Non-Hodgkin lymphoma State of the art of treatment Stephen M. - - PowerPoint PPT Presentation

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Non-Hodgkin lymphoma State of the art of treatment Stephen M. - - PowerPoint PPT Presentation

May 22, 2023 218 likes •482 views

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

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SLIDE 1

Non-Hodgkin lymphoma

State of the art of treatment

Stephen M. Ansell, MD, PhD Chair, Lymphoma Group Mayo Clinic

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SLIDE 2

Disclosures for Stephen Ansell, MD, PhD

N/A = Not Applicable (no conflicts listed)

Research Support/P.I. PI – Seattle Genetics, BMS, Affimed, Regeneron, Pfizer clinical trials Employee N/A Consultant N/A Major Stockholder N/A Speakers’ Bureau N/A Scientific Advisory Board N/A

In compliance with ACCME policy, Mayo Clinic requires the following disclosures to the activity audience:

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SLIDE 3

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
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SLIDE 4

Diffuse Large B-cell Lymphoma

Historical Frontline Outcomes Based on R-CHOP

Nowakowski et al. J Clin Oncol 2015;33:251–257.

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SLIDE 5

How can we improve on R-CHOP?

X-R-CHOP - M

Increase rituximab Substitute with different CD20 antibody Add novel agent (X) X-R-CHOP Intensify chemotherapy DA-EPOCH-R Add maintenance

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SLIDE 6
  • 1. Intensify Therapy –

Phase III study of R-CHOP vs DA-EPOCH-R

R-CHOP 6 cycles DA-EPOCH-R 6 cycles

Key eligibility criteria (N=524)

  • Age ≥18 years
  • Stage II or higher newly

diagnosed DLBCL (Stage I PMBCL)

  • ECOG PS 0–2
  • Fresh/frozen tumor biopsy (4

cores) R A N D O M I Z E 1:1

Wilson et al. ASH 2016. Abstract 469.

Study schema Event-free survival

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SLIDE 7

Presented By Thomas Witzig at 2016 ASCO Annual Meeting.

  • 2. Add maintenance therapy –

Everolimus - PILLAR-2

End points Primary

  • Disease-free survival (DFS): time from randomization to recurrence or death due to any

cause

Secondary

  • Overall Survival (OS): time from randomization to death due to any cause
  • 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)

Treatment for 1 year or until disease relapse, unacceptable toxicity, death,

  • r discontinuation of other reason

Study design: Adjuvant everolimus Disease-free survival

Randomization (1:1) Placebo PO daily for 1 year N=370 Everolimus 10 mg PO daily for 1 year N=372

Patients

  • Age ≥18 years
  • Stage 2 bulky disease,

stage 3, or stage 4 DLBCL

  • 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

N=742

Stratification by R-chemo

  • R-CHOP, n=725
  • R-EPOCH, n=17
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SLIDE 8
  • 3. Increase Rituximab dosing

HOVON Trial

R 1:1

DLBCL Stage II–IV 18–80 years (N = 575) R-CHOP14 R on D1 4 cycles Escalated rituxan R on D1 + D8 4 cycles

PET-CT PD off study

R-CHOP14 R on D1 4 cycles* Escalated rituxan R on D1 4 cycles*

R 1:1

12 x R maintenance at 8 weeks No R maintenance

PET-CT CR

Presented by: PJ Lugtenburg ASCO 2016.

Median follow up 52.7 months

Study design PFS

Escalated rituximab

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SLIDE 9
  • 4. Use a different anti-CD20 antibody

GOYA study

International, open-label, randomized, Phase III study in 1L DLBCL patients

  • Scientific support from the Fondazione Italiana Linfomi

Previously untreated DLBCL

  • Age ≥18 years
  • IPI ≥2 or IPI 1 not due to age

alone or IPI 0 with bulky disease (one lesion ≥7.5cm)

  • Adequate hematologic function
  • ≥1 bi-dimensionally measurable

lesion

  • ECOG PS ≤2
  • Target enrolment: 1,400

G-CHOP arm

G 1,000 mg C1 D1/8/15 and C2–8 D1 CHOP 6 or 8 cycles every 21 days

R-CHOP arm

R 375mg/m2 C1–8 D1 CHOP 6 or 8 cycles every 21 days

Randomized 1:1

  • Number of CHOP cycles pre-planned in advance for all patients at each site
  • Randomization stratification factors:
  • Planned number of CHOP cycles
  • IPI
  • Geographic region

Vitolo et al. ASH 2016. Abstract 470.

Kaplan–Meier plot of investigator-assessed PFS by treatment arm (primary endpoint)

1.0

  • No. of patients at risk

R-CHOP G-CHOP 712 706 616 622 527 540 488 502 413 425 227 240 142 158 96 102 41 39 6 2

R-CHOP (n=712) G-CHOP (n=706) 6 12 18 24 30 36 42 48 54 60

Probability

0.8 0.6 0.4 0.2

Time (months)

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SLIDE 10
  • 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)
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SLIDE 11
  • 5. Add Bortezomib to RCHOP

PYRAMID: Non-GCB DLBCL

Prospective randomized, open-label, Phase II study

Treatment-naïve, non-GCB DLBCL by Hans IHC with measurable disease, ECOG PS 0–2 (N=183)

Bortezomib 1.3 mg/m2 i.v. Days 1, 4 + R-CHOP* 21 days x 6 cycles (n = 92) R-CHOP* 21 days x 6 cycles (n = 91)

Leonard JP, et al. Blood 2015;126:811a. (Updated data presented in oral presentation at ASH annual meeting) VR-CHOP, bortezomib, rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone.

Limits:

  • Patient selection in the PYRAMID trial may have

played a role  R-CHOP alone produced better

  • utcomes than expected
  • IHC based on Hans algorithm

Patients at risk: R-CHOP VR-CHOP

PFS probability Time to event (months)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 5 10 15 20 25 30 35 50 55 60 65 70 75 40 45 91 92 72 75 65 72 61 66 57 61 50 51 37 38 28 27 5 7 2 2 2 1 22 24 15 13 Treatment group: Censored observations: R-CHOP VR-CHOP R-CHOP VR-CHOP R-CHOP (N=91) 25% Events VR-CHOP (N=92) 18%

  • 2-year PFS: 78% R-CHOP vs 82% VR-CHOP

– HR (95% CI): 0.73 (0.43–1.24); p=0.611 PFS Study design

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SLIDE 12

HR=0.841, p=0.225

74.3% 70.1% ITT population: GCB + ABC patients N=719

Median follow-up of surviving patients: 28.4 months

ABC: N=244 GCB: N=475 Unc.: N=199

Davies, et al. Presented at ICML 2017.

  • 5. Add Bortezomib to RCHOP

REMoDL-B Trial

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SLIDE 13

*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 to R-CHOP may

  • vercome the poor outcome of ABC type

Overall Survival by COO (IHC)

1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Alive 1 2 3 4 5 6 7 8 Years 10 20 30 40 50 60 70 80 90 100 % Alive

Censor Logrank P-value: 0.3327 71.7 (59.2-86.9%) 5 Years 15/45 GCB 75.3 (62.3-91.1%) 5 Years 9/40 Non-GCB KM Est (95% CI) Time-Point Events/Total COO

Randomized trial completed – awaiting results

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SLIDE 14

Adding Lenalidomide Maintenance therapy may improve outcome in DLBCL – REMARC

1:1 Random assignment

Placebo Lenalidomide Maintenance: 24 months Induction

R-CHOP 6 or 8 cycles

25 mg/d* for 21 of 28 days

CR PR

Registration 2 Registration 1

DLBCL

  • r other

aggressive B-cell lymphoma Age: 60–80yrs

*10 mg lenalidomide for patients with CrCl 30-60 mL/min

Thieblemont C, et al. J Clin Oncol 2017; 35:1–9.

Study design PFS OS

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SLIDE 15

Adding Ibrutinib to R-CHOP may

  • vercome 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

  • f DLBCL”.

Wilson et al. Nat Med. 2015 Aug;21(8):922-6. Younes et al. Lancet Oncol. 2014 Aug;15(9):1019-26.

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SLIDE 16

Overall Survival in Refractory DLBCL:

Historical Outcomes data – SCHOLAR-1

Crump et al. Blood 2017

  • N = 636
  • ORR = 26%; CR rate = 7%
  • Median OS = 6.3 months
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SLIDE 17

Immune checkpoint therapy (Nivolumab) is not very effective in de novo DLBCL

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SLIDE 18

Ding et al. Blood 2017; submitted

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

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SLIDE 19

Axicabtagene Ciloleucel (KTE-C19, Yescarta) Tisagenlecleucel (CTL019, Kymriah) Lisocabtagene maraleucel (JCAR017)

Company KITE Novartis Celgene/Juno Binding Domain (All Murine ScFv) FMC63 FMC63 FMC63 Indications DLBCL, TFL PMBCL,MCL, ALL, CLL NHL, ALL, CLL Adult NHL, Pediatric ALL, CLL Spacer Domain CD28 CD8𝛃 IgG4 hinge Transmembrane Domain CD28 CD8𝛃 CD28 Stimulatory Domain CD28-CD3𝜂 4-1BB-CD3𝜂 4-1BB-CD3𝜂 Starting Cell Population Selection None None CD4+ and CD8+ Final CD4/CD8 ratio Variable Variable 1:1 Ablation Technology None None EGFRt Viral Vector Gamma retrovirus Lentivirus Lentivirus

Anti-CD19 CAR T Products in Clinical Development

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SLIDE 20

CD19 CAR T NHL Trial Data

ZUMA-1 (Kite) JULIET (Novartis) Transcend (Juno)

Source Phase 2 Primary Analysis ASH 2017 Phase 2 Interim Analysis ASH 2017 Phase 1 Interim Analysis ASH 2017 Enrollment 111 enrolled; 101 dosed 160 enrolled; 99 dosed (81 evaluable for response) 140 enrolled; 108 dosed (4 pending) Population

  • 78% refractory; 0% relapsed
  • 22% post ASCT
  • 16% TFL; 8% PMCBL
  • 41% refractory; 59%

relapsed

  • 47% post ASCT
  • 19% TFL; 0% PMBCL
  • 67% refractory; 24% relapsed
  • 40% post ASCT
  • 21% TFL; 0% PMBCL

Efficacy

  • ORR: 82%; 54% CR
  • ITT ORR: 75%; 50% CR
  • Ongoing: 42%; 40% CR
  • Median follow-up 15.4 m
  • ORR: 53%; 40% CR
  • ITT ORR: 27%; 20% CR
  • Ongoing: 37%; 30% CR
  • Median follow-up 6 m
  • ORR: 74%; 52% CR
  • ITT ORR: 55%; 38% CR
  • Ongoing: 47%; 42% CR
  • Median follow-up 6 m

Safety*

  • G3+ CRS 13%
  • G3+ NE 28%
  • G5 AE 3%
  • G3+ CRS 23%
  • G3+ NE 12%
  • G5 AE X%
  • G3+ CRS 1%
  • G3+ NE 15%
  • G5 AE 4%

* Different grading scales are used to assess CRS, neurotoxicity across trials.

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SLIDE 21

Outcomes in refractory DLBCL: Historical vs. KTE-C19

Overall survival: SCHOLAR-1

Crump et al. Blood 2017

  • N = 636
  • ORR = 26%; CR rate = 7%
  • Median OS = 6.3 months

Neelapu et al, N Eng J Med 2017

Overall survival: KTE-C19

  • N = 108
  • ORR = 82%; CR rate = 58%
  • Median OS = >18 months
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SLIDE 22

Outcomes in refractory DLBCL: Historical vs. CTL019

Overall survival: SCHOLAR-1

Crump et al. Blood 2017

  • N = 636
  • ORR = 26%; CR rate = 7%
  • Median OS = 6.3 months

Schuster et al, N Eng J Med 2017

Overall survival: CTL019

  • N = 28
  • ORR = 53%; CR rate = 40%
  • Median OS = 22.2 months
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SLIDE 23

Outcomes in refractory DLBCL: Historical vs. JCAR017

Overall survival: SCHOLAR-1

Crump et al. Blood 2017

  • N = 636
  • ORR = 26%; CR rate = 7%
  • Median OS = 6.3 months

Abramson et al, ASH 2017

Overall survival: JCAR017

  • N = 68
  • ORR = 75%; CR rate = 53%
  • Median OS = 13.7 months
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SLIDE 24

State of the Landscape in Lymphoma

  • The ‘bar’ is high in DLBCL and it is difficult to improve in

unselected patients

  • Novel agents in combination with RCHOP look somewhat

promising

  • Immune checkpoint blockade may not be effective in most

lymphomas

  • CAR T-cell results look very encouraging