A Phase II Study of Atezolizumab With or Without Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma Patients Viktor Grünwald, 1 David McDermott, 2 Michael Atkins, 3 Robert Motzer, 4 Brian Rini, 5 Bernard Escudier, 6 Lawrence Fong, 7 Richard W. Joseph, 8 Sumanta Pal, 9 Mario Sznol, 10 John Hainsworth, 11 Walter M. Stadler, 12 Thomas Hutson, 13 Alain Ravaud, 14 Sergio Bracarda, 15 Cristina Suarez, 16 Toni Choueiri, 17 YounJeong Choi, 18 Mahrukh A. Huseni, 18 Gregg D. Fine, 18 Thomas Powles 19 1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Centre for Internal Medicine, Hannover Medical School, Germany; 2 Beth Israel Deaconess Medical Center, Boston, MA; 3 Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; 4 Memorial Sloan Kettering Cancer Center, New York, NY; 5 Cleveland Clinic, Cleveland, OH; 6 Gustave Roussy, Villejuif, France; 7 University of California, San Francisco School of Medicine, San Francisco, CA; 8 Mayo Clinic Hospital Florida, Jacksonville, FL; 9 City of Hope Comprehensive Cancer Center, Duarte, CA; 10 Yale School Of Medicine, New Haven, CT; 11 Sarah Cannon Research Institute, Nashville, TN; 12 University of Chicago Medicine, Chicago, IL; 13 Texas Oncology - Baylor Charles A. Sammons Cancer Center, Dallas, TX; 14 CHU Hopitaux de Bordeaux - Hôpital Saint-André, Bordeaux, France; 15 Ospedale San Donato, Arezzo, Italy; 16 Vall d Hebron Institute of Oncology, Vall d Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain; 17 Dana-Farber Cancer Institute, Boston, MA; 18 Genentech, Inc., South San Francisco, CA, USA; 19 Barts Cancer Institute, Queen Mary University of London, London, UK Presented at the Annual Meeting of the German, Austrian and Swiss Associations for Haematology and Medical Oncology, 01-Oct-2017, Stuttgart, Germany.
Disclosure of conflicts of interest 1. Appointment Medical School Hannover 2. Consultant BMS, MSD, Merck Kga, AZ, Eisai, Ipsen, Lilly, Pfizer, Ipsen, Eisai 3. Stocks none 4. Patent none 5. Honoraria Astra Zeneca, BMS, MSD, Merck Serono, Ipsen, Eisai, Novartis, EUSAPharm 6. Financial research support Pfizer (Wyeth), BMS, MSD, Novartis, AZ 7. Other financial support MSD, BMS
Cancer Immunity Cycle IL-2 Priming and activation Cancer antigen presentation Release of cancer cell antigens Trafficking of T cells to tumors Infiltration of T cells into tumors Recognition of cancer cells by T cells Killing of cancer cells Atezolizumab 1,2 Bevacizumab Immune therapy (high dose IL-2) is associated with long-term durable responses in patients with mrcc 3 Atezolizumab (anti PD-L1) monotherapy has demonstrated anti-tumor activity and tolerable safety in mrcc 1,4 Bevacizumab (VEGF inhibitor) + IFN-α-2a is approved for use in first-line mrcc 1. Herbst Nature 2014. 2 Chen Immunity 2013. 3. Yan JCO 2003. 4. McDermott JCO 2016. IL-2, interleukin-2. mrcc, metastatic renal cell carcinoma. Figure adapted from Chen Immunity 2013.
CD8 IHC Atezolizumab + Bevacizumab A Phase Ib study in first-line mrcc showed anti-tumor activity and a tolerable safety profile for atezolizumab + bevacizumab 1,2 Sequential tumor biopsies provided preliminary evidence of enhanced anti-tumor immune responses following treatment with bevacizumab and atezolizumab + bevacizumab 2 Pre-treatment Post bevacizumab Post atezolizumab + bevacizumab 1. Sznol, ASCO GU, 2015. 2. Wallin, Nat Commun, 2016. Figures reprinted from Wallin JJ, et al. Nat Commun. 2016;7:12624. The Authors 2016; licensed under a Creative Commons Attribution 4.0 International License.
IMmotion150 (Phase II) Trial Design Treatment naive, locally advanced or metastatic RCC N = 305 Stratification: Prior nephrectomy PD-L1 IHC expression ( 5% IC level) MSKCC risk category R 1:1:1 First-line treatment Atezolizumab 1200 mg IV + bevacizumab 15 mg/kg q3w Atezolizumab 1200 mg IV q3w Sunitinib 50 mg (4 wk on, 2 wk off) PD Crossover treatment permitted a Atezolizumab + bevacizumab Atezolizumab + bevacizumab The coprimary endpoints are PFS (RECIST v1.1 by IRF) in ITT and PD-L1+ patients IMmotion150 was designed to be hypothesis generating and inform the trial design of the Phase III study IMmotion151 Amendments included: Based on Phase 1a data, the definition of PD-L1 positivity was revised from 5% to 1% of IC expressing PD-L1 1 In addition to ITT patients, PD-L1+ patients were included in the coprimary endpoint of IRF-assessed PFS, after interim analyses IC, tumor-infiltrating immune cells; IRF, independent review facility. 1. McDermott JCO 2016. a Crossover from atezolizumab monotherapy not allowed in Europe.
Baseline Demographics (ITT) Sunitinib n = 101 Atezolizumab + bevacizumab n = 101 Atezolizumab n = 103 Age, median (range), y 61 (25-85) 62 (32-88) 61 (27-81) Male, n (%) 79 (78%) 74 (73%) 77 (75%) KPS 80, n (%) 94 (93%) 99 (99%) 101 (99%) Predominant clear cell histology, n (%) 96 (96%) 97 (96%) 95 (92%) Sarcomatoid component, n (%) 14 (14%) 15 (15%) 16 (15%) Prior nephrectomy, n (%) 88 (87%) 88 (87%) 89 (86%) MSKCC risk category, n (%) Favorable (0) 21 (21%) 30 (30%) 26 (25%) Intermediate (1 or 2) 70 (69%) 62 (61%) 69 (67%) Poor ( 3) 10 (10%) 9 (9%) 8 (8%) 1% of IC expressing PD-L1 (PD-L1+), n (%) 60 (59%) 50 (50%) 54 (52%) Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 20.7 mo.
IRF-Assessed PFS ITT Atezolizumab + bevacizumab Atezolizumab Sunitinib Atezo + bev vs sunitinib Atezo vs sunitinib Stratified HR (95% CI) 1.00 (0.69, 1.45) 1.19 (0.82, 1.71) P Value a 0.982 0.358 Atezo, atezolizumab; Bev, bevacizumab. a P values are for descriptive purposes only and not adjusted for multiple comparisons.
IRF-Assessed PFS ITT Atezolizumab + bevacizumab Atezolizumab Sunitinib Atezo: 6.1 mo (5.4, 13.6) Sunitinib: 8.4 mo (7.0, 14.0) Atezo + bev: 11.7 mo (8.4, 17.3) Atezo + bev vs sunitinib Atezo vs sunitinib Stratified HR (95% CI) 1.00 (0.69, 1.45) 1.19 (0.82, 1.71) P Value a 0.982 0.358 a P values are for descriptive purposes only and not adjusted for multiple comparisons.
IRF-Assessed PFS 1% of IC Expressing PD-L1 Atezolizumab + bevacizumab Atezolizumab Sunitinib Atezo + bev vs sunitinib Atezo vs sunitinib Stratified HR (95% CI) 0.64 (0.38, 1.08) 1.03 (0.63, 1.67) P Value a 0.095 0.917 a P values are for descriptive purposes only and not adjusted for multiple comparisons.
IRF-Assessed PFS 1% of IC Expressing PD-L1 Atezolizumab + bevacizumab Atezolizumab Sunitinib Atezo: 5.5 mo (3.0, 13.9) Sunitinib: 7.8 mo (3.8, 10.8) Atezo + bev: 14.7 mo (8.2, 25.1) Atezo + bev vs sunitinib Atezo vs sunitinib Stratified HR (95% CI) 0.64 (0.38, 1.08) 1.03 (0.63, 1.67) P Value a 0.095 0.917 a P values are for descriptive purposes only and not adjusted for multiple comparisons.
IRF-Assessed PFS in Key Subgroups Atezolizumab + Bevacizumab vs Sunitinib Sarcomatoid Liver metastasis MSKCC risk IC expressing PD-L1 Baseline Factor Yes No Yes No Favorable Intermediate Poor < 1% 1% and < 5% 5% and < 10% 10% All patients (ITT) n 29 171 48 154 51 132 19 89 76 22 12 202 0.23 0.50 0.63 0.82 0.75 0.98 0.91 0.87 0.92 1.22 1.06 1.47 Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 20.7 mo. In favor of atezo + bev In favor of sunitinib 1 Hazard Ratio
IRF-Assessed PFS in Key Subgroups Atezolizumab vs Sunitinib Sarcomatoid Liver metastasis MSKCC risk IC expressing PD-L1 Baseline Factor Yes No Yes No Favorable Intermediate Poor < 1% 1% and < 5% 5% and < 10% 10% All patients (ITT) n 30 172 46 158 47 139 18 83 80 22 12 204 0.53 0.48 0.86 0.68 1.00 1.12 1.15 1.08 1.10 1.54 1.30 1.26 Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 20.7 mo. Hazard Ratio In favor of atezo In favor of sunitinib 3.5
Confirmed IRF-Assessed ORR ITT 1% of IC expressing PD-L1 46% 29% 32% 25% 27% 28% PR 5% 7% 11% 7% 12% 15% CR 75% of responses are ongoing across treatment arms, and the median DOR is not estimable due to an insufficient number of PFS events in responders Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 20.7 mo.
Safety Summary n (%) Sunitinib n = 100 Median treatment duration (range), mo 6.7 (0.1-33.1) Atezolizumab + Bevacizumab n = 101 Atezo: 11.8 (0.7-32.7) Bev: 10.3 (0.0-29.8) Atezolizumab n = 103 7.6 (0.0-33.1) All-Grade AEs, any cause 99 (99%) 101 (100%) 101 (98%) Treatment-related AE 96 (96%) 91 (90%) 86 (83%) Grade 3-4 AEs, any cause 69 (69%) 64 (63%) 41 (40%) Treatment-related Grade 3-4 AEs 57 (57%) 40 (40%) 17 (17%) AEs leading to death a 2 (2%) 3 (3%) 2 (2%) Treatment-related AEs leading to death a 2 (2%) 1 (1%) 0 AEs leading to withdrawal from treatment 10 (10%) 15 (15%) 7 (7%) Treatment-related AEs leading to withdrawal from treatment 9 (9%) 9 (9%) 3 (3%) AEs leading to dose modification or interruption 70 (70%) 61 (60%) 28 (27%) a Sunitinib arm: sudden death (related), intestinal hemorrhage (related). Atezolizumab arm: hematophagic histiocytosis, lower respiratory tract infection. Atezolizumab + bevacizumab arm: intracranial hemorrhage (related), hemorrhage, pneumonia. Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 20.7 mo.
All-Cause AEs > 5% difference between arms and at a 20% frequency in either arm Fatigue Diarrhea Nausea Palmar-plantar Mucosal inflammation Dysgeusia Decreased appetite Cough Stomatitis Headache Arthralgia Rash Epistaxis Pyrexia Pruritus Proteinuria 80% Atezolizumab + Bevacizumab All-Grade AEs Grade 3-5 AEs Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 20.7 mo. Sunitinib All-Grade AEs Grade 3-5 AEs 60% 40% 20% 0 20% 40% 60% 80%
All-Cause AEs > 5% difference between arms and at a 20% frequency in either arm Fatigue Diarrhea Nausea Palmar-plantar Hypertension Mucosal inflammation Constipation Dysgeusia Decreased appetite Stomatitis Headache Vomiting Rash Pyrexia 80% All-Grade AEs Grade 3-5 AEs Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 20.7 mo. Atezolizumab Sunitinib All-Grade AEs Grade 3-5 AEs 60% 40% 20% 0 20% 40% 60% 80%
Conclusions Atezolizumab + bevacizumab resulted in encouraging efficacy vs sunitinib in the PD-L1+ subgroup of first-line mrcc patients IRF-assessed PFS HR = 0.64 (95% CI, 0.38, 1.08) Median PFS = 14.7 mo with atezolizumab + bevacizumab and 7.8 mo with sunitinib The clinical benefit of atezolizumab + bevacizumab vs sunitinib will be evaluated in the ongoing Phase III study (IMmotion151; NCT02420821) The data corroborate the clinical activity of atezolizumab monotherapy in first-line mrcc 1 ITT: ORR 25%, CR 11%; PD-L1+: ORR 28%, CR 15% (IRF assessment) Safety in the atezolizumab arm and the atezolizumab + bevacizumab arm was consistent with previous data of each drug alone After first-line treatment, 78% of sunitinib and 60% of atezolizumab patients who progressed subsequently received atezolizumab + bevacizumab. Analysis of crossover treatment is currently ongoing 1. Herbst Nature 2014.
Acknowledgments The patients and their families The investigators and clinical study sites Christina Schiff, MD, medical monitor, Jiaheng Qiu, PhD, study statistician and Alpa Thobhani, MSc, clinical development scientist This study is sponsored by F. Hoffmann-La Roche, Ltd Medical writing for this presentation was provided by Jessica Bessler, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.