LINFOMA DI HODGKIN: RUOLO DEI CHECKPOINT INHIBITORS Armando Santoro - - PowerPoint PPT Presentation

LINFOMA DI HODGKIN: RUOLO DEI CHECKPOINT INHIBITORS Armando Santoro

CANCER IMMUNOTHERAPY TODAY

TUMORS RESPONSIVE TO ANTI-PD1 OR ANTI-PD-L1 THERAPY MELANOMA RCC NSCLC UROTHELIAL CANCER HEAD AND NECK CANCER MERKEL CELL CARCINOMA MSI

Study Design

CHECKMATE-205 : PHASE 2 STUDY WITH NIVOLUMAB IN R/R HL

CHECKMATE 205: PHASE II STUDY IN cHL- Cohort B

EFFICACY OBJECTIVE RESPONSE: 66.3%, CR 9%, PR 58% MEDIAN DOR: 7.8 MS

COHORT B NIVO IN ASCT+BV ( 60 PTS)

CHECKMATE 205: PHASE II STUDY IN cHL- Cohort B

COHORT B NIVO IN ASCT+BV ( 60 PTS)

Nivolumab for Relapsed/Refractory Classical Hodgkin Lymphoma After Autologous Transplant: Full Results After Extended Follow-Up

• f the Phase 2 CheckMate 205 Trial

Michelle Fanale,1 Andreas Engert,2 Anas Younes,3 Philippe Armand,4 Stephen Ansell,5 Pier Luigi Zinzani,6 John M Timmerman,7 Graham P Collins,8 Radhakrishnan Ramchandren,9 Jonathon B Cohen,10 Jan Paul De Boer,11 John Kuruvilla,12 Kerry J Savage,13 Marek Trneny,14 Scott Rodig,15 Margaret Shipp,4 Kazunobu Kato,16 Anne Sumbul,16 Benedetto Farsaci,16 Armando Santoro17

1University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2University Hospital of Cologne, Cologne, Germany; 3Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4Dana-Farber Cancer Institute, Boston, MA, USA; 5Mayo Clinic,

Rochester, MN, USA; 6Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy; 7University of California, Los Angeles, CA, USA; 8Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, UK; 9Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; 10Winship Cancer Institute, Emory University, Atlanta, GA, USA; 11Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands, on behalf of Lunenburg Lymphoma Phase I/II Consortium (LLPC); 12University of Toronto and Princess Margaret Cancer Centre, Toronto, ON, Canada; 13British Columbia Cancer Agency, Vancouver, BC, Canada; 14Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic; 15Brigham and Women’s Hospital, Boston, MA, USA; 16Bristol-Myers Squibb, Princeton, NJ, USA; 17Humanitas Cancer Center – Humanitas University, Rozzano–Milan, Italy

Presented at the 14th International Conference on Malignant Lymphoma (ICML); Lugano, Switzerland; June 14–17, 2017

125

Change in Target Lesion per IRC

>95% of evaluable patients showed a reduction in tumor burden

Asterisks (*) denote responders

Best Overall Response After Extended Follow-Up

BV naïve (Cohort A) n = 63 BV after auto-HSCT (Cohort B) n = 80 BV before and/or after auto-HSCT (Cohort C) n = 100 Overall N = 243 Objective response per IRC,a % (95% CI) 65 (52, 77) 68 (56, 78) 73 (63, 81) 69 (63, 75) Best overall response per IRC, % Complete remissionb Partial 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 investigator assessment, 33% of patients achieved CR and 39% achieved PR
• In post-hoc analyses, responses were similar irrespective of BV treatment sequence

aDefined according to 2007 International Working Group criteria. bAll CRs were confirmed by FDG-PET scan.

Duration of Response by Best Overall Response

All values are medians (95% CI); NE = not evaluable

DOR by cohort Cohort A n = 63 Cohort B n = 80 Cohort C n = 100 Overall N = 243 Median DOR in all responders, months 20 (13, 20) 16 (8, 20) 15 (9, 17) 17 (13, 20) Median DOR in CR patients, months 20 (NE, NE) 20 (4, NE) 15 (8, NE) 20 (16, NE) Median DOR in PR patients, months 17 (9, NE) 11 (7, 18) 13 (9, 17) 13 (9, 17) DOR (months)

40 128 36 99 32 76 30 57 25 36 14 19 6 7 Number of patients at risk CR PR

CR: 20 (16, NE) months PR: 13 (9, 17) months 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 6 9 12 15 18 Proportion of patients in response 0.2 0.1

Progression-Free Survival by Best Overall Response

All values are medians (95% CI). SD = stable disease

Number of patients 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

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 CR: 22 (19, NE) months PR: 15 (11, 19) months SD: 11 (6, 18) months

• Median PFS for all 243 patients was 15 (11–19) months

Progression-Free Survival by Cohort

0.9 0.8 0.7 0.6 0.5 0.4 0.1 0.0 Probability of PFS 0.3 0.2 PFS (months) 3 6 9 12 15 18 BV naïve (Cohort A) BV after auto-HSCT (Cohort B) BV before and/or after auto-HSCT (Cohort C) Cohort C: 12 (11, 18) months Cohort B: 15 (11, 20) months Cohort A: 18 (11, 22) months

Number of patients at risk Cohort A 63 56 41 36 26 18 14 Cohort B 80 70 50 42 33 27 27 Cohort C 100 85 56 44 25 8 4

All values are medians (95% CI)

1.0

Chen et al., Journal of Clinical Oncology 25 April 2017

Cohort 1 ASCT and subsequent BV Cohort 2 Salvage chemotherapy and BV (ineligible for ASCT) Cohort 3 ASCT but not BV

KEYNOTE-087 : PHASE 2 STUDY WITH PEMBROLIZUMAB IN R/R HL

Decrease from baseline in tumor burden (le@) and Kaplan-Meier esDmates of

• bjecDve response duraDon (right) on the basis of central review in paDents

with response. All cohorts

Chen et al., Journal of Clinical Oncology 25 April 2017

Tumor burden ObjecDve response duraDon

KEYNOTE-087 : PHASE 2 STUDY WITH PEMBROLIZUMAB IN R/R HL

RUOLO DEL TRAPIANTO

CONSOLIDARE LA RISPOSTA CON IL TRAPIANTO ?

AUTOLOGO? ALLOGENICO?

Study Design

CHECKMATE-205 : PHASE 2 STUDY WITH NIVOLUMAB IN R/R HL

NIVOLUMAB IN HODGKIN’S LYMPHOMA

Chen et al., Journal of Clinical Oncology 25 April 2017

Cohort 1 ASCT and subsequent BV Cohort 2 Salvage chemotherapy and BV (ineligible for ASCT) Cohort 3 ASCT but not BV

KEYNOTE-087 : PHASE 2 STUDY WITH PEMBROLIZUMAB IN R/R HL

• Median number of treatment cycles
• 12 (range 1, 21)
• Median (range) time to response
• 2.8 (2.2-5.6) months
• Response duration ≥6 months: 70%

→ → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → → →

Months

n at risk Cumulative Event Rate, % Months

10

20

30 40 50 60 70 80 90 100 3 6 9 12 15 52 31 9

+

Treatment Ongoing Complete Response Partial Response Progressive Disease Last Dose

+

Death

KEYNOTE-087 : PHASE 2 STUDY WITH PEMBROLIZUMAB IN R/R HL COHORT B INELIGIBLE TO ASCT

Clinical Evaluation of PD-1 Blockade Relapsed/Refractory cHL

ALLOGENICO PD-1 In RUOLO DEL TRAPIANTO: PD-1 In POST-ALLO

IPILIMUMAB AFTER ALLOTRANSPLANT IN HL

Davids MS et al, NEJM 2016

Key Points:

• PD-1 blockade with nivolumab provides durable disease control

a@er allo-HCT

• PD-1 blockade with nivolumab a@er allo-HCT is associated with

30% acute GVHD

September 18th, 2017 Charles Herbaux et al.

This study retrospecDvely assessed the efficacy and toxicity

• f nivolumab (PD-1 pathway blocking monoclonal anDbody)

as a single agent in 20 HL paDents relapsing a@er allo-HCT

Bradley M. Haverkos et al.

PD-1 blockade for relapsed lymphoma post–allogeneic hematopoie^c cell transplant: high response rate but frequent GVHD

Key Points

• Checkpoint blockade via anD–PD-1 mAbs was associated

with a high overall response rate in relapsed HL allo-HCT paDents.

• Checkpoint blockade via anD–PD-1 mAbs a@er allo- HCT can

be complicated by rapid onset of severe and treatment- refractory GVHD.

ALLOGENICO?

RUOLO DEL TRAPIANTO: ALLO POST-PD1 IN

COHORT B NIVO IN ASCT+BV ( 60 PTS)

CHECKMATE-205 : PHASE 2 STUDY WITH NIVOLUMAB IN R/R HL

Progression-Free Survival by Cohort

0.9 0.8 0.7 0.6 0.5 0.4 0.1 0.0 Probability of PFS 0.3 0.2 PFS (months) 3 6 9 12 15 18 BV naïve (Cohort A) BV after auto-HSCT (Cohort B) BV before and/or after auto-HSCT (Cohort C) Cohort C: 12 (11, 18) months Cohort B: 15 (11, 20) months Cohort A: 18 (11, 22) months

Number of patients at risk Cohort A 63 56 41 36 26 18 14 Cohort B 80 70 50 42 33 27 27 Cohort C 100 85 56 44 25 8 4

All values are medians (95% CI)

1.0

• M. Fanale et al ICML 2017

Decrease from baseline in tumor burden (le@) and Kaplan-Meier esDmates of

• bjecDve response duraDon (right) on the basis of central review in paDents

with response. All cohorts

Chen et al., Journal of Clinical Oncology 25 April 2017

Tumor burden ObjecDve response duraDon

KEYNOTE-087 : PHASE 2 STUDY WITH PEMBROLIZUMAB IN R/R HL

ASH 2016

Outcomes After Allogeneic HSCT

Unknown aGVHD onset dates imputed to allo-HSCT date and GVHD of unknown grade imputed to G4. Death was considered a competing risk to aGVHD (2/44 competing events) and cGVHD (6/44 competing events). Post-transplant progression was considered a competing risk to TRM (3/44 competing events). Data are % (95% CI). aGVHD = acute graft versus host disease; cGVHD = chronic GVHD; G = grade; TRM = transplant-related mortality

• 1. Sureda A, et al. J Clin Oncol 2008;26:455–462; 2. Devetten MP, et al. Biol Blood Marrow Transplant 2009;15:109–117; 3. Robinson SP, et al. Haematologica 2009;94:230–238; 4. Marcais A, et al.

Haematologica 2013;98:1467–1475; 5. Anderlini P, et al. Biol Blood Marrow Transplant 2016;22:1333–1337

50 100 150 200 Cumulative incidence rate Time from subsequent allo-HSCT (days)

Graft versus host disease

aGVHD G2–4 aGVHD G3–4 cGVHD 0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1.0

0.2 0.1

27% (14, 41) 17% (7, 30) 10% (3, 21) 30% (16, 45) 20% (9, 34) 15% (6, 29)

• Median post-transplant follow-up for 44 patients who received allo-HSCT after nivolumab was 5.5 months (019.0)
• Median time from last dose of nivolumab to allo-HSCT was 1.6 months (0.5–13.5)
• Historical 100-day incidence of aGVHD and TRM was 26–60% and 6–28%, respectively1-5

0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1.0

Cumulative incidence rate Time from subsequent allo-HSCT (days)

Transplant-related mortality

0.2 0.1 50 100 150 200

100-day incidence 13% (5, 25) 6-month incidence 13% (5, 25)

ALLOGENICO?

RUOLO DEL TRAPIANTO: ALLO POST-PD1 IN YES

CHECKPOINT INHIBITORS: RESPONSE EVALUATION Pt #270 - Baseline Cycle 3

CHECKPOINT INHIBITORS: RESPONSE EVALUATION

Pt #238 Baseline Cycle 9 Cycle 13 Cycle 20

Lymphoma Response to Immunomodulatory therapy Criteria (LyRIC)

CHECKPOINT INHIBITORS: RESPONSE EVALUATION

Cheson B et al, Blood 2016

LYmphoma Response to Immunomodulatory therapy Criteria

IR Defini^on IR1

Increase in overall tumor burden (SD)≥50% of up to 6 measurable lesions in the first 12 ws of therapy without clinical deteriora\on

IR2

Appearance of new lesions, or growth of one or more exis\ng lesions ≥50% at any \me during treatment, occuring in the context of lack of

• verall progression of overall tumor burden

IR3

Increase in FDG uptake of one or more lesions without a concomitant increase in lesion size or number

INDETERMINATE RESPONSE CATEGORY

CHECKPOINT INHIBITORS: TREATMENT DURATION

NO ALLO-TRANSPLANT

2 YEARS?

ALLO- TRANSPLANT 8 COURSES?

Younes A et al Lancet Oncol 2016

• MORE COMMON AE: FATIGUE (25%), IRR (20%), RASH (16%)
• MORE COMMON SAES ≥GR3: NEUTROPENIA (5%), INCREASED LIPASE LEVEL (5%)
• MOST COMMON SAE ANY GRADE: FEVER

CHECKPOINT INHIBITORS: SAFETY

PD1-blockade: safety profiles

• Nivolumab: Median time for appearance of immune-related adverse events

Pneumonitis Hepatitis

25

PD1-blockade and Hodgkin Lymphoma: Safety Issues

• Autoimmune encephalitis

I-O Therapies Have Unique Safety Profiles1-5

Grade Management Continue the study drug?

Low Delay the dose Resume Nivolumab when AEs resolve to grade ≤ 1 or baseline Moderate ∼ High Administer Corticosteroids ± Immunosuppressants (anti-TNF, mycophenolate, etc) Discontinue Nivolumab permanently (Delay in some situations)

GENERAL RULES: MANAGEMENT OF NIVOLUMAB-RELATED SELECT AES

CHECKPOINT INHIBITORS: BIOMARKERS

Roemer MGM et al, JCO 2016

PFS by 9p24.1 alterations Frequency of 9p24.1 alterations by stage

• PD-L1/PD-L2 altera^ons are a defining feature of cHL (97%)
• Amplifica^on of 9p24.1 are more common in advanced

stage pts and correlate with shorter PFS

• Near-uniform altera^ons of PD-L1/PD-L2 loci explain the

remarkable ac^vity of PD-1 blockade in cHL

Roemer MGM et al, ASH 2016

CHECKMATE 205: BIOMARKERS - Cohort B-C

Nuove tecnologie in RT: diverso ranking o diverse indicazioni?

PD-1 INHIBITOR REPRESENTS A REAL ACHIEVEMENT IN HL PATIENT CARE

NIVOLUMAB IN HODGKIN’S LYMPHOMA

WHAT THE NEXT STEP?

THE NEXT SCENARIOS IN HL TREATMENT

1st-line ABVD OR BEACOPP +/- RT 2nd-line BeGEV + ASCT 3rd-line BV +/- ALLO-TMO ≥ 4th-line EXPERIMENTAL

RECHALLENGE

HOW TO COMBINE PD-1/PD-LI INHIBITORS

Interim Results From a Phase 1/2 Study of Brentuximab Vedotin in Combination With Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma

Alex F. Herrera1, Alison J. Moskowitz2, Nancy L. Bartlett 3, Julie M. Vose4, Radhakrishnan Ramchandren5, Tatyana A. Feldman6, Ann S. LaCasce7, Stephen M. Ansell8, Craig H. Moskowitz2, Keenan Fenton9, Carol Anne Ogden9, David Taft9, Qu Zhang9, Kazunobu Kato10, Mary Campbell9, Ranjana H. Advani11

1City of Hope National Medical Center, Duarte, CA, USA; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Washington University School of Medicine, St. Louis, MO, USA; 4University of Nebraska Medical Center, Omaha, NE, USA; 5Karmanos Cancer Institute, Detroit, MI, USA; 6Hackensack University Medical Center, Hackensack, NJ, USA; 7Dana Farber

Cancer Institute, Boston, MA, USA; 8Mayo Clinic, Rochester, MN, USA; 9Seattle Genetics, Inc., Bothell, WA, USA;

10Bristol-Myers Squibb, Princeton, NJ, USA; 11Stanford University Medical Center, Palo Alto, CA, USA

Presented at the 14th International Conference on Malignant Lymphoma (ICML); Lugano, Switzerland; June 14–17, 2017

74

Tumor Response

N = 59 n (%) Complete response (CR) 37 (63) Deauville ≤ 2 29 (49) Deauville 3 7 (12) Deauville 5a 1 (2) Partial response (PR) 13 (22) Deauville 4 7 (12) Deauville 5 6 (10) No metabolic response (SD) 5 (8) Deauville 5 5 (8) Progressive disease (PD) 3 (5) Deauville 5 2 (3) Missing 1 (2) Clinical Progression (CP) 1 (2) 85% objective response rate with 63% complete responses

SPD change from baseline Max SUV change from baseline

• a. 1 pt had uptake in lymph node, but no evidence of disease was found on biopsy

SPD = sum of the product of the diameters; SUV = standard uptake value

THE NEXT SCENARIOS IN HL TREATMENT

PD-1/PD-L1 + CHT PD-1/PD-L1 + BV PD-1/PD-L1 +

• ther IO-T

PD-1/PD-L1

+ NEW TARGETED TH

BeGEV

Santoro A et al, JCO 2016

Bendamus^ne 90 mg/mq d 2-3, Gemcitabine 800 mg/mq d 1-4, Vinorebine 20 mg/mq d 1

CR (n = 43) PR (n = 6) SD (n = 1) PD (n = 8) Drop out (n = 1) 20 40 60 80 100 Responses (%)

73% 10% 2% 2% 13%

Median CD34+ cells/kg 8.8 x 10^6

PFS@2ys: 62.2%

WHY NOT ?

Bendamus^ne 90 mg/mq d 2-3, Gemcitabine 800 mg/mq d 1-4, Vinorebine 20 mg/mq d 1