1 Article type: Original Report - Clinical Cancer Research · 34 Georgetown-Lombardi Comprehensive Cancer Center 35 3800 Reservoir Road, NW 36 Washington, DC 20007 37 Phone: 202-687-2795

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

http://clincancerres.aacrjournals.org/


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





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





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





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





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





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





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





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





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





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





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





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





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





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





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



http://www.clinicalstudydatarequest.com/

https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx

http://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm

http://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm



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





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





registration trials: FDA analysis of data submitted and future directions. Clin 590

Trials 2019;16:322-6 591

592

593

594

595





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





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





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)





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







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




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




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




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







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




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)


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




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)


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




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)


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




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

[email protected] at

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



http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-19-2838

http://clincancerres.aacrjournals.org/content/suppl/2020/03/03/1078-0432.CCR-19-2838.DC1

http://clincancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]

http://clincancerres.aacrjournals.org/content/early/2020/03/03/1078-0432.CCR-19-2838


Documents

1 Article type: Original Report - Clinical Cancer Research · 34 Georgetown-Lombardi Comprehensive Cancer Center 35 3800 Reservoir Road, NW 36 Washington, DC 20007 37 Phone: 202-687-2795