1 Article type: Original Report - Clinical Cancer Research · 34 Georgetown-Lombardi Comprehensive...
Transcript of 1 Article type: Original Report - Clinical Cancer Research · 34 Georgetown-Lombardi Comprehensive...
Confidential | Not for distribution | Page 1 of 23
Article type: Original Report 1
Target journal: Clinical Cancer Research 2
Working title: Patient-reported outcomes from the phase 3 randomized IMmotion151 trial: 3 atezolizumab + bevacizumab vs sunitinib in treatment-naive metastatic renal cell carcinoma 4
5 Running title: IMmotion151 PROs with atezolizumab plus bevacizumab in mRCC 6
7
Michael B. Atkins,1 Brian I. Rini,2 Robert J. Motzer,3 Thomas Powles,4 David F. McDermott,5 8 Cristina Suarez,6 Sergio Bracarda,7 Walter M. Stadler,8 Frede Donskov,9 Howard Gurney,10 9 Stephane Oudard,11 Motohide Uemura,12 Elaine T. Lam,13 Carsten Grüllich,14 Caroleen Quach,15 10 Susheela Carroll,15,* Beiying Ding,15 Qian (Cindy) Zhu,15 Elisabeth Piault-Louis,15 Christina 11 Schiff,15 Bernard Escudier16 12
13 1Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; 2Cleveland Clinic 14 Taussig Cancer Institute, Cleveland, OH; 3Memorial Sloan Kettering Cancer Center, New York, 15 NY; 4Barts Cancer Institute and the Royal Free Hospital, Queen Mary University of London, 16 London, UK; 5Beth Israel Deaconess Medical Center, Boston, MA; 6Vall d’Hebron Institute of 17 Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; 7Azienda Ospedaliera Santa 18 Maria, Terni, Italy; 8 The University of Chicago Medical Center, Chicago, IL; 9Aarhus University 19 Hospital, Aarhus, Denmark; 10Macquarie University, Sydney, NSW, Australia; 11Paris Descartes 20 University, Paris, France; 12Osaka University Graduate School of Medicine, Osaka, Japan; 21 13University of Colorado Anschutz Medical Campus, Aurora, CO; 14National Center for Tumor 22 Diseases (NCT), Heidelberg, Germany; 15Genentech, Inc., South San Francisco, CA; 16Gustave 23 Roussy, Villejuif, France 24 25 * Currently an employee of Calithera Biosciences, South San Francisco, CA. 26
27
Key words: patient-reported outcomes, atezolizumab, bevacizumab, IMmotion151, renal cell 28 carcinoma 29
Financial support: This study was sponsored by F. Hoffmann-La Roche Ltd/Genentech, Inc, a 30 member of the Roche Group. 31
Corresponding author: 32
Michael B. Atkins, MD 33 Georgetown-Lombardi Comprehensive Cancer Center 34
3800 Reservoir Road, NW 35
Washington, DC 20007 36 Phone: 202-687-2795 37 Fax: 202-687-1370 38 [email protected] 39
40
Authors’ disclosures of potential conflicts of interest: 41
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 2 of 23
M. B. A. has received honoraria or fees for serving on advisory boards for Bristol-Meyers Squibb 42
(BMS), Merck, Novartis, Arrowhead, Pfizer, Galactone, Werewolf, Fathom, Pneuma, and Leads; 43
consulting fees from BMS, Merck, Novartis, Pfizer, Genentech/Roche, Exelixis, Eisai, Aveo, 44
Array, AstraZeneca, Ideera, Aduro, ImmunoCore, Boehringer-Ingelheim, Iovance, Newlink, 45
Pharma, Surface, Alexion, Acceleron, Cota, and Amgen; institutional support from BMS, Merck, 46
Pfizer, and Genentech; and owns stock options in Werewolf and Pyxis Oncology. B. I. R. has 47
received grants and honoraria from Roche–Genentech and Pfizer; grants to his institution and 48
honoraria for consulting roles from Merck, Peloton, Aveo, BMA; grants to his institution from 49
AstraZeneca; honoraria for consulting roles from Novartis, Synthorx, Compugen, Corvus, and 50
Exelixis; and owns stock in PTC therapeutics. R. J. M. has received honoraria for consulting 51
roles from BMS, Genentech/Roche, Pfizer, Novartis, Exelixis, Eisai, Incyte, Eli Lilly, and Merck, 52
and institutional support from BMS, Genentech/Roche, Pfizer, Novartis, Exelixis, and Eisai. T. P. 53
has received research funding from AstraZeneca and Genentech/Roche; and honoraria and 54
travel support from BMS, Ipsen, Exelixis, Roche, Merck, Pfizer, Novartis, AstraZeneca, Incyte, 55
and Seattle Genetics. D. F. M. has received consulting fees from BMS, Pfizer, Merck, Novartis, 56
Array BioPharma, Eli Lilly, EMD Serono, Jounce Therapeutics, Peloton, and Alkermes; and 57
research grants from Prometheus Laboratories and BMS. C. Suárez has received grants from 58
Roche for conduct of the study; advisory board, speaking and travel fees from BMS and Pfizer; 59
advisory board and speaking fees from Ipsen and Astellas; advisory board fees from Sanofi, 60
Bayer and Merck Sharp & Dohme; and travel expenses from Roche. S. B. has received 61
honoraria and travel support for advisory roles from Novartis, Astellas, Janssen, Pfizer, BMS, 62
Roche, Bayer and Ipsen; honoraria from Astellas and Janssen and travel support from Exelixis 63
and AstraZeneca. W. M. S. has received consulting fees from AstraZeneca, Bayer, BMS, 64
Caremark/CVS, Clovis, Eisai, Genentech, Merck, Pfizer, and Sotio; institutional support from 65
AbbVie, AstraZeneca, Astellas/Medivation, Bayer, BMS, Boehringer Ingelheim, Calithera, 66
Clovis, Eisai, Exelixis, Genentech/Roche, Johnson & Johnson/Janssen, Merck, Novartis, Pfizer, 67
Seattle Genetics, Tesaro, X4 Pharmaceuticals; has served on the speaker bureau the following 68
CME providers (sponsorship unknown): Applied Clinical Education, Dava Oncology, Global 69
Academy for Medical Education, OncLive, PeerView, Vindico; and serves as an editor for 70
Cancer and UpToDate. F. D. has received grants to his institution from Pfizer and Ipsen. H. G. 71
has received honoraria for advisory roles from BMS, Astellas, Pfizer, Ipsen, Roche, and MSD. 72
S. O. has received honoraria for advisory roles from Novartis, MSD, BMS, Bayer, Pfizer, Ipsen, 73
Genentech/Roche, Astellas, Sanofi, and Janssen. M. U. has received honoraria for advisory 74
roles from Chugai Pharmaceuticals. E. T. L. has received clinical trial funding from 75
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 3 of 23
Genentech/Roche, Calithera, BMS, Peloton, Merck, and Pfizer. C. G. has received travel 76
support and honoraria for advisory roles from Ipsen, BMS, and Genentech/Roche; travel 77
support and has been an advisor for Novartis; has been an advisor for Pfizer; has received 78
honoraria for advisory roles from Eisai; and honoraria from MSD. C. Q., B. D., and E. P.-L. are 79
employees and hold stock options in Genentech/Roche. S. C. was previously employed and 80
previously owned stock options in Genentech/Roche and is currently employed and owns stock 81
in Calithera Biosciences. C. Schiff was previously employed and previously owned stock options 82
in Genentech/Roche. Q. Z. is a contracted employee of Genentech/Roche. B. E. has received 83
grants and honoraria from BMS and AVEO; grants from Novartis; and honoraria from 84
Genentech/Roche, Pfizer, Oncorena, and Ipsen. 85
86
Role of the funder/sponsor: F. Hoffmann-La Roche, Ltd. sponsored the study and was 87
involved in the design and conduct of the study; management, analysis and interpretation of the 88
data; and preparation, review and approval of the manuscript. 89
90
91
Figures and/or table limit: 6 92
Currently: 2 Tables, 4 Figures, 2 Supplementary Tables, 5 Supplementary Figures 93
Word Count: 3926/5000 (excluding abstract, references, figures, and tables) 94
Reference Count: 32/50 95
96
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 4 of 23
Statement of translational relevance (130/150): 97
Patients with metastatic renal cell carcinoma (mRCC) generally still have a poor prognosis and 98
frequently experience therapy-associated toxicity. Thus, understanding the effects of new 99
agents on the health-related quality of life (HRQOL) of this patient population has become 100
increasingly important. Here, we report a comprehensive analysis of patient-reported outcomes 101
(PROs) from the phase 3 IMmotion151 trial. Patients with untreated mRCC who received 102
atezolizumab plus bevacizumab reported milder symptoms, less impairment in and delayed 103
deterioration of daily functioning, better HRQOL, and less bother from treatment-related side 104
effects than those who received sunitinib, one of the present standards of care. Together with 105
previously reported efficacy and safety data, PROs from IMmotion151 suggest that patients with 106
treatment-naive mRCC experience lower symptom and treatment burden overall with 107
atezolizumab plus bevacizumab compared with sunitinib, providing further evidence for the 108
clinical benefit of this regimen. 109
110
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 5 of 23
ABSTRACT (250/250 WORDS) 111
Purpose. Patient-reported outcomes (PROs) were evaluated in the phase 3 IMmotion151 trial 112
(NCT02420821) to inform overall treatment/disease burden of atezolizumab plus bevacizumab 113
versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (mRCC). 114
Experimental design. Patients were randomized 1:1 to receive atezolizumab 1200 mg IV q3w 115
plus bevacizumab 15 mg/kg IV q3w or sunitinib 50 mg PO QD 4 weeks on/2 weeks off. Patients 116
completed the MD Anderson Symptom Inventory (MDASI), National Comprehensive Cancer 117
Network Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and 118
Brief Fatigue Inventory (BFI) at baseline, q3w during treatment, at end-of-treatment, and during 119
survival follow-up. Longitudinal and time to deterioration (TTD) analyses for core and RCC 120
symptoms and their interference with daily life, treatment side-effect bother, and health-related 121
quality of life (HRQOL) were evaluated. 122
123
Results. The ITT population included 454 and 461 patients in the atezolizumab plus 124
bevacizumab and sunitinib arms, respectively. Completion rates for each instrument were 83%-125
86% at baseline and ≥ 70% through week 54. Milder symptoms, less symptom interference and 126
treatment side-effect bother, and better HRQOL at most visits were reported with atezolizumab 127
plus bevacizumab versus sunitinib. The TTD HR (95% CI) favored atezolizumab plus 128
bevacizumab for core (HR, 0.50 [0.40, 0.62]) and RCC symptoms (HR, 0.45 [0.37, 0.55]); 129
symptom interference (HR, 0.56 [0.46, 0.68]); and HRQOL (HR, 0.68 [0.58, 0.81]). 130
131
Conclusion. PROs in IMmotion151 suggest lower overall treatment burden with atezolizumab 132
plus bevacizumab compared with sunitinib in patients with treatment-naive mRCC and provide 133
further evidence for clinical benefit of this regimen. 134
135
136
137
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 6 of 23
INTRODUCTION 138
For patients with metastatic renal cell carcinoma (mRCC) with predominant clear cell histology, 139
tyrosine kinase inhibitors (TKIs) have been a standard first-line treatment option for the past 140
decade (1). However, few patients achieve complete or durable responses with these agents, 141
and most patients eventually experience disease progression within 5 to 11 months (2). Several 142
phase 3 trials have recently shown that combination immunotherapy has efficacy in certain 143
mRCC patient populations, and this approach is now considered standard of care in the first-line 144
setting, with other new antiangiogenic plus immunotherapy combinations emerging (3-6). 145
The PD-1 checkpoint inhibitor nivolumab, in combination with the anti-cytotoxic T-lymphocyte–146
associated antigen 4 antibody, ipilimumab, showed significantly longer overall survival (OS) 147
compared with sunitinib (HR, 0.63 [99.8% CI, 0.44, 0.89]; P < 0.001) (3,7,8). Grade 3/4 148
treatment-related adverse events (TRAEs) occurred in 46% of patients treated with nivolumab 149
plus ipilimumab versus 63% in those treated with sunitinib; discontinuation occurred in 22% and 150
12% of patients, respectively (3). Progression-free survival (PFS) was significantly longer with 151
the anti–PD-L1 inhibitor, avelumab, in combination with axitinib (TKI) versus sunitinib in patients 152
with mRCC with programmed death-ligand 1 (PD-L1)–positive tumors who received these 153
agents in the first-line setting (HR 0.61; P < 0.001) (4,9). The rate of grade 3 or higher TRAEs 154
was similar between treatment arms (approximately 70%); adverse events (AEs) that occurred 155
during treatment led to discontinuation of both avelumab and axitinib in 8% of patients and of 156
sunitinib in 13% of patients (4). In addition, treatment with pembrolizumab (anti–PD-1) plus 157
axitinib resulted in significantly longer PFS (HR, 0.69; P < 0.001) as well as prolonged OS (HR, 158
0.53; P < 0.0001) versus sunitinib as first-line treatment for mRCC across risk groups (6,10). 159
TRAEs that were grade ≥ 3 occurred in 63% versus 58% of patients, respectively; and led to 160
discontinuation of treatment in 8% of patients versus 0% (6). In the phase 3 IMmotion151 study 161
(NCT02420821), atezolizumab (anti–PD-L1) combined with bevacizumab (TKI) prolonged PFS 162
in patients across all risk groups with untreated mRCC who had PD-L1+ disease (≥ 1% of 163
tumor-infiltrating immune cells [IC] expressing PD-L1; HR, 0.74; P = 0.0217) (5). The 164
combination of atezolizumab plus bevacizumab had a tolerable safety profile that was 165
consistent with results from the phase 2 IMmotion150 study (NCT01984242) and previous data 166
for each drug alone (5,11,12). Forty percent of patients treated with atezolizumab plus 167
bevacizumab had grade 3/4 TRAEs versus 54% who were treated with sunitinib; 5% and 8%, 168
respectively, had all-grade TRAEs leading to discontinuation of the regimen (5). 169
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 7 of 23
Patient-reported outcomes (PROs) supplement the assessment of treatment benefit and help to 170
characterize the tolerability and efficacy of new therapies (13,14) by allowing patients to provide 171
their unique perspective on disease- and treatment-related symptoms, the impacts of those 172
symptoms on daily life, and overall burden of side effects (15). Patients treated with sunitinib, for 173
instance, have reported more toxicity vs placebo but no clinically meaningful deterioration in 174
most, but not all, QOL measures (16). Additionally, improvements in efficacy made with 175
targeted-therapies do not typically coincide with improved QOL for patients with mRCC (17-19). 176
Because poor prognosis and toxicity have been frequently associated with mRCC therapies, it is 177
critical to understand the effects of new treatment agents on HRQOL in this patient population 178
(18) and to identify new therapeutic combinations and treatment sequences that can reduce any 179
potential decrement to patients’ functioning and QOL. 180
181
PRO analyses have been reported for the nivolumab plus ipilimumab combination, showing 182
fewer symptoms and better HRQOL than sunitinib in patients with intermediate or poor risk 183
mRCC (20). In light of the increasing importance that patient perspectives play in drug 184
development, PRO measures were included in the phase 2 IMmotion150 study to inform the 185
PRO assessment in the phase 3 IMmotion151 trial. Results from IMmotion150 suggested that 186
patients receiving atezolizumab alone or with bevacizumab maintained daily function with 187
minimal symptom interference versus patients receiving sunitinib (21). These measures were 188
subsequently evaluated as secondary and exploratory endpoints in IMmotion151 to determine 189
key aspects of the patient experience of their disease and treatment. We hypothesized that the 190
combination of atezolizumab plus bevacizumab would not significantly increase overall 191
treatment or symptom burden from the patient’s perspective versus sunitinib. Here, we report a 192
comprehensive analysis of PROs from IMmotion151 to inform overall treatment burden in 193
patients with mRCC receiving atezolizumab plus bevacizumab. 194
MATERIALS AND METHODS 195
Study Design and Patients 196
Details of the study design for the phase 3, global, open-label, randomized IMmotion151 trial 197
have been described previously (5) (Supplementary Fig S1). Briefly, patients with mRCC were 198
stratified by PD-L1 expression (< 1% versus ≥ 1% IC expressing PD-L1 as assessed by 199
immunohistochemistry [VENTANA PD-L1 SP142 assay; Ventana Medical Systems, Tucson, 200
AZ]), presence of liver metastases (yes versus no), and Memorial Sloan Kettering Cancer 201
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 8 of 23
Center (MSKCC) prognostic risk score (0, 1-2, ≥ 3). Patients received atezolizumab 1200 mg 202
intravenous (IV) infusions every 3 weeks (q3w) plus bevacizumab 15 mg/kg IV q3w or sunitinib 203
50 mg/day orally (4 weeks on, 2 weeks off). Patients could continue treatment beyond disease 204
progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 if evidence 205
of clinical benefit was observed per investigator discretion; no crossover from sunitinib to 206
atezolizumab plus bevacizumab was allowed. 207
Patients had scheduled tumor assessments at baseline, week 12, and every 6 weeks through 208
week 78 followed by every 12 weeks thereafter. Tumor assessments continued until disease 209
progression per RECIST 1.1 or loss of clinical benefit, regardless of whether treatment was 210
discontinued (e.g., for toxicity). The clinical data cutoff was September 29, 2017. The study 211
protocol was approved by the institutional review board or independent ethics committee for 212
each study site and was conducted in full accordance with the Guideline for Good Clinical 213
Practice and the Declaration of Helsinki. All patients gave written informed consent. 214
Study Assessments: PRO Instruments and Scoring 215
Patients’ perspectives regarding treatment and disease burden were captured by 3 instruments: 216
MD Anderson Symptom Inventory (MDASI), National Comprehensive Cancer Network 217
Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (FKSI-19), and 218
Brief Fatigue Inventory (BFI) (Supplementary Table S1, Supplementary Fig S2). 219
The MDASI is a validated and reliable instrument developed for clinical and research use in 220
patients with cancer (22-24). Symptom severity items for the MDASI were scored individually or 221
as a multi-item scale. Seventeen individual item scores, a 13-item core symptom severity scale 222
score, and a 4-item RCC symptom severity scale score were evaluated. The core symptom 223
severity scale asked patients to rate how severe their symptoms were “at their worst” in the last 224
24 hours: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, difficulty 225
remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness 226
or tingling. Patients rated the severity of 4 additional symptoms specific to RCC and its 227
treatment: mouth/throat sores, rash or skin change, headache, and diarrhea. The symptom 228
interference with daily life scale included 6 items asking patients to rate how much their 229
symptoms interfered in the last 24 hours with general activity, walking, work, mood, relations 230
with other people, and enjoyment of life. The range for each symptom severity and symptom 231
interference score was 0 to 10, where higher scores indicated greater symptom severity and 232
interference. 233
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 9 of 23
The FKSI-19 is a 19-item instrument that assesses symptoms and QOL in kidney cancer 234
(25,26) and is composed of 4 domains: physical disease-related symptoms, emotional disease-235
related symptoms, treatment side effects, and function/well-being. Each item was scored on a 5-236
point scale with response categories of “not at all,” “a little bit,” “somewhat,” “quite a bit,” and 237
“very much.” The total scale score, which included all 19 items, ranged from 0 to 76, where 76 238
indicated best possible HRQOL. The patient’s perspective on overall side-effect burden was 239
captured by the GP5 item, where patients self-reported how bothered they were by their 240
treatment side effects. This standalone item is a valid summary measure of the overall impact of 241
treatment-related toxicities in cancer and complements safety reporting by clinicians (27). 242
The BFI was used to assess the severity and impact of cancer-related fatigue on patients’ daily 243
life (28). The first 3 items assess patients’ fatigue at present, their usual level of fatigue in the 244
past 24 hours, and fatigue at its worst in the past 24 hours; in this study, we focused on the item 245
of fatigue at its worst for conceptual efficiency (fatigue severity). Additional items assess the 246
impact of fatigue on 6 global domains in the last 24 hours (i.e., general activity, mood, walking 247
ability, normal work, relations with other people, enjoyment of life). Similar to the MDASI, each 248
BFI item was rated from 0 to 10, with 0 indicating “no fatigue” or “does not interfere” with the 249
patient’s daily life and 10 indicating that fatigue was “as bad as you can imagine” or “completely 250
interferes” with the patient’s life. 251
Patients completed these PRO assessments on an electronic device at scheduled clinic visits 252
until loss of clinical benefit. Specifically, assessments were completed at baseline, on days 1 253
and 22 of each 6-week cycle, at end of treatment (EoT), and during survival follow-up (6, 12, 24, 254
and 36 weeks after EoT) (Supplementary Table S1). PROs were also required to be collected 255
prior to administration of study treatment (while on treatment) and/or prior to any other study 256
assessment(s) at each PRO visit. The PRO assessment schedule was also aligned with the 257
study visit schedule to minimize patient completion burden. Due to the 2 different routes of 258
administration and dosing schedules, patients in the sunitinib arm were without treatment for 2 259
weeks at day 1 assessment visits; they received their 28-day treatment at day 22 assessment 260
visits, which were required for sunitinib patients during the first year only. BFI data were 261
collected weekly during the first 12 weeks to capture and better characterize the subtle changes 262
after initiation of study treatment; patients completed BFI assessments at home if they did not 263
have a scheduled visit (e.g., days 8, 15, 29, 36). PRO instruments were translated as required 264
in the local language, distributed by the investigator staff, and completed in their entirety by the 265
patient. Site staff reviewed assessments for completeness only. 266
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 10 of 23
Statistical Analyses 267
Full details for statistical analyses of the primary and secondary endpoints have been previously 268
reported (5). PROs were pre-specified as secondary and exploratory endpoints in the ITT 269
population without type I error control. P values were not adjusted for multiplicity and are 270
presented for descriptive purposes. Completion rates were calculated as the number of patients 271
who completed assessments divided by the number of patients expected to complete 272
assessments (i.e., still on study) at each scheduled visit. Per developers’ user manuals, for 273
scales with > 50% of the constituent items completed, a pro-rated score was computed. For 274
scales with ≤ 50% of the items completed, the scale score was considered missing. 275
Descriptive summaries of scores and score change from baseline for each visit by treatment 276
arm were examined. A patient’s last PRO assessment within the 30 days prior to disease 277
progression per RECIST 1.1 was also identified. 278
Longitudinal models included PRO data collected at study treatment visits up to but not 279
including the EoT visit and assumed that data were missing at random (29,30). The primary 280
longitudinal analysis to estimate least-squares mean change in each PRO score from baseline 281
to each visit was based on repeated-measures models. Each model assumed a first-order 282
autoregressive covariance structure and included covariates for visit (categorical), treatment, a 283
treatment-by-visit interaction, baseline score, and stratification factors. As supportive analyses, 284
linear mixed-effects models estimated least-squares mean change in each PRO score from 285
baseline up to EoT. Each linear model assumed an unstructured covariance matrix and random 286
effects of intercepts and slopes and included covariates for time (continuous), treatment, 287
baseline score, and stratification factors. The difference in change between treatment arms (i.e., 288
atezolizumab + bevacizumab versus sunitinib) was summarized at each visit, at visits through 289
cycle 10 day 1 (i.e., week 54), and over the entire study treatment period. Effect sizes (ES) 290
supported interpretation of differences between treatment arms, where the absolute value of ES 291
≥ 0.20 likely represented a clinically important difference (31). ES was calculated as the 292
difference in score change divided by the pooled standard deviation. For the MDASI and BFI 293
scales, negative ES values indicated favor toward atezolizumab + bevacizumab, and positive 294
ES values indicated favor toward sunitinib. Conversely, for the FKSI-19 scale, positive ES 295
values denoted favor toward atezolizumab + bevacizumab, and negative ES values denoted 296
favor toward sunitinib. 297
Time-to-event analyses were evaluated as time to clinically meaningful deterioration, defined as 298
a patient’s first ≥ 2-point score increase above baseline on the MDASI (core symptom scale, 299
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 11 of 23
RCC symptom scale, symptom interference scale) and BFI (fatigue severity item and fatigue 300
interference scale) or a patient's first ≥ 5-point score decrease from baseline on the FKSI-19 301
total score. The hazard ratios and 95% confidence intervals comparing atezolizumab plus 302
bevacizumab with sunitinib were estimated using a stratified Cox regression model where the 303
stratification factors were the same as those used in the repeated-measures models. Kaplan-304
Meier methodology was used to estimate the probability of deterioration. Patients with a missing 305
baseline PRO or post-baseline assessment were censored at randomization, and patients 306
without a deterioration event were censored at the date of the last non-missing PRO 307
assessment. 308
Post hoc analyses of associations between PFS and baseline or change from baseline PRO 309
were also performed in the intent-to-treat (ITT) population. Time-dependent stratified Cox 310
proportional hazards regression models for PFS included a term for baseline PRO score and a 311
term for PRO score change from baseline as a time-dependent covariate and adjusted for 312
treatment arm (for the overall model only). KM estimates of PFS were grouped by median PRO 313
score at baseline (i.e., greater than or equal to median score vs less than median PRO score). 314
Descriptive summaries and longitudinal model analyses were performed on patients with a non-315
missing baseline PRO assessment and ≥ 1 post-baseline PRO assessment. Time to 316
deterioration analyses were performed on all randomized patients. Analyses were conducted 317
using SAS version 9.4. 318
RESULTS 319
Patient Disposition and PRO Completion Rates 320
The study enrolled 915 patients with mRCC between May 20, 2015, and October 12, 2016, at 321
152 sites across 21 countries, with 454 patients randomized to receive atezolizumab plus 322
bevacizumab and 461 patients randomized to receive sunitinib alone. Patient characteristics 323
were well balanced across arms prior to study treatment (5) (Table 1). At baseline, 386 patients 324
(86%) in the atezolizumab plus bevacizumab arm and 369 patients (83%) in the sunitinib arm 325
completed the MDASI and FKSI-19; 389 patients (86%) and 370 patients (83%) completed the 326
BFI, respectively. In both arms, prior to receiving study treatment, patients reported mild 327
symptom severity and mild symptom interference with daily life (Table 2). Additionally, baseline 328
FKSI-19 total scores (Table 2) were comparable to those of the US adult general population 329
(32). 330
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 12 of 23
PRO data were collected during study treatment until week 111 (atezolizumab plus 331
bevacizumab) or week 114 (sunitinib). Completion rates for each instrument were similar 332
between arms at on-study assessment points through the week 54 assessment (each ≥ 70%) 333
(Supplementary Fig S3). After week 54, completion rates at day 22 visits were lower in the 334
sunitinib arm than in the atezolizumab plus bevacizumab arm, likely because day 22 clinic visits 335
for patients randomized to the sunitinib arm were not required after the first year. Given 336
differential completion rates between arms at day 22 visits after week 54, we focused on PRO 337
data collected through week 54 (inclusive). 338
Changes From Baseline in Symptoms and Functioning 339
During study treatment, patients in the atezolizumab plus bevacizumab arm reported 340
numerically milder symptoms for the 17 symptoms assessed by MDASI. The difference between 341
arms based on linear mixed-effects models for 16 symptoms was each P < 0.05, with the 342
exception of headache (5) (Figure 1). ES ≤ -0.20 favoring atezolizumab plus bevacizumab 343
versus sunitinib was reported for 12 symptoms: mouth/throat sores, rash or skin change, 344
diarrhea, nausea, lack of appetite, vomiting, dry mouth, shortness of breath, fatigue, sadness, 345
distress, and drowsiness. When evaluated as composite scores using the core symptom scale 346
and RCC symptom scale, symptoms were reported as less severe in the atezolizumab plus 347
bevacizumab arm versus the sunitinib arm (Figure 2 A, B). Based on repeated-measures 348
models, symptom severity score changes from baseline also indicated significantly milder 349
symptoms with atezolizumab plus bevacizumab versus sunitinib (P < 0.05) at visits through 350
week 54, with the exception of week 6 for core symptoms. The average difference in least-351
squares mean score changes at visits through week 54 was -0.63, with a mean ES of -0.40 (ES 352
range, -0.66 to -0.12) for the core symptom scale and -0.75 with a mean ES of -0.52 (ES range, 353
-0.83 to -0.23) for the RCC symptom scale. 354
Patients receiving atezolizumab plus bevacizumab also reported less interference of symptoms 355
with day-to-day life versus patients receiving sunitinib (P < 0.05) at most visits through week 54 356
(Figure 2C). The average differences in least-squares mean score changes at visits through 357
week 54 was -0.61, with a mean ES of -0.29 (range, -0.51 to 0.10). Repeated measures model 358
estimates were consistent with linear mixed-effects model estimates: the difference in least-359
squares mean change from baseline up to EoT was -0.62 (95% CI: -0.87, -0.37; P < 0.0001), 360
with an ES of -0.28 favoring atezolizumab plus bevacizumab versus sunitinib. 361
Patients treated with atezolizumab plus bevacizumab reported less worsening in HRQOL 362
compared with patients treated with sunitinib (Figure 2D). Differences in least-squares mean 363
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 13 of 23
score changes from baseline favored atezolizumab plus bevacizumab versus sunitinib (P < 364
0.05) at each visit through week 54, with the exception of week 6. The average difference in 365
least-squares mean score changes for atezolizumab plus bevacizumab versus sunitinib at visits 366
through week 54 was 3.67, and the mean ES was 0.42 (range, 0.16 to 0.67). The linear mixed-367
effects model of least-squares mean change from baseline up to EoT estimated a difference in 368
change of 3.39 (95% CI: 2.37, 4.42; P < 0.0001) and a corresponding ES of 0.35 favoring 369
atezolizumab plus bevacizumab versus sunitinib. Patients in the atezolizumab plus 370
bevacizumab arm also reported considerably less bother from side effects throughout study 371
treatment compared with patients in the sunitinib arm (Figure 3). Differences in proportions of 372
patients reporting “not at all” or “a little bit” of bother between arms ranged from 14 to 35 373
percentage points. 374
Descriptive summaries by visit were consistent with repeated measures model estimates (data 375
not shown), including lower symptom burden (milder symptoms and less functional impairment, 376
as measured by the MDASI scales) and better HRQOL at disease progression (as measured by 377
the FKSI-19 total scale) with atezolizumab plus bevacizumab versus sunitinib. BFI results 378
generally supported the fatigue results measured by the MDASI (Supplementary Fig S4). 379
Time to Deterioration in Symptoms and Functioning 380
Delayed time to symptom deterioration, interference of symptoms with patients’ day-to-day life, 381
and HRQOL deterioration was observed with atezolizumab plus bevacizumab versus sunitinib 382
(Figure 4). The median time to core symptom deterioration was not estimable (NE) (95% CI: 383
16.4, NE) in the atezolizumab plus bevacizumab arm and was 5.6 months (95% CI: 4.3, 6.9) in 384
the sunitinib arm, with a stratified HR of 0.50 (95% CI: 0.40, 0.62) (Figure 4A). The median time 385
to RCC symptom deterioration was 13.9 months (95% CI: 10.0, NE) with atezolizumab plus 386
bevacizumab and 3.3 months (95% CI: 2.8, 4.3) with sunitinib, with a stratified HR of 0.45 (95% 387
CI: 0.37, 0.55) (Figure 4B). As previously reported (5), the median time to symptom 388
interference with daily life in the atezolizumab plus bevacizumab and sunitinib arms was 11.3 389
months (95% CI: 8.3, 17.5) and 4.3 months (95% CI: 3.1, 5.6), respectively, with a stratified HR 390
of 0.56 (95% CI: 0.46, 0.68) (Figure 4C). Delayed deterioration of HRQOL as measured by the 391
FKSI-19 total scale was also observed for the atezolizumab plus bevacizumab arm versus the 392
sunitinib arm, with a median of 2.8 months (95% CI: 2.1, 3.0) versus 1.5 months (95% CI: 1.4, 393
2.1; HR 0.68 [95% CI: 0.58, 0.81]) (Figure 4D). 394
Per the BFI, time to deterioration for fatigue severity was similar between arms (stratified HR, 395
0.89 [95% CI: 0.75, 1.04]). A modest delay in time to meaningful fatigue-related interference 396
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 14 of 23
was observed with atezolizumab plus bevacizumab versus sunitinib, with a stratified HR of 0.75 397
(95% CI: 0.63, 0.89) (Supplementary Fig S5). 398
Association Between PFS and PROs 399
Baseline PRO scores were associated with median PFS (Supplementary Table S2). 400
Significant associations (P < 0.05) were observed between PFS and baseline score as well as 401
PFS and score change from baseline for the MDASI core symptom severity, MDASI symptom 402
interference, and FKSI-19 total scales based on time-dependent stratified Cox proportional 403
hazards models (Supplementary Figure S6). For the 3 MDASI scales, worse PFS (HR > 1) 404
was associated with worse baseline PROs as well as worsening PROs during study treatment. 405
Similarly, for the FKSI-19 total scale, better PFS (HR < 1) was associated with better baseline 406
HRQOL and improvement of HRQOL during the study. For example, a one-unit increase in 407
MDASI core symptom severity change from baseline (i.e., worsening) is associated with an 18% 408
increase in risk of PFS in the atezolizumab plus bevacizumab arm (based on the HR of 1.18 for 409
one unit of worsening in MDASI core symptom severity). A comparable increase in PFS risk 410
was observed in the sunitinib arm. Similarly, a one-unit increase in FKSI-19 total score change 411
from baseline (i.e., improvement) is associated with 4% and 3% decrease in PFS risk in the 412
atezolizumab plus bevacizumab and sunitinib arms, respectively. 413
DISCUSSION 414
When evaluating new RCC therapies, particularly in a largely non-curative setting, it is important 415
that disease and treatment do not significantly compromise patients' day-to-day function. This 416
analysis, based on high-quality complete PRO data, represents a comprehensive evaluation of 417
the patient experience while undergoing treatment with atezolizumab plus bevacizumab or 418
sunitinib in the first year. For patients enrolled in the phase 3 IMmotion151 trial, those receiving 419
atezolizumab plus bevacizumab reported milder symptoms, less functional impairment and a 420
delay in meaningful deterioration of daily functioning, better HRQOL, and less bother from 421
treatment side effects vs those receiving sunitinib. While direct comparisons were not made to 422
reconcile safety and PRO data, taken together, patient-reported symptom severity, symptom 423
interference, and overall side-effect bother further support the tolerable safety profile of 424
atezolizumab plus bevacizumab. 425
HRQOL with TKI therapies in the first-line setting for mRCC have been reported, such as in a 426
phase 3 trial of pazopanib vs sunitinib where pazopanib showed similar efficacy but a more 427
favorable safety profile and better HRQOL scores than sunitinib (19). PRO results have also 428
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 15 of 23
been reported for checkpoint inhibitor therapy in a phase 3 trial evaluating nivolumab plus 429
ipilimumab vs sunitinib in patients with untreated mRCC (20). Results from this study showed 430
fewer symptoms and better HRQOL with the combination versus sunitinib in patients with 431
intermediate or poor risk mRCC (FKSI-19 total score: HR, 0.54 [95% CI: 0.46, 0.63]; FACT-G 432
total score: HR, 0.63 [95% CI: 0.52, 0.75]; EQ-5D-3L visual analogue rating scale score: HR, 433
0.75 [95% CI: 0.63, 0.89], and EQ-5D-3L UK utility score: HR, 0.67 [95% CI: 0.57, 0.80]) (20). 434
These findings, together with those from IMmotion151, which assessed PROs in patients with 435
mRCC from all prognostic groups, suggest better PROs with checkpoint inhibitor therapy versus 436
sunitinib. Unfortunately, PRO results from other trials evaluating checkpoint inhibitors in first-line 437
mRCC have not been published yet. It is critical that we fully understand treatment impacts on 438
patients’ functioning and ability to pursue day-to-day activities as novel agents and 439
combinations become available. Future research should examine how PRO data could be used 440
to personalize and better support clinician and patient treatment decision making in practice. 441
The significant association between PFS and PROs provide evidence of the clinical relevance of 442
PROs with respect to PFS outcomes in mRCC. However, further investigation is needed to 443
better understand the prognostic role of PROs in clinical care practice. 444
Strengths of the PRO analyses conducted in this study include the large number of patients 445
evaluated in a randomized study. Further, study procedures concerning the administration of 446
PRO assessments were consistent with published guidelines for ensuring high-quality PRO 447
data. Per protocol, patients completed PRO assessments alone, before administration of study 448
treatment or any other assessments, and without interactions that could bias their responses. 449
Potential limitations of these analyses include the open-label design of IMmotion151, as it may 450
have influenced how patients perceived their symptoms and HRQOL. Additionally, as sunitinib-451
related toxicities tend to be worse towards the end of the 28-day treatment cycle (33), PRO data 452
captured at day 22 may not represent the worst toxicities experienced by patients in this 453
treatment arm. Additionally, it is not unusual to have lower completion rates as the study 454
progresses and more patients drop out, which may lead to biased estimates. Unfortunately, 455
reasons for non-completion were not captured in this study. Lastly, the PRO instruments 456
included in the study were developed before the era of checkpoint inhibitors. Still, they do 457
capture relevant symptoms such as fatigue, rash, cough, musculoskeletal pain, diarrhea, fever, 458
and chills (associated with atezolizumab) as well as fatigue and rash (associated with 459
bevacizumab). These PRO instruments also measure seven of the eight most frequently 460
reported symptomatic AEs associated with anti-PD-1/PD-L1 inhibitor immunotherapies 461
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 16 of 23
according to an FDA review, including shortness of breath, fatigue, cough, musculoskeletal 462
(bone) pain, fever, diarrhea, and rash (34). 463
Together with the previously reported efficacy data and extensive safety data in patients with 464
mRCC (5,11,12), PROs from IMmotion151 suggest that, overall, atezolizumab in combination 465
with bevacizumab does not significantly increase symptom or treatment burden compared with 466
sunitinib. 467
ACKNOWLEDGMENTS 468
We thank the patients participating in this trial and their families; the nurses, research 469 coordinators, data managers, and clinical study site investigators. The authors would like to 470 acknowledge Yong Wang for statistical analyses. Patients treated at Memorial Sloan Kettering 471 Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support 472 Grant/Core Grant (P30 CA008748). Medical writing assistance for this manuscript was provided 473 by Paige S. Davies, PhD, of Health Interactions, Inc, and funded by F. Hoffmann-La Roche, Ltd. 474
DATA SHARING STATEMENT 475
Qualified researchers may request access to individual patient-level data through the clinical 476
study data request platform (http://www.clinicalstudydatarequest.com). Further details on 477
Roche's criteria for eligible studies are available here 478
(https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further 479
details on Roche’s Global Policy on the Sharing of Clinical Information and how to request 480
access to related clinical study documents, see here 481
(http://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/o482
ur_commitment_to_data_sharing.htm). 483
484
REFERENCES 485
1. National Comprehensive Cancer N. NCCN Clinical Practice Guidelines in 486
Oncology. Kidney Cancer, Version 1.2020. 2019. 487
2. Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. 488
N Engl J Med 2017;376:354-66 489
3. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri 490
TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell 491
Carcinoma. N Engl J Med 2018;378:1277-90 492
4. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. 493
Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N 494
Engl J Med 2019;380:1103-15 495
5. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. 496
Atezolizumab plus bevacizumab versus sunitinib in patients with previously 497
untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-498
label, phase 3, randomised controlled trial. Lancet 2019;393:2404-15 499
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 17 of 23
6. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. 500
Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell 501
Carcinoma. N Engl J Med 2019;380:1116-27 502
7. Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Meyers Squibb 503
Company; 2018. 504
8. Yervoy (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb 505
Company; 2018. 506
9. Bavencio (avelumab) [package insert]. Rockland, MA: EMD Serono; 2019. 507
10. Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck 508
Sharp & Dohme Corp; 2018. 509
11. Suarez C, Choueiri T, McDermott D, Escudier B, Atkins M, Powles T, et al. 510
Safety and Tolerability of Atezolizumab Plus Bevacizumab vs Sunitinib in 511
Untreated Metastatic Renal Cell Carcinoma: Pooled Analysis of IMmotion150 512
and IMmotion151. Annals of Oncology 2018;29:(suppl_8):viii303-viii31 513
12. McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. 514
Clinical activity and molecular correlates of response to atezolizumab alone or in 515
combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 516
2018;24:749-57 517
13. Kim J, Singh H, Ayalew K, Borror K, Campbell M, Johnson LL, et al. Use of PRO 518
Measures to Inform Tolerability in Oncology Trials: Implications for Clinical 519
Review, IND Safety Reporting, and Clinical Site Inspections. Clinical cancer 520
research : an official journal of the American Association for Cancer Research 521
2018;24:1780-4 522
14. Kluetz PG, O'Connor DJ, Soltys K. Incorporating the patient experience into 523
regulatory decision making in the USA, Europe, and Canada. Lancet Oncol 524
2018;19:e267-e74 525
15. Kluetz PG, Slagle A, Papadopoulos EJ, Johnson LL, Donoghue M, Kwitkowski 526
VE, et al. Focusing on Core Patient-Reported Outcomes in Cancer Clinical Trials: 527
Symptomatic Adverse Events, Physical Function, and Disease-Related 528
Symptoms. Clinical cancer research : an official journal of the American 529
Association for Cancer Research 2016;22:1553-8 530
16. Staehler M, Motzer RJ, George DJ, Pandha HS, Donskov F, Escudier B, et al. 531
Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy 532
management, and patient-reported outcomes in the S-TRAC trial. Ann Oncol 533
2018;29:2098-104 534
17. Choueiri TK, Larkin JMG, Oya M, Thistlethwaite FC, Martignoni M, Nathan PD, et 535
al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell 536
carcinoma (aRCC): Results from a phase Ib trial. JCO 2017;35:4504- 537
18. Cella D. Beyond traditional outcomes: improving quality of life in patients with 538
renal cell carcinoma. Oncologist 2011;16 Suppl 2:23-31 539
19. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib 540
versus sunitinib in metastatic renal-cell carcinoma. The New England journal of 541
medicine 2013;369:722-31 542
20. Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, et al. 543
Patient-reported outcomes of patients with advanced renal cell carcinoma treated 544
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 18 of 23
with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, 545
phase 3 trial. Lancet Oncol 2019;20:297-310 546
21. Pal S, McDermott D, Atkins M, Escudier B, Rini B, Motzer R, et al. Patient-547
Reported Outcomes in IMmotion150: Atezolizumab Alone or With Bevacizumab 548
vs Sunitinib in First-Line Metastatic Renal Cell Carcinoma. J Clin Oncol 549
2019;37:(suppl; abstr 4515) 550
22. Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, et al. 551
Development of the National Cancer Institute's patient-reported outcomes 552
version of the common terminology criteria for adverse events (PRO-CTCAE). 553
Journal of the National Cancer Institute 2014;106:10.1093/jnci/dju244. Print 2014 554
Sep 555
23. Cleeland CS, Mendoza TR, Wang XS, Chou C, Harle MT, Morrissey M, et al. 556
Assessing symptom distress in cancer patients: the M.D. Anderson Symptom 557
Inventory. Cancer 2000;89:1634-46 558
24. Shi Q, Mendoza TR, Wang XS, Cleeland CS. Using a symptom-specific 559
instrument to measure patient-reported daily functioning in patients with cancer. 560
Eur J Cancer 2016;67:83-90 561
25. Rao D, Butt Z, Rosenbloom S, Robinson D, Von Roenn J, Kuzel TM, et al. A 562
Comparison of the Renal Cell Carcinoma-Symptom Index (RCC-SI) and the 563
Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI). J 564
Pain Symptom Manage 2009;38:291-8 565
26. Rothrock NE, Jensen SE, Beaumont JL, Abernethy AP, Jacobsen PB, Syrjala K, 566
et al. Development and initial validation of the NCCN/FACT symptom index for 567
advanced kidney cancer. Value Health 2013;16:789-96 568
27. Pearman TP, Beaumont JL, Mroczek D, O'Connor M, Cella D. Validity and 569
usefulness of a single-item measure of patient-reported bother from side effects 570
of cancer therapy. Cancer 2018;124:991-7 571
28. Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et 572
al. The rapid assessment of fatigue severity in cancer patients: use of the Brief 573
Fatigue Inventory. Cancer 1999;85:1186-96 574
29. DL F. Design and Analysis of Quality of Life Studies in Clinical Trials. Boca 575
Raton, FL: Chapman & Hall/CRC; 2002. 576
30. GM F, N L, J W. Applied Longitudinal Analysis. New York, NY: John Wiley; 2004. 577
31. Revicki DA, Cella D, Hays RD, Sloan JA, Lenderking WR, Aaronson NK. 578
Responsiveness and minimal important differences for patient reported 579
outcomes. Health Qual Life Outcomes 2006;4:70 580
32. Butt Z, Peipert J, Webster K, Chen C, Cella D. General population norms for the 581
Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI). 582
Cancer 2013;119:429-37 583
33. Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. 584
Randomized phase II trial of sunitinib on an intermittent versus continuous dosing 585
schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 586
2012;30:1371-7 587
34. King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal 588
GM, et al. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy 589
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 19 of 23
registration trials: FDA analysis of data submitted and future directions. Clin 590
Trials 2019;16:322-6 591
592
593
594
595
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 20 of 23
TABLES 596
Table 1. Baseline characteristics in the ITT population 597
Characteristic Atezo + bev (n = 454)
Sunitinib (n = 461)
Age, mean (SD), years 62 (10) 60 (10)
Sex
Male 317 (70%) 352 (76%)
Female 137 (30%) 109 (24%)
Karnofsky Performance Status
< 80 40 (9%) 35 (8%)
80-90 242 (53%) 228 (49%)
100 172 (38%) 198 (43%)
MSKCC risk score
Favorable (0) 89 (20%) 90 (20%)
Intermediate (1 or 2) 311 (69%) 318 (69%)
Poor (≥ 3) 54 (12%) 53 (11%)
Disease PD-L1 expression
≥ 1% on IC 178 (39%) 184 (40%)
< 1% on IC 276 (61%) 277 (60%)
Predominant histology
Clear cell carcinoma 420 (93%) 425 (92%)
Sarcomatoid 22 (5%) 22 (5%)
Othera 12 (3%) 14 (3%)
Sarcomatoid differentiationb 68 (15%) 74 (16%)
Data are n (%) unless noted otherwise. Chi-square tests and t-tests for differences between arms were performed. 598 Each p-value was > 0.05, except for age and sex. 599 a Includes papillary, chromophobe, and oncocytoma. 600
b Any component of sarcomatoid differentiation regardless of predominant histology. 601
Reprinted from The Lancet, Rini BI, et al. 2019;393(10189):P2024-2415, Copyright 2019, with permission from 602 Elsevier. 603 Atezo, atezolizumab; bev, bevacizumab; IC, tumor-infiltrating immune cell; ITT, intent-to-treat; MSKCC, Memorial 604 Sloan Kettering Cancer Center; PD-L1, programmed death-ligand 1. 605
606
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 21 of 23
Table 2. Baseline PRO Scores 607
Atezo + beva Sunitiniba
MDASIb
Patients, n 364 345
MDASI core symptoms, mean (SD) 1.57 (1.59) 1.63 (1.70)
Pain 1.81 (2.66) 1.79 (2.53)
Fatigue 2.64 (2.79) 2.52 (2.59)
Nausea 0.71 (1.77) 0.79 (1.82)
Disturbed sleep 2.11 (2.64) 2.35 (2.83)
Distress 2.13 (2.63) 2.36 (2.77)
Shortness of breath 1.35 (2.18) 1.50 (2.24)
Difficulty remembering things 1.25 (1.94) 1.38 (2.09)
Lack of appetite 1.52 (2.62) 1.44 (2.46)
Drowsiness 2.04 (2.58) 2.01 (2.52)
Dry mouth 1.55 (2.49) 1.41 (2.23)
Sadness 2.08 (2.67) 2.10 (2.75)
Vomiting 0.37 (1.31) 0.40 (1.38)
Numbness or tingling 0.80 (1.73) 1.12 (2.13)
MDASI RCC symptoms 0.39 (0.79) 0.47 (0.96)
Mouth/throat sores 0.18 (0.74) 0.25 (0.92)
Rash or skin change 0.37 (1.11) 0.50 (1.41)
Headache 0.65 (1.51) 0.70 (1.52)
Diarrhea 0.34 (1.21) 0.43 (1.28)
MDASI Symptom Interference 1.82 (2.22) 1.84 (2.21)
General activity 1.93 (2.60) 1.79 (2.52)
Mood 1.79 (2.44) 1.97 (2.51)
Work (including around the house) 2.10 (2.83) 2.03 (2.69)
Relations with other people 1.37 (2.32) 1.43 (2.36)
Walking 1.82 (2.65) 1.72 (2.68)
Enjoyment of life 1.91 (2.71) 2.12 (2.79)
FKSI-19c
Patients, n 364 345
FKSI-19 total, mean (SD) 59.81 (9.83) 59.47 (9.44)
BFId
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 22 of 23
608
t-tests for differences between arms were performed. Each p-value was > 0.05. 609 a
Patients with non-missing baseline and ≥ 1 post-baseline PRO assessment for MDASI or FKSI-19 (atezo + bev, n = 610 373; sunitinib, n = 359) and BFI (atezo + bev, n = 389; sunitinib, n = 383). 611 b Higher scores indicated greater symptom severity or interference (range, 0-10). 612
c Higher scores indicated better HRQOL (range, 0-76); mean normative FKSI-19 total score for the US adult general 613
population is 59.8 (32). 614
d Higher scores indicated greater fatigue severity or interference (range, 0-10). 615
BFI, Brief Fatigue Inventory; FKSI-19, National Comprehensive Cancer Network Functional Assessment of Cancer 616 Therapy-Kidney Symptom Index; HRQOL, health-related quality of life; MDASI, MD Anderson Symptom Inventory; 617 PRO, patient-reported outcome; RCC, renal cell carcinoma; SD, standard deviation. 618
Patients, n 381 368
BFI fatigue severity, mean (SD) 2.98 (2.69) 3.08 (2.66)
BFI fatigue interference with daily life, mean (SD)
2.08 (2.38) 2.11 (2.23)
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Confidential | Not for distribution | Page 23 of 23
FIGURES 619
Figure 1. Mean change in individual symptom severity during first-line treatment as 620 assessed by the MDASI. Least-squares mean change from baseline up to end-of-treatment in 621 symptom severity reported by patients receiving atezolizumab plus bevacizumab versus the 622 sunitinib based on linear mixed-effects models. Score range for each MDASI symptom item is 0 623 (“not present”) to 10 (“as bad as you can imagine”). Symptoms are presented from largest 624 numeric increase to smallest numeric increase in the Atezo + bev arm. Reprinted from The 625 Lancet, Rini BI, et al. 2019;393(10189):P2024-2415, Copyright 2019, with permission from 626 Elsevier. 627 628 Figure 2. Mean change from baseline in symptom severity, symptom interference and 629 QOL by visit for patients randomized to atezolizumab plus bevacizumab versus sunitinib. 630 Data points are least-squares mean change from baseline. Error bars are standard errors and 631 are from a mixed-model repeated measures analysis. The number of patients at each timepoint 632 are those with a non-missing score with an evaluable questionnaire. A, MDASI core symptom 633 scale. B, MDASI RCC symptom scale. C, MDASI symptom interference scale. D, FKSI-19 total 634 scale. Score range was 0-10 for the MDASI scales and 0-76 for the FKSI-19 total scale. 635 636 Figure 3. Treatment side effect impact by visit for patients receiving atezolizumab plus 637 bevacizumab versus sunitinib. The patient’s perspective on overall side-effect burden was 638 captured by the GP5 item of the FKSI-19 scale for patients in the atezolizumab plus 639 bevacizumab arm versus the sunitinib arm. 640
641
Figure 4. Time to deterioration in symptom severity, symptom interference and QOL for 642 patients randomized to atezolizumab plus bevacizumab versus sunitinib. A, MDASI core 643 symptom scale. B, MDASI RCC symptom scale. C, MDASI symptom interference scale 644 (Reprinted from The Lancet, Rini BI, et al. 2019;393(10189):P2024-2415, Copyright 2019, with 645 permission from Elsevier). D, FKSI-19 total scale. 646
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Week
Me
an
Sc
ore
Ch
an
ge
Fro
m B
as
elin
e
± S
E in
Co
re S
ym
pto
ms
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
1.5
1.0
0.5
0.0
2.0Atezo + bevSunitinib
364 305 297 266 238 224 200 192 185
345 276 253 230 211 198 173 161 146
No. at risk
Atezo + bev
Sunitinib
169
131
↑ More severe compared with baseline
Figure 2A
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Week
Me
an
Sc
ore
Ch
an
ge
Fro
m B
as
elin
e
± S
E in
RC
C S
ym
pto
ms
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
1.5
1.0
0.5
0.0
2.0Atezo + bevSunitinib
↑ More severe compared with baseline
364 305 297 266 238 224 200 192 185
345 276 253 230 211 198 173 161 146
No. at risk
Atezo + bev
Sunitinib
169
131
Figure 2B
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Week
Me
an
Ch
an
ge
Fro
m B
as
elin
e
± S
E in
Sy
mp
tom
In
terf
ere
nc
e
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
1.5
1.0
0.5
0.0
2.0
364 305 297 266 238 224 200 192 185
345 276 253 230 211 198 173 161 146
No. at risk
Atezo + bev
Sunitinib
169
131
Atezo + bevSunitinib
↑ Greater interference compared with baseline
Figure 2C
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
0.0
-2.0
-4.0
-6.0
-8.0
364 305 297 266 238 223 200 191 185
345 276 253 230 210 198 173 161 146
169
131
Week
Me
an
Ch
an
ge
Fro
m B
as
elin
e
± S
E in
HR
QO
L
Figure 2D
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
No. at risk
Atezo + bev
Sunitinib
Atezo + bevSunitinib
↓ Worse HRQOL compared with baseline
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
454 222 183 149 45 16 5
4
279 94
461 137 108 76 30 13200 47
No. at risk
Atezo + bev
Sunitinib
Atezo + bev
Sunitinib
NE (16.4, NE)
5.6 (4.3, 6.9)
HR, 0.50 (95% CI: 0.40, 0.62)
Median time to deterioration, mo (95% CI)
Figure 4A
Dete
rio
rati
on
-Fre
e R
ate
in
MD
AS
I
Co
re S
ym
pto
m S
everi
ty (
%)
100
60
40
20
80
3 9 15 24186 12 21 27 300
0
Months
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
454 204 158 128 41 17 4
1
267 85
461 98 70 52 18 8163 32
No. at risk
Atezo + bev
Sunitinib
Atezo + bev
Sunitinib
13.9 (10.0, NE)
3.3 (2.8, 4.3)
HR, 0.45 (95% CI: 0.37, 0.55)
Median time to deterioration, mo (95% CI)
Figure 4B
Dete
rio
rati
on
-Fre
e R
ate
in
MD
AS
I
RC
C S
ym
pto
m S
everi
ty (
%)
100
60
40
20
80
3 9 15 24186 12 21 27 300
0
Months
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
454 196 154 128 35 12 3256 74
461 119 87 60 25 7 1178 38
No. at risk
Atezo + bev
Sunitinib
Atezo + bev
Sunitinib
11.3 (8.3, 17.5)
4.3 (3.1, 5.6)
HR, 0.56 (95% CI: 0.46, 0.68)
Median time to deterioration, mo (95% CI)
Dete
rio
rati
on
-Fre
e R
ate
in
MD
AS
I
Sym
pto
m In
terf
ere
nce (
%)
Figure 4C
100
60
40
20
80
3 9 15 24186 12 21 27 300
0
Months
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
454 96 67 50 12 4 2158 27
461 44 29 19 7 397 12
No. at risk
Atezo + bev
Sunitinib
Atezo + bev
Sunitinib
2.8 (2.1, 3.0)
1.5 (1.4, 2.1)
HR, 0.68 (95% CI: 0.58, 0.81)
Median time to deterioration, mo (95% CI)
Figure 4D
Dete
rio
rati
on
-Fre
e R
ate
in
FK
SI-
19 Q
uality
of
Lif
e (
%)
100
60
40
20
80
3 9 15 24186 12 21 27 300
0
Months
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838
Published OnlineFirst March 3, 2020.Clin Cancer Res Michael B. Atkins, Brian I. Rini, Robert J. Motzer, et al. treatment-naive metastatic renal cell carcinomaIMmotion151 trial: atezolizumab + bevacizumab vs sunitinib in Patient-reported outcomes from the phase 3 randomized
Updated version
10.1158/1078-0432.CCR-19-2838doi:
Access the most recent version of this article at:
Material
Supplementary
http://clincancerres.aacrjournals.org/content/suppl/2020/03/03/1078-0432.CCR-19-2838.DC1
Access the most recent supplemental material at:
Manuscript
Authoredited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been
E-mail alerts related to this article or journal.Sign up to receive free email-alerts
Subscriptions
Reprints and
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Permissions
Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)
.http://clincancerres.aacrjournals.org/content/early/2020/03/03/1078-0432.CCR-19-2838To request permission to re-use all or part of this article, use this link
Research. on June 13, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2838