BackgroundThe endothelin B receptor (ETBR) is upregulated in many types of cancer and is associated with poor overall survival and a paucity of TILs (tumor infiltrating lymphocytes).1 The ETBR ...prevents T-cell extravasation and tumor infiltration by a mechanism involving adhesion molecule downregulation in the tumor vasculature. Thus ETBR expression may mediate resistance to immunomodulatory therapy. ENB-003 is a small molecule ETBRi (ETBR inhibitor) which overcomes resistance to anti-PD1 across multiple cancer types in preclinical studies. Part 1 of this study seeks to evaluate the safety and tolerability of ENB-003 in combination with pembrolizumab in refractory advanced ETBR+ solid tumors. Part 2 of the study is an expansion cohort basket trial assessing the efficacy of ENB-003 in combination with pembrolizumab in anti-PD1 refractory melanoma, platinum resistant ovarian cancer and refractory pancreatic cancer.MethodsStudy ENB-003-101 (MK-3475-951) is a multicenter, Phase 1/2, open-label study of ENB-003 in combination with pembrolizumab in adult subjects with advanced solid tumors. The part 1 dose escalation is enrolling subjects with ETBR+ tumors and includes 5 doses of ENB-003 in combination with a fixed dose of pembrolizumab. The primary objective of part 1 is to assess safety and tolerability, the secondary objective is to evaluate anti-tumor effect (RECIST 1.1 and iRECIST). Exploratory objectives are to examine biomarkers/pharmacodynamics.ResultsENB-003, as a single agent and in combination with anti-PD1, was investigated in a variety of syngeneic preclinical models. ENB-003 enhanced the anti-tumor activity of anti-PD1 in anti-PD1 resistant models of melanoma, ovarian cancer, pancreatic cancer, bladder cancer and SCC. For example, the combination of ENB-003 plus anti-PD1 in an anti-PD1-resistant melanoma model resulted in complete tumor eradication in 21 days as well as the formation of TLOs (tertiary lymphoid organs). The combination of ENB-003 plus pembrolizumab was well tolerated in the first 2 cohorts of the ongoing Phase 1 trial in patients with advanced refractory solid tumors that are ETBR+. Best overall responses from the first 2 cohorts (n=6) demonstrates disease stabilization (SD) in 2 patients as well as a partial response (PR) in an ovarian cancer patient with ~60% reduction in target lesions.ConclusionsETBRi is a novel approach to overcoming immunotherapy resistance. The combination of ENB-003 and pembrolizumab is well tolerated thus far and is demonstrating promising early signals of anti-tumor efficacy. Trial updates will be reported.Trial RegistrationNCT04205227Ethics ApprovalThis study was approved by an institutional Review Board at each investigational site.ReferenceKandalaft L, Facciabene A, Buckanovich R, Coukos G. Endothelin B Receptor, a New Target in Cancer Immune Therapy. Clin Cancer Res 2009;15(14):4521-4528.
Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk ...models underperform in cohorts with lung and gastrointestinal cancers.
To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers.
This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies TARGET-TP) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts.
High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control).
The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation.
Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years range, 30-88 years; 176 male 54%). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio HR, 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001).
In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population.
ANZCTR Identifier: ACTRN12618000811202.
BACKGROUND
The prior Australasian Leukaemia and Lymphoma Group (ALLG) CLL5 Study showed dose-reduced oral fludarabine and cyclophosphamide plus rituximab (FCR3) was safe, tolerable and effective in ...fit elderly patients for front-line therapy for CLL. The German CLL11 Study showed chlorambucil plus obinutuzumab (Cbl+G) was superior to chlorambucil alone or with rituximab in unfit patients requiring initial therapy. We conducted a randomized study to assess the safety, tolerability, and efficacy of dose-reduced FC + obinutuzumab (G) (FC+G) versus Cbl+G in unfit (i.e. with comorbidity), elderly patients with CLL.
METHODS
Patients aged ≥65 years and considered “unfit” defined by co-morbidities using the Cumulative Illness Rating Scale CIRS ≥6 were eligible for the ALLG CLL7 study. Patients with any single organ system score ≥4 were excluded. Previously untreated patients with progressive CLL aged ≥65 and CIRS ≥6 were randomised to one of 2 therapy arms: (i) Chlorambucil 0.5mg/kg D1+15 p.o. + obinutuzumab (“G”) (i.v. 1000mg/m2 cycle 1, Day 1, 8, 15, and 1000mg/m2 D1 cycles 2-6), or (ii) FC(rd)+G: F-24mg/m2 p.o. and C-150mg/m2 p.o. D1-3 + G (same schedule above) at 4 weekly intervals for planned 6 cycles. Early stopping for toxicity was mandated: treatment could be delayed for 2 weeks for grade 3+ toxicity, but if unresolved by 2 weeks, patients were taken off study. The primary end-point was grade 3+ non-hematological, and grade 4 hematological adverse events. Secondary objectives were overall response rate (ORR), complete remission (CR), partial remission (PR), progression-free survival (PFS) and overall survival (OS) and minimal residual disease (MRD) negativity. Final staging was performed between 2-3 months following final treatment cycle.
RESULTS
Patient characteristics Patient recruitment was terminated early due to poor recruitment. At the time of study closure, there were 32 patients, with 15 on Cbl+G and 17 on FC(rd)+G. The mean age was 74.2 years (range 66-85 years) with 23 females (71.9%) and 9 males (28.1%). The CIRS score was 6 in 4 patients (12.5%), 6-8 in 14 (43.8%), 8-10 in 11 (34.4%) and >10 in 3 (9.4%). Binet stage at registration was stage A 18.2%, B 27.3% and C 54.5%.
Tolerability Both therapies were tolerable with 15/17 (88.2%) completing all 6 cycles of FC(rd)+G and 12/15 (92.3%) completing six cycles of Cbl+G.
Toxicity Most toxicity was hematological and manageable. Grade 3/4 hematological toxicity was more common with FC(rd)+G than Cbl+G occurring in 60% with FC(rd)+G and 38.5% with Cbl+G (Table 1). There was one death due to progressive CLL on the FC(rd)+G arm.
Response rate A complete remission (CR), confirmed by bone marrow (BM) trephine, was achieved in 86.6% of patients on FC(rd)+G versus (vs) 53.9% on Cbl+G, partial response (PR/nPR) in 1 (6.7%) on FC(rd)+G, and 6 (46.2%) on Cbl+G, and either stable or progressive disease (SD or PD) on 1 on FC(rd)+G, and nil on Cbl+G. BM MRD-negativity rates were 3/17 (20.0%) FC(rd)+G vs 1/15 (7.7%) Cbl+G (Table 2).
CONCLUSION
This randomized trial of dose-reduced FC(rd)+G vs Cbl+G in elderly patients aged ≥65 and with co-morbidities (CIRS ≥6) was terminated early due to poor recruitment. Due to the dose-reduced FC, and early stopping rule, treatment was safe and tolerable and most patients completed all 6 cycles of planned therapy. Grade 3/4 toxicity was mainly hematological and manageable, with higher rates of neutropenia with the FC (60%) vs Cbl (35.7%) backbone. FC(rd)+G compared to Cbl+G resulted a higher CR rate of 86.6%% versus 53.9%, and higher MRD-negativity (20% vs 7.7%). Progression-free and overall survival are being evaluated.
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Badoux:Roche: Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Background:
Carfilzomib lenalidomide and dexamethasone (KRd) is FDA-approved for the treatment relapsed/refractory multiple myeloma (RRMM) based on data from the ASPIRE study (Stewart K et al. NEJM ...2015). Thalidomide, a first generation immunomodulatory drug (IMiD) is less costly than lenalidomide and is synergistic in combination with proteasome inhibitors in the treatment of MM. ALLG MM018/ AMN003 is an open label phase II study of carfilzomib thalidomide and dexamethasone (KTd) for patients with RRMM. The primary end point is progression free survival (PFS). Secondary endpoints include overall response rate (ORR), duration of response (DOR), safety and health related quality of life.
Method:
Eligible patients were those with RRMM who have had 1-3 prior lines of treatment. The KTd regimen consisted of carfilzomib 20mg/m2 IV C1D1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from C1D8 onwards, thalidomide (100mg po nocte) and dexamethasone 40mg (20mg for patients age ≥75 years) po weekly, in a 28-day cycle. After 12 cycles, thalidomide was omitted and Kd carfilzomib 56mg/m2 (36/m2 for patients age ≥75 years) on days 1,2,15,16 and dexamethasone 40mg (20mg for patients age ≥75 years) on days 1,15 every 28 dayswas continued for a further 6 cycles. Peripheral blood and bone marrow aspirate and trephine for correlative studies were collected from the first 30 patients, at baseline, after cycle 6 and at confirmed disease progression. The aim of the correlative study was to assess for immunological correlates to clinical outcome. Immunological parameters that will be assessed include NK and T cells subsets on peripheral blood via mass cytometry (CyTOF). On the bone marrow trephine, NK cells, T cells, GRP78 expression within CD38 positive plasma cells, PD1 and PDL1 expression will be assessed at the myeloma site and the surrounding microenvironment using OPAL multiplex immunohistochemistry technology.
Results: Between March 2017 to June 2018, 56 patients (median age 66 years, range 56-79; 77% Caucasian and 23% Asian) out of the planned 100 were enrolled, with a median follow up of 4.9 (range, 1.0-13.7) months. Response rates in 39 evaluable patients were ≥MR (97%), ≥PR (89%) and ≥VGPR (66%). Median PFS is not reached, and no patients with ≥MR have relapsed. Grade ≥3/4 AEs occurred in 56% of patients, the most common of which were peripheral sensory neuropathy (13%), dyspnoea (13%) and infections (7%). All grade cardiovascular AEs included dyspnoea (27%), cardiac complications (5%), systemic-hypertension (9%) and pulmonary-hypertension (1.9%), however very few were grade ≥3. Three patients have died on study from disease complications, haemorrhage, and primary cardiac ischaemic event. Thus far, we have not found a significant difference in rates or profile of adverse events between the Caucasian versus Asian subgroups of patients.
Conclusion: This preliminary analysis demonstrates that the KTd combination is a tolerable regimen for patients with RRMM with a safety profile in line with previous reports for each of carfilzomib and thalidomide. Initial response rates appear very promising and durable with responses up to 13.7 months thus far in some patients. Patient accrual is ongoing.
Quach:Janssen Cilag: Consultancy; Sanofi Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Harrison:Janssen-Cilag: Other: Scientific advisory board. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie:Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Chng:ASLAN Pharmaceuticals: Research Funding.
Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its ...combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% n = 14; FL, 14% n = 5). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.
•Zanubrutinib plus obinutuzumab was safely administered to patients with CLL/SLL and FL, and deep responses were observed.
Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML). Pleural effusions, an adverse event related dasatinib treatment, may lead to intolerance ...and drug discontinuations. Strategies aimed at minimising this may improve outcomes. In the Phase III Dasision study, pleural effusion affected ~22% of patients after 4 years of dasatinib treatment at 100mg/d (Cortes et al, 2016 JCO 34(20) 2333-40). The elderly are at particular risk (Latagliata et al 2013 Hem Onc 31(2) 103-9), and there is suggestion that higher dasatinib trough (Cmin) levels may increase the risk of pleural effusions. The randomised OPTIM study (EHA 2014 abstract 5678) has previously reported that patients with Cmin >3nM benefited from dose reductions with preservation of molecular responses. The CML12 (DIRECT) study, run by the Australasian Leukaemia & Lymphoma Group (ALLG) with financial support from BMS, is a single arm phase II study with the aim of minimizing dasatinib related toxicity whilst preserving efficacy using a similar treatment schema to the OPTIM study. Here, we report results of a per-protocol interim analysis based on early molecular response (EMR; BCR-ABL1 ≤10% at 3 months) and MMR (BCR-ABL1 ≤0.1%) at 12 months, both key secondary endpoints of the study. The primary endpoint of the study- the cumulative incidence of pleural effusion at 24 months - is not yet evaluable.
DIRECT initially only enrolled patients >60 years old, predicted to derive the greatest potential benefit from a reduction in toxicity. The protocol was amended after 34 pts were accrued to include patients >18 years old at the recommendation of the trial management committee. All patients started treatment with dasatinib 100mg/day. Dasatinib Cmin was taken at 7, 28 and 56 days after treatment commencement. All Cmin directed dose adjustments were made prior to assessment of BCR-ABL1 at 3 months. Patients sequentially dose reduced to 70mg/day, then to 50mg/day, for Cmin results >3nM. Doses <50mg/day were permitted temporarily only for toxicity management.
As of June 2019, 71 patients (of 80 planned) from 14 centres have been enrolled, with a median follow up of 7 months (range 0-31). Median age was 64 years (range 21-86) and 48% were female. Sokal risk was low in 40% and high in 9.2%. The median dasatinib Cmin at days 7, 28, 56 and 90 were 4.9, 3.5, 3.5 and 2.7nM respectively (Table). At these time points, 83%, 59%, 73% and 44% of patients had Cmin ≥3nM. There was a trend to lower Cmin after protocol directed dose reduction. The number of patients remaining on 100mg/day after 1, 2 and 3 months of therapy were 11/69 (16%), 5/63 (8%) & 5/55 (9%) respectively.
Molecular response data were available for 48 patients at 3 months and 22 patients at 12 months. At 3 months, BCR-ABL1 ≤ 10% was achieved by 46 of 48 patients (96%), of whom 13 (27%) had achieved MMR (27%). At 12 months, MMR was achieved by 20/22 patients (91%), of whom 7 have achieved MR4.5 (BCR-ABL1 <0.0032%; 32%). The cumulative incidence of MMR by 12 months was 88% (80% CI 75-96%). There was no association between dasatinib dose and molecular response.
Adverse events occurred in 91.5% of patients at all grades - the majority of which were mild. Grade III/IV events occurred in 36.6% and 1.4% of patients respectively. Six of the 71 patients have discontinued dasatinib treatment early, all due to adverse events / dasatinib intolerance. Detailed adverse event data is embargoed until primary endpoint analysis. No patient has progressed to accelerated or blast phase CML.
The DIRECT study demonstrated the feasibility of using dasatinib Cmin levels to optimise dosing. Early molecular response rates are encouraging and predict for excellent achievement of long-term molecular response. Long term efficacy and safety data are awaited.
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Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria. Grigg:Abbvie: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Shanmuganathan:Novartis: Honoraria, Other: Travel Support; Bristol-Myers Squibb: Honoraria, Other: Travel Support; Amgen: Other: Travel Support; Janssen: Other: Travel Support; Gilead: Other: Travel Support. White:BMS: Honoraria, Research Funding; AMGEN: Honoraria, Speakers Bureau. Branford:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Qiagen: Consultancy, Honoraria; Cepheid: Consultancy, Honoraria. Mills:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Speaker Fees; Amgen: Other: Conference Sponsorship; Specialised Therapeutics: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Ross:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Harrup:Cancer Council of Tasmania: Membership on an entity's Board of Directors or advisory committees; Cooperative Trial Group for NeuroOncolog: Other: Collaborative Clinical Trials Group. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel.
Introduction: Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion (Rickert, 2013; Aalipour, 2013; ...Choe, 2016). The BCR pathway is an established therapeutic target in chronic lymphocytic leukemia (CLL), and pathway members are frequently mutated in follicular lymphoma (FL) (Byrd, 2016; Krysiak, 2017). Ibrutinib, the first-generation BTK inhibitor, has activity in FL and CLL in combination with rituximab (Fowler, 2016; Burger, 2014). BGB-3111 is a potent and specific BTK inhibitor, designed to minimize off-target inhibition of TEC and EGFR family kinases. BGB-3111 has minimal inhibitory effects against ITK and does not inhibit ITK-mediated rituximab-induced antibody-dependent cell-mediated cytotoxicity. Here we present updated interim results of an ongoing study of BGB-3111 in combination with obinutuzumab in patients with CLL/small lymphocytic lymphoma (SLL) and FL.
Methods: This is an ongoing, open-label, multicenter, phase 1b study of the combination of BGB-3111 and obinutuzumab in patients with B-cell malignancies with indication-specific expansion cohorts. Eligible patients had Eastern Cooperative Oncology Group performance status of 0-2, absolute neutrophil count >1000/μL, platelets >40,000/μL, adequate renal and hepatic function, and no significant cardiovascular disease. Growth factors and transfusions were allowed. Concomitant anticoagulation was also permitted. The primary endpoint of the expansion cohorts was response rate and duration of response using standard International Working Group (IWG) criteria for each disease. A key secondary endpoint was to evaluate the safety of the combination.
Results: As of Jun 1, 2017, 45 patients with CLL/SLL (20 pts with treatment-naïve TN; 25 patients with relapsed/refractory R/R), and 22 patients with R/R FL were enrolled. Demographic and disease characteristics are shown in the Table. Median follow-up time was 8.4 months (range, 2.6-16.0) for patients with CLL/SLL and 7.7 months (range, 0.3-16.3) for patients with FL. BGB-3111 plus obinutuzumab was well tolerated. One fatal adverse event (AE) occurred (squamous cell carcinoma in a CLL patient with prior squamous cell carcinoma). Serious AEs (SAEs) were reported in 12 (27%) CLL/SLL pts and 5 (23%) FL pts; there was only 1 SAE related to treatment (infusion-related reaction) and 1 SAE related to BGB-3111 (pneumonia). The most common (>20%) any-grade AEs for CLL patients were neutropenia (40%), contusion (22%), and thrombocytopenia; for FL patients, they were thrombocytopenia (27%), contusion (23%), fatigue (23%), and upper respiratory tract infection (23%). Grade 3-4 neutropenia was the only AE that occurred in >2 patients (22% for CLL; 14% for FL). There were no AEs of atrial fibrillation. Patients were evaluable for response if they had completed baseline and ≥1 on-treatment response assessments. Objective response rates (complete response CR + partial response) were 89%, 92%, and 69% in TN CLL/SLL, R/R CLL/SLL, and R/R FL, respectively, with 5 CRs in TN CLL/SLL, 4 CRs in R/R CLL/SLL, and 5 CRs in FL. Four patients (1 R/R CLL;3 FL) experienced disease progression; no instances of disease transformation occurred.
Conclusions: BGB-3111 plus obinutuzumab is well tolerated and highly active in CLL/SLL and FL. Few patients have discontinued, and responses remain durable within the larger patient sample with continued follow-up.
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Quach:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Badoux:Roche: Consultancy. Prince:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Eek:Border Medical Oncology: Employment; Ramsey Private Hospital Albury Wodonga: Membership on an entity's Board of Directors or advisory committees. Huang:BeiGene: Employment. Zhang:BeiGene: Employment. Wang:BeiGene: Employment. Hedrick:BeiGene: Employment. Novotny:BeiGene: Employment. Flinn:Constellation: Research Funding; Curis: Research Funding; Gilead: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Trillium: Research Funding; KITE: Research Funding; Janssen: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Agios: Research Funding; Infinity: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics LLC: Research Funding; Verastem: Research Funding; AbbVie Company: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Novartis: Research Funding; Beigene: Research Funding; Forty Seven: Research Funding.
Background: Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, remains incurable with standard therapies. The highly selective, potent Bruton tyrosine kinase (BTK) inhibitor ...acalabrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data showing a high rate of durable responses and a favorable safety profile (Lancet 2017;391:659-667). Here, we present long-term follow-up in these patients.
Methods: Eligible patients were aged ≥18 years, had confirmed MCL, Eastern Cooperative Oncology Group performance status ≤2, and had relapsed and/or were refractory to 1-5 prior therapies. Exclusion criteria included prior BTK or BCL-2 inhibitor exposure and concomitant warfarin or equivalent vitamin K antagonists. Oral acalabrutinib 100 mg twice daily was administered until progressive disease or unacceptable toxicity. Response was assessed by investigators based on the Lugano classification (J Clin Oncol 2014;32:3059-3068).Analysis of minimal residual disease using next-generation sequencing (10-6) is ongoing for a subset of patients with available samples and will be presented upon completion.
Results: A total of 124 patients were treated; 80% were men, and median age was 68 years (range, 42-90 years) with 65% aged ≥65 years. At baseline, 93% of patients had Eastern Cooperative Oncology Group performance status ≤1, 8% had bulky lymph nodes ≥10 cm, 72% had extranodal involvement, and 44%/17% had intermediate-/high-risk simplified MCL International Prognostic Index scores. The median number of prior therapies was 2 (range, 1-5); 24% were refractory to the most recent prior treatment.
As of February 12, 2018, median time on study was 26.3 months (range, 0.3-35.1 months), and 40% of patients remain on treatment. Median relative dose intensity (ratio of actual to planned cumulative dose during drug exposure period) was 99% (range, 27%-100%). Investigator-assessed overall response rate was 81% (95% CI: 73%, 87%), with 43% (95% CI: 34%, 52%) achieving complete response (Table). Overall response rates were consistent across prespecified subgroups of tumor bulk, presence of refractory disease and number/type of prior treatment.
Median duration of response was 25.7 months (95% CI: 17.5 months, not reached). Median progression-free survival (PFS) was 19.5 months (95% CI: 16.5 months, 27.7; Figure). Median overall survival (OS) was not reached; the estimated 24-month OS rate was 72% (95% CI: 64%, 80%).
The most frequent adverse events (AEs; ≥20%) were primarily Grade 1/2 and included headache (38%), diarrhea (36%), fatigue (28%), cough (22%) and myalgia (21%). Grade 3/4 AEs (≥5%) included anemia (10%), neutropenia (10%) and pneumonia (6%). There were 13 patients (10%) with 16 cardiac events, including 4 Grade 3/4 events (3%) in 1 patient each (acute coronary syndrome, acute myocardial infarction, cardiorespiratory arrest, coronary artery disease). Four patients had hypertension events (3%); 1 event was Grade 3. The most common bleeding events were contusion (13%) and petechiae (9%); all bleeding events were Grade 1/2 except for 3 Grade 3 events (gastrointestinal hemorrhage, hematuria, hematoma). Grade 3/4 infections occurred in 15% of patients and none were Grade 5; there was one case of cytomegalovirus viremia and one case of pneumocystis jiroveci pneumonia (both Grade 2).
Treatment discontinuation was primarily due to progressive disease (n=54; 44%) and AEs (n=10; 8%).Twelve AEs led to discontinuation in 10 patients; all of these AEs occurred in only 1 patient each.There were 43 deaths (35%), most commonly from progressive disease (n=29; 23%) or AEs (n=6; 5%). Deaths due to AEs included bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, and non-small cell lung cancer; none were considered to be related to acalabrutinib.
Conclusion: Response to acalabrutinib remained consistent during long-term (>24-month) follow-up, including high response rates, median PFS of 19.5 months, and a median OS that has not yet been reached, confirming efficacy in patients with relapsed/refractory MCL. The AE profile was largely similar to earlier reporting, with limited additional safety events observed with an additional year of follow-up.
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Wang:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding. Rule:Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees. Zinzani:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau. Casasnovas:MSD: Honoraria; Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Smith:Genentech: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck Sharpe Dohme and Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Panizo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Davies:Janssen: Consultancy, Honoraria; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; ADC Therapeutics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding. Jacobsen:Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy. Kater:Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Acerta/AZ: Research Funding; Genentech: Honoraria, Research Funding. Robak:Gilead: Consultancy; Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. Dua:Acerta Pharma: Employment. Frigault:AstraZeneca: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Nguyen:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership. Yin:Acerta Pharma: Employment. Jurczak:European Medicines Agency: Consultancy; Astra Zeneca/Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Celgene:
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