2020 year in review: diffuse large b-cell lymphoma

Sonali M. Smith, MD FASCOElwood V. Jensen Professor of MedicineChief, Section of Hematology/Oncology

Co-Leader Cancer Service Line

2020 Year in Review: Diffuse large B-cell lymphoma

and Hodgkin lymphoma

Overview: Five parts • Diffuse large B-cell lymphoma (high-risk, relapsed/refractory)

– Shifting role of CAR-T – Management options for non-transplant/non-CAR-T patients

• Hodgkin lymphoma

– Frontline management for advanced stage disease – Post-transplant consolidation – Relapsed/refractory disease

Courtesty of Sonali M Smith, MD

HIGH-RISK OR R/R DLBCL


Many subsets of DLBCL are not cured with R-CHOP

Curability

High IPIElderlyNon-GC phenotypeDouble hit lymphomaDual protein overexpression

R-CHOP

Low IPILow stageGC phenotype

Time to move beyond R-CHOP for

all

Key challenges: • Increase number of patients

cured with 1L treatment

• Improve options for patients 2L+


Crump M, et al. Blood. 2017;130:1800-1808

Expected survival for R/R DLBCL Treated with Salvage Chemotherapy

Patients unable to undergo autologous stem cell transplant have median survivals < 1 year


Adapted from van der Steegan et al. Nat Rev Drug Discov, 2015

CD19 Directed CAR T Cell Products in Clinical Development

Axi-cel Tisa-cel Liso-cel


Liso-cel (TRANSCEND NHL-001)

Duration of Response Progression-free survivalOverall Survival

Key patient features: 269 of 344 pts received product42% over age 65y 67% chemo-refractory 7 pts with secondary CNSL

Abramson JS et al. Lancet. 2020 Sep 19;396(10254):839-852 Courtesty of Sonali M Smith, MD

Matching-Adjusted Indirect Comparison (MAIC) of Liso-cel vs Axi-celand Tisagenlecleucel in R/R Large B-Cell Lymphoma

Is there a “best-in-class” CAR-T product?

Cartron G et al. ASH 2020; Abstract 2116 Courtesty of Sonali M Smith, MD

Liso-cel vs. Axi-cel and Liso-cel vs. Tisa-cel

Cartron G et al. ASH 2020; Abstract 2116

• Pairwise matching-adjusted comparison study with matching and then adjustment of ZUMA-1, TRANSCEND, JULIET

• Better safety and comparable efficacy: liso-cel versus axi-cel• Better efficacy and comparable safety: liso-cel versus tisa-cel


Multivariate analyses of JULIET trial:

• high levels of pre-infusion LDH associated with NRs at month 3 as well as worse PFS and OS

• Pre-infusion Grade 3/4 thrombocytopenia

• analyses suggest that a subset of pts with aggressive disease at infusion and/or pts with severe CRS/NE had poorer outcomes in the JULIET trial

Can we identify non-responders vs. responders?

Westin JR et al. ASH 2019; Abstract 4103.Schuster SJ et al. N Engl J Med. 2019 Jan 3;380(1):45-56

JULIET Trial


Interim Analysis of ZUMA-12 Trial of Axi-cel as First-Line Therapy for Patients with High-Risk Large B-Cell Lymphoma

Moving CAR T-cell therapy earlier: high-risk DLBCL

Neelapu SS et al. ASH 2020; Abstract 405

Med f/u 9.5m

Are CAR-T cells “better” if utilized earlier?

• Higher frequency of CCR7+CD45RA+ T-cells

• Greater CAR-T cell expansion


Impact of CAR-T in high-risk and R/R DLBCL Impact on Patient Care and Treatment Algorithm• There soon will be three anti-CD19 CAR-T products available: axi-cel, liso-cel, and tisa-cel, with

an approximately 30-40% rate of durable remissions in 3L DLBCL

• Liso-cel appears to have more favorable toxicity profile

• Identifying predictors of response/non-response is key

Implications for Future Research• If toxicity can be minimized, is outpatient CAR-T coming soon? Can CAR-T be safely delivered

in the community?

• Early identification of chemoresistance may allow CAR-T to be utilized earlier in the treatment paradigm


OPTIONS FOR NON-CAR-T/NON-TRANSPLANT CANDIDATES


Selinexor: oral XPO1 inhibitor


SADAL: phase 2 trial of selinexor monotherapy in R/R DLBCL

Patient characteristics: N=127 with med age 67y45% of pts > 70y72% refractory to last regimen

Results: ORR 28%CR 12%Med DR 9.3m

--med DR for CR pts 23m--med DR for PR pts 4.4m

No impact of COO

Kalakonda N et al. Lancet Haematol 2020;7(7):e511-22. Courtesty of Sonali M Smith, MD

Tafasitamab MOA

Salles et al. ICML 2019. #124.Hortonet al., 2008; Awanet al., 2010; Richter et al., 2013; MorphoSys data on file; Wu et al., 2008; Lapalombella et al., 2008; Zhang et al., 2013, Wiernik et al., 2008; Witzig et al., 2011; Czuczman et al., 2017; Jurczak et al, 2018

L-MIND trial: phase 2 trial of tafa-len x 12 cycles in R/R DLBCL

Tafasitamab


L-MIND Results: very long response duration for CR pts

Salles G et al. Lancet Oncol. 2020 Jul;21(7):978-988

PFS All responders

OS All pts

PFS All pts

DR

Patient characteristics: N=81 with med age 72y50% of pts 2L42% R-ref, 44% ref

Results: ORR 60%, CR 43% Med DR 22m but NR for CR pts


ASH 2020: Advent of Bispecifics in Lymphoma • CD20 x CD3

• REGN1979 — Bannerji ASH 2020 #400• Mosunetuzumab — Olszewski ASH 2020 #401• Epcoritamab — Hutchings ASH 2020 #402• Glofitamab — Hutchings ASH 2020 #403

• CD19 x CD3• MB-CART2019.1 — Borchman ASH 2020 #404


Expanding options for non-CAR-T/non-transplant patientswith R/R DLBCL Impact on Patient Care and Treatment Algorithm• There are now three new approved non-CAR-T regimens for R/R DLBCL • There are no data on sequencing

• Responses seem durable

Implications for Future Research• Bispecifics are coming soon! • Patient selection for “aggressive” vs. “non-aggressive” treatment is needed


HODGKIN LYMPHOMA


Snapshot of frontline standard treatment approach prior to targeted agents

RAPID NEJM 2015CALGB 50604 Blood 2018

IA, IIA

IIB, IIX

III, IV

Non-PET adapted

PET-adapted

Non-PET adapted

PET-adapted

ABVD2 + IFRT 20GyABVD4-6

ABVD6Stanford VescBEACOPP

RATHL NEJM 2016S0816 JCO 2016


Evolution of care: two “new” targets

http://pleiad.umdnj.edu/~dweiss/hd_types/hdImmuno_img.html

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 372;4 nejm.org january 22, 2015318

light the importance of the PD-1 immune eva-sion pathway and the genetically defined sensi-tivity to PD-1 blockade in this disease.

Supported by Bristol-Myers Squibb, by grants from the Na-tional Institutes of Health (U54CA163125 and P01AI056299, to Dr. Freeman; and R01CA161026, to Dr. Shipp), and by a grant from the Miller Fund (to Dr. Shipp).

Dr. Ansell reports receiving grant support from Seattle Genet-ics, Celldex Therapeutics, Millennium, Idera, and Regeneron; Dr. Lesokhin, receiving consulting fees and grant support from Bristol-Myers Squibb; Dr. Halwani, receiving grant support from Seattle Genetics, Millennium, Kyowa Hakko Kirin, AbbVie, Genentech, and Bristol-Myers Squibb; Dr. Freeman, receiving royalties from patents related to PD-1, PD-L1, and PD-L2 pathways (US 6808710, US 6936704, US 7038013, US7101550, US 7432059,

chr9:5,270,000PDL1 PDL2

chr9:5,700,000

100 kb

PDL1/2 Gain PDL1/2 Amplification

RP11-599H20 RP11-635N21

A

D

B

C

PD-L

2/pS

TAT3

PD-L

1/PA

X5

CEP9PD-L1PD-L2

12345678910

Cytogenetic Alterations

NuclearpSTAT3

EBERIHC-positiveHRS cells

Patient No.

PDL1/2Gain

PDL1/2Amplification

PD-L2PD-L1Polysomy9p

++++++++––

++++++++++

++++++++++

++++++++++

–––++++++–

––––––++++

–––––+––––

Figure 2. Genetic and Immunohistochemical Analyses of PDL1 and PDL2 Loci, PD-L1 and PD-L2 Protein Expression, and Epstein–Barr Virus Status in Patients with Hodgkin’s Lymphoma.

Shown are the results of analyses of the PDL1 and PDL2 loci and PD-L1 and PD-L2 protein expression in Reed–Sternberg cells. Panel A shows the location and color labeling of bacterial artificial chromosome clones used for the fluorescence in situ hybridization (FISH) assay for PDL1 (red) and PDL2 (green) on chromosome 9p24.1. Representative images obtained from patients show a copy-number gain in PDL1 and PDL2 (Panel B, left), with six green–red (yellow over-lap) signals (signifying a fusion signal), as compared with three centromeric signals (aqua), or PDL1 and PDL2 amplification (Panel B, right), with more than three times as many green–red (yellow overlap) sig-nals as centromeric signals (aqua). In Panel C, the ex-pression of PD-L1 (upper row) and PD-L2 (lower row) is indicated by brown staining in Reed–Sternberg cells obtained from the same patients as in Panel B. Arrows indicate malignant cells. PD-L1 is evaluated in con-junction with PAX5 to identify PAX5-positive cells (shown in red in the upper row). PD-L2 is assessed in association with phosphorylated signal transducer and activator of transcription 3 (pSTAT3), which reflects Janus kinase–STAT activation (shown in red in the lower row). The scale bars represent 50 µm. Panel D shows PD-L1 and PD-L2 protein expression and status with respect to Epstein–Barr virus–encoded messen-ger RNA (EBER) in study patients who could be evalu-ated. All the patients who were included in the analy-sis had structural bases for increased copy numbers in PDL1 and PDL2 on chromosome 9p24.1, including ex-tra copies of 9p (polysomy 9p), copy gain in PDL1 or PDL2, or amplification in PDL1 or PDL2 (Table S2 and Fig. S2 in the Supplementary Appendix). Epstein–Barr virus status was evaluated by means of a FISH assay. HRS denotes Hodgkin’s Reed–Sternberg, and IHC im-munohistochemical.

The New England Journal of Medicine Downloaded from nejm.org at University of Chicago Library on August 16, 2019. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Ansell et al. N Engl J Med. 2015 Jan 22;372(4):311-9; Younes et al. J Clin Oncol. 2012 Jun 20;30(18):2183-9; J Clin Oncol. 2017 Jul 1;35(19):2125-2132

Nivolumab in Relapsed or Refr actory Hodgkin’s Lymphoma

n engl j med 372;4 nejm.org january 22, 2015 317

of 87% and a rate of progression-free survival of 86% at 24 weeks. Adverse events were mainly of grade 1 or 2. The rate of adverse events was sim-ilar to that in trials of nivolumab in patients with solid tumors.4 Given the limited therapeutic op-tions for patients with Hodgkin’s lymphoma whose disease progresses after autologous stem-cell transplantation21-23 and the relatively short-lived responses to brentuximab after relapse,24 nivolumab-mediated PD-1 blockade may repre-sent a promising targeted treatment for these patients.

The frequent chromosome 9p24.1 amplifica-tion and associated PD-1 ligand overexpression in Hodgkin’s lymphoma and the pronounced but ineffective inflammatory response seen in in-volved lymph nodes provided a compelling ratio-nale for evaluating the efficacy of PD-1 blockade in patients with relapsed or refractory disease. In this study, all the patients with available tu-mor specimens had concurrent gain of the PDL1 and PDL2 loci, increased expression of the PD-1 ligands, and evidence of active JAK-STAT signal-ing. In this group of patients, the incidence of a copy-number gain in PDL1 and PDL2 was higher than in previously reported series of patients with newly diagnosed Hodgkin’s lymphoma,14,25 suggesting that this disease-specific genetic al-teration may have adverse prognostic signifi-cance. The low rate of EBV positivity (1 of 10 patients) that was observed is consistent with the low predominance of EBV in Hodgkin’s lym-phoma of the nodular-sclerosis type.26

In available biopsy samples obtained from the patients, tumor-infiltrating T cells largely ex-pressed low levels of PD-1 on standard immuno-histochemical analysis. Previous studies have suggested that PD-1 blockade selectively en-hances the function of CD8+ T cells that have low or intermediate, rather than high, levels of PD-1 expression.27 The levels of PD-1 on tumor-infiltrating T cells were significantly less predic-tive of response to nivolumab therapy than was PD-L1 expression on solid tumors in recent clinical trials,6 findings that are consistent with our results.

The frequent clinical responses to nivolumab therapy in heavily pretreated patients with re-lapsed or refractory Hodgkin’s lymphoma and genetic alterations of the PD-1 ligand loci high-

Patient No.20

1819

1716

1413

11

15

12

10

89

76

43

1

5

2

0 8 16 24 32 40 48 56 64 72 80 88

Weeks

Cha

nge

(%)

10

−10

0

−20

−30

−50

−60

−80

−40

−70

−90

−100Individual Patient Data (N=23)

B Change in Tumor Burden

A Response Characteristics

ASCT failure andbrentuximab failure

No ASCT and brentuximab failure

No brentuximab

StableDisease

CompleteResponsePartial Response

First complete responseFirst partial responseTherapy durationTransplantationOngoing response

Figure 1. Response Characteristics and Changes in Tumor Burden in Patients with Hodgkin’s Lymphoma Receiving Nivolumab.

Panel A shows the response onset and duration for the 20 study patients who had a response to treatment with nivolumab. The color of each bar in-dicates whether previous autologous stem-cell transplantation (ASCT) or brentuximab therapy had failed in that patient. The length of the bar shows the time until the patient had a complete response or a partial response, along with the duration of the response. Six patients elected to discontinue the study in order to undergo stem-cell transplantation after having a re-sponse to nivolumab. Eleven patients continued to have a response at the time of this writing (indicated by an arrowhead). Panel B shows the per-centage reduction in tumor burden from baseline in all 23 study patients. Two patients met the criteria for a complete response without having a 100% decrease in tumor burden. One patient with a partial response had a 99% decrease in tumor burden but had positive results on positron-emission tomography.

The New England Journal of Medicine Downloaded from nejm.org at University of Chicago Library on August 15, 2019. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

patients (55%) experienced adverse events of grade 3 or higher. Be-sides peripheral sensory neuropathy (8%), the majority of grade 3 orhigher adverse events were laboratory abnormalities including neu-tropenia (20%), thrombocytopenia (8%), and anemia (6%). No casesof febrile neutropenia were observed. There were no deaths within 30days from the last drug administration, and no deaths were attributedto the study drug.

Twenty patients had adverse events that led to treatment discon-tinuation; the most common of these were peripheral sensory neurop-athy in six patients and peripheral motor neuropathy in three patients.Doses of brentuximab vedotin were delayed because of adverse eventsin 47% of patients. Overall, 8% of doses were delayed. The mostcommon events leading to dose delays were neutropenia (16%) andperipheral sensory neuropathy (13%). Doses of brentuximab ve-

dotin were prospectively reduced from 1.8 to 1.2 mg/kg in 11patients; 10 of the 11 patients received a dose reduction because ofperipheral neuropathy, and the other patient had a dose reductionbecause of grade 4 thrombocytopenia.

Fifty-six patients experienced peripheral neuropathy events (asidentified by Standardized Medical Dictionary for Regulatory Activi-ties Query) of any grade; 20% of patients had peripheral neuropathy

Tum

or S

ize

(% c

hang

e fr

om b

asel

ine)

-100

-50

0

50

100

Individual Patients (n = 98)

Best Clinical Response per IRFComplete responsePartial responseStable diseaseProgressive disease

Fig 1. Maximum percent reduction in thesum of the product of diameters in indi-vidual patients (n ! 98) per Cheson et al.12

Tumor size reductions were observed in96 (94%) of 102 patients. Four patientswere not included in the analysis; threepatients had no measurable lesions perindependent review facility (IRF), and onepatient had no postbaseline scans.

Table 2. Key Response Results

Parameter

No. ofPatients

(N ! 102) %

Objective response 76 75Complete remission 35 34Partial remission 41 40

Stable disease 22 22Progressive disease 3 3Not evaluable 1 1Duration of objective response, months

Median 6.795% CI 3.6 to 14.8

Duration of response for patients with completeremission, months (n ! 35)

Median 20.595% CI 10.8 to NE

Progression-free survival, monthsMedian 5.695% CI 5.0 to 9.0

Overall survival, monthsMedian 22.495% CI 21.7 to NE

Abbreviation: NE, not estimable.

A

ITT patients 102 28 22.4n Events

Median(months)

B

ITT patients 102 69 5.6n Events

Median(months)

0

Ove

rall

Surv

ival

(%)

Time (months)

100908070605040302010

3 6 9 12 15 18 21 24

102 (0)No. at risk (events)

)82(0)11(68)6(19)3(69)1(101 14 (26)59 (19)78 (18)

0

Prog

ress

ion-

Free

Sur

viva

l (%

)

Time (months)

100

908070605040302010

3 6 9 12 15 18 21 24

102 (0)No. at risk (events)

)96(0)36(72)75(63)15(34)91(08 5 (67)18 (66)23 (65)

Fig 2. Secondary end points of overall survival (A) and progression-free survival(B). ITT, intent to treat.

Younes et al

2186 © 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by University of Chicago Library on August 15, 2019 from 205.208.116.024Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

A

–100–80–60–40–20

020406080

100

Chan

ge F

rom

Bas

elin

e (%

)

No. at risk

No. at risk

Patie

nts

in R

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(%)

Time (months)

102030405060708090

100110

0 3 6 9 12 15

145 89 31 1 0 0

C

–100–80–60–40–20

020406080

100

Chan

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rom

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)

No. at risk

No. at risk

Time (months)

102030405060708090

100110

0 3 6 9 12 15

52 31 9 0 0 0

Patie

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(%)

B

–100–80–60–40–20

0

20406080

100

Chan

ge F

rom

Bas

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e (%

)

Time (months)

102030405060708090

100110

0 3 6 9 12 15

51 34 13 1 0 0

Patie

nts

in R

espo

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(%)

D

–100–80–60–40–20

020406080

100

Chan

ge F

rom

Bas

elin

e (%

)

Time (months)

102030405060708090

100110

0 3 6 9 12 15

42 24 9 0 0 0

Patie

nts

in R

espo

nse

(%)

Fig 2. Decrease from baseline in tumorburden (left) and Kaplan-Meier estimates ofobjective response duration (right) on thebasis of central review in patients withresponse. (A) All cohorts; (B) cohort 1; (C)cohort 2; (D) cohort 3.

jco.org © 2017 by American Society of Clinical Oncology 2129

Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma

Downloaded from ascopubs.org by University of Chicago Library on August 15, 2019 from 205.208.116.024Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

BV FDA-app 2011 Nivo FDA-app 2016Pembro FDA-app 2011


Integration of targeted agents into frontlinemanagement of advanced stage cHL: ECHELON-1

TimeA+AVD

(95% CI)ABVD

(95% CI)2-year 82.1

(78.7–85.0)77.2

(73.7–80.4)

Median follow-up (range): 24.9 months (0.0–49.3)

CategoryA+AVDN=117

ABVDN=146

Progression 90 102

Death 18 22

Modified progressionChemotherapyRadiotherapy

972

22157

1.0

0.8

0.6

0.4

0.2

0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

664670

640644

623626

606613

544522

530496

516476

496459

474439

447415

350328

334308

311294

200179

187168

174153

9978

8568

7762

2716

2413

2112

61

41

41

00

00

Time from randomization (months)

Prob

abili

ty o

f mod

ified

PFS

No. of patients at risk:A+AVDABVD

HR 0.77 (95% CI: 0.60–0.98)Log-rank test p-value: 0.035

A+AVDABVD

CensoredCensored

0.9

0.7

0.5

0.3

0.1

Modified PFS estimates

Number of events

Connors et al. NEJM online 2017; slide courtesy of Alex Herrera Courtesty of Sonali M Smith, MD

ASH 2020: 5-year follow up of ECHELON-1

Auth

or

Conc

lusio

ns

Strauss DJ et al. Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study.

ASH 2020; Abstract 2973. PosterCourtesty of Sonali M Smith, MD

BV-AVD in frontline advanced stage cHLImpact on Patient Care and Treatment Algorithm

• BV-AVD is a well-tolerated and effective option

• Avoids bleomycin AND avoids need for interim PET

Implications for Future Research

• Is this ”the” or “a” new standard of care?

– Will 5-year outcomes translate to a higher cure rate? • BV-AVD is the control arm in S1826 US Intergroup trial compared to nivo-AVD

(NCT03907488)


What about older patients with cHL?

Part A: BV monotherapyPart B: BV (1.8mg/kg) + DTIC Part C: BV + benda (70mg/m2)Part D: BV + nivo

Closed due to excess toxicity

Yasenchak CA et al. ASH 2020; Abstract 471


BV-based frontline treatment in older patients with cHL: BV + DTIC and BV-nivo promising

Part B: BV (1.8mg/kg) + DTIC

Part D: BV + nivo

Med f/u 63mMed PFS 46m

Med f/u 26m

Yasenchak CA et al. ASH 2020; Abstract 471


BV plus nivo in TN older patients with cHL• Phase II trial BV plus nivo q21d x 8 cycles

Med f/u 21.2m

Cheson BD et al. Lancet Haematol. 2020 Nov;7(11):e808-e815 Courtesty of Sonali M Smith, MD

Results:CMR 65% Med PFS 18m

BV plus nivo in TN older patients with cHL

Toxicity: One-third needed dose adjustments 48% peripheral neuropathy (11% grade 3) 1 death from cardiac arrest

Cheson BD et al. Lancet Haematol. 2020 Nov;7(11):e808-e815

A ”negative” phase 2 trial?

Connors JM et al. Lancet Haematol. 2020 Nov;7(11):e776-e777 Courtesty of Sonali M Smith, MD

Treatment of older patients with treatment-naïve cHLImpact on Patient Care and Treatment Algorithm

• Promising use of targeted agents in frontline setting that avoids bleomycin and reduces use of cytotoxic agents

• BV-benda is too toxic in older patients


• There remains an unmet need for a less toxic treatment of older patients with cHL

• Should BV-nivo be further pursued?


Treatment approach for relapsed cHL

Monotherapy with: Brentuximab vedotinNivolumabPembrolizumab

R/R #1

ASCT elig

ASCT inelig

SalvageCR, PR

ASCT BV consol


5-year follow up of post-ASCT BV (AETHERA TRIAL)

published.3 Briefly, eligible BV-naive patients with HL must haveundergone auto-HSCT before randomization and have been athigh risk of relapse after auto-HSCT based on having eitherrelapsed or progressive HL that occurred ,12 months from theend of frontline therapy; a history of refractory HL, defined asprogression during or failure to achieve a complete remissionafter frontline therapy; or extranodal involvement at the time

of pre–auto-HSCT relapse. As previously reported,3 patientsprovided written informed consent in accordance with theDeclaration of Helsinki, and the study was approved by theinstitutional review board at each study site.

A total of 329 patients were randomized to receive 1.8 mg/kg ofBV or placebo once every 3 weeks for up to 16 cycles starting 30

0

0 4

10

20

30

40

50

60

Patie

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ree

of p

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dea

th, %

Months

70

80

90

100A

B

8 12 16 20 24 28

N Events Median PFS, months HR (95% CI)

32 36 40 44 48 52 56 60 64 68 72 76 80 84 88

0

0 4

10

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ree

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8 12

136N Events Median PFS (95% Cl) Stratified HR (95% Cl)

8414483

56 ------36

86 9.7 (6.1-15.8)(3.3-11.9)6.363PBO + BSC ≥ 3 risk factors

BV + BSC ≥ 2 risk factors 0.424 (0.302-0.596)0.390 (0.255-0.596)BV + BSC ≥ 3 risk factors

16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88

BV + BSC164165

9366

15.8 0.521 (0.379-0.717)--

No. at risk (events)

No. at risk (events ≥ 2 risk factors)

Placebo + BSC

BV + BSC

Placebo+BSC 164 (0) 113 (48) 92 (67) 83 (76) 77 (81) 72 (85) 66 (88) 64 (90) 62 (90) 61 (90) 59 (90) 58 (91) 58 (91) 55 (92) 54 (93) 52 (93) 44 (93) 32 (93) 27 (93) 17 (93) 2 (93) 1 (93) 0 (93)

136 (0) 85 (48) 68 (63) 59 (72) 53 (77) 50 (80) 45 (83) 44 (84) 43 (84) 42 (84) 41 (84) 40 (85) 40 (85) 38 (86) 38 (86) 36 (86) 30 (86) 23 (86) 20 (86) 11 (86) 1 (86) 0 (86) 0 (86)

144 (0) 130 (11)117 (23)107 (31) 98 (39) 91 (45) 90 (46) 87 (49) 86 (50) 85 (51) 81 (54) 78 (54) 75 (55) 74 (55) 73 (55) 70 (55) 59 (56) 42 (56) 38 (56) 23 (56) 6 (56) 2 (56) 0 (56)

165 (0) 149 (12)133 (27)122 (36)112 (45)104 (52)100 (55) 97 (58) 96 (59) 94 (61) 90 (64) 87 (64) 84 (65) 83 (65) 82 (65) 78 (65) 66 (66) 47 (66) 43 (66) 26 (66) 7 (66) 3 (66) 0 (66)

Placebo+BSC

No. at risk (events ≥ 3 risk factors)

84 (0) 49 (34) 36 (45) 29 (52) 24 (57) 22 (59) 20 (61) 19 (62) 18 (62) 18 (62) 17 (62) 17 (62) 17 (62) 15 (63) 15 (63) 14 (63) 11 (63) 9 (63) 9 (63) 6 (63) 0 (63) 0 (63) 0 (63)

82 (0) 73 (7) 63 (17) 56 (24) 49 (30) 46 (32) 46 (32) 44 (34) 44 (34) 44 (34) 42 (36) 42 (36) 41 (36) 40 (36) 39 (36) 38 (36) 31 (36) 26 (36) 24 (36) 15 (36) 3 (36) 1 (36) 0 (36) BV+BSC

BV+BSC

PBO + BSC ≥ 2 risk factors

PBO + BSC

Figure 1. Five-year PFS. PFS at 5 years per investigator (A) and in patients with $2 or $3 risk factors (B). BSC, best supportive care; PBO, placebo.

2640 blood® 20 DECEMBER 2018 | VOLUME 132, NUMBER 25 MOSKOWITZ et al

For personal use only. on August 17, 2019. at UNIVERSITY OF CHICAGO LIBRARY www.bloodjournal.orgFrom

Moskowitz et al. Blood. 2018 Dec 20;132(25):2639-2642.

16 doses of BV 1.8mg/kg q21d post-ASCT


Is there a shorter, less toxic post-transplant option?

Treatment: 30-75 days post AHCT

1.8mg/kg BV and 3mg/kg nivo q21d x 8 doses

Primary endpoint 18m PFS

Patients: N=59Med age 30 (18-72y) 32% primary refractory disease 39% EN disease 51% prior BV42% prior PD-1 inhibitors

Herrera AF et al. ASH 2020; Abstract 472


Post-autologous stem cell transplant BV + nivo

Only 49% completed both agentsMost common AEs were neuropathy, neutropenia27% had immune-related AE’s requiring steroids

19m PFS is 92% (med f/u is 18m)

Herrera AF et al. ASH 2020; Abstract 472


Post-transplant BV + nivoImpact on Patient Care and Treatment Algorithm

• Shorter consolidation is appealing

• Intolerance rate seems high


• Role of post-transplant consolidation will need to be refined

• What if patients receive BV and/or nivo in 1st and 2nd line settings?


KEYNOTE-204: Pembro vs. BV in R/R cHL

Kuruvilla J et al. ASCO 2020; Abstract 8005. Oral, HoDZinzani P et al. EHA 2020; Abstract LB2600. Late Breaking

Kuruvilla J et al.. ASH 2020; Abstract 1158. Poster

• Med PFS 13.2 vs. 8.3m favoring pembro

• Most pts BV-naive


Exploratory analysis of pembro vs. BV in R/R cHL by line of therapy (KEYNOTE-204)

Percent pts over 65y: 1L: 36-44% 2L+: 10-12%

Kuruvilla J et al. ASCO 2020; Abstract 8005. Oral, HoDZinzani P et al. EHA 2020; Abstract LB2600. Late Breaking

Kuruvilla J et al.. ASH 2020; Abstract 1158. Poster

allo-SCT.


Combination targeted therapy in R/R cHLSequential phase I trial with multiple groups

(all 21d cycles)

Ipilimumab (1mg/kg or 3mg/kg) + BV 1.8mg/kg

Nivolumab 3mg/kg + BV (1.2mg/kg or 1.8mg/kg)

Ipilimumab (1mg/kg) + nivolumab (3mg/kg) + BV (1.2mg/kg or 1.8mg/kg)

Diefenbach CS et al. Lancet Haematol. 2020 Sep;7(9):e660-e670. Courtesty of Sonali M Smith, MD

Combination targeted therapy in R/R cHL

Grade 3-4 AE’s seen in all groupsslightly higher in Ipi-groups (43% ipi vs. 50% in triplet vs. 16% in nivo groups)

Grade 5 toxicity 2 deaths from pneumonitis (nivo group and triplet group)

Houot R, Merryman RW, Morschhauser F.. Lancet Haematol. 2020 Sep;7(9):e629-e630 Courtesty of Sonali M Smith, MD

Targeted therapy in R/R cHLImpact on Patient Care and Treatment Algorithm

• Monotherapy with pembrolizumab has improved PFS compared to monotherapy with brentuximab vedotin

• Doublet and triplet therapy with immunotherapy has activity (but also toxicity)


• Unclear impact of these agents if frontline standard of care changes

• There are no data on sequencing

• Combination regimens need further investigation regarding PFS and durability of response


Thank you

2020 year in review: diffuse large b-cell lymphoma

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