-threatening or disabling; Grade 5=Death related to AE. AEs leading to death include deaths that occurred more than 30 days after the last dose of study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Primary tissue from patient's surgery must be epidermal growth factor receptor (EGFR)-positive by certain tests

• Patients may have up to 4 cycles of chemotherapy after surgery

• Complete removal of the tumor by surgery

• Able to start drug under the following timelines:

• 6 months from the day of surgery for patients who get chemotherapy

• 3 months from the day of surgery for those who do not get chemotherapy

• Confirmed diagnosis of Stage IB-IIIA NSCLC

• Patients must be accessible for follow-up visits

Exclusion Criteria:

• History of prior radiotherapy for NSCLC either before or after surgery

• History of heart disease or uncontrolled heart arrhythmias within the previous year

• History of poorly controlled gastrointestinal (GI) disorders that could affect the absorption of study drug

• History of other cancer except certain skin or cervical cancers, patients who have had other cancer are eligible if they have remained disease free for at least 5 years

• Patients who have received chemotherapy for NSCLC before surgery

• Tumors with mixed histology of NSCLC and Small Cell Lung Cancer (SCLC). Patients with carcinoid tumors are not eligible.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Arizona Cancer Center	Tucson	Arizona	United States	85724
3	University of Arkansas for Medical Science	Little Rock	Arkansas	United States	72205
4	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211
5	City of Hope Nat'l Medical Center	Duarte	California	United States	91010
6	Loma Linda University Medical Center	Loma Linda	California	United States	92354
7	USC/ Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
8	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
9	Hoag Memorial Hospital Presbyterian	Newport Beach	California	United States	92658
10	Comprehensive Cancer Center at Desert Regional Medical Center	Palm Springs	California	United States	92262
11	Bay Area Cancer Research Group, LLC	Pleasant Hill	California	United States	94523
12	University of California, San Francisco Comprehensive Cancer Center	San Francisco	California	United States	94143-1770
13	City of Hope Medical Group (COHMG)	South Pasadena	California	United States	91030
14	Rocky Mountain Cancer Center- Aurora	Aurora	Colorado	United States	80012
15	University of Colorado Hospital	Aurora	Colorado	United States	80045
16	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado	United States	80303
17	Penrose St. Francis Health Services	Colorado Springs	Colorado	United States	80907
18	Rocky Mountain Cancer Center	Colorado Springs	Colorado	United States	80907
19	Rocky Mountain Cancer Center	Colorado Springs	Colorado	United States	80909
20	Rocky Mountain Cancer Center-Midtown	Denver	Colorado	United States	80218
21	Rocky Mountain Cancer Centers- Rose	Denver	Colorado	United States	80220
22	Rocky Mountain Cancer Centers	Lakewood	Colorado	United States	80228
23	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado	United States	80120-4413
24	Rocky Mountain Cancer Center-Sky Ridge	Lone Tree	Colorado	United States	80124
25	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado	United States	80501
26	Rocky Mountain Cancer Center-Parker	Parker	Colorado	United States	80138
27	Rocky Mountain Cancer Centers	Thornton	Colorado	United States	80260
28	Yale University	New Haven	Connecticut	United States	06520
29	Smilow Cancer Hospital Care Center	Sharon	Connecticut	United States	06069
30	Hematology Oncology, P.C.	Stamford	Connecticut	United States	06902
31	Smilow Cancer Hospital Care Center	Torrington	Connecticut	United States	06790
32	Florida Cancer Institute-New Hope	Hudson	Florida	United States	34667
33	Cancer Specialists of North Florida	Jacksonville	Florida	United States	32204
34	Cancer Specialists of North Florida	Jacksonville	Florida	United States	32216
35	Watson Clinic LLP	Lakeland	Florida	United States	33805
36	Advanced Medical Specialties	Miami	Florida	United States	33176
37	Florida Cancer Institute- New Hope	New Port Richey	Florida	United States	34655
38	Florida Cancer Specialists	Orlando	Florida	United States	32806
39	Hematology Oncology Associates of the Treasure Coast	Port St. Lucie	Florida	United States	34952
40	Peachtree Hematology-Oncology Consultants, P.C.	Atlanta	Georgia	United States	30318
41	Central Georgia Cancer Care, PC	Macon	Georgia	United States	31201
42	Northwest Georgia Oncology Centers, PC	Marietta	Georgia	United States	30060
43	Mountain States Tumor Institute	Boise	Idaho	United States	83712
44	Mountain States Tumor Institute	Meridian	Idaho	United States	83642
45	Kootenai Cancer Center	Post Falls	Idaho	United States	83854
46	Mountain States Tumor Institute	Twin Falls	Idaho	United States	83301
47	Rush University Medical Center	Chicago	Illinois	United States	60612
48	University of Chicago, Section of Hematology/Oncology	Chicago	Illinois	United States	60637
49	Joliet Oncology Hematology Assoc., LTD	Joliet	Illinois	United States	60435
50	Loyola University Medical Center	Maywood	Illinois	United States	60153
51	Indiana University Health	Carmel	Indiana	United States	46032
52	Indiana University Health	Fishers	Indiana	United States	46037
53	Indiana University Health	Greenfield	Indiana	United States	46140
54	Indiana University Health	Indianapolis	Indiana	United States	46219
55	Indiana University Health	Indianapolis	Indiana	United States	46227
56	University of Kansas Medical Center	Westwood	Kansas	United States	66205
57	Norton Healthcare, Inc.	Louisville	Kentucky	United States	40202
58	Leonard J. Chabert Medical Center	Houma	Louisiana	United States	70363
59	Cancer Care of Maine	Brewer	Maine	United States	04412
60	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
61	St. Joseph Medical Center's Cancer Institute	Towson	Maryland	United States	21204
62	Caritas St. Elizabeth's Medical Center	Boston	Massachusetts	United States	02135
63	St. Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
64	Minnesota Oncology Hematology, P.A.	Burnsville	Minnesota	United States	55337
65	Minnesota Oncology Hematology, P.A.	Edina	Minnesota	United States	55435-2150
66	Minnesota Oncology Hematology, P.A.	Maplewood	Minnesota	United States	55109
67	Minnesota Oncology Hematology, P.A.	Minneapolis	Minnesota	United States	55404
68	Minnesota Oncology Hematology	St. Paul	Minnesota	United States	55102-2389
69	Minnesota Oncology Hematology, P.A.	Woodbury	Minnesota	United States	55125
70	Missouri Cancer Associates	Columbia	Missouri	United States	65201
71	Heartland Regional Medical Center d/b/a Heartland Clinic	St. Joseph	Missouri	United States	64507
72	St. Francis Cancer Treatment Center	Grand Island	Nebraska	United States	68803
73	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
74	Comprehensive Cancer Centers of Nevada	Henderson	Nevada	United States	89052
75	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89128
76	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89148
77	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
78	NH Oncology-Hematology PA (Co)	Concord	New Hampshire	United States	03301
79	NH Oncology-Hematology PA	Hooksett	New Hampshire	United States	03106
80	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
81	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
82	University of New Mexico Health Science Center	Albuquerque	New Mexico	United States	87131
83	Christus St. Vincent Regional Cancer Center	Santa Fe	New Mexico	United States	87505
84	Interlakes Oncology Hematology, PC	Brockport	New York	United States	14420
85	Montefiore Medical Center	Bronx	New York	United States	10467
86	Interlakes Oncology Hematology, PC	Canadaigua	New York	United States	14424
87	Interlakes Oncology Hematology, PC	Geneva	New York	United States	14456
88	Advanced Oncology Associates	New Rochelle	New York	United States	10801
89	The New York Presbyterian-Weill Medical College of Cornell University	New York	New York	United States	10065
90	Interlakes Oncology Hematology, PC	Rochester	New York	United States	14623
91	Interlakes Oncology Hematology, PC	Rochester	New York	United States	14626
92	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
93	Raleigh Hematology Oncology Associates d/b/a Cancer Center of North Carolina	Cary	North Carolina	United States	27511
94	Carolina Oncology Specialists PA	Hickory	North Carolina	United States	28602
95	Raleigh Hematology Oncology Associates	Raleigh	North Carolina	United States	27607
96	Raleigh Hematology Oncology Associates	Raleigh	North Carolina	United States	27609
97	Aultman Hospital/ North Canton Medical Foundation	Canton	Ohio	United States	44710
98	University Hopsitals of Cleveland	Cleveland	Ohio	United States	44106
99	Hematology Oncology Consultants Inc.	Columbus	Ohio	United States	43228
100	Earle A Chiles Research Institute	Portland	Oregon	United States	97213
101	Northwest Cancer Specialists, PC	Portland	Oregon	United States	97213
102	Northwest Cancer Specialists, PC	Portland	Oregon	United States	97225
103	Northwest Cancer Specialists, PC	Portland	Oregon	United States	97227
104	Northwest Cancer Specialists, PC	Tualatin	Oregon	United States	97062
105	Cancer Care Associates - Medical Oncology	Bethlehem	Pennsylvania	United States	18015
106	The Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
107	Allegheny General Hospital	Pittsburg	Pennsylvania	United States	15212
108	South Carolina Oncology Assoc., PA	Columbia	South Carolina	United States	29210
109	Cancer Centers of the Carolinas	Easley	South Carolina	United States	29640
110	Cancer Centers of the Carolinas	Greenville	South Carolina	United States	29605
111	Cancer Centers of the Carolinas	Greenville	South Carolina	United States	29615
112	Cancer Centers of the Carolinas, Seneca	Seneca	South Carolina	United States	29672
113	Cancer Centers of the Carolinas	Spartanburg	South Carolina	United States	29307
114	Cookeville Regional Medical Center	Cookeville	Tennessee	United States	38501
115	Bostin Baskin Cancer Foundation	Germantown	Tennessee	United States	38138
116	Tennessee Cancer Specialists	Knoxville	Tennessee	United States	37909
117	Bostin Baskin Cancer Foundation	Memphis	Tennessee	United States	38104
118	Family Cancer Center Foundation, Inc.	Memphis	Tennessee	United States	38119
119	West Clinic	Memphis	Tennessee	United States	38120
120	Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
121	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
122	Texas Oncology, P.A. - Amarillo	Amarillo	Texas	United States	79106
123	Texas Oncology Beaumont	Beaumont	Texas	United States	77702-1449
124	Texas Oncology Texas Cancer Center at Medical City	Dallas	Texas	United States	75230-2510
125	Baylor Charles A Sammons Cancer Center	Dallas	Texas	United States	75246
126	Texas Oncology - Flower Mound	Flower Mound	Texas	United States	75028
127	Texas Oncology Southwest Forth Worth	Fort Worth	Texas	United States	76132
128	Texas Oncology, Fort Worth	Ft. Worth	Texas	United States	76104
129	Texas Oncology, Garland	Garland	Texas	United States	75042-5788
130	Cancer Care Centers of South Texas - HOAST	New Braunfels	Texas	United States	78131
131	Texas Oncology - Paris	Paris	Texas	United States	75460-5004
132	Texas Oncology - Plano East	Plano	Texas	United States	75075-7787
133	Cancer Care Centers of South Texas-HOAST	San Antonio	Texas	United States	78229
134	Texas Oncology -Tyler	Tyler	Texas	United States	75702
135	Texas Oncology Cancer Care and Research Center	Waco	Texas	United States	76712
136	Onc and Hem Associates of SW VA, Inc. d/b/a Blue Ridge Cancer Care	Christiansburg	Virginia	United States	24073
137	Onc and Hem Associates of SW VA, Inc.	Christiansburg	Virginia	United States	24073
138	Virginia Oncology Associates	Hampton	Virginia	United States	23666
139	Virginia Oncology Associates	Newport News	Virginia	United States	23606
140	Virginia Oncology Associates	Norfolk	Virginia	United States	23502
141	Onc and Hem Associates of SW VA, Inc. d/b/a Blue Ridge Cancer Care	Roanoke	Virginia	United States	24014
142	Onc and Hem Assoc of SW VA, Inc d/b/a Blue Ridge Cancer Care	Salem	Virginia	United States	24153
143	Onc and Hem Associates of SW VA, Inc. d/b/a Blue Ridge Cancer Care	Wytheville	Virginia	United States	24382
144	Univ. of Washington/ Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
145	Cancer Care Northwest-Valley	Spokane Valley	Washington	United States	99216
146	Cancer Care Northwest	Spokane	Washington	United States	99202
147	Cancer Care Northwest-North	Spokane	Washington	United States	99218
148	Northwest Cancer Specialists, P.C.	Vancouver	Washington	United States	98684
149	Northwest Cancer Specialist, P.C.	Vancouver	Washington	United States	98686
150	Hospital Italiano de Buenos Aires	Buenos Aires		Argentina	C1181ACH
151	Hospital de Rehabilitación Respiratoria María Ferrer	Buenos Aires		Argentina	C1272AAA
152	COIR	Mendoza		Argentina	M5500AYB
153	Hospital Espanol de Rosario	Rosario, Santa Fe		Argentina	S2001SBL
154	ISIS Centro Especializado De Luce S.A.	Santa Fé		Argentina	S3000FFU
155	Campbelltown Hospital	Campbelltown	New South Wales	Australia	2560
156	Liverpool Hospital	Liverpool	New South Wales	Australia	2170
157	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
158	Monash Medical Centre	East Bentleigh	Victoria	Australia	3165
159	St Vincent's Hospital Melbourne	Fitzroy	Victoria	Australia	3065
160	Austin Hospital	Heidelberg	Victoria	Australia	3084
161	Respiratory Clinical Trials Pty., Ltd	Adelaide		Australia	5067
162	Ashford Cancer Centre	Ashford		Australia	SA 5037
163	Universitaetsklinikum Innsbruck	Innsbruck		Austria	6020
164	Allgemeines Krankenhaus der Stadt Linz	Linz		Austria	4021
165	Landeskrankenhaus SalzburgUniversitaetsklinikum der PMUUniversitaetsklinik für Pneumologie	Salzburg		Austria	5020
166	AKH Wien	Wien		Austria	1090
167	Krankenhaus Hietzing	Wien		Austria	1130
168	SMZ Baumgartner Hoehe - Otto Wagner Spital	Wien		Austria	1140
169	SMZ Baumgartner Höhe - Otto- Wagner-Spital	Wien		Austria	A-1140
170	Hôpital Erasme	Brussels		Belgium	1070
171	Cliniques Universitaires Saint-Luc	Brussels		Belgium	1200
172	Le Grand Hôpital de Charleroi	Charleroi		Belgium	6000
173	Centre Hospitalier Jolimont-Lobbes	La Louvière		Belgium	7100
174	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
175	Cancer Center of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 5P9
176	Trillium Health Partners - Credit Valley Hospital	Mississauga	Ontario	Canada	L5M 2N1
177	Stronach Regional cancer Centre at Southlake	Newmarket	Ontario	Canada	L3Y 2P9
178	RS MacLaughlin Durham Regional Cancer Centre	Oshawa	Ontario	Canada	L1G 2B9
179	Sault Area Hospital	Sault Ste Marie	Ontario	Canada	P6A 5K7
180	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario	Canada	P7B 6V4
181	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
182	McGill Dept. of Oncology	Montreal	Quebec	Canada	H2W 1S6
183	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
184	Montreal General Hospital	Montreal	Quebec	Canada	H3G 1A4
185	St. Joseph's Health Centre	Toronto		Canada	M6R 1B5
186	Nemocnice Ceske Budejovice, a.s.	Ceske Budejovice		Czech Republic	370 87
187	Fakultni nemocnice OstravaKlinika tuberkulozy a respiracnich nemoci	Ostrava-Poruba		Czech Republic	70852
188	FN Bulovka Klinika plincni a hrrudni chirurgie	Praha		Czech Republic	8 18081
189	CHU Larrey Service de Pneumologie, Clinique des voies respiratoires	Toulouse	Cedex 9	France	31059
190	Centre d'Oncologie et de Radiothérapie du Pays Basque	Bayonne		France	64100
191	C.H.U. Morvan, Institut de Cancerologie et d'Hématologie	Brest cedex		France	29609
192	CHU de Caen - Service de pneumologie	Caen Cedex		France	14033
193	CHU Clermont Ferrand - Hôpital Gabriel Montpied - Service de pneumologie	Clermont-Ferrand cedex 1		France	63003
194	Hopital De La Croix-Rousse Service de Pneumologie	Lyon cedex 04		France	69317
195	Institut Paoli-Calmettes	Marseille cedex 9		France	13273
196	Fondation Hôpital Saint Joseph	PARIS cedex 14		France	75014
197	Hôpital de Tenon	Paris		France	75012
198	Centre Catalan d'Oncologie	Perpignan		France	66000
199	CHU - Hopital Pontchaillou - Service de pneumologie	Rennes cedex 9		France	35033
200	Institut de Cancérologie de la Loire	Saint Priest en Jarez		France	42271
201	Hôpital de Brabois	Vandoeuvre-lès-Nancy Cedex		France	54511
202	Zentralklinik Bad Berka	Bad Berka		Germany	99437
203	HELIOS Klinikum Emil von Behring GmbH	Berlin		Germany	14165
204	Augusta-Krankenanstalt Bochum	Bochum		Germany	44791
205	Fachkrankenhaus Coswig	Coswig		Germany	01640
206	Universitaetsklinikum Essen	Essen		Germany	45122
207	Krankenhaus Nordwest	Frankfurt/Main		Germany	60488
208	Universitätsklinikum Freiburg	Freiburg		Germany	79106
209	Lungenclinic Großhansdorf	Großhansdorf		Germany	22927
210	Universitätsklinikum Göttingen	Göttingen		Germany	37075
211	Städtisches Krankenhaus Martha-Maria, Halle-Dölau	Halle (Saale)		Germany	06120
212	Asklepios Klinik Harburg	Hamburg		Germany	21075
213	Thoraxklinik Heidelberg	Heidelberg		Germany	69126
214	Lungenklink Hemer des Deutschen Gemeinschafts-Diakonieverbandes GmbH	Hemer		Germany	58675
215	St. Vincentius-Kliniken Karlsruhe	Karlsruhe		Germany	76137
216	Universitaetsklinikum Schleswig-Holstein	Lübeck		Germany	23538
217	Universitätsklinikum Mainz	Mainz		Germany	55131
218	Asklepios Klinikum Gauting	Muenchen-Gauting		Germany	82131
219	Pius Hospital Oldenburg	Oldenburg		Germany	26121
220	Schwarzwald-Baar Klinikum	Villingen-Schwenningen		Germany	78050
221	IASO GENERAL Hospital of Athens	Athens		Greece	15562
222	"Papageorgiou" General Hospital of Thessaloniki	Thessaloniki		Greece	54603
223	"G. Papanikolaou" General Hospital of Thessaloniki	Thessaloniki		Greece	57010
224	Országos Korányi TBC és Pulmonológiai Intézet	Budapest		Hungary	1121
225	Semmelweis Egyetem Altalanos Orvostudomanyi Kar Pulmonologiai Klinika	Budapest		Hungary	1125
226	Csongrad Megyei Onkormanyzat, Mellkasi Betegsegek Szakkorhaza	Deszk		Hungary	6772
227	Pecsi Tudomany Egyete m Klinikai Kozpont, I.sz Belgyogyaszati Klinika Pulmonologiai Munkacsoport	Pécs		Hungary	7623
228	Fejer Megyei Szent Gyorgy Korhaz	Szekesfehervar		Hungary	8000
229	Vas Megyei Markusovszky Lajos Altalanos Rehabilitacios es Gyogyfurdo Korhaz, Egyetemi Oktatoko Zarkoruen Mukodo Nonprofit Reszveny Tarsasag	Szombathely		Hungary	9700
230	Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I	Ancona		Italy	60020
231	Ospedale Bellaria	Bologna		Italy	40139
232	Ospedale Garibaldi Nesima	Catania		Italy	95100
233	Istituto Nazionale per la Ricerca e la Cura del Cancro	Genova		Italy	16132
234	Azienda Ospedaliero- Universitaria di Parma	Parma		Italy	43100
235	Ospedale S. Maria della Misericordia	Perugia		Italy	06132
236	Azienda Ospedaliera San Camillo Forlanini	Roma		Italy	00152
237	Saint Vincent's Hospital	Gyeonggi-Do		Korea, Republic of	442-723
238	Gachon Medical School Ghil Medical Center	Incheon		Korea, Republic of	405-760
239	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
240	Severance Hospital, Yonsei Univ. College of Medicine	Seoul		Korea, Republic of	120-752
241	Asan Medical Center	Seoul		Korea, Republic of	138-736
242	Samodzielny Publiczny Szpital Kliniczny Nr 4	Lublin		Poland	20-954
243	Mazowieckie Centrum Leczenia Chorob Pluc i Gruzlicy	Otwock		Poland	05-400
244	Wielkoposkie Centrum Pulmonologii i Torakochirurgii, Oddzial Onkologii Klinicznej z Pododdzialem Dziennej Chemioterapii	Poznan		Poland	60-569
245	Specjalistyczny Szpital im. prof.Alfreda Sokolowskiego	Szczecin		Poland	70-891
246	Centrum Onkologii - Instytut im. Marii Skllodowskiej - Curie	Warsaw		Poland	02-781
247	Dolnoslaskie Centrum Chorob Pluc we Wroclawiu, Katedra i Klinika Pulmonologii i Nowotworow Pluc Akademii Medycznej	Wroclaw		Poland	53-439
248	Spitalui Clinic Judetean de Urgenta, Sectia de Oncologie	Oradea	Bihor	Romania	410032
249	Oncoloab SRL	Craiova	Dolj	Romania	200535
250	Institutul Oncologic Al. Trestioreanu Sectia Oncologie Medicala II	Bucuresti		Romania	022328
251	Institutul Oncologic Al. Trestioreanu	Bucuresti		Romania	022328
252	Institutul Oncologic Prof. Dr. Ion Chiricuta	Cluj-Napoca		Romania	400015
253	Centrul de Oncologie Medicala	Iasi		Romania	700106
254	Spitalul Clinic Judetean Sibiu	Sibiu		Romania	550245
255	State Healthcare Institution "Arkhangelsk Regional Clinical Oncology Dispensary"	Arkhangelsk		Russian Federation	163045
256	State Healthcare Institution "Regional Clinical Oncology Dispensary"	Kemerovo		Russian Federation	650036
257	State Healthcare Institution "Region Clinical Hospital # 1 n.a. professor S.V. Ochapovsky"	Krasnodar		Russian Federation	350086
258	State Institution "Central Military Clinical Hospital n.a. academician N.N. Burdenko under the Ministry of Defense of Russia"	Moscow		Russian Federation	105229
259	Institution of the RAMS "Russian Oncology Scientific Centre n.a. N.N. Blokhin under the Russian Academy of Medical Sciences"	Moscow		Russian Federation	115478
260	State Educational Institution of Higher Professional Education "Saint-Petersburg State Medical University n.a. ac. I.P. Pavlov of the Ministry of Healthcare and Social Development of the Russian Federation"	Saint-Petersburg		Russian Federation	197022
261	Federal State Institution "Petrov Scientific Research Institute of Oncology of Rosmedtechnology"	Saint-Petersburg		Russian Federation	197758
262	Saint-Petersburg State Healthcare Institution "City Clinical Oncology Dispensary"	Saint-Petersburg		Russian Federation	198255
263	Regional State Budget Healthcare Instiution"Tomsk Regional Oncology Dispensary"	Tomsk		Russian Federation	634050
264	State Healthcare Institution of Yaroslavl Region "Regional Clinical Oncology Hospital"	Yaroslavl		Russian Federation	150040
265	ICO (Institut Catalá d´Oncología)	L' Hospitalet de Llobregat	Barcelona	Spain	08907
266	Fundació Althaia	Manresa	Barcelona	Spain	08243
267	Corporació Sanitaria Parc Taulí	Sabadell	Barcelona	Spain	08208
268	Hospital Puerta de Hierro Majadahonda	Majadahonda	Madrid	Spain	28222
269	Hospital Oncologico MD Anderson	Madrid		Spain	28033
270	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
271	Hospital Universitario La Paz	Madrid		Spain	28046
272	Hospital Carlos Haya	Málaga		Spain	29010
273	Hospital Clínico Virgen de la Victoria	Málaga		Spain	29010
274	Clinica Universitaria de Navarra	Pamplona		Spain	31008
275	Hospital Universitario Marques de Valdecilla	Santander		Spain	39008
276	Hospital Universitario de Valme	Sevilla		Spain	41700
277	Hospital Virgen de la Salud de Toledo	Toledo		Spain	45004
278	Hospital General Universitario de Valencia	Valencia		Spain	46014
279	Changhua Christian Hospital	Changhua		Taiwan	500-06
280	Chang Gung Medical Foundation	Kaohsiung		Taiwan	833
281	Chung Shan Medical University Hospital	Taichung		Taiwan	402
282	China Medical University Hospital	Taichung		Taiwan	404
283	Taichung Veterans General Hospital	Taichung		Taiwan	407
284	Taipei Veterans General Hospital	Taipei		Taiwan	112
285	Chang Gung Memorial Hospital	Taoyuan		Taiwan	333
286	Birmingham Heartlands Hospital	Birmingham		United Kingdom	B9 5SS
287	Bristol Haematology and Oncology Centre	Bristol		United Kingdom	BS2 8ED
288	Ninewells Hospital	Dundee		United Kingdom	DD1 9SY
289	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
290	The Royal Surrey County Hospital NHS Trust	Guildford		United Kingdom	GU2 7XX
291	Leicester Royal Infirmary	Lecester		United Kingdom	LE1 5WW
292	St James' Institute of Oncology, Bexley Wing, St James' University Hospital	Leeds		United Kingdom	LS9 7TF
293	Guy's Hospital	London		United Kingdom	SE1 9RT
294	Royal Marsden Hospital	London		United Kingdom	SW3 6JJ
295	Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• OSI Pharmaceuticals

Investigators

• Study Director: Medical Monitor, Astellas Pharma Global Development

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to results on Astellas Clinical Study Results website

Publications

None provided.

• Responsible Party: OSI Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00373425
• Other Study ID Numbers: OSI-774-302; 2005-001747-29
• First Posted: Sep 8, 2006
• Last Update Posted: Sep 17, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by OSI Pharmaceuticals: Adjuvant Non-small Cell Lung Cancer; Tarceva; Early-stage Lung Cancer; Adjuvant; RADIANT; NSCLC; EGFR-positive tumor; Stage IB Non-small Cell Lung Cancer; Stage II Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride

Study Results

Participant Flow

Recruitment Details	Patients with stage IB to IIIA epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) were enrolled globally. 1252 patients were enrolled however 2 patients did not have adequate Health Insurance Portability and Accountability Act (HIPAA) documentation and were removed from the database.
Pre-assignment Detail	Participants randomized prior to 7 November 2007 comprise the Breached-Protocol Cohort (BPC); those who had not discontinued were offered open-label erlotinib for up to 2 years. Participants randomized subsequently are referred to as the Randomized Cohort.

Arm/Group Title	RC: Erlotinib	RC: Placebo	BPC-NOLC: Erlotinib/Placebo	BPC-NOLC: Placebo Only	BPC-OLC: Erlotinib
Arm/Group Description	Participants in the randomized cohort (RC) who received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants in the randomized cohort (RC) who received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	The BPC no open-label cohort (BPC-NOLC) includes participants randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period, and received at least one dose of erlotinib.	The BPC no open-label cohort (BPC-NOLC) includes participants randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period, and did not receive any erlotinib.	The BPC open-label cohort (BPC-OLC) includes participants randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who entered the open-label erlotinib period. Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.
Period Title: Overall Study
STARTED	623	350	134	11	132
Received Treatment	612	342	134	7	132
COMPLETED	253	197	0	0	60
NOT COMPLETED	370	153	134	11	72

Baseline Characteristics

Arm/Group Title	RC: Erlotinib	RC: Placebo	BPC-NOLC: Erlotinib/Placebo	BPC-NOLC: Placebo Only	BPC-OLC: Erlotinib	Total
Arm/Group Description	Participants in the randomized cohort (RC) who received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants in the randomized cohort (RC) who received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	The BPC no open-label cohort (BPC-NOLC) includes participants randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period, and received at least one dose of erlotinib.	The BPC no open-label cohort (BPC-NOLC) includes participants randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period, and did not receive any erlotinib.	The BPC open-label cohort (BPC-OLC) includes participants randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who entered the open-label erlotinib period. Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.	Total of all reporting groups
Overall Participants	623	350	134	11	132	1250
Age (years) [Mean (Standard Deviation) ]
Randomized Cohort	62.0 (9.28)	61.8 (9.34)	NA (NA)	NA (NA)	NA (NA)	61.9 (9.30)
Breached Protocol Cohort, No Open label	NA (NA)	NA (NA)	64.4 (9.33)	62.7 (6.23)	NA (NA)	64.3 (9.13)
Breached Protocol Cohort, Open label	NA (NA)	NA (NA)	NA (NA)	NA (NA)	61.8 (9.35)	61.8 (9.35)
Sex: Female, Male (Count of Participants)
Female	257 41.3%	141 40.3%	47 35.1%	2 18.2%	57 43.2%	504 40.3%
Male	366 58.7%	209 59.7%	87 64.9%	9 81.8%	75 56.8%	746 59.7%
Race/Ethnicity, Customized (participants) [Number]
White	500 80.3%	279 79.7%	114 85.1%	10 90.9%	111 84.1%	1014 81.1%
Black	14 2.2%	11 3.1%	4 3%	0 0%	4 3%	33 2.6%
Asian	107 17.2%	60 17.1%	15 11.2%	1 9.1%	17 12.9%	200 16%
American Indian/Alaska Native	1 0.2%	0 0%	1 0.7%	0 0%	0 0%	2 0.2%
Other	1 0.2%	0 0%	0 0%	0 0%	0 0%	1 0.1%
Race/Ethnicity, Customized (participants) [Number]
Not Hispanic or Latino	583 93.6%	322 92%	123 91.8%	11 100%	124 93.9%	1163 93%
Hispanic or Latino	40 6.4%	28 8%	11 8.2%	0 0%	8 6.1%	87 7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
Grade 0	385 61.8%	211 60.3%	75 56%	5 45.5%	77 58.3%	753 60.2%
Grade 1	230 36.9%	134 38.3%	55 41%	6 54.5%	54 40.9%	479 38.3%
Grade 2	6 1%	5 1.4%	3 2.2%	0 0%	1 0.8%	15 1.2%
Not measured	2 0.3%	0 0%	1 0.7%	0 0%	0 0%	3 0.2%
Cigarette Smoking History (participants) [Number]
Never smoked or ≤ 100 cigarettes in lifetime	129 20.7%	70 20%	19 14.2%	1 9.1%	19 14.4%	238 19%
Former smoker	423 67.9%	240 68.6%	103 76.9%	9 81.8%	104 78.8%	879 70.3%
Current smoker	71 11.4%	40 11.4%	12 9%	1 9.1%	9 6.8%	133 10.6%
Histology (participants) [Number]
Adenocarcinoma	367 58.9%	211 60.3%	73 54.5%	3 27.3%	76 57.6%	730 58.4%
Squamous cell carcinoma	196 31.5%	111 31.7%	48 35.8%	8 72.7%	49 37.1%	412 33%
Undifferentiated large cell	22 3.5%	8 2.3%	6 4.5%	0 0%	4 3%	40 3.2%
Mixed NSCLC	29 4.7%	18 5.1%	5 3.7%	0 0%	1 0.8%	53 4.2%
Other	9 1.4%	2 0.6%	2 1.5%	0 0%	2 1.5%	15 1.2%
Extent of Disease at Diagnosis (participants) [Number]
Stage IA	1 0.2%	2 0.6%	1 0.7%	0 0%	0 0%	4 0.3%
Stage IB	329 52.8%	167 47.7%	64 47.8%	4 36.4%	80 60.6%	644 51.5%
Stage IIA	42 6.7%	24 6.9%	10 7.5%	1 9.1%	9 6.8%	86 6.9%
Stage IIB	155 24.9%	99 28.3%	36 26.9%	4 36.4%	23 17.4%	317 25.4%
Stage IIIA	93 14.9%	58 16.6%	21 15.7%	1 9.1%	17 12.9%	190 15.2%
Stage IIIB	2 0.3%	0 0%	2 1.5%	0 0%	3 2.3%	7 0.6%
Stage IV	1 0.2%	0 0%	0 0%	1 9.1%	0 0%	2 0.2%
Adjuvant Chemotherapy (participants) [Number]
Yes	315 50.6%	200 57.1%	63 47%	5 45.5%	68 51.5%	651 52.1%
No	308 49.4%	150 42.9%	71 53%	6 54.5%	64 48.5%	599 47.9%
Epidermal Growth Factor Receptor (EGFR) Mutation Status (participants) [Number]
Activating mutation-positive	102 16.4%	59 16.9%	10 7.5%	0 0%	16 12.1%	187 15%
Wild-type	458 73.5%	245 70%	116 86.6%	11 100%	107 81.1%	937 75%
Undetermined	29 4.7%	16 4.6%	1 0.7%	0 0%	1 0.8%	47 3.8%
Activating mutation not positive	30 4.8%	27 7.7%	5 3.7%	0 0%	6 4.5%	68 5.4%
Not Available	4 0.6%	3 0.9%	2 1.5%	0 0%	2 1.5%	11 0.9%
EGFR Gene Amplification (participants) [Number]
Positive	445 71.4%	255 72.9%	84 62.7%	8 72.7%	100 75.8%	892 71.4%
Negative	167 26.8%	87 24.9%	49 36.6%	3 27.3%	32 24.2%	338 27%
Undetermined	11 1.8%	8 2.3%	1 0.7%	0 0%	0 0%	20 1.6%

Outcome Measures

1. Primary Outcome

Title	Disease Free Survival (DFS)
Description	DFS is the time from the date of randomization until the first day non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis set (all randomized participants).

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	623	350
Median (95% Confidence Interval) [months]	50.5	48.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Erlotinib, Placebo
	Comments	The null hypothesis that DFS distributions of the 2 arms were equivalent was tested using an unstratified 2-sided log-rank test at the 0.05 level. The primary analysis of DFS was performed when at least 410 events had accrued. If the result of the primary analysis of DFS was statistically significant favoring the erlotinib treatment arm, the null hypothesis of no treatment difference of key secondary efficacy variables was tested under a hierarchical testing procedure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3235
	Comments	If the primary analysis of DFS was not statistically significant, the hierarchical testing procedure would stop and all key secondary efficacy analyses would be nonsignificant; any further analysis of these outcomes would be considered exploratory.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.741 to 1.104
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio: erlotinib to placebo

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis set

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	623	350
Median (95% Confidence Interval) [months]	NA	NA

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis set

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	623	350
Median (95% Confidence Interval) [months]	NA	NA

4. Secondary Outcome

Title	Disease-free Survival in Participants With EGFR Mutation - Positive Tumors
Description	Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis set participants who are EGFR mutation positive

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	102	59
Median (95% Confidence Interval) [months]	46.4	28.5

5. Secondary Outcome

Title	Disease-free Survival in Participants With EGFR Mutation - Positive Tumors
Description	Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis set participants who are EGFR mutation positive

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	102	59
Median (95% Confidence Interval) [months]	47.8	28.5

6. Primary Outcome

Title	Disease Free Survival (DFS)
Description	DFS is the time from the date of randomization until the first day that non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cutoff date of 11 June 2014 (maximum time on follow-up was 78 months).

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis set (all randomized participants).

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	623	350
Median (95% Confidence Interval) [months]	55.0	56.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Erlotinib, Placebo
	Comments	The null hypothesis that DFS distributions of the 2 arms were equivalent was tested using an unstratified 2-sided log-rank test at the 0.05 level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5620
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.780 to 1.144
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Overall Survival in Participants With EGFR Mutation - Positive Tumors
Description	Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months)

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis participants who were EGFR mutation positive

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	102	59
Median (95% Confidence Interval) [months]	NA	NA

8. Secondary Outcome

Title	Overall Survival in Participants With EGFR Mutation - Positive Tumors
Description	Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.
Time Frame	Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months)

Outcome Measure Data

Analysis Population Description

Randomized cohort full analysis participants who were EGFR mutation positive

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	102	59
Median (95% Confidence Interval) [months]	NA	NA

9. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	An AE was defined as any untoward medical occurrence in a study participant and did not necessarily have a causal relationship with study treatment. An AE was considered serious if it resulted in death, a life-threatening situation, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant, other important medical events, or is on the Astellas Always Serious List. A drug-related AE was any AE with at least a possible relationship to study treatment as assessed by the investigator. Severity was graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0, where Grade 1=Mild AE; Grade=2 Moderate AE; Grade 3=Severe AE; Grade 4=Life-threatening or disabling; Grade 5=Death related to AE. AEs leading to death include deaths that occurred more than 30 days after the last dose of study drug.
Time Frame	From the date of first dose of study drug until 30 days after the last dose. The median time on treatment was 11.9 months for erlotinib and 21.9 months for placebo. Data are based off the 11 June 2014 data cut-off date.

Outcome Measure Data

Analysis Population Description

Randomized Cohort, safety analysis set: all randomized participants who received at least one dose of study drug. One participant in the Randomized Cohort assigned to the erlotinib arm received placebo instead due to a dispensing error and is included in the placebo group for safety analyses.

Arm/Group Title	Erlotinib	Placebo
Arm/Group Description	Participants received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.	Participants received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.
Measure Participants	611	343
Any adverse event (AE)	599 96.1%	307 87.7%
Grade 3 or higher adverse event	279 44.8%	96 27.4%
Serious adverse event (SAE)	118 18.9%	79 22.6%
AE leading to discontinuation of study drug	205 32.9%	29 8.3%
AE leading to death	14 2.2%	5 1.4%
AE leading to dose reduction	150 24.1%	9 2.6%
AE leading to dose interruption	114 18.3%	23 6.6%
AE leading to dose interruption and reduction	156 25%	5 1.4%
Drug-related AE	572 91.8%	181 51.7%
Drug-related serious AE	15 2.4%	5 1.4%
Drug-related AE leading to discontinuation	163 26.2%	8 2.3%

Adverse Events

Time Frame	From the first dose of study drug until 30 days after the last dose. Maximum time on treatment for the Randomized Cohort was 24 months; maximum time on treatment for the BPC was 13 months on blinded study drug and 26 months on open-label erlotinib.
Adverse Event Reporting Description	One participant in the Randomized Cohort assigned to the erlotinib arm received placebo instead due to a dispensing error and is included in the placebo group for safety analyses. For the Breached Protocol Cohort safety analyses are based on the total no open-label and open-label populations. Safety data are based on the 11 June 2014 cut-off date.
Arm/Group Title	RC: Erlotinib		RC: Placebo		BPC-NOLC: Erlotinib/Placebo		BPC-NOLC: Placebo Only		BPC-OLC: Erlotinib
Arm/Group Description	Participants in the randomized cohort (RC) who received 150 mg/day erlotinib orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.		Participants in the randomized cohort (RC) who received matching placebo tablets orally for 2 years or until relapse, death, participant request or investigator decision to discontinue study drug, or intolerable toxicity.		The BPC no open-label cohort (BPC-NOLC) includes participants randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period, and received at least one dose of erlotinib.		The BPC no open-label cohort (BPC-NOLC) includes participants randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period, and did not receive any erlotinib.		The BPC open-label cohort (BPC-OLC) includes participants randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who entered the open-label erlotinib period. Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.
All Cause Mortality
	RC: Erlotinib		RC: Placebo		BPC-NOLC: Erlotinib/Placebo		BPC-NOLC: Placebo Only		BPC-OLC: Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	RC: Erlotinib		RC: Placebo		BPC-NOLC: Erlotinib/Placebo		BPC-NOLC: Placebo Only		BPC-OLC: Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	118/611 (19.3%)		79/343 (23%)		21/134 (15.7%)		1/11 (9.1%)		41/132 (31.1%)
Blood and lymphatic system disorders
Anaemia	4/611 (0.7%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Lymphadenopathy	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Haemolytic anaemia	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cardiac disorders
Myocardial infarction	3/611 (0.5%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pericarditis	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Acute myocardial infarction	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Atrial fibrillation	1/611 (0.2%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		1/132 (0.8%)
Cardiac failure	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cardio-respiratory arrest	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pericardial effusion	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Acute coronary syndrome	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Angina pectoris	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Angina unstable	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Arrhythmia	0/611 (0%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		1/132 (0.8%)
Ischaemic cardiomyopathy	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Coronary artery disease	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		1/132 (0.8%)
Cardiac failure congestive	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Congenital, familial and genetic disorders
Rathke's cleft cyst	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Atrial septal defect	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Ear and labyrinth disorders
Deafness	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Deafness neurosensory	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Endocrine disorders
Thyroid cyst	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Eye disorders
Cataract	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Blindness	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Retinal haemorrhage	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Gastrointestinal disorders
Diarrhoea	4/611 (0.7%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		1/132 (0.8%)
Duodenal ulcer	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Gastrointestinal haemorrhage	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Abdominal pain	1/611 (0.2%)		3/343 (0.9%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Dysphagia	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Gastric ulcer	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Gingival bleeding	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Haematemesis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Ileus	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Intestinal obstruction	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Oesophagitis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Small intestinal obstruction	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Subileus	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Volvulus	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Colitis ischaemic	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Enterovesical fistula	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Gastrooesophageal reflux disease	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Nausea	0/611 (0%)		1/343 (0.3%)		2/134 (1.5%)		0/11 (0%)		1/132 (0.8%)
Pancreatitis	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Rectal haemorrhage	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Vomiting	0/611 (0%)		1/343 (0.3%)		2/134 (1.5%)		0/11 (0%)		1/132 (0.8%)
Diarrhoea haemorrhagic	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Peptic ulcer perforation	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Peritonitis	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Enteritis	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Gastric dysplasia	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Haemorrhoids	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Tooth resorption	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Upper gastrointestinal haemorrhage	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
General disorders
Asthenia	3/611 (0.5%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Fatigue	2/611 (0.3%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Chest pain	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Death	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
General physical health deterioration	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Multi-organ failure	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pyrexia	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pain	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Performance status decreased	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Sudden death	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Hepatobiliary disorders
Cholecystitis acute	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cholangitis acute	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cholecystitis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Jaundice	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Immune system disorders
Anaphylactic shock	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Infections and infestations
Pneumonia	8/611 (1.3%)		2/343 (0.6%)		2/134 (1.5%)		0/11 (0%)		3/132 (2.3%)
Respiratory tract infection	4/611 (0.7%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Bronchitis	2/611 (0.3%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Sepsis	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Urinary tract infection	2/611 (0.3%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Appendicitis	1/611 (0.2%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Bronchopneumonia	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cellulitis	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Clostridial infection	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Dermatitis infected	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Diverticulitis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Eczema infected	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Empyema	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Haematoma infection	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Osteomyelitis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pertussis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pyelonephritis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Upper respiratory tract infection	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Bronchitis acute	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Clostridium difficile colitis	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Herpes zoster	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Lobar pneumonia	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Lung infection	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Meningitis viral	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pulmonary tuberculosis	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Wound infection staphylococcal	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Device related infection	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Arthritis infective	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Bacterial infection	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Nasal abscess	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Nasopharyngitis	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pneumonia bacterial	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Injury, poisoning and procedural complications
Fall	3/611 (0.5%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Clavicle fracture	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Haemothorax	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Injury	1/611 (0.2%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Laceration	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Polytraumatism	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Post procedural haematoma	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Procedural pain	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Rib fracture	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Spinal compression fracture	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Ankle fracture	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Bronchial anastomosis complication	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Concussion	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Femur fracture	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Road traffic accident	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pelvic fracture	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		1/132 (0.8%)
Suture rupture	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Hip fracture	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Incisional hernia	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Postoperative fever	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Investigations
Blood bilirubin increased	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Weight decreased	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Blood creatinine increased	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Metabolism and nutrition disorders
Dehydration	3/611 (0.5%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Anorexia	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Fluid retention	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Hypokalaemia	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Hyponatraemia	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Oral intake reduced	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Hypercalcaemia	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Back pain	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Bone pain	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Flank pain	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Muscular weakness	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pain in extremity	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Spinal column stenosis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Arthralgia	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Muscle haemorrhage	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Musculoskeletal chest pain	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Musculoskeletal pain	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Rotator cuff syndrome	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Osteoarthritis	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Spondylolisthesis	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	4/611 (0.7%)		3/343 (0.9%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Laryngeal cancer	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Lung squamous cell carcinoma stage unspecified	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Metastases to central nervous system	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Neurilemmoma	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Prostate cancer	3/611 (0.5%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		3/132 (2.3%)
Throat cancer	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cancer pain	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Chronic myeloid leukaemia	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Colon cancer	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Renal cell carcinoma stage unspecified	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Sarcoma	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Colon adenoma	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Lung neoplasm	5/611 (0.8%)		3/343 (0.9%)		0/134 (0%)		0/11 (0%)		2/132 (1.5%)
Small cell lung cancer stage unspecified	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		2/132 (1.5%)
Basal cell carcinoma	1/611 (0.2%)		5/343 (1.5%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Bladder cancer	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Conjunctival neoplasm	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Malignant ascites	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Malignant melanoma	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Prostate cancer stage I	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Squamous cell carcinoma	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Squamous cell carcinoma of skin	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Thyroid cancer	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Thyroid neoplasm	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Tonsil cancer	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Uterine cancer	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Nervous system disorders
Cerebrovascular accident	3/611 (0.5%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Hemiparesis	3/611 (0.5%)		4/343 (1.2%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Headache	2/611 (0.3%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		1/132 (0.8%)
Loss of consciousness	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cerebral infarction	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cerebral ischaemia	1/611 (0.2%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Intracranial pressure increased	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Memory impairment	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Monoparesis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Neuropathy peripheral	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Peripheral motor neuropathy	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Presyncope	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Convulsion	1/611 (0.2%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Dysphasia	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
IIIrd nerve paralysis	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Peripheral sensory neuropathy	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Syncope	0/611 (0%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Transient ischaemic attack	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cerebral artery embolism	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Facial paresis	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Normal pressure hydrocephalus	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Sudden onset of sleep	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Balance disorder	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Brain mass	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Dizziness	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Ischaemic stroke	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Neuralgia	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Cerebellar infarction	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Epilepsy	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Psychiatric disorders
Confusional state	1/611 (0.2%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Disorientation	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Mental status changes	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		2/132 (1.5%)
Inappropriate affect	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Renal and urinary disorders
Renal failure acute	4/611 (0.7%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Nephrolithiasis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Urinary bladder haemorrhage	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Urinary incontinence	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Calculus ureteric	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Urethral obstruction	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Reproductive system and breast disorders
Uterovaginal prolapse	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	6/611 (1%)		5/343 (1.5%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pulmonary embolism	3/611 (0.5%)		5/343 (1.5%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pleural effusion	2/611 (0.3%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Asthma	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Bronchial hyperreactivity	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Cough	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Epistaxis	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Hypoxia	1/611 (0.2%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Lung disorder	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pneumonia aspiration	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pulmonary congestion	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Respiratory failure	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Chronic obstructive pulmonary disease	0/611 (0%)		3/343 (0.9%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Lower respiratory tract inflammation	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Pneumothorax	0/611 (0%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pulmonary infarction	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Acute respiratory distress syndrome	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Apnoea	0/611 (0%)		0/343 (0%)		0/134 (0%)		1/11 (9.1%)		0/132 (0%)
Interstitial lung disease	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Bronchial fistula	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Hydrothorax	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pneumonitis	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pulmonary granuloma	0/611 (0%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pleural fibrosis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Pulmonary fibrosis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Skin and subcutaneous tissue disorders
Dermatitis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Skin ulcer	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Rash	0/611 (0%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Vascular disorders
Cardiovascular insufficiency	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Deep vein thrombosis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Hypotension	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Peripheral arterial occlusive disease	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Temporal arteritis	1/611 (0.2%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Aortic aneurysm	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Aortic occlusion	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Hypertension	0/611 (0%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		1/132 (0.8%)
Hypertensive crisis	0/611 (0%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		0/132 (0%)
Other (Not Including Serious) Adverse Events
	RC: Erlotinib		RC: Placebo		BPC-NOLC: Erlotinib/Placebo		BPC-NOLC: Placebo Only		BPC-OLC: Erlotinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	590/611 (96.6%)		288/343 (84%)		125/134 (93.3%)		4/11 (36.4%)		130/132 (98.5%)
Blood and lymphatic system disorders
Anaemia	16/611 (2.6%)		6/343 (1.7%)		2/134 (1.5%)		0/11 (0%)		4/132 (3%)
Ear and labyrinth disorders
Vertigo	6/611 (1%)		6/343 (1.7%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Eye disorders
Conjunctivitis	34/611 (5.6%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		5/132 (3.8%)
Dry eye	31/611 (5.1%)		3/343 (0.9%)		6/134 (4.5%)		0/11 (0%)		5/132 (3.8%)
Eye irritation	8/611 (1.3%)		3/343 (0.9%)		2/134 (1.5%)		0/11 (0%)		4/132 (3%)
Gastrointestinal disorders
Diarrhoea	318/611 (52%)		54/343 (15.7%)		54/134 (40.3%)		0/11 (0%)		86/132 (65.2%)
Nausea	84/611 (13.7%)		44/343 (12.8%)		17/134 (12.7%)		1/11 (9.1%)		28/132 (21.2%)
Stomatitis	61/611 (10%)		4/343 (1.2%)		8/134 (6%)		0/11 (0%)		15/132 (11.4%)
Vomiting	55/611 (9%)		23/343 (6.7%)		10/134 (7.5%)		0/11 (0%)		12/132 (9.1%)
Constipation	35/611 (5.7%)		23/343 (6.7%)		7/134 (5.2%)		0/11 (0%)		14/132 (10.6%)
Abdominal pain	34/611 (5.6%)		11/343 (3.2%)		6/134 (4.5%)		0/11 (0%)		14/132 (10.6%)
Dyspepsia	30/611 (4.9%)		14/343 (4.1%)		4/134 (3%)		0/11 (0%)		15/132 (11.4%)
Abdominal pain upper	28/611 (4.6%)		20/343 (5.8%)		0/134 (0%)		0/11 (0%)		11/132 (8.3%)
Dry mouth	21/611 (3.4%)		3/343 (0.9%)		7/134 (5.2%)		0/11 (0%)		7/132 (5.3%)
Gastrooesophageal reflux disease	20/611 (3.3%)		8/343 (2.3%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Cheilitis	4/611 (0.7%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		8/132 (6.1%)
Mouth ulceration	13/611 (2.1%)		1/343 (0.3%)		1/134 (0.7%)		0/11 (0%)		5/132 (3.8%)
Flatulence	11/611 (1.8%)		6/343 (1.7%)		2/134 (1.5%)		0/11 (0%)		4/132 (3%)
General disorders
Fatigue	118/611 (19.3%)		49/343 (14.3%)		23/134 (17.2%)		0/11 (0%)		34/132 (25.8%)
Asthenia	37/611 (6.1%)		21/343 (6.1%)		6/134 (4.5%)		0/11 (0%)		6/132 (4.5%)
Mucosal inflammation	27/611 (4.4%)		2/343 (0.6%)		6/134 (4.5%)		0/11 (0%)		12/132 (9.1%)
Pyrexia	23/611 (3.8%)		13/343 (3.8%)		6/134 (4.5%)		1/11 (9.1%)		9/132 (6.8%)
Xerosis	19/611 (3.1%)		5/343 (1.5%)		0/134 (0%)		0/11 (0%)		1/132 (0.8%)
Oedema peripheral	18/611 (2.9%)		11/343 (3.2%)		1/134 (0.7%)		0/11 (0%)		5/132 (3.8%)
Chest pain	15/611 (2.5%)		12/343 (3.5%)		2/134 (1.5%)		0/11 (0%)		4/132 (3%)
Non-cardiac chest pain	12/611 (2%)		9/343 (2.6%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Infections and infestations
Paronychia	39/611 (6.4%)		2/343 (0.6%)		4/134 (3%)		0/11 (0%)		6/132 (4.5%)
Upper respiratory tract infection	30/611 (4.9%)		15/343 (4.4%)		0/134 (0%)		0/11 (0%)		13/132 (9.8%)
Nasopharyngitis	29/611 (4.7%)		30/343 (8.7%)		2/134 (1.5%)		0/11 (0%)		17/132 (12.9%)
Bronchitis	21/611 (3.4%)		12/343 (3.5%)		1/134 (0.7%)		0/11 (0%)		9/132 (6.8%)
Rash pustular	19/611 (3.1%)		1/343 (0.3%)		3/134 (2.2%)		0/11 (0%)		13/132 (9.8%)
Urinary tract infection	19/611 (3.1%)		12/343 (3.5%)		1/134 (0.7%)		0/11 (0%)		3/132 (2.3%)
Sinusitis	7/611 (1.1%)		8/343 (2.3%)		3/134 (2.2%)		0/11 (0%)		7/132 (5.3%)
Ear infection	2/611 (0.3%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		5/132 (3.8%)
Nail infection	2/611 (0.3%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		5/132 (3.8%)
Rhinitis	12/611 (2%)		6/343 (1.7%)		1/134 (0.7%)		0/11 (0%)		5/132 (3.8%)
Localised infection	4/611 (0.7%)		2/343 (0.6%)		0/134 (0%)		0/11 (0%)		4/132 (3%)
Pneumonia	16/611 (2.6%)		5/343 (1.5%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Skin infection	3/611 (0.5%)		0/343 (0%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Injury, poisoning and procedural complications
Procedural pain	9/611 (1.5%)		6/343 (1.7%)		4/134 (3%)		0/11 (0%)		5/132 (3.8%)
Investigations
Weight decreased	56/611 (9.2%)		19/343 (5.5%)		2/134 (1.5%)		0/11 (0%)		19/132 (14.4%)
Weight increased	16/611 (2.6%)		20/343 (5.8%)		1/134 (0.7%)		0/11 (0%)		6/132 (4.5%)
Blood sodium decreased	0/611 (0%)		0/343 (0%)		0/134 (0%)		1/11 (9.1%)		0/132 (0%)
Alanine aminotransferase increased	7/611 (1.1%)		6/343 (1.7%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Metabolism and nutrition disorders
Anorexia	80/611 (13.1%)		24/343 (7%)		20/134 (14.9%)		1/11 (9.1%)		20/132 (15.2%)
Dehydration	5/611 (0.8%)		1/343 (0.3%)		4/134 (3%)		0/11 (0%)		4/132 (3%)
Musculoskeletal and connective tissue disorders
Back pain	40/611 (6.5%)		24/343 (7%)		3/134 (2.2%)		0/11 (0%)		12/132 (9.1%)
Muscle spasms	36/611 (5.9%)		7/343 (2%)		1/134 (0.7%)		0/11 (0%)		10/132 (7.6%)
Musculoskeletal chest pain	28/611 (4.6%)		10/343 (2.9%)		1/134 (0.7%)		0/11 (0%)		3/132 (2.3%)
Arthralgia	23/611 (3.8%)		25/343 (7.3%)		4/134 (3%)		0/11 (0%)		14/132 (10.6%)
Pain in extremity	23/611 (3.8%)		12/343 (3.5%)		3/134 (2.2%)		0/11 (0%)		12/132 (9.1%)
Musculoskeletal pain	20/611 (3.3%)		23/343 (6.7%)		2/134 (1.5%)		0/11 (0%)		9/132 (6.8%)
Myalgia	18/611 (2.9%)		6/343 (1.7%)		4/134 (3%)		0/11 (0%)		6/132 (4.5%)
Nervous system disorders
Headache	42/611 (6.9%)		40/343 (11.7%)		10/134 (7.5%)		0/11 (0%)		13/132 (9.8%)
Dizziness	26/611 (4.3%)		22/343 (6.4%)		9/134 (6.7%)		1/11 (9.1%)		13/132 (9.8%)
Dysgeusia	26/611 (4.3%)		4/343 (1.2%)		5/134 (3.7%)		0/11 (0%)		13/132 (9.8%)
Paraesthesia	20/611 (3.3%)		15/343 (4.4%)		1/134 (0.7%)		0/11 (0%)		0/132 (0%)
Lethargy	2/611 (0.3%)		0/343 (0%)		0/134 (0%)		1/11 (9.1%)		0/132 (0%)
Somnolence	4/611 (0.7%)		0/343 (0%)		0/134 (0%)		1/11 (9.1%)		0/132 (0%)
Neuropathy	9/611 (1.5%)		2/343 (0.6%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Peripheral sensory neuropathy	9/611 (1.5%)		4/343 (1.2%)		2/134 (1.5%)		0/11 (0%)		4/132 (3%)
Psychiatric disorders
Insomnia	40/611 (6.5%)		21/343 (6.1%)		6/134 (4.5%)		0/11 (0%)		16/132 (12.1%)
Depression	33/611 (5.4%)		12/343 (3.5%)		5/134 (3.7%)		0/11 (0%)		6/132 (4.5%)
Anxiety	20/611 (3.3%)		14/343 (4.1%)		5/134 (3.7%)		0/11 (0%)		7/132 (5.3%)
Aggression	0/611 (0%)		0/343 (0%)		0/134 (0%)		1/11 (9.1%)		0/132 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	121/611 (19.8%)		69/343 (20.1%)		17/134 (12.7%)		0/11 (0%)		29/132 (22%)
Dyspnoea	85/611 (13.9%)		61/343 (17.8%)		15/134 (11.2%)		0/11 (0%)		18/132 (13.6%)
Epistaxis	47/611 (7.7%)		4/343 (1.2%)		4/134 (3%)		0/11 (0%)		11/132 (8.3%)
Haemoptysis	20/611 (3.3%)		4/343 (1.2%)		3/134 (2.2%)		0/11 (0%)		4/132 (3%)
Rhinorrhoea	19/611 (3.1%)		12/343 (3.5%)		3/134 (2.2%)		0/11 (0%)		7/132 (5.3%)
Productive cough	16/611 (2.6%)		14/343 (4.1%)		3/134 (2.2%)		0/11 (0%)		6/132 (4.5%)
Pleural fibrosis	0/611 (0%)		0/343 (0%)		0/134 (0%)		1/11 (9.1%)		0/132 (0%)
Nasal ulcer	5/611 (0.8%)		0/343 (0%)		0/134 (0%)		0/11 (0%)		5/132 (3.8%)
Pharyngolaryngeal pain	13/611 (2.1%)		8/343 (2.3%)		3/134 (2.2%)		0/11 (0%)		5/132 (3.8%)
Dyspnoea exertional	9/611 (1.5%)		9/343 (2.6%)		2/134 (1.5%)		0/11 (0%)		4/132 (3%)
Skin and subcutaneous tissue disorders
Rash	356/611 (58.3%)		58/343 (16.9%)		51/134 (38.1%)		0/11 (0%)		72/132 (54.5%)
Pruritus	161/611 (26.4%)		51/343 (14.9%)		21/134 (15.7%)		0/11 (0%)		29/132 (22%)
Dry skin	127/611 (20.8%)		50/343 (14.6%)		15/134 (11.2%)		0/11 (0%)		41/132 (31.1%)
Dermatitis acneiform	111/611 (18.2%)		19/343 (5.5%)		37/134 (27.6%)		0/11 (0%)		45/132 (34.1%)
Alopecia	67/611 (11%)		11/343 (3.2%)		12/134 (9%)		0/11 (0%)		22/132 (16.7%)
Rash erythematous	30/611 (4.9%)		6/343 (1.7%)		6/134 (4.5%)		0/11 (0%)		12/132 (9.1%)
Rash maculo-papular	28/611 (4.6%)		3/343 (0.9%)		4/134 (3%)		0/11 (0%)		7/132 (5.3%)
Skin fissures	26/611 (4.3%)		2/343 (0.6%)		1/134 (0.7%)		0/11 (0%)		9/132 (6.8%)
Acne	25/611 (4.1%)		10/343 (2.9%)		6/134 (4.5%)		0/11 (0%)		3/132 (2.3%)
Rash papular	25/611 (4.1%)		5/343 (1.5%)		1/134 (0.7%)		0/11 (0%)		7/132 (5.3%)
Erythema	24/611 (3.9%)		5/343 (1.5%)		10/134 (7.5%)		0/11 (0%)		13/132 (9.8%)
Nail disorder	23/611 (3.8%)		2/343 (0.6%)		1/134 (0.7%)		0/11 (0%)		9/132 (6.8%)
Skin exfoliation	23/611 (3.8%)		4/343 (1.2%)		6/134 (4.5%)		0/11 (0%)		8/132 (6.1%)
Exfoliative rash	19/611 (3.1%)		2/343 (0.6%)		2/134 (1.5%)		0/11 (0%)		11/132 (8.3%)
Blister	8/611 (1.3%)		0/343 (0%)		5/134 (3.7%)		0/11 (0%)		1/132 (0.8%)
Night sweats	3/611 (0.5%)		0/343 (0%)		4/134 (3%)		1/11 (9.1%)		1/132 (0.8%)
Rash pruritic	10/611 (1.6%)		1/343 (0.3%)		1/134 (0.7%)		1/11 (9.1%)		5/132 (3.8%)
Dermatitis	4/611 (0.7%)		1/343 (0.3%)		0/134 (0%)		0/11 (0%)		4/132 (3%)
Eczema	11/611 (1.8%)		5/343 (1.5%)		0/134 (0%)		0/11 (0%)		4/132 (3%)
Skin lesion	15/611 (2.5%)		4/343 (1.2%)		1/134 (0.7%)		0/11 (0%)		4/132 (3%)
Rash macular	18/611 (2.9%)		7/343 (2%)		2/134 (1.5%)		0/11 (0%)		8/132 (6.1%)
Vascular disorders
Hypertension	22/611 (3.6%)		14/343 (4.1%)		2/134 (1.5%)		0/11 (0%)		8/132 (6.1%)

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Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript at least 60 days prior to publication for review and comment. Sponsor may delay the publication for up to 6 months to seek patent protection.