Non-Hodgkin lymphoma State of the art of treatment Stephen M. Ansell, MD, PhD Chair, Lymphoma Group Mayo Clinic
Disclosures for Stephen Ansell, MD, PhD In compliance with ACCME policy, Mayo Clinic requires the following disclosures to the activity audience: PI – Seattle Genetics, BMS, Affimed, Regeneron, Research Support/P.I. Pfizer clinical trials Employee N/A Consultant N/A Major Stockholder N/A Speakers ’ Bureau N/A Scientific Advisory Board N/A N/A = Not Applicable (no conflicts listed)
Lessons Learned So Far • Improving on R-CHOP is proving difficult • Immune Checkpoint Therapies are not as effective as expected • CAR T-cell approaches look very promising
Diffuse Large B-cell Lymphoma Historical Frontline Outcomes Based on R-CHOP Nowakowski et al. J Clin Oncol 2015;33:251 – 257.
How can we improve on R-CHOP? Increase Substitute with different rituximab CD20 antibody Add X-R-CHOP - M maintenance Add novel Intensify agent (X) chemotherapy X-R-CHOP DA-EPOCH-R
1. Intensify Therapy – Phase III study of R-CHOP vs DA-EPOCH-R Study schema Event-free survival R A Key eligibility criteria R-CHOP N (N=524) 6 cycles • Age ≥18 years D • Stage II or higher newly O M diagnosed DLBCL (Stage I 1:1 I PMBCL) • ECOG PS 0 – 2 Z • Fresh/frozen tumor biopsy (4 E DA-EPOCH-R cores) 6 cycles Wilson et al. ASH 2016. Abstract 469 .
2. Add maintenance therapy – Everolimus - PILLAR-2 Study design: Adjuvant everolimus Disease-free survival Everolimus Patients 10 mg PO daily • Age ≥18 years for 1 year • Stage 2 bulky disease, N=372 stage 3, or stage 4 DLBCL Randomization (1:1) • Poor risk (IPI, 3-5) • First-line therapy with R-chemo (5-8 cycles) • PET confirmed CR to first-line R-chemo • ECOG PS 0-2 Placebo PO daily for 1 year N=370 N=742 Stratification by R-chemo • R-CHOP, n=725 End points • R-EPOCH, n=17 Primary • Disease-free survival (DFS): time from randomization to recurrence or death due to any cause Treatment for 1 year or until disease Secondary relapse, unacceptable toxicity, death, • Overall Survival (OS): time from randomization to death due to any cause or discontinuation of other reason • Lymphoma-specific survival (LSS): time from randomization to death due to lymphoma • Safety Exploratory • DFS and OS by subgroups: IPI (3 vs 4+5); Gender (male vs female); Age (<65 vs ≥65 years); Tumor type (GCB vs non-GCB vs other); Race (Caucasian vs Asian vs other) Presented By Thomas Witzig at 2016 ASCO Annual Meeting.
3. Increase Rituximab dosing HOVON Trial Study design PFS DLBCL R-CHOP14 R-CHOP14 Stage II – IV R on D1 R on D1 18 – 80 years No R 4 cycles* 4 cycles (N = 575) maintenance Escalated rituximab PET-CT R PET-CT PD off R CR 1:1 study 1:1 12 x R Escalated Escalated maintenance rituxan rituxan at 8 weeks R on D1 + D8 R on D1 4 cycles 4 cycles* Median follow up 52.7 months Presented by: PJ Lugtenburg ASCO 2016.
4. Use a different anti-CD20 antibody GOYA study International, open-label, randomized, Phase III study in 1L DLBCL patients Kaplan – Meier plot of investigator-assessed PFS by • Scientific support from the Fondazione Italiana Linfomi treatment arm (primary endpoint) 1.0 0.8 G-CHOP arm Previously untreated DLBCL G 1,000 mg C1 D1/8/15 and C2 – 8 D1 • Age ≥18 years CHOP 6 or 8 cycles every 21 days • IPI ≥ 2 or IPI 1 not due to age 0.6 alone or IPI 0 with bulky disease Probability (one lesion ≥ 7.5cm) Randomized 1:1 • Adequate hematologic function • ≥1 bi -dimensionally measurable 0.4 lesion R-CHOP arm • ECOG PS ≤2 R 375mg/m 2 C1 – 8 D1 • Target enrolment: 1,400 CHOP 6 or 8 cycles every 21 days 0.2 R-CHOP (n=712) G-CHOP (n=706) 0 0 6 12 18 24 30 36 42 48 54 60 • Number of CHOP cycles pre-planned in advance for all patients at each site Time (months) • Randomization stratification factors: No. of patients at risk R-CHOP 712 616 527 488 413 227 142 96 41 6 • Planned number of CHOP cycles G-CHOP 706 622 540 502 425 240 158 102 39 2 • IPI • Geographic region Vitolo et al. ASH 2016. Abstract 470.
5. Add New Drugs to RCHOP XR-CHOP • What X? • Bortezomib: Bor-RCHOP (Phase III – Pyramid/ReModel) • Ibrutinib: IR-CHOP (Phase III - Phoenix) • Everolimus: EveR-CHOP (Phase Ib) • Lenalidomide: R2-CHOP (Phase III – Robust, Intergroup)
5. Add Bortezomib to RCHOP PYRAMID: Non-GCB DLBCL Study design PFS Prospective randomized, open-label, Phase II study 1.0 0.9 0.8 Bortezomib 1.3 mg/m 2 i.v. Days 1, 4 + 0.7 Treatment-naïve, R-CHOP* 21 days x 6 cycles PFS probability non-GCB DLBCL 0.6 (n = 92) by Hans IHC with measurable disease, 0.5 ECOG PS 0 – 2 0.4 (N=183) 0.3 R-CHOP* 21 days x 6 cycles R-CHOP VR-CHOP 0.2 (n = 91) (N=91) (N=92) Treatment group: Censored observations: 25% 18% 0.1 Events R-CHOP VR-CHOP R-CHOP VR-CHOP 0.0 Limits: 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Time to event (months) • Patient selection in the PYRAMID trial may have Patients at risk: R-CHOP 91 72 65 61 57 50 37 28 22 15 5 2 0 0 0 0 played a role R-CHOP alone produced better VR-CHOP 92 75 72 66 61 51 38 27 24 13 7 2 2 1 0 0 outcomes than expected • IHC based on Hans algorithm • 2-year PFS: 78% R-CHOP vs 82% VR-CHOP – HR (95% CI): 0.73 (0.43 – 1.24); p=0.611 VR-CHOP, bortezomib, rituximab, cyclophosphamide, Leonard JP, et al. Blood 2015;126:811a. hydroxydaunorubicin, vincristine, prednisone. (Updated data presented in oral presentation at ASH annual meeting)
5. Add Bortezomib to RCHOP REMoDL-B Trial ITT population: GCB + ABC patients N=719 ABC: N=244 GCB: N=475 74.3% 70.1% HR=0.841, p=0.225 Unc.: N=199 Median follow-up of surviving patients: 28.4 months Davies, et al. Presented at ICML 2017.
Adding Lenalidomide to R-CHOP may overcome the poor outcome of ABC type Overall Survival by COO (IHC) 100 100 90 90 80 80 70 70 60 60 % Alive % Alive 50 50 40 40 30 30 20 20 COO Events/Total Time-Point KM Est (95% CI) Non-GCB 9/40 5 Years 75.3 (62.3-91.1%) 10 10 GCB 15/45 5 Years 71.7 (59.2-86.9%) Logrank P-value: 0.3327 Censor 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 Years Years Randomized trial completed – awaiting results *As defined by Hans et al. Blood 2004;103:275 – 282. Nowakowski et al. J Clin Oncol 2015;33:251 – 257. Castellino et al. ASCO 2018
Adding Lenalidomide Maintenance therapy may improve outcome in DLBCL – REMARC Study design PFS OS Induction Maintenance: 24 months Lenalidomide Random assignment DLBCL or other R-CHOP 25 mg/d* for 21 of 28 days aggressive 1:1 6 or 8 B-cell cycles lymphoma Age: 60 – 80yrs Placebo CR PR *10 mg lenalidomide for patients with Registration 1 Registration 2 CrCl 30-60 mL/min Thieblemont C, et al. J Clin Oncol 2017; 35:1 – 9 .
Adding Ibrutinib to R-CHOP may overcome the poor outcome of ABC type Phase Ib trial of ibrutinib + RCHOP • 33 patients • Combination was well tolerated • ORR – 91% • CR rate – 70% • No clear difference by COO • Randomized trial completed – “ did not meet the primary endpoint of EFS in patients with non-GCB subtype of DLBCL, including ABC subtype of DLBCL”. Wilson et al. Nat Med. 2015 Aug;21(8):922-6. Younes et al. Lancet Oncol. 2014 Aug;15(9):1019-26.
Overall Survival in Refractory DLBCL: Historical Outcomes data – SCHOLAR-1 • N = 636 • ORR = 26%; CR rate = 7% • Median OS = 6.3 months Crump et al. Blood 2017
Immune checkpoint therapy (Nivolumab) is not very effective in de novo DLBCL
Modest ORR in Indolent lymphoma patients receiving pembrolizumab. • 23 patients • ORR in follicular patients – 11% (2/18) • ORR in WM/MZL patients – 40% (2/5 - MR) • 11 patients had stable disease Ding et al. Blood 2017; submitted
Anti-CD19 CAR T Products in Clinical Development Axicabtagene Ciloleucel Tisagenlecleucel Lisocabtagene (KTE-C19, Yescarta) (CTL019, Kymriah) maraleucel (JCAR017) Company KITE Novartis Celgene/Juno Binding Domain FMC63 FMC63 FMC63 (All Murine ScFv) Indications DLBCL, TFL PMBCL,MCL, NHL, ALL, CLL Adult NHL, Pediatric ALL, ALL, CLL CLL Spacer Domain CD28 CD8 𝛃 IgG4 hinge Transmembrane Domain CD28 CD8 𝛃 CD28 CD28-CD3 𝜂 4-1BB-CD3 𝜂 4-1BB-CD3 𝜂 Stimulatory Domain Starting Cell Population None None CD4+ and CD8+ Selection Final CD4/CD8 ratio Variable Variable 1:1 Ablation Technology None None EGFRt Viral Vector Gamma retrovirus Lentivirus Lentivirus
Recommend
More recommend
