PET-adapted therapies in the management of younger patients (age 60) with classical Hodgkin lymphoma

PET-adapted therapies in the management of younger patients (age 60) with classical Hodgkin lymphoma Ryan Lynch MD Assistant Professor, University of Washington Assistant Member, Fred Hutchinson Cancer Research Center Seattle, Washington

Outline PET-adapted strategies in advanced stage HL PET-adapted strategies in early stage HL The future is coming? Brentuximab vedotin in upfront treatment of advanced HL

Outline PET-adapted strategies in advanced stage HL PET-adapted strategies in early stage HL The future is coming? Brentuximab vedotin in upfront treatment of advanced HL

Hodgkin Lymphoma Expected outcomes and goals of therapy in 2017 Stage Early stage favorable (Stage I-II) Early stage unfavorable (stage I, II with risk factors*) Advanced stage (bulky, IIB, III, IV) % Cured with primary therapy Therapeutic Priority 90 Reduce Toxicity 80-85 Increase Efficacy 75 Increase Efficacy * Large mediastinal mass, extranodal extension, 3 nodal sites, elevated ESR; age 50, MC histology Adapted from slide courtesy of Ranjana Advani

Advanced HL: Chemotherapy ABVD x 6 cycles considered standard of care in North America Gordon LI, et al. J Clin Oncol 31:684-91, 2013

Advanced HL: Chemotherapy escbeacopp x 6 cycles considered standard of care in Europe (GHSG) Time (months) Engert A, et al. Lancet 379:1791-9, 2012

Importance of long term follow-up: HD2000 ABVD x 6 vs. escbeacopp x 4 + BEACOPP baseline x 2 Median follow up 10 years OS Secondary Malignancies PFS Merli F, Luminari S, Gobbi PG, et al:. J Clin Oncol, 2015

Increased risk of sterility with BEACOPP Amenorrhea 6-8 cycles escbeacopp 2+2 Behringer K, et al. J Clin Oncol 31:231-9, 2013

escbeacopp is not for everyone Treatment-related mortality risk score Points Age PS 0 < 40 0-1 1 40-49 2 2 50 Wongso D, et al. J Clin Oncol 31:2819-24, 2013

Negative interim PET after 2 cycles of ABVD associated with significantly improved PFS Prognosis independent of IPS at diagnosis Gallamini et al. J Clin Oncol 25:3746-52, 2007

Can treatment decisions be made based on interim-pet? Should therapy be escalated with a positive interim-pet (PET2)? Should therapy be de-escalated with a negative PET2? Does this have the potential to improve outcomes?

Initial treatment Trial # of patients Stage PET-adapted treatment HD 0607 773 IIB-IV + 4+4 vs. R-4+4 ABVD x 2 escbeacopp x 2 Gallamani et al. SWOG 0816 Press et al. RATHL Johnson et al. HD 0801 Zinzani et al. AHL 2011 Casasnovas et al. HD18 Borchman et al. - ABVD x 4 357 III-IV + escbeacopp x 6 - ABVD x 4 1214 II-IV + escbeacopp x 6 or BEACOPP-14 x 8 - ABVD x 4 vs. AVD x 4 519 IIB-IV + IGEV + auto HSCT - ABVD x 4 823 IIB-IV + escbeacopp x 4 - escbeacopp x 4 vs. ABVD x 4 1100 IIB-IV + escbeacopp x 6 vs. R-escBEACOPP x 6 - escbeacopp x 4 vs. escbeacopp x 2 Adapted from Lynch RC, Advani RH, ASCO Education Book 2016

RATHL Trial: Study design Stage IIA with bulk and/or 3 sites Stage IIB-IV Radiotherapy at MD discretion Characteristic Number or % Median age 33 (18-79) Male 55% Stage II III IV 41% 31% 28% B symptoms 61% Bulky disease 31% PS 0-1 96% IPS 0-1 2-3 4 34% 49% 18% Johnson P, et al. N Engl J Med 374:2419-29, 2016

RATHL Trial: Study design Stage IIA with bulk and/or 3 sites Stage IIB-IV Goals Assumptions: Johnson P, et al. N Engl J Med 374:2419-29, 2016 Characteristic Number or % Median age 33 (18-79) Male 55% Stage II III IV 41% 31% 28% B symptoms 61% Bulky disease 31% 75% PET-2 negative; 3-yr PFS 95% in PET-2 negative patients Non-inferiority design 90% power to exclude AVD being > 5% worse Radiotherapy at MD discretion PS 0-1 96% IPS 0-1 2-3 4 Statistics: 1200 pts and 3 years follow-up; primary endpoint 3-yr PFS 34% 49% 18%

RATHL Trial: Results in PET2 negative patients Median follow up 41 months ITT analysis HR 1.13 (0.81-1.57, p=0.48) ABVD 3-year PFS 85.7% (82.1%-88.6%) AVD 3-year PFS 84.4% (80.7%-87.5%) Difference 1.6% (-3.2% to 5.3%) 3-year OS ABVD 97.2% (95.1 to 98.4) AVD 97.6% (95.6 to 98.7) No statistical difference in 3-year PFS and OS Just outside pre-determined non-inferiority margin of 5%

RATHL Trial: Results Increased toxicity in BEACOPP arms Grade 3/4 AE ABVD, Cycles 1 and 2 (n = 1203) ABVD, Cycles 3-6 (n = 468) AVD, Cycles 3-6 (n = 457) BEACOPP-14 (n = 94) Neutropenia 695 (58%) 275 (59%) 269 (59%) 59 (63%) 52 (67%) Thrombocytopenia 16 (1%) 6 (1%) 15 (3%) 18 (19%) 33 (42%) Any infection 76 (6%) 68 (15%) 47 (10%) 35 (37%) 33 (42%) Febrile neutropenia 24 (2%) 22 (5%) 10 (2%) 10 (11%) 20 (26%) Any pulmonary event 8 (1%) 15 (3%) 3 (1%) 4 (4%) 4 (5%) Any grade 3/4 AE 771 (64%) 322 (69%) 299 (65%) 75 (80%) 65 (83%) escbeacopp (n = 78) Johnson P, et al. N Engl J Med 374:2419-29, 2016

RATHL trial: Results in PET2 positive patients PET2+ Group 3-year PFS 67.5% (95% CI, 59.7 to 74.2), PET2+ Group 3-year OS 87.8% (95% CI, 81.5 to 92.1) Improved PFS in PET2 positive patients compared to historical controls Johnson P, et al. N Engl J Med 374:2419-29, 2016

RATHL trial: Results Risk factor Number (%) 3-year PFS Bulk Present 119 (34.7%) 91.5 (84.8 95.3) Absent 224 (65.3%) 91.7 (87.1-94.7) B symptoms Present 206 (59.4%) 92.0 (87.3 95.0) Absent 141 (40.6%) 90.6 (84.4 94.4) B symptoms or bulk Present 257 (74.5%) 90.9 (86.6 93.8) Absent 88 (25.5%) 94.1 (86.3 97.5) 348 total stage II patients were PET2 negative and did not receive radiotherapy Similar 3-year PFS in patients with or without bulk Johnson P, et al. N Engl J Med 374:2419-29, 2016

HD0801: Study design PET-2 neg ABVD x2 PET-2 pos Stage IIB-IV IPS 0-7 Characteristic Number or % Median age 33 (18-68) Male 54% ABVD x4 IGEV Salvage IPS 0-2 3 56% 44% PET neg BEAM-Auto PET pos Allo if matched donor, Auto if no matched donor PS 0 1 2 Stage II III IV 66% 28% 6% 19% 35% 46% B symptoms 64% Bulk 35% Zinzani PL, et al. J Clin Oncol 34:1376-85, 2016

HD0801: Results PFS in PET2 positive patients similar to PET2 negative patients ITT 2-year PFS PET2-neg 81% (95% CI, 76% to 84%) PET2-pos 76% (95% CI, 66% to 84%) Per protocol PET2-pos 74% (95% CI, 62% to 82%) Median follow up 25 months 20/101 patients in PET2 pos group did not receive IGEV salvage/transplant

Summary: PET-adapted trials in advanced HL Results of escalation/de-escalation strategies are similar PET2 negative rate ~80% in most studies after ABVD x2 Bleomycin can be safely omitted with negative PET2 Some treatment failures seen even in PET2-negative patients Intensification of therapy to escbeacopp with positive PET2 may improve outcome over historical results with ABVD No control arm with continuing with ABVD Increased toxicity issues

Outline PET-adapted strategies in advanced stage HL PET-adapted strategies in early stage HL The future is coming? Brentuximab vedotin in upfront treatment of advanced HL

RAPID trial PET adapted elimination of XRT in early stage HL Deauville 1-2 * No difference in OS Radford J et al: N Engl J Med 372:1598-607, 2015

EORTC H10 Interim analysis finds increased events in PET-negative experimental arm Early stage favorable PET2 negative Early stage unfavorable PET2 negative PET-negative experimental arm closed by independent data monitoring committee Andre MPE, et al. J Clin Oncol 35:1786-1794, 2017

Early stage favorable HL- abbreviated chemo plus radiation GHSG HD10 trial ABVD X 2 + 20 Gy IFRT = ABVD X 4 + 30 Gy IFRT GHSG unfavorable criteria ESR > 50, > 30 if B symptoms MMR > 0.33 More than 2 nodal sites Any E lesion Engert A, et al: N Engl J Med 363:640-52, 2010

Take home points early stage HL Very favorable early HL patients have excellent outcomes with abbreviated chemo/rt PET can identify low risk population that may do well without radiation However, there is a small benefit to radiation in preventing relapse Requires personalized treatment decision (patient preference, age, gender, sites of disease)

Outline PET-adapted strategies in advanced stage HL PET-adapted strategies in early stage HL The future is coming? Brentuximab vedotin in upfront treatment of advanced HL

Brentuximab vedotin Anti-CD30 antibody-drug conjugate FDA approved Relapsed HL after auto HSCT Failure of 2 regimens in patients not eligible for transplant Consolidation for high risk HL patients after auto HSCT Relapsed ALCL???Untreated Advanced HL??? Deng C, et al. Clin Cancer Res 19:22-7, 2013

Brentuximab active in patients who relapsed after autologous transplant 5 year end of study analysis 9% (9/100) of patients achieved sustained CR without additional therapy Chen R, et al: Blood 128:1562-6, 2016

Characteristic Number or % Median age Age 45 Age 60 Male 58% Stage III IV 36 (18-83) 34% 14% 36% 64% Connors et al. ASH 2017

A+AVD associated with prolonged 2-year PFS vs. ABVD PFS favoring A-AVD (HR 0.770 [95% CI 0.603 0.982]; p=0.035) 2 year PFS by independent review A-AVD: 82.1% (95% CI 78.7-85.0) ABVD: 77.2% (95% CI 73.7 80.4) Sub-group analysis favors A-AVD, data to be presented at ASH Connors et al. ASH 2017

A-AVD associated with higher rates of toxicity A-AVD: 7/9 on study deaths due to neutropenia (no primary GCSF)in the A+AVD arm were associated with neutropenia ABVD: 11/13 on study deaths due to pulmonary toxicity Protocol later amended to give A- AVD patients primary GCSF (n=83) Febrile neutropenia reduced from 19% to 11% Grade 3 infections reduced from 18% to 11%. Toxicity A-AVD ABVD Neutropenia 58% 45% Febrile neutropenia Grade 3 infection Peripheral neuropathy Peripheral neuropathy grade 3 Pulmonary toxicity grade 3 19% 8% 18% 10% 67% 43% 11% 2% 1% 3% Connors et al. ASH 2017

Special Issues!!! No bone marrow biopsy needed at diagnosis if PET used for staging Avoid growth factors with ABVD due to increased risk of pulmonary toxicity (no primary use) No dose delays with ABVD due to neutropenia treat on time with standard doses. Inferior outcomes with decreased dose intensity. Consider prophylactic antibiotics Repeat biopsy with refractory disease or relapse prior to starting subsequent therapy.

Questions? Thank you!

Hodgkin lymphoma staging Stage I II III IV Definition single lymph node or extranodal site two or more involved lymph node regions on the same side of the diaphragm lymph node involvement on both sides of the diaphragm presence of diffuse or disseminated involvement of one or more extralymphatic organs A absence of B symptoms B Presence of B symptoms Stage I-II Early stage Favorable Unfavorable Stage III-IV - Advanced stage Risk stratified by International Prognostic Score (IPS)

NCCN Guidelines, Hodgkin Lymphoma, Version 3.2016 Unfavorable Criteria

IPS: risk stratification for advanced HL Remains prognostic in ABVD era Serum albumin <4 g/dl Hemoglobin <10.5 g/dl Male gender Age >45 years Stage IV disease White blood cell count 15,000/microL Absolute lymphocyte count <600/uL and/or <8 percent of the total white blood cell count. Moccia et al. J Clin Oncol 30:3383-8, 2012

Advanced stage HL results: ABVD vs. BEACOPP Treatment 5-y PFS Diff. (%) 5-y OS Diff. (%) Reference ABVD x 6 68 13 84 8 HD2000: Federico et al, 4 + 2 81 92 JCO 2009 IPS 0-7 ABVD x 6-8 73 12 84 5 Viviani et al, NEJM 2011 4 + 4 85 89 IPS 3 ABVD x 8 73 11 87 3 EORTC 20012: Carde et al, 4 + 4 84 90 JCO 2016 IPS 3 ABVD x 8 75 18 92 7 LYSA H34: Mounier et al, 4 + 4 93 99 Ann Oncol 2014 IPS 0-2 *Statistically significant Adapted from slide courtesy of Ranjana Advani 4 + 4 = 4 escbeacopp + 4 BEACOPP baseline 4 + 2 = 4 escbeacopp + 2 BEACOPP baseline

EORTC H10 Interim analysis finds increased events in PET-negative experimental arm PET2 positive All early stage PFS PET2 positive All early stage PFS PET-negative experimental arm closed by independent data monitoring committee Andre MPE, et al. J Clin Oncol 35:1786-1794, 2017

Background Classical Hodgkin lymphoma (CHL) represents ~ 10% of all lymphomas 9000 new cases annually in the United States Highly curable with frontline therapy (chemotherapy +/- RT) Early stage > 90% Advanced stage ~ 80%

US Intergroup S0816 trial: Study design Advanced HL Stage III-IV IPS 0-7 Characteristic Number (%) Median age 32 (18-60) Male 56% Stage III IV 52% 48% B symptoms 62% Bulk (> 10 cm) 18% IPS 0-2 3-7 49% 51% No Radiotherapy Press OW, et al: J Clin Oncol, 2016

US Intergroup S0816 trial: Results Median follow up 39.7 months escbeacopp x6 after positive PET-2 improves PFS compared to historical controls Press OW, et al: J Clin Oncol, 2016

Single agent brentuximab highly active in upfront treatment of patients age 60 Median follow up: 17 months Median age: 78 ORR: 92%, CR: 73% Median DOR: 9.1 months Median PFS: 10.5 months Peripheral neuropathy All grades: 89% Grade 3: 30% Forero-Torres A, et al. Blood 126:2798-804, 2015

A + AVD in untreated advanced HL n = 25 BV + ABVD associated with increased pulmonary AEs Median 5 year follow up n = 26 Connors, JM, et al. Blood 2017

A + AVD x 4 + RT in early stage unfavorable patients PFS by intention to treat (n = 30) Median follow up 18.8 months 1-year PFS 93.3% Kumar A, et al: Blood 128:1458-64, 2016 Current cohorts using lower dose of ISRT (20 Gy) or conformational volume radiotherapy (CVRT, 30 Gy)