ALBERT

Beschreibung: Background:Treatment options for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) are limited. Ibrutinib is a first-in-class small-molecule inhibitor of Bruton's tyrosine kinase. These extended access programs (EAP) provided patient access to ibrutinib in Brazil and real-world safety data was collected, at a time when the medication was not commercially available in Brazil. Methods:These two prospective, multicenter, open-label EAPs of single-agent ibrutinib were conducted between April 2013 and August 2017, and enrolled Brazilian patients with relapsed/refractory CLL or MCL. Eligible patients must have progressive disease after at least one prior therapy and not suitable for retreatment with purine analogue therapy. After a 30-day screening, eligible patients received once-daily oral ibrutinib 420 mg (CLL) or 560 mg (MCL) continuously until disease progression, unacceptable toxicity, absence of clinical benefit, or end of EAP, whichever occurred first. Doses could be withheld or reduced based on toxicity. Patients were monitored for safety and disease evaluations were conducted per routine local standard of care practices. Results:Of 33 CLL patients enrolled, 32 received one dose of drug or more and were included in the safety analysis. Median age was 62.5 years, and most patients were male (n=24; 75%) and white (n=27; 84.4%). The median time from CLL diagnosis to study inclusion was 83.8 months and from diagnosis to relapsed/refractory state, 42.0 months. The median number of ibrutinib cycles was 12.0 (1.0-16.0) with a median treatment duration of 11.1 (0.9-11.6) months. Eight patients discontinued due to adverse event (AE; n = 4; 12.5%), consent withdrawal (n = 2; 6.3%), death (n = 1; 3.1%), or disease progression (n = 1; 3.1%). AEs leading to treatment discontinuation were intestinal bleeding, neutropenia, infection, and gastric tumor (one patient each). Three (9.4%) patients had dose reductions: one (3.1%) for neutropenia, febrile neutropenia with pneumonia, or worsening fatigue. 21 patients (65.6%) had at least one Grade ≥3 (G3) AE or serious AE (SAE). The most frequent G3 or SAEs included neutropenia in 8 (25.0%), fatigue (1), leukocytosis (1), and pneumonia (3). No atrial fibrillation or bleeding AEs were reported. Among the 47 G3 or SAEs, 17 (36.2%) were serious, 38 (80.9%) were suspected to be related to ibrutinib, and 39 (83.0%) were resolved without sequelae. All 13 MCL patients enrolled in the study were included in the safety analysis. The median age was 60.0 years, and most patients were male (n=9; 69.2%) and white (n=9; 69.2%). The median number of prior treatment regimens were 3. The median time from diagnosis to the first dose of ibrutinib was 20.4 months. The median number of ibrutinib cycles was 19 (4.0-34.0) with a median treatment duration of 16.8 (3.6-30.5) months. Eight patients discontinued because of either death (n=3; 23.1%) or disease progression (n=5; 38.5%). The three patients died with treatment-emergent G4 or higher AEs, including pneumonia (G5; probably treatment-related [TR]), sepsis (G5; not TR), and dyspnea (G4; doubtful TR); 8 patients (61.5%) had at least one G3 or higher treatment-emergent AE. The most frequent AE was diarrhea (n=3; 23.1%), and other AEs were reported in one patient each (i.e. abdominal hernia, anemia, appendicitis, dyspnea, febrile neutropenia, influenza, leukocytosis, neutropenia, pneumonia, productive cough, renal failure/insufficiency, retroperitoneal abscess, thrombocytopenia). Three (23.1%) patients had ibrutinib dose modifications: one (7.7%) each because of appendicitis/tuberculosis, thrombocytopenia, and diarrhea/retroperitoneal abscess/dyspnea. No atrial fibrillation or bleeding AEs were reported. Among the 20 G3 or higher treatment-emergent AEs, 14 (70%) were suspected to be related to ibrutinib and 15 (75%) were resolved. Conclusions: This is the first real-world experience with ibrutinib monotherapy for CLL and MCL in Brazil. Overall, treatment was well tolerated with no unexpected toxicities. No atrial fibrillation or bleeding AEs were reported. Of 32 patients with relapsed/refractory CLL, 24 (80%) remained on therapy, 4 (12.5%) discontinued due to AEs, 1 (3.1%) each died or experienced disease progression. Among 13 patients with relapsed/refractory MCL, 5 (38.5%) remained on the therapy, 3 (23.1%) died and 5 (38.5%) experienced disease progression. Disclosures Chiattone: Janssen: Honoraria, Research Funding. Fogliatto:Novartis: Consultancy; Janssen: Honoraria, Research Funding; Roche: Consultancy, Speakers Bureau. Scheinberg:Novartis: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding; Pfizer: Speakers Bureau. Bigni:Janssen: Honoraria, Research Funding. Rodrigues:Janssen: Honoraria, Research Funding. Garicochea:Janssen: Honoraria, Research Funding. Pimenta:Janssen: Honoraria, Research Funding. Boechat:Janssen: Honoraria, Research Funding. Musacchio:Janssen: Honoraria, Research Funding. Goncalves:Janssen: Honoraria, Research Funding. Vieira:Janssen: Honoraria, Research Funding. Santos:Janssen: Employment. Grings:Janssen: Employment. Parisi:Janssen: Employment. Barreyro:Janssen: Employment.

Beschreibung: Introduction: The open-label, international, randomized, phase 3 KEYNOTE-204 (NCT02684292) study showed that in pts with R/R cHL, the PD-1 inhibitor pembro was superior to BV and demonstrated statistically significant, clinically meaningful improvement in PFS, with safety consistent with previous reports. This post hoc exploratory analysis of KEYNOTE-204 evaluated pembro vs BV by number of prior lines of therapy. Methods: Eligible pts were aged ≥18 y, had measurable disease and ECOG PS 0 or 1, and were post−autologous stem cell transplant (auto-SCT) or ineligible for auto-SCT. Pts who were BV-naive or BV-exposed were also eligible. Pts were randomized 1:1 to pembro 200 mg IV Q3W or BV 1.8 mg/kg IV Q3W. Randomization was stratified by status after 1L therapy (primary refractory vs relapsed

Beschreibung: Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs 〉75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients 〉75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: 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; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.