To evaluate patterns of rrHL after contemporary first-line treatment we studied 409 patients with first rrHL (HD13: n = 87, HD14: n = 118, HD15: n = 188, HDR3i: n = 51) at a median age of 37.4 years ...(18.4-76.8) from the GHSG database. Time to first relapse was ≤12 months in 49% and stage III/IV rrHL present in 52% of patients. In total, 291 patients received high-dose chemotherapy and autologous stem-cell transplantation (ASCT) and intended ASCT failed in 38 patients. ASCT was primarily not intended in 80 patients largely due to low risk disease or age/comorbidities. Overall, 10-year progression-free (PFS) and overall survival (OS) rates after first relapse were 48.2% (95% CI 41.9-54.2%) and 59.4% (95% CI 53.0-65.2%), respectively, with significant differences between subgroups. Inferior survival was observed with no ASCT due to advanced age/comorbidities (five-year PFS 36.2%, 95% CI 17.7-55.0%) or failure of salvage therapy (five-year PFS 36.3%, 95% CI 19.7-53.2%). Similarly, presence of primary refractory disease or stage IV at rrHL conferred inferior survival. In patients with low-risk disease, however, survival appeared favorable even without ASCT (10 y PFS 72.6%, 95% CI 53.7-84.8%). We herein confirm the curative potential of current rrHL treatments providing a robust benchmark to evaluate novel therapeutic strategies in rrHL. Approximately 50% of rrHL patients experienced a consecutive relapse.
The KEYNOTE-013 study was conducted to evaluate pembrolizumab monotherapy in hematologic malignancies; classical Hodgkin lymphoma (cHL) was an independent expansion cohort. We present long-term ...results based on >4 years of median follow-up for the cHL cohort. The trial enrolled cHL patients who experienced relapse after, were ineligible for, or declined autologous stem cell transplantation and experienced progression with or did not respond to brentuximab vedotin. Patients received IV pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety and complete response (CR) rate by central review. Enrolled patients (N = 31) had received a median of 5 therapies (range, 2 to 15). After a median follow-up of 52.8 months (range, 7.0 to 57.6 months), CR rate was 19%, and median duration of response (DOR) was not reached; 24-month and 36-month DOR rates were both 50% by the Kaplan-Meier method. Median overall survival was not reached; 36-month overall survival was 81%. Six patients (19%) experienced grade 3 treatment-related adverse events (AEs); there were no grade 4 or 5 treatment-related AEs. With long-term follow-up among a heavily pretreated cohort, pembrolizumab had a favorable safety profile; some patients maintained long-term response with pembrolizumab years after end of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01953692.
•Pembrolizumab provided durable responses over long-term follow-up in a subset of heavily pretreated patients with classical Hodgkin lymphoma.•Pembrolizumab had a favorable safety profile in heavily pretreated patients with classical Hodgkin lymphoma over long-term follow-up.
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The multicohort phase 1b KEYNOTE-013 study (NCT01953692) evaluated the safety and efficacy of pembrolizumab in patients with relapsed or refractory NHL who were ineligible for or failed hematopoietic ...cell transplantation (HCT). Patients received pembrolizumab (cohort 4) or pembrolizumab plus lenalidomide (cohort 5). Primary end points were safety and objective response rate (ORR) per IWG 2007 criteria. Cohort 4 included 89 patients. ORR was 22% (19/86; 90% CI 15-31; 10 CR, nine PR); ORRs by disease type were 48% (10/21), 10% (2/20), 12% (5/41), and 50% (2/4), for PMBCL, FL, DLBCL, and 'other' NHL, respectively. Toxicity was as predicted. Cohort 5 included 19 patients. ORR was 39% (90% CI 20-61; four CR, three PR). Hematologic toxicities were the most common treatment-related AEs. In conclusion, pembrolizumab following HCT ineligibility/failure confirms prior experience in PMBCL but not with NHL subtypes in this study. Additional analyses in DLBCL may not be warranted.
Background: Carfilzomib (Car, 2012), pomalidomide (Pom, 2013), and panobinostat (Pano, 2015) were approved for the treatment of rrMM patients after failure of at least two prior standard therapies. ...There is limited real-world data on utilization of these medications, health care resource utilization (HCRU) and costs in patients with rrMM at the US population level. This study aimed to describe treatment pattern, HCRU, and costs in rrMM patients who received at least two prior therapies using a large administrative claims database.
Methods: This was a retrospective database analysis using the Truven Health MarketScan Commercial and Medicare Database. Patients (pts) were included if they were diagnosed with MM between Jan 1, 2006 and May 31, 2015, were ≥18 yrs, had no claim for stem cell transplant, and had ≥6 mos continuous enrollment before and ≥1 mos after the 1st MM diagnosis (index date) and treatment initiation (TI). Only patients who had ≥6 mos continuous enrollment after TI were included in HCRU and cost evaluation. If two or more drugs started within 90 days, they were considered as 1 regimen. End of a line of therapy (LOT) was defined when a new treatment was introduced or there was a treatment gap >90 days or end of follow-up, whichever occurred first. Third line of therapy (3L) was identified following 2 prior lines of therapy. Time to next treatment (TTNT) was defined from initiation of the LOT to initiation of subsequent LOT. Duration of treatment (DOT) and TTNT were estimated based on Kaplan-Meier method. Regimens were classified into 6 mutually-exclusive categories, including bortezomib (Bor), lenalidomide (Len), Pom, Car, thalidomide (Thal), and Other based therapies. HCRU and cost (per patient per month, PPPM) were calculated. The total costs included inpatient costs, outpatient costs and pharmacy costs.
Results: A total of 9,960 pts were identified with initiation of 1L therapy. Median age was 67 yrs. And 57.4% were male. During an average of 20.0 mos follow-up post TI, 3,282 (33.0%), 1,103 (11.1%) and 400 (4%) pts initiated 2L, 3L, and 4L therapies, respectively. During 3L therapy, Bor (43.5%, including 10.5% for Bor-Len) and Len based regimens (29.8%) were most commonly observed. Median DOTs ranged from Car (3.7 mos) to Len (8.1 mos) based regimens. Median TTNT from short to long was Car, Pom, Bor, Len, Other, and Thal based regimens. On average, each patient with rrMM had 4.5 outpatient visits, 0.1 inpatients visits, 0.1 ER visits and 0.004 hospice care visits per month. The average PPPM costs were $14,286, $13,377, $11,919, for Bor, Len, Thal based regimens and $25,850 and $21,180 for Pom and Car based regimens, respectively.
Conclusions: Although novel agents were added to rrMM treatment, Bor and/or Len based regimens remained the most commonly used therapies in 3L setting. Compared to Bor, Len and Thal based therapies, PPPM costs were higher for Pom and Car based regimens. These data could be useful for treatment consideration and economic evaluation.
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Shao:Merck & Co., Inc.: Employment. Monberg:Merck & Co.: Employment. Cao:Merck & Co.: Employment. Zhou:Merck & Co.: Employment. Zhong:Merck & Co., Inc.: Employment. Marinello:Merck & Co., Inc.: Employment.
Introduction: Standard of care for patients (pts) with relapsed or refractory classic Hodgkin lymphoma (R/R cHL) remains salvage chemotherapy with subsequent autologous stem cell transplantation ...(ASCT), which leads to long-term remission in about half of pts. Prognosis is poor for pts who relapse or progress after ASCT, particularly among pts who relapse after prior treatment with brentuximab vedotin (BV). Programmed death 1 (PD-1) inhibitors are an effective therapeutic option. Previous analyses of the multicohort phase 2 KEYNOTE-087 (NCT02453594) study showed that PD-1 pathway inhibition with pembrolizumab (pembro) led to effective antitumor activity and acceptable safety in pts with R/R cHL. KEYNOTE-087 results led to FDA approval of pembro for adult and pediatric pts with R/R cHL who relapsed after ≥3 prior lines of therapy. Long-term durability of response is a key clinical question for pts receiving immunotherapy. We present efficacy and safety of patients in KEYNOTE-087 who received 3 y of follow-up and evaluate antitumor activity in pts who were re-treated after disease progression.
Methods: Pts with R/R cHL who progressed after ASCT and subsequent BV therapy (cohort 1), underwent salvage chemotherapy and BV and were ineligible for ASCT (cohort 2), or progressed after ASCT but were not treated with BV after ASCT (cohort 3) were enrolled and received pembro 200 mg IV Q3W. Pts who discontinued pembro after initial confirmed CR after ≥6 mo of treatment and then experienced disease progression were eligible to receive an additional ≤17 cycles (~1 y) of pembro (second course). Response was assessed Q12W per 2007 Revised Response Criteria for Malignant Lymphomas. Primary end points were safety and overall response rate (ORR) per blinded independent central review in all pts in each cohort. Secondary end points included complete remission (CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Results: At data cutoff, median follow-up was 39.5 mo (range, 1.0-44.8). In the total population (N=210), 46 pts completed 2 y of treatment, 164 pts discontinued (primary reason, progressive disease n=86). ORR was 71.0% (95% CI, 64.3-77.0) with 58 CRs (27.6%) and 91 PRs (43.3%). ORR was 78.3% (CR, n=18; PR, n=36) in cohort 1 (n=69), 64.2% (CR, n=21; PR, n=31) in cohort 2 (n=81), and 71.7% (CR, n=19; PR, n=24) in cohort 3 (n=60). Overall median DOR was 16.6 mo (95% CI, 0.0+ to 39.1+). 45.1% of pts had a response duration ≥24 mo; 26.9% had a response duration ≥36 mo. 19/149 (12.8%) pts had an ongoing response. Median DOR was 25.0 mo in cohort 1, 11.1 mo in cohort 2, and 16.8 mo in cohort 3. In the total population, median PFS was 13.6 mo (95% CI, 11.1-16.7) and the 36-mo PFS rate was 18.8%. Median PFS was 16.4 mo (95% CI, 11.3-27.6) in cohort 1, 11.1 mo (95% CI, 7.3-13.5) in cohort 2, and 19.4 mo (95% CI, 8.4-22.1) in cohort 3. Median OS was not reached in the total population or in the cohorts; 36-mo OS rate was 86.4% in the total population, 86.3% in cohort 1, 85.7% in cohort 2, and 87.6% in cohort 3. 17 pts entered the second-course phase, of whom 16 were evaluable for response (8 in cohort 1, 6 in cohort 2, 2 in cohort 3). 4 pts completed 17 cycles of treatment; 7 pts have ongoing treatment. Second-course ORR was 68.8% with 5 CRs (31.3%) and 6 PRs (37.5%); 4 pts (25.0%) had stable disease. ORR for cohorts 1, 2, and 3 was 75.0% (CR, n=1; PR, n=5), 83.3% (CR, n=4; PR, n=1), and 0.0%, respectively. Both pts in cohort 3 had stable disease; 1 completed 17 cycles of pembro and the other is still receiving treatment. Treatment-related adverse events (AEs) of any grade occurred in 72.9% of pts; the most commonly reported were hypothyroidism (14.3%), pyrexia (11.4%), fatigue (11.0%), and rash (11.0%). Grade 3-4 treatment-related AEs occurred in 11.9% of pts; only neutropenia (n=5) and diarrhea (n=2) occurred in ≥2 pts. No grade 5 treatment-related AEs occurred.
Conclusions: With a median of 39.5 mo of follow-up, pembro continued to demonstrate clinically important antitumor activity in pts with R/R cHL. In the total population and in pts with different treatment histories, ORRs were high and responses were durable. Second-course pembro was able to re-induce remission in most patients who previously reached CR. Safety was manageable, and no unexpected AEs occurred.
Zinzani:VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy. Armand:Sigma-Tau: Research Funding; Otsuka: Research Funding; Pfizer Inc: Research Funding; Merck & Co.: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Affimed: Research Funding; Serventa: Research Funding; Bristol Myers Squibb Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Infinity Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Employment; Roche: Research Funding. Johnson:Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria. Brice:Millennium Takeda: Research Funding; BMS: Honoraria; Takeda France: Consultancy, Honoraria. Radford:Novartis: Consultancy, Honoraria; GSK: Equity Ownership; BMS: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Equity Ownership, Research Funding. Ribrag:Incyte: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; Infinity: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Epizyme: Consultancy, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses . Molin:Merck & Co., Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Roche Holding AG: Honoraria. Vassilakopoulos:Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others; Genesis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tomita:Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Taiho Pharma: Research Funding. Von Tresckow:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Amgen: Honoraria; Celgene: Honoraria; Merck Sharp & Dohme Corp: Research Funding. Shipp:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Merck & Co.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astr
Introduction: Currently available therapy options for primary mediastinal large B-cell lymphoma (PMBCL) generally yield poor treatment outcomes. Like classical Hodgkin lymphoma (cHL), PMBCL ...frequently exhibits 9p24.1/PD-L1/PD-L2 copy number alterations and rearrangements and associated PD-L1 and/or PD-L2 overexpression, which may facilitate immune evasion. The genetics of PMBCL could thus make it susceptible to PD-1 blockade. KEYNOTE-013 (NCT01953692) is an ongoing multicenter, multicohort Phase 1b trial evaluating safety, tolerability, and antitumor activity of pembrolizumab, a humanized anti-PD-1 monoclonal antibody, in patients with hematologic malignancies. Here we report results from the first 19 patients enrolled in the PMBCL cohort of KEYNOTE-013, with a follow-up of up to 2 years.
Methods: This independent cohort of KEYNOTE-013 is enrolling patients with relapsed/refractory (R/R) PMBCL who have relapsed after or are ineligible for autologous stem cell transplant (SCT). Patients received pembrolizumab IV 10 mg/kg every 2 weeks (Q2W), which was later changed by protocol amendment to a fixed dose of 200 mg every 3 weeks (Q3W), following PK/PD studies demonstrating both regimens to be equivalent. Treatment continues for up to 2 years or until unacceptable toxicity or confirmed disease progression. Treatment response is evaluated using IHP 2007 criteria by positron emission tomography and computed tomography at weeks 6 and 12, and every 9 weeks thereafter. Primary end points are safety and objective response rate (ORR). Secondary end points include complete remission (CR) rate and duration of response (DOR). The safety population consists of all patients who receive ≥1 dose of study drug and the efficacy population of all patients who progress prior to or reach the first efficacy evaluation. Whole blood was collected at predefined time points before and during pembrolizumab treatment for RNA and DNA extraction and biomarker analysis using a number of genomic-based assays, including NanoString and RNA sequencing.
Results: As of the analysis cutoff date (May 27, 2016), 19 patients were enrolled in the PMBCL cohort, 18 were treated, and 16 had ≥1 post-baseline efficacy evaluation. The first 11 patients were to receive pembrolizumab IV 10 mg/kg Q2W (1 was not treated due to early progressive disease); all subsequent patients received 200 mg Q3W. Median age was 30.5 years (range, 22-62). Most patients (72%) were female. 61% of patients had ≥3 prior lines of therapy, 33% had prior autologous SCT, and 61% prior radiation. In the efficacy population, 16 patients were evaluable for response: one discontinued treatment based on clinical progression before the first response assessment (this patient was considered a nonresponder), the other had not reached the first assessment.The ORR was 41% (7/17), with 2 patients achieving a CR and 5 patients a partial response; 35% (6/17) had stable disease as best response. Overall, 81% (13/16) of evaluable patients had target lesion reductions (Figure). With a median follow-up duration of 11.3 months (range, 3.4 to 27.4 months), median DOR was not reached, and there were 6 ongoing responses at time of current data cutoff. DOR ranged from 2.4+ to 22.5+ months; DOR in the 2 patients with CR was 2.4+ and 20.5+ months. Two patients received an allogeneic SCT: one had SD, the other PD on pembrolizumab. Ten patients discontinued treatment: 5 due to progressive disease based on imaging, 4 for clinical progression, and 1 due to physician decision. Two patients reached the maximum 2 years of treatment and remain in remission. Six patients experienced serious AEs, and none discontinued due to AEs. Eleven patients (61%) experienced treatment-related adverse events (TRAEs), mostly grade 1-2. One patient experienced a TRAE of grade 3 neutropenia and another a TRAE of grade 4 venoocclusive liver disease (VOD; after allogeneic SCT during the follow-up period after pembrolizumab was discontinued), the only serious TRAE. The patient recovered from the VOD. There were no treatment-related deaths.
Conclusions: These results from an on-going study in heavily pretreated R/R PMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a manageable safety profile and promising antitumor activity. Due to these results, a pivotal global multi-center Phase 2 trial, KEYNOTE-170, is further evaluating single agent pembrolizumab in patients with R/R PMBCL.
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Zinzani:MorphoSys: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Abbvie: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees. Ribrag:Esai: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees; Infinity: Membership on an entity’s Board of Directors or advisory committees; Pharmamar: Membership on an entity’s Board of Directors or advisory committees; ArgenX: Research Funding; Incyte: Membership on an entity’s Board of Directors or advisory committees; NanoString: Membership on an entity’s Board of Directors or advisory committees. Moskowitz:Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy; Genentech BioOncology: Consultancy. Michot:Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees. Kuruvilla:Merck & Co., Inc.: Consultancy, Honoraria. Balakumaran:Merck & Co.: Employment, Other: stock, stock options. Zhang:Merck & Co., Inc.: Employment, Other: stock, stock options. Marinello:Merck & Co., Inc.: Employment, Other: stock, stock options. Chlosta:Merck & Co., Inc.: Employment, Other: stock, stock options. Gustafson:Merck & Co., Inc.: Employment, Other: stock, stock options. Shipp:Merck & Co., Inc.: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Armand:Otsuka: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Infinity: Consultancy; Roche: Research Funding; Sequenta: Research Funding; Tensha: Research Funding; Sigma Tau: Research Funding.
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