Polatuzumab vedotin + obinutuzumab + lenalidomide in patients with relapsed/refractory follicular lymphoma: interim analysis of a phase Ib/II trial
Catherine Diefenbach,1 Brad Kahl,2 Lalita Banerjee,3 Andrew McMillan,4 Rod Ramchandren,5,6 Fiona Miall,7 Javier Briones,8 Raul Cordoba,9 Eva Maria Gonzalez-Barca,10 Carlos Panizo,11 Jamie Hirata,12 Naomi Chang,13 Lisa Musick,12 Pau Abrisqueta14
1Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA; 2Division of Oncology, Washington University, St Louis, MO, USA; 3Oncology Centre, Maidstone and Tunbridge Wells NHS Trust, Kent, UK; 4Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK; 5Division of Oncology, University of Tennessee, Knoxville, TN, USA; 6Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; 7Department of Haematology, University Hospitals of Leicester NHS Trust, Leicester, UK; 8Department of Hematology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; 9Fundación Jiménez Díaz, Madrid, Spain; 10Institut Català D'Oncologia, Barcelona, Spain; 11Clínica Universidad de Navarra, Pamplona, Spain; 12Genentech, Inc., South San Francisco, CA, USA; 13F. Hoffmann-La Roche Ltd, Mississauga, Canada; 14Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain
1 Catherine Diefenbach http://bit.ly/2JjV5Jn Disclosures
CD holds stock in Gilead Sciences; has a consulting/advisory role for Seattle Genetics, Bayer, Bristol-Myers Squibb, Genentech/Roche, and Merck; has received research funding from Seattle Genetics, Genentech, Incyte, LAM Therapeutics, Merck, Bristol-Myers Squibb, Millennium, and MEI Pharma. BK has a consulting/advisory role for Roche, Genentech, Celgene, AbbVie, Pharmacyclics, and Acerta Pharma; has received research funding from Genentech, Acerta Pharma, and BeiGene; has provided expert testimony for Genentech. LB has received travel/accommodation expenses from Novartis, Takeda, and Gilead Sciences. AM has received honoraria from Roche, Celgene, Novartis, MSD, Bristol-Myers Squibb, and Sandoz; has participated in speakers’ bureaus for Roche and Celgene; has received research funding from Pfizer; has received travel/accommodation expenses from Roche and Celgene. RR has a consulting/advisory role for Pharmacyclics, Genentech, Celgene and Bristol-Myers Squibb; has received research funding from Merck, Pharmacyclics, and Janssen; has received travel/accommodation expenses from Caris MPI. FM has received honoraria from, and has a consulting/advisory role with, Takeda and Roche; has received travel/accommodation expenses from Takeda, Roche, and Janssen. JB has received honoraria from Roche, Takeda, Novartis, and Gilead Sciences; has a consulting/advisory role with Takeda, Novartis, and Celgene; has participated in a speakers’ bureau for Roche; has received travel/accommodation expenses from Roche, Celnet, Janssen, and Gilead Sciences. RC has a consulting/advisory role for Celgene and Janssen; has participated in speakers’ bureaus for Janssen, Roche and Servier; has received travel/accommodation expenses from Janssen, Roche, and AbbVie. EG-B has a consulting advisory role for Celltrion, Janssen, Gilead Sciences, Sandoz, and Kyowa Hakko Kirin; has participated in speakers’ bureaus for Janssen, AbbVie, Takeda, and Roche; has received travel/accommodation expenses from AbbVie, Janssen, and Roche. CP has a consulting/advisory role with Roche and Johnson & Johnson; has received travel/accommodation expenses from Roche; has provided expert testimony for Takeda, Bristol-Myers Squibb, and Mundipharma. JH is an employee of Genentech and holds stock in Roche. NC is an employee of, and holds stock in Roche. LM is an employee of Genentech and holds stock in Roche. PA has received honoraria from Janssen, AbbVie, and Roche; has a consulting/advisory role with Janssen, AbbVie, and Roche; has participated in speakers’ bureaus for Janssen, AbbVie, and Roche; has received travel/accommodation expenses from Janssen and AbbVie.
Editorial assistance was provided by Angela Rogers of Gardiner-Caldwell Communications, Macclesfield, UK and funded by F. Hoffmann-La Roche Ltd
2 Catherine Diefenbach http://bit.ly/2JjV5Jn Background
• Polatuzumab vedotin (pola) is an antibody-drug conjugate (ADC) targeting CD79b expressed in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)1
MMAE inhibits microtubule Pola binds to cell-surface Binding to CD79b polymerization, disrupts cell division, antigen CD79b triggers internalization and triggers apoptosis
• In 2017, polatuzumab vedotin received Breakthrough Therapy Designation (BTD) and Priority Medicines (PRIME) designation by the FDA and EMA for R/R DLBCL
MMAE, monomethyl auristatin E; R/R, relapsed/refractory 1. Polson AG, et al. Blood 2007;110:616–23
3 Catherine Diefenbach http://bit.ly/2JjV5Jn Antitumor effects of Pola-G and Len-G
Pola-G was well tolerated and showed evidence Len-G showed promising results
of clinical activity in patients with R/R FL1 in patients with untreated FL2 %)
( 20 20 size
0 UENRNRPRPRNRPRPRCRPRPRPRNRPRPRCRCRCRPRCRPRPRCRUECRCRPDCRCRPRCR (%) size 0 tumor -20 tumor -20
-40 -40
-60 -60
-80 -80 Best response Tumor regression at end of -100 -100
induction
Change in from baseline Change in from baseline
• Pola-G-Len may further enhance antitumor response in R/R FL • Here, we report the safety and efficacy results from the interim analysis of this novel triplet combination3
G, obinutuzumab; Len, lenalidomide; Pola, polatuzumab vedotin; NR, not 1. Phillips T, et al. Blood 2016;128(suppl 22):abstr 622; 2. Morschhauser F, et al. reported; UE, unevaluable Blood 2018;132(suppl 1):abstr 446; 3. GO29834 (ClinicalTrials.gov: NCT02600897)
4 Catherine Diefenbach http://bit.ly/2JjV5Jn Study design Open-label, single-arm, phase Ib/II study in patients with R/R FL
DOSE ESCALATION Pola IV Pola: 1.4mg/kg or 1.8mg/kg (Day 1 of 28-day cycles 16) Obinutuzumab IV Len: 10mg, 15mg, or 20mg (Every 2 months for 24 Obinutuzumab (G): 1000mg Obinutuzumab IV months) (Days 1, 8, 15 of 28-day MAINTENANCE INDUCTION cycle 1 and day 1 of cycles 26) Len 10mg PO G-Len Pola-G-Len CR/PR/SD (Daily, days 121 of each RP2D Len PO 28-day cycle for 12 Pola: 1.4mg/kg (Daily, days 121 of each months) Len: 20mg 28-day cycle)
Primary efficacy endpoint: CR at EOI, as determined by the IRC on the basis of PET-CT scans (by Modified Lugano 2014 criteria)
EOI, end of induction; IRC, independent review committee; Len, lenalidomide; pola, polatuzumab vedotin
5 Catherine Diefenbach http://bit.ly/2JjV5Jn Study population
INCLUSION CRITERIA EXCLUSION CRITERIA
• Age ≥18 years • Grade 3b FL • R/R FL (Grade 1, 2, 3a) • Prior allogeneic stem cell transplant • At least one bi-dimensionally measurable lesion • Autologous stem cell transplant within 100 days prior ≥1.5cm in its longest dimension to Cycle 1, Day 1 • Histologically documented CD20-positive cells • Current Grade >1 peripheral neuropathy • ECOG PS 02 • History of resistance to lenalidomide • Inadequate hematologic, renal or liver function • Positive test for hepatitis (HBsAg, HBcAb, HCV)
ECOG PS, Eastern Cooperative Oncology Group Performance Status; HBcAb, hepatitis B virus core antibody; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus
6 Catherine Diefenbach http://bit.ly/2JjV5Jn Interim analysis population
Not at RP2D n=10 Dose-escalation population n=16 RP2D induction completed Safety-evaluable n=6 Efficacy-evaluable population population n=52 RP2D n=18 induction complete Dose-expansion n=12 population n=36 Ongoing induction treatment Median duration of follow up: 6 months n=24
Clinical cut-off date: 06 July 2018 RP2D, recommended Phase II dose
7 Catherine Diefenbach http://bit.ly/2JjV5Jn Baseline characteristics
Efficacy population Safety population Characteristic n=18 n=52 Median age, years (range) 58 (5368) 62 (3287) ECOG PS 0–1, n (%) 17 (94) 51 (98) Ann Arbor Stage III/IV, n (%) 17 (94) 46 (88) Bulky disease (≥7cm), n (%) 4 (22) 9 (17) FLIPI ≥3, n (%) 8 (44) 30 (58) Number of prior lines of treatment, n (%) 1 3 (17) 11 (21) 2 4 (22) 11 (21) ≥3 11 (61) 30 (58) Median prior lines of treatment (range) 3 (15) 3 (17) Refractory to last prior therapy1, n (%) 9 (50) 26 (50) Clinical cut-off date: 06 July 2018 1. Defined as no response or progression or relapse within 6 months of last anti-lymphoma therapy end date
8 Catherine Diefenbach http://bit.ly/2JjV5Jn Safety summary: all AEs
All AEs, n (%) n=52 Patients with at least one AE 52 (100) Grade 5 AEs 1 (2)1 Grade 34 AEs 39 (75) Serious AEs 21 (40) AEs leading to lenalidomide dose reduction 16 (31) AEs leading to lenalidomide dose interruption 27 (52) AEs leading to any drug discontinuation 8 (15)
Clinical cut-off date: 06 July 2018 1. Grade 5 AE: septic shock after progressive disease and new anti-lymphoma treatment (TAK-659, tyrosine kinase inhibitor)
9 Catherine Diefenbach http://bit.ly/2JjV5Jn Safety summary All grade AEs (≥10%)
All AEs All AEs n=52 n=52 n (%) n (%) Infections1 29 (56) Asthenia 8 (15) Neutropenia 27 (52) Cough 8 (15) Thrombocytopenia 19 (37) AST increased 7 (14) Infusion-related reaction 18 (35) Blood creatinine increased 7 (14) Pyrexia 18 (35) Constipation 7 (14) Anemia 17 (33) Decreased appetite 7 (14) Diarrhea 15 (29) Nausea 7 (14) Rash 11 (21) ALT increased 10 (19) Hypokalemia 6 (12) Fatigue 10 (19) Nasopharyngitis 6 (12) Peripheral neuropathy2 9 (17) Pruritis 6 (12)
Clinical cut-off date: 1. Infections presented as Systems Organ Class terms - all other AEs are reported by ‘preferred terms’; 2. Peripheral neuropathy standard 06 July 2018 MedDRA query included: peripheral motor neuropathy, peripheral sensory neuropathy, neuropathy peripheral, and paresthesia
10 Catherine Diefenbach http://bit.ly/2JjV5Jn Safety summary Grade 34 AEs (≥2 patients)
Grade 34 AEs n=52 n (%) Total number of patients with Grade 34 AEs 39 (75) Hematologic Neutropenia1 24 (46) Thrombocytopenia 9 (17) Anemia 6 (12) Febrile neutropenia 2 (4) Non-hematologic Infections2 6 (12)3 ALT increased 2 (4) Lipase increased 2 (4) Hypokalemia 2 (4) Tumor lysis syndrome 2 (4) Clinical cut-off date: 1. GCSF use reported in 24 (46%) patients; 2. Infections presented as Systems Organ Class terms - all other AEs are reported by ‘preferred 06 July 2018 terms’; 3. Lower respiratory tract infection (n=2), septic shock, epididymitis, cavernous sinus thrombosis, and urinary tract infection
11 Catherine Diefenbach http://bit.ly/2JjV5Jn Efficacy summary Interim analysis efficacy evaluable population (n=18)
End of induction response Modified Lugano 20141 Lugano 2014 n (%) INV IRC INV IRC
Objective response 16 (89) 16 (89) 16 (89) 16 (89)
Complete response 11 (61)2 12 (67)2 14 (78) 14 (78)
Partial response 5 (28) 4 (22) 2 (11) 2 (11)
Stable disease 1 (6) 1 (6) 1 (6) 1 (6)
Disease progression 0 0 0 0
Missing/not evaluable/not available 1 (6)3 1 (6)3 1 (6)3 1 (6)3
Clinical cut-off date: 06 July 2018; 1. Modified Lugano requires a negative bone marrow biopsy to confirm PET-CR and PET-PR must also meet CT-PR INV, investigator assessed; criteria; 2. CR downgraded to PR due to missing bone marrow biopsy in three patients by INV and two patients by IRC; IRC, independent review committee assessed 3. One patient had PR by CT (interim scan) but no PET at EOI performed before stem cell transplant
12 Catherine Diefenbach http://bit.ly/2JjV5Jn Updated follow up Interim analysis efficacy-evaluable population (n=18)
• Median duration of follow up: Duration of response 16.6 (3.2–25.1) months
• Median PFS: not reached
• 12-month PFS rate: 90%
• Of 17 responders, two patients have experienced disease progression to date
• The remaining patients have ongoing responses with the longest >21 months
Clinical cut-off date: 12 March 2019
13 Catherine Diefenbach http://bit.ly/2JjV5Jn Conclusions
• Polatuzumab vedotin with obinutuzumab and lenalidomide is tolerable
• The safety profile is consistent with the known profiles of the individual drugs; AEs were manageable with supportive care
• Response rates at the end of induction are promising, with high CR rates; 90% of patients remain progression free at 12 months
• This novel triplet combination has a potential place as therapy for patients with R/R follicular lymphoma
• The primary analysis will be presented at a future congress
14 Catherine Diefenbach http://bit.ly/2JjV5Jn Acknowledgments
• The authors would like to thank the participating patients and their families, and the study investigators and research staff
15 Catherine Diefenbach http://bit.ly/2JjV5Jn