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Meet The Professors Hodgkin Lymphoma 2018

Meet The Professors Hodgkin Lymphoma 2018

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Meet The Professors Hodgkin Lymphoma 2018

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  1. Meet The Professors Hodgkin Lymphoma 2018

  2. Hodgkin Lymphoma (HL) by the Numbers Optimal Upfront Treatment 8700 pts 700 Pts ≥70 years No standard TX Favorable ES Unfavorable ES Unfavorable ES with Bulk Favorable AS Unfavorable AS 1000 2500 1000 2500 1000 100 Fail 300 Fail 200 Fail 500 Fail 300 Fail TREATMENT FAILS IN 1400 PATIENTS ES = early stage, AS = advanced stage Courtesy of Dr Craig Moskowitz

  3. Relapsed/Refractory HL: 1400 pts/year Salvage therapy (1-2) PET neg. PET pos. PR No Response 17% 63% 20% 882 pts 280 pts 238 pts 705 Pts Cured with ASCT 130 pts Cured with ASCT 177 pts Treatment Failure 150 pts Treatment Failure 565 pts Allo vs CPI Courtesy of Dr Craig Moskowitz

  4. ECHELON-1: Open-label, global, randomized, phase 3 study of A+AVD versus ABVD in patients with newly diagnosed advanced cHL ECHELON-1: Open-label, global, randomized, phase 3 study of A+AVD versus ABVD in patients with newly diagnosed advanced cHL 2018 study sites in 21 countries worldwide Follow-up Every 3 months for 36 months, then every 6 months until study closure ABVD x 6 cycles (n = 670) ScreeningCT/PET scan 1:1 randomization(N = 1,334) EOTCT/PET scan A+AVD x 6 cycles (n = 664)Brentuximabvedotin: 1.2 mg/kg IV infusionDays 1 & 15 • Inclusion criteria • cHL stage III or IV • ECOG PS 0, 1 or 2 • Age ≥18 years • Measurable disease • Adequate liver and renal function • End-of-cycle-2 PET scan • Deauville 5; could receive alternate therapy per physician’s choice (not a modified PFS event) cHL, classic Hodgkin lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; EOT, end-of-treatment; PFS, progression-free survival Connors JM et al. Proc ASH 2017;Abstract 6.

  5. ECHELON-1: Primary endpoint definition ECHELON-1: Primary endpoint definition • Primary endpoint: modified PFS per IRF • A modified PFS event was defined as the first of • Progression • Death from any cause • PET6 = D3, 4, 5 after completion of front-line therapy followed by subsequent anticancer therapy Per IRF No event Dx Tx PET6 = D1, 2 Follow-up Dx Tx PET6 = D1, 2 Follow-up Tx No event No event Dx Tx PET6 = D3, 4, 5 Follow-up PD/death at any time Event PET6 = D1-5 Dx Tx Follow-up Tx w/o “Cheson” progression Event Dx Tx PET6 = D3, 4, 5 Follow-up D, Deauville score; Dx, diagnosis; IRF, independent review facility; PD, progressive disease; PET6, end-of-cycle-6 PET; Tx, treatment Connors JM et al. Proc ASH 2017;Abstract 6.

  6. Disease characteristics comparable between A+AVD and ABVD Disease characteristics comparable between A+AVD and ABVD * Percentages do not total 100% due to rounding; † Unknown/missing data for 5% and 4% in the A+AVD and ABVD groups, respectively; IPS, International Prognostic Score Connors JM et al. Proc ASH 2017;Abstract 6.

  7. Modified PFS per independent review Modified PFS per independent review Number of events 1.0 0.9 0.8 0.7 0.6 0.5 A+AVD ABVD Probability of modified PFS Censored Censored HR 0.77 (95% CI: 0.60-0.98) Log-rank test p-value: 0.035 0.4 Modified PFS estimates 0.3 0.2 0.1 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 Time from randomization (months) Median follow-up (range): 24.9 months (0.0-49.3) No. of patients at risk: A+AVD ABVD 664 670 640 644 623 626 606 613 544 522 530 496 516 476 496 459 474 439 447 415 350 328 334 308 311 294 200 179 187 168 174 153 99 78 85 68 77 62 27 16 24 13 21 12 6 1 4 1 4 1 0 0 0 0 Connors JM et al. Proc ASH 2017;Abstract 6.

  8. Most clinically important treatment-emergent adverse eventsIncidence (any grade) ≥20% + febrile neutropenia Most clinically important treatment-emergent adverse events Incidence (any grade) ≥20% + febrile neutropenia * Partial list focusing on the most clinically important adverse events. Adverse events (≥20% any grade in either arm) excluded from the table include nausea, alopecia, weight decreased, and anemia Connors JM et al. Proc ASH 2017;Abstract 6.

  9. Summary of treatment-emergent febrile neutropenia and adverse events by primary prophylaxis with G-CSF Summary of treatment-emergent febrile neutropenia and adverse events by primary prophylaxis with G-CSF 100 50 100 ≥Grade 3 Grade 1-2 90 90 73% 80 40 80 87% 70 70 57% 30 60 60 67% 50 Patients (%) Patients (%) 50 Patients (%) 35% 40 20 57% 40 30 47% 30 21% 21% 20 10 20 10 10 11% 0 0 0 8% 7% No (n = 579) Yes (n = 83) Yes (n = 43) No (n = 616) G-CSF primary prophylaxis† A+AVD ABVD No (n = 579) Yes (n = 83) No (n = 616) Yes (n = 43) No (n = 579) Yes (n = 83) No (n = 616) Yes (n = 43) • G-CSF primary prophylaxis for A+AVD resulted in an overall safety profile comparable to ABVD • G-CSF primary prophylaxis is recommended for all A+AVD patients A+AVD ABVD ABVD A+AVD * Includes preferred terms of ‘neutropenia’ and ‘neutrophil count decreased’; † Defined as G-CSF use by Day 5 of study treatment; TEAEs, treatment-emergent adverse events Connors JM et al. Proc ASH 2017;Abstract 6.

  10. Peripheral neuropathy and pulmonary events Peripheral neuropathy (PN) and pulmonary events 67% 80 Interstitial lung disease† 70 43% 60 50 40 30 Patients (%) 20 • 67% of pts with PN in the A+AVD arm had resolution or improvement by ≥1 grade at last follow-up • Of those with ongoing PN at last follow-up: • Grade 1 64% • Grade 2 29% • Grade 3 7% 10 • Drug discontinuations due to PN: • A+AVD 7% • ABVD 2% Interstitial lung disease was more frequent and more severe in ABVD arm 0 A+AVD ABVD All A+AVD ABVD Grade ≥3 *Includes the preferred terms peripheral sensory neuropathy, PN, hypoesthesia, polyneuropathy, paraesthesia, muscular weakness, peripheral motor neuropathy, peroneal nerve palsy, muscle atrophy, hypotonia, autonomic neuropathy, neuralgia, burning sensation, dysesthesia, gait disturbance, toxic neuropathy, neurotoxicity, and sensory disturbance †Includes the preferred terms lung infiltration, pneumonitis, interstitial lung disease, acute respiratory distress syndrome, organizing pneumonia, pulmonary fibrosis, and pulmonary toxicity Connors JM et al. Proc ASH 2017;Abstract 6.

  11. BREACH: Phase II Study Design R Standard arm PET-CT 0 PET-CT 2 PET-CT 4* PET-CT EoT Arm A Radiotherapy 2W 2W 2W 2W 2W 2W 2W 3 to 4W 10-12 W 30Gy C1 C2 C3 C4 Refractory patients:Prematurewithdrawal PET-CT 0 PET-CT 2 PET-CT 4* PET-CT EoT Radiotherapy Arm B 2W 2W 2W 2W 2W 2W 2W 3 to 4W 10-12 W 30Gy C1 C2 C3 C4 AVD + Brentuximabvedotin Experimental arm: • BV 1.2 mg/kg every 2 weeks • G-CSF mandatory Experimental arm Fornecker LM et al. Proc ASH 2017;Abstract 736.

  12. BREACH: PET-Based Response After 2 Cycles (IRC Assessment) Fornecker LM et al. Proc ASH 2017;Abstract 736.

  13. Select Adverse Events (Cycles 1 and 2) * 2 patients with no studydrug administration due to consent withdrawal Reasons for permanent BV discontinuation: Weightloss, hyponatremia, febrileneutropenia, epilepticseizure, peripheralneuropathy, hepatitis and cutaneous rash Fornecker LM et al. Proc ASH 2017;Abstract 736.

  14. Common Grade 3-4 AEs (Cycles 1 and 2) Fornecker LM et al. Proc ASH 2017;Abstract 736.

  15. AETHERA: Phase III Trial Design Study treatment start D30-45post-ASCT Additional stratification factor Eligibility criteriastratification • Randomization stratified by • Risk factors after frontline therapy; • Best clinical response to salvage therapy before ASCT. • Patients with progressive disease after salvage therapy were not eligible. Restage Moskowitz CH et al. Lancet 2015;385(9980):1853-62.

  16. Risk Factors on AETHERA Only 10% of patients had one unfavorable prognostic factor • Initial remission duration < 1 year • PET positive response to most recent salvage therapy • 1 of 5 risk factors • ≥2 salvage therapies • Extranodal disease at pre-ASCT relapse • B symptoms at pre-ASCT relapse • I administer maintenance to patients with >1 risk factor Courtesy of Dr Craig Moskowitz

  17. AETHERA: PFS Per Investigator: ≥2 Risk Factors Percent of subjects free of PD or death Time (months)

  18. The issues concerning AETHERA • Neuropathy • 90% resolution to grade I or less; remember to dose reduce if grade II • Overall survival • With the cross over design and the new era with CPI; only time will tell if there will be a difference but unlikely • Indefinite palliative therapy is not fun • Previous BV therapy • Common sense approach • Pre-ASCT PET and outcome • Only 1 of 5 risk factors in this study • Not prospectively done, read centrally or defined by Deauville criteria Courtesy of Dr Craig Moskowitz

  19. 6 studies: Same goal – PET negative CR • Sequential immuno-chemotherapy (published) • BV as a single agent and sequential administration of ICE or other salvage therapy only if < CR is achieved (MSKCC, COH studies respectively) • Concomitant immuno-chemotherapy (abstract only) • BV + bendamustine – in review • BRAVE: BV + DHAP – presented at ISHL • BR-ESHAP – ASH 2016 • BV + ICE – (Seattle) poster at ASH 2016 Courtesy of Dr Craig Moskowitz

  20. Current State of Salvage Therapy Courtesy of Dr Craig Moskowitz

  21. Tumor Response on a Phase 1/2 Study of Brentuximab Vedotin plus Nivolumab in Patients with Relapsed/Refractory Hodgkin Lymphoma 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 At the time of this analysis, 37 patients had proceeded to ASCT Herrera AF et al. Proc ASH 2016;Abstract 1105.

  22. Current State of Salvage Therapy

  23. I recommend sequential therapy • There is no evidence that a CR to single agent BV is inferior to that of chemotherapy or chemo-immunotherapy • Nearly 40% of patients can avoid chemotherapy for salvage if BV is used first • Chemotherapy alone without BV offers a CR rate of 60-73% with ICE or BeGV • BV can be used as salvage number 2 • Bendamustine-BV seems no better than BeGV • Platinum based salvage regimens combined with BV are “challenging” • BV-nivo – need to wait for long term data, but the cost is shocking and the gain is suspect at best Courtesy of Dr Craig Moskowitz

  24. Analysis of over 100,000 patients with cancer for CD274 (PD-L1) amplification: Implications for treatment with immune checkpoint blockade Goodman A et al. Proc ASCO SITC 2018;Abstract 47.

  25. Analysis of CD274 (PD-L1) Gene Amplification in Patients with Cancer • Analysis of CD274 gene copy number amplification (CNA) in >100,000 patient samples from Foundation Medicine database and UC San Diego. • CD274 CNAs detected in 0.7% of all tumor samples: • 9 patients with CD274 CNAs received PD-1/PD-L1 blockade at UC San Diego: • Response rate = 6/9 (67%); median PFS = 15.1 mo Goodman A et al. Proc ASCO SITC 2018;Abstract 47.

  26. Blood 2017;130(20):2196-203.

  27. Prognostic Significance of Baseline Metabolic Tumor Volume (bMTV) Moskowitz AJ et al. Blood 2017;130(20):2196-203. MTV < 109.5 cm3, n = 48, censored 44 Event-free survival for low (<109.5 cm3) or high (>109.5 cm3) bMTV MTV ≥ 109.5 cm3, n = 12, censored 4 p < 0.001