Treatment approaches in relapsed/refractory HL Andreas Engert, MD - - PowerPoint PPT Presentation

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Treatment approaches in relapsed/refractory HL Andreas Engert, MD - - PowerPoint PPT Presentation

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German Hodgkin Study Group Deutsche Hodgkin Studiengruppe Treatment approaches in relapsed/refractory HL Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne R/R Hodgkin Lymphoma Key issues Background

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SLIDE 1

Treatment approaches in relapsed/refractory HL

Andreas Engert, MD

Chairman, German Hodgkin Study Group University Hospital of Cologne

German Hodgkin Study Group

Deutsche Hodgkin Studiengruppe

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SLIDE 2
  • Background
  • Relapsed HL
  • PD1
  • Summary

R/R Hodgkin Lymphoma

Key issues

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SLIDE 3

HDR2: European Study for

Relapsed Hodgkin Lymphoma*

D H A P D H A P B E A M R E G I S T R A T I O N D H A P D H A P R A N D O M I Z A T I O N C T X M T X VP 16 B E A M

PBSC

*GHSG, EORTC, EBMT, GELTAMO

Josting A, et al. J Clin Oncol. 2010;28(34):5074-5080

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SLIDE 4

HDR2 Study for Relapsed HL

PFS by treatment arm (final analysis)

P = 0.505 Time, months

Standard (at 3y: 72%) Intensified (at 3y: 67%)

Probability

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 12 24 36 48 60

HL, Hodgkin lymphoma; PFS, progression free survival

Jos\ng A et al, J Clin Oncol. 2010:28:5074-80

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SLIDE 5

auto-HSCT = autologous hematopoie\c stem cell transplant

Post-progression survival (years) 0.0 5 10 15 20 0.2 0.4 0.6 0.8 1.0

Months to relapse following auto-HSCT

Probability of survival

>12 mo (n=214) >6–12 mo (n=203) >3–6 mo (n=169) 0–3 mo (n=170)

Survival in Hodgkin Lymphoma

Relapse AFer Autologous HSCT

Arai S et al. Leukemia & Lymphoma 2013;54:2531–2533.

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SLIDE 6

AETHERA

PFS per Investigator

Percent of Subjects Free of PD or Death 10 20 30 40 50 60 70 80 90 100

Time (Months)

4 8 12 16 20 24 28 32 36 40 44 48 52

N Events (Months) Median Stratified Hazard Ratio Placebo+BSC 164 89 15.8 BV+BSC 165 60

  • 0.50

164 (0) 113 (48) 92 (67) 83 (76) 77 (81) 71 (85) 61 (88) 45 (89) 28 (89) 23 (89) 13 (89) 3 (89) 3 (89) 0 (89) 165 (0) 149 (12) 133 (27) 122 (36) 111 (45) 103 (52) 90 (55) 62 (58) 40 (59) 33 (60) 16 (60) 4 (60) 3 (60) 0 (60) N at Risk (Events) Pla+BSC BV+BSC

HR = 0.50 [95% CI (0.36, 0.70)] Median BV = NE (–, –); Placebo = 15.8m (8.5, –) 24-month PFS rate BV = 65%; Placebo = 45%

Moskowitz et al, Lancet 2015;385:1853-62

PFS, progression free survival; HR, hazard ratio; BV, brentuximab vedotin; NE, non evaluable; BSC, best supportive care; Pla, placebo

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SLIDE 7

37 % at 1yr 49 % at 2yrs 59 % at 3 yrs 0.00 0.20 0.40 0.60 0.80 1.00 12 24 36 48

Time after Allo-SCT, months CI Relapse

60

Median time to relapse: 6m (3-35)

≥3 lines of tx, RR 1.7 (1.2 – 2.5), P = .03 Refractory disease, RR 2.1 (1.5 – 2.9), P = .01

RIC-Allo Trial in Relapsed

  • r Refractory HL (Relapse Rate)

Sureda A, et al. Blood. 2009;114: A 658 RIC-allo - reduced-intensity conditioning allogenic stem cell transplantation; HL – Hodgkin lymphoma; tx – therapy; allo-SCT- allogeneic stem cell transplantation

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SLIDE 8
  • Lenalidomide (IMID)
  • Everolimus, Temsirolimus (mTor-inhibitor)
  • Rituximab, Ofatumumab (an\-CD20)
  • Panobinostat, Vorinostat (H-DAC Inhibitors)
  • TKI´s, JAK2i, PARPi
  • Brentuximab Vedo\n (an\-CD30 ADC)
  • PD-1 inhibitors

AnIbodies and other drugs used

in Hodgkin Lymphoma

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SLIDE 9
  • Background
  • Relapsed HL
  • PD1
  • Summary

R/R Hodgkin Lymphoma

Key issues

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SLIDE 10

PD1 InhibiIon in Classical HL

Mechanism of acIon

  • Pa\ents with cHL show high frequency of 9p24.1 altera\ons and
  • verexpression of PD-L1 and PD-L21
  • Nivolumab is a fully human immunoglobulin G4 monoclonal an\body

targe\ng the programmed death-1 (PD-1) receptor immune checkpoint pathway

cHL = classical Hodgkin lymphoma; MHC = major histocompa\bility complex; NFκB = nuclear factor kappa B; PD-L1/2 = programmed death ligand 1/2; PI3K = phosphoinosi\de-3–kinase; Shp-2 = Src homology region 2-containing protein tyrosine phosphatase

Nivolumab blocks signaling through the PD-1 receptor

  • 1. Roemer MGM et al, J Clin Oncol 2016;34:2690–7
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SLIDE 11

Lymphoma n ORR (%) F´-up (w) Response (w) Mul\ple Myeloma 27 4 46 12+ DLBCL 11 36 23 6-77+ Follicular NHL 10 40 91 27-82+ CTCL/MF 13 15 43 24-50+ PTCL 5 40 31 11-79+ HL 23 87 86 2-91+

Nivolumab in Lymphoma PaIents

DuraIon of Response Phase 1b*

*74 weeks median follow-up

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SLIDE 12

PD-L1 and PD-L2 Expression in cHL

with 9p24.1 AmplificaIon

Chen et al, Clin Cancer Res. 2013; 19:3462

PD-L1 PD-L2

Courtesy of S. Rodig

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SLIDE 13

Published 20161

Cohort B n = 80 Cohort A n = 63 Cohort C n = 100 BV naïve BV a(er auto-HSCT

Primary endpoint

  • ORR by IRC

Addi\onal endpoints

  • CR/PR rate
  • Dura\on of CR/PR
  • PFS by IRC
  • OS
  • Safety

Nivolumab 3 mg/kg IV Q2W

Treatment unIl

disease progression or unacceptable toxicity Extended follow-up (December 2016 lock)

Median: 23 mo Median: 16 mo Median: 19 mo

BV before and/or a(er auto-HSCT

Phase 2 CheckMate 205

Study Design

CR = complete response; DOR = duration of response; IRC = Independent Radiology Review Committee; ORR = objective response rate; OS =

  • verall survival; PFS = progression-free survival; PR = partial response; Q2W = every 2 weeks.

Pa\ents in CR for 1 year to discon\nue

Pa\ents could elect to discon\nue Nivolumab and proceed to allogeneic (allo)-HSCT

  • 1. Younes A et al, Lancet Oncol 2016;17:1283–94
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BV naïvea (Cohort A) n = 63 BV aqer auto- HSCT (Cohort B) n = 80 BV before and/or aqer HSCT (Cohort C) n = 100 Overall N = 243 Age, years 33 (18–65) 37 (18–72) 32 (19–69) 34 (18–72) Male, % 54 64 56 58 ECOG PS (%) 0 1 62 38 53 48 50 50 54 46 Disease stage at study entry, % IV 38 68 61 57 Previous lines of therapy Prior radiotherapy, % 2 (2–8) 59 4 (3–15) 74 4 (2–9) 69 4 (2–15) 68 Time from diagnosis to first dose

  • f nivolumab, years

3.1 (1.0–30.6) 6.2 (1.3–25.1) 3.5 (1.0–24.9) 4.5 (1.0–30.6) Time from auto-HSCT to first dose of nivolumab, years 1.0 (0.3–18.2) 3.4 (0.2–19.0) 1.7 (0.2–17.0) 2.0 (0.2–19.0)

aAll pts received auto-HSCT. Data are median (range) unless otherwise stated. ECOG PS = Eastern Coopera\ve Oncology Group performance status

Phase 2 CheckMate 205

Demographics

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SLIDE 15

100 75 50 25 –25 –50 –75 –100 Best reduc\on from baseline in target lesion (%) Pa\ents BV naïve (Cohort A) BV aqer auto-HSCT (Cohort B) BV before and/or aqer auto-HSCT (Cohort C)

Asterisks (*) denote responders

Phase 2 CheckMate 205

Change in Target Lesion per IRC

Engert et al, EHA 2017

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SLIDE 16

Phase 2 CheckMate 205

Best Overall Response

BV naïve (Cohort A) n = 63 BV aqer auto- HSCT (Cohort B) n = 80 BV before and/or aqer auto-HSCT (Cohort C) n = 100 Overall n = 243 Objec\ve resp.a % (95% CI) 65 (52, 77) 68 (56, 78) 73 (63, 81) 69 (63, 75) Best overall response, % Complete remissionb Par\al remission Stable disease Progressive disease Unable to determine 29 37 24 11 13 55 21 8 4 12 61 15 10 2 16 53 19 9 2

Per inves\gator assessment, 33% pts achieved CR and 39% PR

aDefined according to 2007 Interna\onal Working Group criteria. Responses were assessed by IRC; bAll CRs

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SLIDE 17

Pa\ents with drug-related AEs (≥10%), serious AEs (≥1%),

  • r AEs leading to discon\nua\on (≥1%)

Overall popula\on n = 243 Drug-related AEs, % Any grade Grade 3–4

Fa\gue 23 1 Diarrhea 15 1 Infusion-related reac\on 14 <1 Rash 12 1 Drug-related serious AEs, % Infusion-related reac\on 2 <1 Pneumoni\s 1 Drug-related AEs leading to discon\nua\on, % Pneumoni\s 2 Autoimmune hepa\\s 1 1

Phase 2 CheckMate 205

Safety Outcomes aFer Extended Follow-up

Engert et al, EHA 2017

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SLIDE 18

Number of pa\ents at risk CR PR SD 16 21 8 40 128 47 40 126 44 33 89 25 32 71 19 27 46 11 20 25 8

CR: 22 (19, NE) months SD: 11 (6, 18) months

0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 18 3 6 9 12 15 Probability of PFS PFS (months) 0.2 0.1

PR: 15 (11, 19) months Median (95% CI) PFS for overall pa\ents (N = 243) was 15 (11, 19) months

Phase 2 CheckMate 205

PFS by Best Overall Response

Engert et al, EHA 2017

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SLIDE 19

Cohort C: NR (19, NE) Cohort B: NR (NE, NE) Cohort A : NR (NE, NE)

0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 6 9 12 15 18 Probability of survival OS (months) 0.2 0.1

Number of pa\ents at risk Cohort A Cohort B Cohort C 36 63 17 63 80 100 61 78 97 61 75 93 59 74 90 55 71 83 54 68 65

BV naïve (Cohort A) BV aqer auto-HSCT (Cohort B) BV before and/or aqer auto-HSCT (Cohort C) All values are medians (95% CI). NR = not reached

Phase 2 CheckMate 205

Overall Survival

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SLIDE 20

May 2015 October 2014 February 2015

PaIent M.M.; 39 years

Diagnosed 2011 (5 prior therapies)

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21

  • Up to 16 total cycles of combina\on therapy
  • Standard dosing of both drugs
  • Staggered dosing for cycle 1 only
  • Pts could go on to HDCT & ABMT
  • Risk of pneumoni\s

Nivo 3mg/kg BV 1.8 mg/kg Cycle 1 Weeks 3 6 9 C2 C3 12 C4 CT CT/PET* C16

EOT

1 2 Alex F Herrera et al, ASH 2016 A1105

Phase 1/2 Study

BV and Nivolumab in Pts with r&r cHL

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SLIDE 22

An\body Target Company Nivolumab PD1 BMS Pembrolizumab PD1 MSD REGN2810 PD1 Regeneron Durvalumab PD-L1 Celgene Avelumab PD-L1 Pfizer Ipilimumab CTLA-4 BMS

Immunomodifiers in Lymphoma

SelecIon

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SLIDE 23

Ovarian Cancer3 Urothelial Cancer4 Hodgkin Lymphoma1 Esophageal Cancer7 Hepatocellular Carcinoma2 Small Cell Lung Cancer5

(Nivolumab 1 mg/kg BW + Ipilimumab 3 mg/kg BW)

Colorectal Cancer – MSI-H6

(Nivolumab 3 mg/kg BW)

Anal Cancer8

PD1 InhibiIon, klinische Studien

Hohe EffekIvität beim Hodgkin Lymphom

1.Younes ASCO 2016, A7535. 2. Sangro ASCO 2016, A4078. 3. Hamanishi JCO 2015. 4.Sharma ASCO 2016, A4501. 5.Antonia ASCO 2016, A100. 6.Overman ASCO-GI 2017. 7.Van Morris ASCO 2016 A503

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  • Background
  • Relapsed HL
  • PD1
  • Summary

R/R Hodgkin Lymphoma

Key issues

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SLIDE 25
  • HL has become one of the best curable cancers; long-term side

effects of chemo- and radiotherapy

  • PD1 inhibitors in cHL demonstrated durable responses

irrespec\ve of prior BV treatment or refractoriness to prior therapies

  • CR rate of 29% in BV-naïve pts; acceptable safety profile
  • Nivolumab offers long-term treatment op\on for a broad

spectrum of pa\ents with cHL progressing aqer auto-HSCT

  • Ongoing trials evaluate Nivolumab in other sevngs, including

frontline

  • Future trials including BV and an\-PD1 Moabs will increasingly

replace chemo- and radiotherapy in HL

R/R Hodgkin Lymphoma

Summary

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SLIDE 26
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SLIDE 27

200 Probability of OS from subsequent allo-HSCT PFS from subsequent allo-HSCT (days) Number of pa\ents at risk: 0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1.0

0.2 0.1 44 32 21 50 100 150

Overall survival

OS: Cohort A+B+C: NR (NE, NE)

100-day rate 87% (72, 95) 6-month rate 87% (72, 95)

Progression-free survival

Probability of PFS from subsequent allo-HSCT PFS from subsequent allo-HSCT (days) Number of pa\ents at risk: 0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1.0

0.2 0.1 44 32 19 50 100 150 200 PFS: Cohort A+B+C: NR (NE, NE)

100-day rate 87% (72, 95) 6-month rate 82% (65, 91)

Values are % (95% CI) or median (95% CI)

PD1 InhibiIon

Outcomes AFer Allo-HSCT (n=44)

Morschhauser ISHL10, 2016

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SLIDE 28

Number of patients at risk Non-TBP

OS (months)

138 133 126 15 74 35 30 23 12 TBP 70 66 60 30 7 PGF 1

0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 3 21 24 18 0.2 0.1 6 9 12 15 1.0 1 2 5 4 8 7 11 10 14 13 17 16 20 19 23 22

Probability of survival

PGF TBP Non-TBP

135 34 69 135 32 69 132 28 66 129 26 66 123 21 57 105 19 44 54 9 21 45 4 14

PGF, progression-free pa\ents

Overall N = 243 PGF n = 138 TBP n = 70 Non-TBP n = 35

12-month OS, % (95% CI) 92 (88, 95) 96 (90, 98) 93 (83, 97) 80 (62, 90)

Nivolumab beyond Progression

Outcomes in R/R cHL - Survival

Cohen et al; ASH 2017: A650