65 Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma From the Phase 2 CheckMate 25 Study Jonathon B. Cohen, 1 Andreas Engert, 2 Stephen M. Ansell, 3 Anas Younes, 4 Marek Trneny, 5 Kerry J. Savage, 6 Radhakrishnan Ramchandren, 7 Graham Collins, 8 Michelle A. Fanale, 9 Philippe Armand, 1 Pier Luigi Zinzani, 11 Jan Paul De Boer, 12 Margaret A. Shipp, 1 Armando Santoro, 13 John M. Timmerman, 14 Mariana Sacchi, 15 Oumar Sy, 15 John Kuruvilla 16 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA; 2 University Hospital of Cologne, Cologne, Germany; 3 Mayo Clinic, Rochester, MN, USA; 4 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5 Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic; 6 British Columbia Cancer Agency, Vancouver, BC, Canada; 7 Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; 8 Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, UK; 9 University of Texas MD Anderson Cancer Center, Houston, TX, USA; 1 Dana-Farber Cancer Institute, Boston, MA, USA; 11 Institute of Hematology L. e A. Seràgnoli, University of Bologna, Bologna, Italy; 12 Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, on behalf of the LLPC (Lunenburg Phase I/II Consortium); 13 Humanitas Cancer Center, Humanitas University, Rozzano Milan, Italy; 14 University of California Los Angeles Medical Center, Los Angeles, CA, USA; 15 Bristol- Myers Squibb, Princeton, NJ, USA; 16 University of Toronto and Princess Margaret Cancer Centre, Toronto, ON, Canada Presented at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9 12, 217; Atlanta, GA, USA
Nivolumab for Relapsed/Refractory Classical Hodgkin Lymphoma Nivolumab, a fully human immunoglobulin G4 monoclonal antibody, targets the programmed death-1 (PD-1) receptor immune checkpoint pathway CheckMate 25 is a phase 2 study of nivolumab in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (chl) after failure of autologous hematopoietic cell transplantation (auto-hct) that demonstrated: 1,2 High objective response rate (ORR): 69% Durable efficacy Prolonged overall survival (OS) in patients with stable or progressive disease (PD) Acceptable safety profile CR, complete response; NE, not estimable; PR, partial response; PFS, progression-free survival; SD, stable disease 1. Younes A et al. Lancet Oncol 216;17:1283 94. 2. Fanale M et al. ICML 217 [Oral 125] Probability of PFS 1..9.8.7.6.5.4.3.2.1 PFS in CheckMate 25 3 6 9 12 15 PFS (months) CR: 22 (19, NE) months PR: 15 (11, 19) months SD: 11 (6, 18) months Median (range) follow-up: 18 (1, 27) months PD: 2 (2, 2) months Figure modified from Fanale M et al. ICML 217 [Oral 125] 18
Atypical Responses to Checkpoint Inhibitor Therapy In chl, patients who have radiographic progression while on chemotherapy do not benefit from continued treatment beyond initial progression In contrast, atypical response patterns including pseudo-progression with checkpoint inhibitors led to clinical benefits in some patients with solid tumors who had been treated beyond progression 1,2 A protocol amendment to the CheckMate 25 study (July 214) allowed patients with stable performance status and perceived clinical benefit to be treated beyond investigator-assessed disease progression (TBP) Disease progression was classified into 3 categories (IWG 27 criteria) 3 1) Increase in overall tumor burden a 2) Non-target lesion growth b 3) Development of new lesion c a 5% increase from nadir in sum of the product of the diameters. b Defined as unequivocal progression as determined by investigator assessment per protocol. c Appearance of any new lesion >1.5 cm in any axis, even if other lesions decreasing in size IWG, International Working Group 1. George S et al. JAMA Oncol 216;2:1179 86. 2. Long GV et al. JAMA Oncol 217;3:1511-19. 3. Cheson BD et al. J Clin Oncol 27;25:579 86
Phase 2 CheckMate 25 chl Study Design Cohort A BV naïve n = 63 Nivolumab 3 mg/kg IV every 2 weeks Treatment until disease progression or unacceptable toxicity; patients could elect to discontinue and proceed to allogeneic (allo)-hct Primary endpoint ORR by IRC in each cohort R/R chl after failure of auto-hct N = 243 Cohort B BV after auto-hct n = 8 Cohort C BV before and/or after auto-hct n = 1 Newly diagnosed advancedstage Cohort D Nivolumab plus AVD N=51 ASH abstract #651 BV, brentuximab vedotin; FDG-PET, fluorodeoxyglucose positron emission tomography; IRC, Independent Radiology Review Committee
Phase 2 CheckMate 25 R/R chl Study Design Cohort A BV naïve n = 63 Nivolumab 3 mg/kg IV every 2 weeks Treatment until disease progression or unacceptable toxicity; patients could elect to discontinue and proceed to allogeneic (allo)-hct Primary endpoint ORR by IRC in each cohort R/R chl after failure of auto-hct N = 243 Cohort B BV after auto-hct n = 8 Cohort C BV before and/or after auto-hct n = 1 Progression n = 15 Not treated beyond progression n = 35 Cohort A n = 19 Treatment beyond progression a n = 7 Cohort B n = 23 Cohort C n = 28 Prespecified exploratory endpoint Tumor burden change Patients with investigator-assessed progression could continue to receive treatment until further progression ( 1% greater increase in tumor burden) a Patients eligible for treatment beyond investigator-assessed progression (IWG 27 criteria) were required to have perceived clinical benefit and stable performance status, and not to have rapid disease progression. FDG-PET scans were not mandated after investigator-assessed progression BV, brentuximab vedotin; FDG-PET, fluorodeoxyglucose positron emission tomography; IRC, Independent Radiology Review Committee
Baseline Patient Demographics Characteristic All patients N = 243 TBP n = 7 Non-TBP n = 35 Age, years 34 (18 72) 37 (18 72) 34 (23 63) Male, % 58 67 54 ECOG PS, % 1 Stage IV disease at initial diagnosis, % 27 27 17 54 46 Previous lines of therapy 4 (2 15) 3 (2 5) 4 (3 9) B symptoms, % 22 2 34 Bulky disease, % 2 19 23 Extra lymphatic involvement, % 43 46 51 Time from diagnosis to first dose of nivolumab, years 4 (1 31) 6 (1 3) 3 (1 31) Time from first dose of nivolumab to initial progression date, months - 6 (1 22) 7 (1 22) Compared with patients who progressed but did not receive further treatment (non-tbp), patients in the TBP group had better ECOG PS and fewer B symptoms at baseline 61 39 34 66 Data are median (range) unless stated otherwise. ECOG PS, Eastern Cooperative Oncology Group performance status; TBP, treated beyond progression
Characteristics of Progressive Disease Primary causes of radiographic progression reported per IWG 27, n TBP n = 7 Non-TBP n = 35 Increase in overall tumor burden a 13 7 Non-target lesion growth b 17 2 Development of new lesion c 47 13 Patients may have had multiple findings, and other characteristics may have been used by investigators to assess disease progression a 5% increase from nadir in sum of the product of the diameters. b Defined as unequivocal progression as determined by investigator assessment per protocol. c Appearance of any new lesion >1.5 cm in any axis, even if other lesions decreasing in size
Patient Disposition All patients N = 243 TBP n = 7 Non-TBP n = 35 Patients still on treatment, % 4 3 Reason off treatment, % Disease progression Study drug toxicity AEs unrelated to study drug Maximum clinical benefit Completed treatment Other Due to HCT a 26 8 2 1 3 21 12 56 4 1 9 3 63 17 3 17 6 Median of 8 (range 1 43) nivolumab doses received after initial progression in patients TBP Median follow-up time after initial progression of 4 (range <1 17) months in patients TBP a Patients may have discontinued for additional reasons and subsequently received allo-hct AE, adverse event
Treatment-Related Adverse Events Before and After Initial Progression Event Before progression n = 7 After progression n = 7 Any Grade Grade 3 4 Any Grade Grade 3 4 Drug-related AEs ( 1%), % 64 9 46 13 Infusion-related reaction 19 1 Fatigue 17 9 Rash 11 Pruritus 1 4 Lipase increased 9 4 6 3 Drug-related serious AEs ( 1%), % 9 3 3 3 Infusion-related reaction 6 1 Hyponatremia 1 1 Pneumonitis 1 Increased aspartate aminotransferase 1 1 Hypercalcemia 1 1 3 (4%) patients TBP discontinued due to drug-related AEs; a 2 (3%) patients due to increase in aspartate aminotransferase, 1 (1%) patient due to increase in alanine aminotransferase, and 1 (1%) patient due to pneumonitis There were no deaths due to study drug toxicity in patients TBP a Patients may have experienced more that 1 AE leading to discontinuation
Best Overall Response Prior to Initial Progression Best overall response prior to progression, n (%) TBP n = 7 Non-TBP n = 35 Complete remission 5 (7) 8 (23) Partial remission 31 (44) 12 (34) Stable disease 2 (29) 9 (26) Progressive disease 13 (19) 4 (11) Non-evaluable 1 (1) 2 (6)
Change in Target Lesion Burden After Initial Progression 1 Best reduction from first progression in target lesion tumor burden (%) 75 5 25 25 5 75 Best overall response prior to initial progression: CR PR PD SD Evaluable patients with target lesion reductions, n (%) a TBP n = 51 No reduction 24 (47) Any reduction 27 (53) >25% 16 (31) >5% 7 (14) 1% 1 (2) 19 patients were not evaluable for postprogression tumor burden change 1 Patients (n = 51) Patients with missing post-first progression tumor data are not included. Horizontal reference line indicates the 5% reduction consistent with a response per revised IWG 27 criteria. a Best change is defined as the maximum reduction or minimum increase in tumor burden recorded after the first progression date. BOR, best overall response; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease
Tumor Burden Change Over Time in Patients TBP BOR of complete remission prior to initial progression (n = 5) BOR of partial remission prior to initial progression (n = 31) 1 1 Change from baseline in target lesion tumor burden (%) 75 5 25 25 5 75 Change from baseline in target lesion tumor burden (%) 75 5 25 25 5 75 1 1 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 96 12 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 96 12 Time since first treatment date (weeks) Time since first treatment date (weeks) Before first progression After first progression Off treatment All assessments are per investigator using 27 IWG criteria; horizontal reference line indicates the 5% reduction consistent with a response. Patients TBP are defined as patients whose last available dose date is after the date of initial progression per 27 IWG based on investigator assessment; figure includes patients with missing post-progression assessments. Data shown for patients with consistent tumor evaluations. One patient with no evaluable BOR was excluded. BOR, best overall response
Tumor Burden Change Over Time in Patients TBP BOR of stable disease prior to initial progression (n = 2) BOR of progressive disease prior to initial progression (n = 13) 1 1 Change from baseline in target lesion tumor burden (%) 75 5 25 25 5 75 Change from baseline in target lesion tumor burden (%) 75 5 25 25 5 75 1 1 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 96 12 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 96 12 Time since first treatment date (weeks) Time since first treatment date (weeks) Before first progression After first progression Off treatment % change truncated to 1% All assessments are per investigator using 27 IWG criteria; horizontal reference line indicates the 5% reduction consistent with a response. Patients TBP are defined as patients whose last available dose date is after the date of initial progression per 27 IWG based on investigator assessment; figure includes patients with missing post-progression assessments. Data shown for patients with consistent tumor evaluations. One patient with no evaluable BOR was excluded. BOR, best overall response
Time to Response and Duration of Response in Patients TBP Lines show time from first dose to last dose, according to reduction in tumor burden after initial progression First PR First CR Treatment before progression First progression On treatment Off treatment Patients Death Next therapy start Median time to first response prior to progression (n = 36) was 2 (range 2 6) months Median duration of response prior to progression was 6 (95% CI 4 7) months 8 16 24 32 4 48 56 64 72 Time since first dose (weeks) 8 88 96 14 112
Time to Response and Duration of Response in Patients TBP Lines show time from first dose to last dose, according to reduction in tumor burden after initial progression Treatment before progression Patients First PR First CR First progression On treatment Off treatment Death Next therapy start Best reduction in tumor burden a 5% >25 <5% > 25% % Not determined Median duration of treatment beyond progression was 5 (95% CI 3 9) months Median overall time from first dose to next therapy in patients TBP was 17 (95% CI 14 NE) months 8 16 24 32 4 48 56 64 72 Time since first dose (weeks) 8 88 96 14 112 a Best change is defined as the maximum reduction or minimum increase in tumor burden recorded after the first progression date
Time From Initial Progression to Next Therapy 1. Probability of patients free of next treatment.9.8.7.6.5.4.3.2.1 TBP, median 8.8 (5.5, NE) months Non-TBP, median 1.5 (.6, 3.3) months. 2 4 6 8 1 12 14 16 18 2 Number of patients at risk TBP Non-TBP 7 35 Time since first progression (months) 35 13 3 1 Time to next treatment is defined as time of first progression date to first subsequent therapy date or death, whichever occurs first. Data are median (95% CI) unless stated otherwise NE, not estimable
Overall Survival 1. Probability of survival.9.8.7.6.5.4.3.2.1. Overall N = 243 PGF n = 138 TBP n = 7 PGF TBP Non-TBP Non-TBP n = 35 12-month OS, % (95% CI) 92 (88, 95) 96 (9, 98) 93 (83, 97) 8 (62, 9) Number of patients at risk 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 24 OS (months) PGF 138 135 135 133 132 129 126 123 15 74 54 45 15 TBP 7 69 69 66 66 66 6 57 44 3 21 14 7 Non-TBP 35 34 32 3 28 26 23 21 19 12 9 4 1 PGF, progression-free patients
Summary and Conclusions Summary In CheckMate 25, 7 of 15 (67%) patients with investigator-assessed disease progression were TBP New lesions were the most common cause (67%) of initial progression in patients TBP Stable reductions in tumor burden were seen with continued nivolumab treatment in patients TBP OS from first dose of study drug was 93% at 12 months for patients TBP (vs 8% for non-tbp) Median time from initial progression to next therapy was 8.8 months for patients TBP (vs 1.5 months for non-tbp) Nivolumab was well tolerated and had an acceptable safety profile consistent with previous studies Conclusions Patients who have stable performance status and progression according to conventional response criteria may derive long term clinical benefit from continued nivolumab treatment Two proposed updates to conventional response criteria LYRIC and RECIL may help better assess the long-term efficacy of checkpoint inhibitors and help evaluate which patients may benefit from TBP LYRIC, LYmphoma Response to Immunomodulatory therapy Criteria; RECIL, Response Evaluation Criteria in Lymphoma Clinical Trials
Acknowledgments The patients and families for making this trial possible The clinical study teams at 34 sites in 1 countries that participated in the CheckMate 25 trial Study funded by Bristol-Myers Squibb Professional medical writing provided by Simon Wigfield of Caudex, and was funded by Bristol Myers Squibb
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