Hodgkin Lymphoma Barbara Pro, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, Illinois
Hodgkin Lymphoma Successes and Challenges The success 80 % of patients achieve a complete response The ongoing challenges ~ 30% of patients relapse Optimal chemotherapy regimen ABVD vs.. Treatment of older patients Reduce toxicity of standard therapy More effective therapy for advanced stage and primary refractory and relapsed disease
CD30 Targeted Therapy Pivotal study in 102 patients with relapsed/refractory HL after ASCT -75% objective response rate with brentuximab vedotin -34% complete response rate Younes A, et al. J Clin Oncol. 2012;30(18):2183-2189.
PD-1 Immune Checkpoint Pathway Classical Hodgkin lymphoma (chl) is characterized by expression of PD-L1 and PD-L2 on malignant Reed Sternberg cells and on inflammatory cells in the tumor microenvironment PD-L1 expression in chl frequently occurs in the setting of genetic amplification of the 9p24.1 locus PD-L1 expression in chl Copy Gain Amplification PD-L1/L2 copy gains and amplification visible by FISH Chen BJ, et al. Clin Cancer Res. 2013;19(13):3462-3473. Ansell SM, et al. N Engl J Med. 2015;372(4):311-319. Ansell SM, et al. Blood. 2015;126: Abstract 583.
Hodgkin Lymphoma Front-Line Treatment Abstract 6: Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) As Frontline Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients With Previously Untreated Stage III or IV Hodgkin Lymphoma (HL): The Phase 3 Echelon-1 Study Abstract 89: Sequential Brentuximab Vedotin Before and After Adriamycin,Vinblastine, and Dacarbazine (Bv-AVD) for Older Pts with Untreated Hodgkin Lymphoma (HL): Final Results from a Multicenter Phase II Study Abstract 651: Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (chl): Results from the Phase 2 Checkmate 205 Study Salvage Therapy Abstract 694: Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination With Nivolumab in Patients With Relapsed or Refractory Hodgkin Lymphoma Abstract 650: Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma From the Phase 2 Checkmate 205 Study Abstract 738: Phase II Study of Brentuximab Vedotin Plus Ibrutinib for Patients With Relapsed/Refractory Hodgkin Lymphoma
Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) As Frontline Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients With Previously Untreated Stage III or IV Hodgkin Lymphoma (HL): The Phase 3 Echelon-1 Study Abstract 6 Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illes A, Picardi M, Lech-Maranda E, Oki Y, Feldman TA, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen RW, Ramchandren R, Zinzani PL, Cunningham D, Heo DS, Rosta A, Josephson N, Ruffner KL, Sachs J, Liu R, Jolin H, Hubner D, Radford JA
ECHELON-1: Open-Label, Global, Randomized, Phase III Study of a+avd Versus ABVD in Patients With Newly Diagnosed Advanced chl Connors J, et al. Blood. 2017;130: Abstract 6.
Disease Characteristics Comparable Between A+AVD and ABVD Connors J, et al. Blood. 2017;130: Abstract 6.
Modified PFS per Independent Review Connors J, et al. Blood. 2017;130: Abstract 6.
Summary of Subsequent Therapy Connors J, et al. Blood. 2017;130: Abstract 6.
Most Clinically Important Treatment-Emergent Adverse Events Incidence (Any Grade) 20% + Febrile Neutropenia Connors J, et al. Blood. 2017;130: Abstract 6.
Peripheral Neuropathy and Pulmonary Events Connors J, et al. Blood. 2017;130: Abstract 6.
Sequential Brentuximab Vedotin Before and After Adriamycin, Vinblastine, and Dacarbazine (Bv-AVD) for Older Pts With Untreated Hodgkin Lymphoma (HL): Final Results From a Multicenter Phase II Study Abstract 89 Evens AM, Advani RH, Fanale M, Smith SM, Jovanovic B, Helenowski I, Bociek G, Klein AK, Winter JN, Gordon LI, Hamlin PA
Elderly Hodgkin Disease/Lymphoma Defined: age 60 years Under-represented in clinical trials: <5%-10% (vs 15%-25% population) Outcomes disproportionately inferior to younger patients EFS and OS ~ 40-50% No standard treatment approach Evens AM, et al. Blood. 2017;130: Abstract 89.
Incorporation of Brentuximab Vedotin Into Front-Line Therapy PET1 and CT1 (Staging) BV x 2 cycles (1.8 mg/kg q 3 wks) AVD x 6 cycles BV consolidation (1.8 mg/kg q 3 wks x4) PET2 (first 22pts) CT + PET (all pts) Phase II investigator-initiated study Untreated advanced-stage elderly HD ( 60 yo) Participating institutions: Tufts, Northwestern, Univ of Chicago, UMass, Ohio State, MDACC, Stanford, Nebraska, and MSKCC Window (lead-in) study with brentuximab vedotin CGA (CIRS-G) and HRQL assessments Study of early FDG-PET Evens AM, et al. Blood. 2017;130: Abstract 89.
(N = 48) (N = 41) Results: Efficacy BV x 2 AVD x 3 AVD x 3 BV x 4 ORR 87% CR 30% (PET) ORR 98% CR 76% ORR 95% CR 90% ORR 95% CR 93% ITT (n = 48) after 6 AVD: ORR 88% and CR 81% Evens AM, et al. Blood. 2017;130: Abstract 89.
Survival: PFS and OS Evens AM, et al. Blood. 2017;130: Abstract 89. 2-Year PFS 85% and 2-year OS 94% (ITT)
Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (chl): Results From the Phase 2 CheckMate 205 Study Abstract 651 Ramchandren R, Fanale MA, Rueda A, Armand P, Trěný M, Feldman TA, Ansell SM, Provencio M, Jaeger U, Cohen JB, Savage KJ, Willenbacher W, Sacchi M, Sumbul A, Domenech ED
Ramchandren R, et al. Blood. 2017;130: Abstract 651. Study Design
Baseline Demographics and Clinical Characteristics Ramchandren R, et al. Blood. 2017;130: Abstract 651.
Ramchandren R, et al. Blood. 2017;130: Abstract 651. Treatment-Related AEs
Ramchandren R, et al. Blood. 2017;130: Abstract 651. Immune-Mediated AEs
Response by IRC and Investigator-ITT Ramchandren R, et al. Blood. 2017;130: Abstract 651.
Ramchandren R, et al. Blood. 2017;130: Abstract 651. Modified PFS per IRC
Nivolumab Treatment Beyond Investigator- Assessed Progression: Outcomes in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma From the Phase 2 CheckMate 205 Study Abstract 650 Cohen JB, Engert A, Ansell SM, Younes A, Trneny M, Savage KJ, Ramchandren R, Collins G, Fanale MA, Armmand P, Zinzani PL, De Boer JP, Shipp MA, Santoro A, Timmerman JM, Sacchi M, Sy O, Kuruvilla J
Nivolumab for Relapsed Hodgkin Lymphoma Younes A, et al. Lancet Oncol. 2016;17(9):1283-1294. Fanale M, et al. ICML 2017 Cohen JB, et al. Blood. 2017;130: Abstract 650.
Cohen JB, et al. Blood. 2017;130: Abstract 650. Study Design
Phase II CheckMate 205 R/R chl Study Design Cohen JB, et al. Blood. 2017;130: Abstract 650.
70 of 105 (67%) patients with investigator-assessed disease progression were TBP Stable reductions in tumor burden were seen with continued treatment in patients TBP OS from first dose of study drug was 93% at 12 months for patients TBP Median time to next therapy was 8.8 months (vs 1.5 months for non-tbp) Nivolumab was well tolerated with an acceptable safety profile Cohen JB, et al. Blood. 2017;130: Abstract 650. Summary
Results From a Phase 1/2 Study of Brentuximab Vedotin in Combination With Nivolumab in Patients With Relapsed or Refractory Hodgkin Lymphoma Abstract 649 Herrera AF, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, LaCasce AS, Ansell SM, Moskowitz CH, Fenton K, Ogden CA, Taft D, Zhang Q, Kato K, Campbell M, Advani RH
Study Rationale BV activates the immune system and initiates an antitumor response through the induction of immunogenic cell death Nivolumab targets PD-1 and restores an effective antitumor response Herrera AF, et al. Blood. 2017;130: Abstract 649.
Methods Target enrollment: ~55 patients Patients were treated in 21-day cycles for up to 4 cycles (12 weeks) During Cycle 1, BV was administered on Day 1 and Nivo on Day 8 During Cycles 2-4, dosing of both drugs occurred on Day 1 of each cycle After completion of the Cycle 4 response assessment, patients were eligible to undergo ASCT Investigator assessment of lymphoma response and progression was per the Lugano Classification Revised Staging System for malignant lymphoma (Cheson et al, 2014) Herrera AF, et al. Blood. 2017;130: Abstract 649.
Patient Characteristics and Disposition Herrera AF, et al. Blood. 2017;130: Abstract 649.
Herrera AF, et al. Blood. 2017;130: Abstract 649. Response
Brentuximab Vedotin + Nivolumab BV + Nivo was well tolerated 44% of patients experienced IRRs, 41% Gr 1-2, 3% Gr 3 <10% had potential iraes requiring steroids Treatment did not impact stem cell mobilization and stem cell collection: patients were able to proceed to ASCT uneventfully BV + Nivo treatment resulted in Increasing circulating T-cell numbers, and increase in adaptive immuneactivating cytokines and chemokines Increased ability of memory T-cells to mount an immune response Herrera AF, et al. Blood. 2017;130: Abstract 649.
Phase II Study of Brentuximab Vedotin Plus Ibrutinib for Patients With Relapsed/Refractory Hodgkin Lymphoma Abstract 738 Chen RW, Palmer JM, Herrera AF, Stiller T, Armenian SH, Mei M, Popplewell L, Fueger A, Qasim I, Stiller T, Rosen ST, Forman SJ, Kwak LW
Study Schema Note: There is a safety lead-in portion using only 420 mg oral daily Chen R, et al. Blood. 2017;130: Abstract 738.
Patient Characteristics Characteristic, n (%) Phase II Patients [n = 13] 560 mg Ibrutinib Safety Lead-In Patients [n = 3] 420 mg Ibrutinib All patients [N = 16] Gender Female Male 5 (38) 8 (62) 2 (67) 1 (33) 7 (44) 9 (56) Age 33 (17-69) 33 (21-52) 33 (17-69) Stage at Diagnosis I-II III-IV 7 (54) 6 (46) 1 (33) 2 (67) 8 (50) 8 (50) B symptoms (at diagnosis) 6 (46) 3 (100) 9 (56) Prior Therapy ABVD BEACOPP R-CHOP IGEV BV ICE Clinical Trials PD1 inhibitors 12 (92) 3 (23) 1 (8) 1 (8) 1 (8) 0 0 0 3 (100) 0 0 1 (33) 3 (100) 2 (67) 3 (100) 3 (100) 15 (94) 3 (19) 1 (6) 2 (13) 4 (25) 2 (13) 3(19) 3 (19) Prior Radiation 3 (23) 0 3 (19) Status Prior to Treatment Progressive Disease Relapsed Disease Stable Disease 7 (54) 6 (46) 0 2 (67) 0 1 (33) 9 (56) 6 (38) 1 (6) Best Response to Induction Refractory Relapsed Chen R, et al. Blood. 2017;130: Abstract 738. 5 (38) 8 (62) 3 (100) 0 8 (50) 8 (50)
Efficacy Characteristic, n (%) Phase II Patients [n = 13] 560 mg Ibrutinib Safety Lead-In Patients [n = 3] 420 mg Ibrutinib All Patients [N = 16] Median Number of Cycles 5 (2-9) 2 (2-6) 4 (2-9) Best Response CR PR SD PD 6 (46) 5 (39) 2 (15) 0 0 1 (33) 0 2 (67) 6 (37) 6 (37) 2 (13) 2 (13) Response Rate (PR/CR) 84.6% 33.3% 75.0% Safety lead-in allowed refractory BV pts Chen R, et al. Blood. 2017;130: Abstract 738.
Conclusions Front-line Treatment Brentuximab vedotin in combination with AVD Superior modified PFS G-CSF primary prophylaxis recommended for all patients Brentuximab vedotin incorporated sequentially before and after AVD feasible for older HL pts High CR rate (>90%) and overall well tolerated Nivolumab monotherapy followed by N-AVD well tolerated in patients with advanced stage chl Salvage Therapy Treatment with nivolumab beyond progression associated with long-term clinical benefit Active combinations in the R/R setting Brentuximab + Nivolumab ORR 83%, CR 62% Brentuximab + Ibrutinib ORR 84.6%, CR 46%