Acerta Pharma Research Articles

Measles, Mumps & Rubella Titers Post Autologous Stem Cell Transplant in Multiple Myeloma Patients Induced with Modern Therapy

Multiple Myeloma (MM) is a hematological malignancy resulting in abnormal plasma cells proliferating in the bone marrow. One of the most common treatment strategies for newly diagnosed MM is the combination of induction therapy followed by autologous stem cell transplant (ASCT). Due to the underlying disease and/or the effect of the treatment regimens administered, immunosuppression is a common clinical consequence. It has been shown that ASCT recipients, treated with traditional compounds, have a reduction in the levels of antibody titers to vaccine-preventable diseases such as measles, mumps and rubella (MMR), between one and four years post-transplant. Therefore, re-vaccination is recommended at least two years after ASCT. Therapeutic options have expanded in the past decade, with the introduction of novel agents that have significantly improved MM patient outcomes; however, this may also arguably have new and different implications on a patient's immune system. In this study we sought to analyze the presence of IgG antibodies against MMR in 110 patients with MM post-ASCT. All patients received ASCT between 2014 and 2019 at Mayo Clinic Arizona. Plasma samples were collected approximately 100 days after ASCT (median 92 days) and the antibody titers were tested using the Bio-Rad MMR IgG multiplex flow immunoassay. Sample antibody index values were compared with the assay-specific calibration to determine positivity. For a control population, we utilized the results of fully vaccinated and presumptively immune healthcare workers (HCWs) that were evaluated for the presence of antibodies to measles (n=199), mumps (n=197) and rubella (n=209), using the same method, instrument and laboratory. Overall, 70% of the MM patients were positive for antibodies against measles, compared with 77.4% of HCWs. For mumps, the MM cohort had a positivity of 49.1% versus 84.8% of HCWs. Finally, rubella antibodies were found in 64.5% and 83.7% of MM and HWCs, respectively. Next, we performed testing on serial samples collected from 45 MM patients, comparing the presence of MMR antibodies pre-ASCT (median 130 days) and post-ASCT. The number of patients with positive titers detected pre- and post-transplant was unchanged for each of the three viruses. In summary, our findings do not indicate a significant reduction in relative MMR antibody levels in ASCT recipients. This suggests that earlier re-vaccination is not required post-ASCT in the era of novel MM compounds. However, further validation studies in larger cohorts are necessary prior to considering a change in current vaccination guidelines. Disclosures Braggio: DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Fonseca:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Pharmacyclics: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees.

Selinexor Efficacy and Safety Are Independent of Renal Function in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis from the Pivotal Phase 2b Sadal Study

Selinexor Efficacy and Safety Are Independent of Renal Function in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis from the Pivotal Phase 2b Sadal Study

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)

Recil 2017 Criteria Demonstrated Similar Prognostic Value and Detected a Comparable Treatment Difference between Obinutuzumab- and Rituximab-Chemotherapy Compared with Cheson 2007 and Lugano 2014 Criteria in Patients with Previously Untreated Advanced-Stage Follicular Lymphoma

Recil 2017 Criteria Demonstrated Similar Prognostic Value and Detected a Comparable Treatment Difference between Obinutuzumab- and Rituximab-Chemotherapy Compared with Cheson 2007 and Lugano 2014 Criteria in Patients with Previously Untreated Advanced-Stage Follicular Lymphoma

Rarity of B-Cell Receptor Pathway Mutations in Progression-Free Patients With Chronic Lymphocytic Leukemia (CLL) During First-Line Versus Relapsed/Refractory (R/R) Treatment With Ibrutinib

Rarity of B-Cell Receptor Pathway Mutations in Progression-Free Patients With Chronic Lymphocytic Leukemia (CLL) During First-Line Versus Relapsed/Refractory (R/R) Treatment With Ibrutinib

Long-Term Efficacy of First-Line Ibrutinib Treatment for Chronic Lymphocytic Leukemia (CLL) With 4 Years of Follow-Up in Patients With TP53 Aberrations (del(17p) or TP53 Mutation): A Pooled Analysis From 4 Clinical Trials

Background : The presence of TP53 aberrations (defined as del(17p) or TP53 gene mutation) is a strong negative predictor of survival in patients (pts) with CLL. First-line chemoimmunotherapy is suboptimal in pts with CLL bearing TP53 aberrations, with 3-year progression-free survival (PFS) and overall survival (OS) rates of only 18% and 38%, respectively, with fludarabine, cyclophosphamide, and rituximab (Hallek, Lancet 2010). Ibrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant PFS and OS benefit demonstrated in multiple randomized phase 3 studies (eg, RESONATE-2, ECOG1912) in the first-line treatment of CLL/small lymphocytic lymphoma (SLL). Previous reports of single-agent ibrutinib or ibrutinib-based combination treatments have further demonstrated favorable PFS benefit in pts with TP53 aberrations in both the first-line and relapsed/refractory settings. Despite these study-specific subgroup analyses, there are limited data on long-term outcomes in pts with TP53 aberrations treated with first-line BTK inhibitors. We performed a pooled analysis of data across 4 studies to evaluate the long-term efficacy and safety of first-line ibrutinib-based therapy in pts with CLL bearing TP53 aberrations. Methods : Data for first-line ibrutinib treatment in pts with TP53 aberrations were pooled across 4 clinical trials in CLL/SLL: PCYC-1122e (NCT01500733; single-agent ibrutinib; n=34), PCYC-1130 (NCT02264574; ibrutinib + obinutuzumab; n=18), ECOG1912 (NCT02048813; ibrutinib + rituximab; n=26), and RESONATE-2 (NCT01722487; single-agent ibrutinib; n=11). ECOG1912 and RESONATE-2 excluded pts with del(17p) but did not exclude pts with TP53 mutations. Long-term PFS (assessed by investigator), OS, and safety are reported. Results : Eighty-nine pts with TP53 aberrations receiving first-line ibrutinib treatment were included in this pooled analysis. Median age was 65 years (range 33-87), and 69% of pts were male. At baseline, 53% had Rai stage III/IV, 38% had bulky disease (lymph nodes ≥5 cm), and 69% (of 87 evaluable) had unmutated IGHV. All patients had either del(17p) or TP53 mutation; 53% (of 89 evaluable) had del(17p) and 91% (of 58 evaluable) had TP53 mutation. Among 16 pts with del(17p) who had TP53 sequencing results available, 11 (69%) had both del(17p) and TP53 mutation. Forty-five pts received ibrutinib as a single agent and 44 received ibrutinib in combination with an anti-CD20 agent. With a median follow-up of 50 months (range 0.1 to 95.9 months), median PFS was not reached (95% CI: 67 months to not estimable; Figure 1A). At 48 months, the PFS rate was 79% and the OS rate was 88% (Figure 1B). Median duration of ibrutinib treatment was 46 months (range 0.1 to 95.5 months). Reasons for treatment discontinuation were progressive disease (20%), study closure (12%), adverse event (10%), withdrawal by pt (7%), death (3%), and other (physician decision due to scheduled pt surgery; 1%). Grade ≥3 adverse events of clinical interest with up to 8 years of treatment with ibrutinib were infection (22%; most commonly pneumonia in 7%), hypertension (13%), atrial fibrillation (12%), and major hemorrhage (7%). With the current follow-up, 46% of pts with TP53 aberrations remained on ibrutinib treatment. Conclusions : With a median follow-up of 4 years, first-line ibrutinib-based treatment resulted in sustained efficacy with high PFS and OS rates in CLL pts with TP53 aberrations, a population with historically poor outcomes. Although pts with TP53 aberrations remain at risk for progression, first-line treatment with ibrutinib has partially overcome the poor prognosis in this high-risk population with 4-year PFS and OS rates of 79% and 88%, respectively. No new safety signals were identified in this analysis. These results from a large, pooled, multi-study dataset demonstrated the long-term benefit of first-line ibrutinib-based treatment in pts with TP53 aberrations. Disclosures Allan: Janssen, AbbVie, and AstraZeneca: Other: Travel/accommodations/expenses; Celgene, Genentech, AstraZeneca, TG Therapeutics, and Janssen: Research Funding; AstraZeneca, Pharmacyclics LLC, an AbbVie Company, Genentech, AbbVie, Ascentage, and Cellectar: Consultancy; Janssen, AstraZeneca, and AbbVie: Honoraria. Shanafelt:Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding; Mayo Clinic: Patents & Royalties: and other intellectual property. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Moreno:Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy; AbbVie and Janssen: Research Funding; Janssen: Speakers Bureau. O'Brien:Eisai: Consultancy; Juno Therapeutics: Consultancy; Aptose Biosciences: Consultancy; GlaxoSmithKline: Consultancy; Sunesis: Research Funding; Acerta: Research Funding; Amgen: Consultancy; Celgene: Consultancy; Pfizer: Research Funding; Pharmacyclics: Research Funding; Astellas: Consultancy; Gilead: Consultancy; TG Therapeutics: Research Funding; Vida Ventures: Consultancy; KITE: Research Funding; Vaniam Group LL: Consultancy; Alexion: Consultancy; Regeneron: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Janssen Oncology: Consultancy. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Liu:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Dean:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Lai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Other: Travel/accommodations/expenses.

A Multi-Center Analysis of the Impact of Dose Level of R-EPOCH on Outcomes of Patients with Double/Triple-Hit B-Cell Lymphoma

A Multi-Center Analysis of the Impact of Dose Level of R-EPOCH on Outcomes of Patients with Double/Triple-Hit B-Cell Lymphoma

Ixazomib-Rituximab in Untreated Indolent B-NHL: An Effective, Very Low Toxicity Regimen

Ixazomib-Rituximab in Untreated Indolent B-NHL: An Effective, Very Low Toxicity Regimen

Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

Increasing Karyotypic Complexity Predicts Outcomes in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Introduction: Our group and others have previously shown that the presence of complex karyotype (>/= 3 cytogenetic abnormalities) is an important prognostic factor in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) patients treated with ibrutinib (Woyach JCO 2017, Thompson Cancer 2015, Maddocks JAMA Oncology 2015). It has been shown recently that increasing karyotypic complexity is a prognostic marker (Baliakis Blood 2019), but whether this is relevant for patients treated with novel therapies is unclear. Here, we aimed to determine whether the degree of karyotypic complexity beyond the dichotomy of complex versus not is a prognostic variable for patients with CLL treated with ibrutinib. Methods: We conducted a retrospective analysis of all patients with CLL treated with ibrutinib as a single agent or in combination with a monoclonal anti-CD20 antibody (MOAB) from 2010 through 2019 at The Ohio State University. We included patients with both treatment-naïve (TN) and RR disease. To determine karyotype, cells were stimulated with mitogen cocktail (PWM/PMA/CpG-ODN) and analyzed according to standard laboratory procedures. FISH using probes for D13S319, D12Z3, ATM, and TP53 were done according to manufacturer's recommendations. PCR was used to determine IGHV mutational status. Cytogenetic testing was included in the analysis if done <6 months before or within 60 days after ibrutinib initiation. All characteristics were measured at ibrutinib start. Multivariable Cox proportional hazards models were built to correlate karyotypic complexity (defined as a continuous variable with 1 unit increases) with progression free survival (PFS) and overall survival (OS), adjusted for age, RR status, ECOG performance status (PS), lactate dehydrogenase (LDH), white blood cell (WBC) count, hemoglobin (HgB), platelet (PLT) count, presence of del17p13 and IGHV mutational status. Multivariable models were fit in imputed datasets, and estimates were obtained from combining results from across 30 imputed datasets. Results: We analyzed 561 patients with a median age of 65 (range 26-91). 86% were treated with ibrutinib monotherapy, 22% were TN, and median number of prior therapies was 2 (range 0-13). 96% had an ECOG performance status (PS) of 0 or 1. Median LDH, WBC, HgB and PLT were 213 U/L, 23.2 K/uL, 11.2 g/dL, and 115 K/uL respectively. With available data, del13q14, trisomy 12, del11q22, and del17p13 was present in 50%, 22%, 30%, and 29% of patients respectively; 74% of patients were IGHV unmutated. 63 patients were excluded from cytogenetic analyses as the test was not done during the specified time window. Of the 458 evaluable, 50% had >3 cytogenetic abnormalities including 30% with >5 abnormalities. After a median follow up of 55.5 months, for the entire cohort estimated median PFS was 61.6 months (95% CI 56.1-69.5), and estimated median OS was 95.4 months (95% CI 86.3-not reached). On univariable analysis, older age, RR status, higher ECOG PS and LDH, lower HgB and PLT, presence of del17p13 and increasing karyotypic complexity were found to be statistically significant predictors of worse PFS and OS. To illustrate the relationship between increasing karyotypic complexity and clinical outcome, Kaplan-Meier plots are provided grouping pts with 0-2, 3-4, and 5 or higher aberrations (Figure 1). Accounting for statistically and clinically important factors on multivariate analysis (MVA, Table 1), increasing karyotypic complexity continued to be a statistically significant predictor of both PFS (p=0.01, HR 1.08 (95% CI 1.02-1.15)) and OS (p=0.001, HR 1.14 (95% CI 1.05-1.23)). Del17p13 did not retain statistical significance independently of karyotypic complexity on MVA. The interaction effect between prior treatment status and karyotypic complexity term was not significant for OS (p=0.89) and PFS (p=0.46), suggesting the prognostic effect of karyotypic complexity is similar across TN and RR cohorts. Conclusions: In this single center retrospective analysis, we found that increasing karyotypic complexity predicts inferior survival for patients with CLL treated with ibrutinib. This highlights that it is not only important to dichotomize presence of complex karyotype as >3 abnormalities, but to describe the number of karyotypic abnormalities in subsequent studies. Disclosures Bond: Seattle Genetics: Honoraria. Byrd:Acerta Pharma: Research Funding; Trillium: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Syndax: Research Funding. Rogers:AstraZeneca: Other: Travel; Abbvie, Acerta, AstraZeneca, Pharmacyclics: Consultancy; Abbvie, Genetech, Janssen: Research Funding. Woyach:Pharmacyclics: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Loxo: Research Funding; Verastem: Research Funding.

Meta-Analysis of Genome-Wide Association Studies of Acute Myeloid Leukemia (AML) Patients Identifies Variants Associated with Risk of 11q23/KMT2A-Translocated and Core-Binding Factor (CBF) AML and Suggests a Role for Transcription Elongation in Leukemogenesis

Meta-Analysis of Genome-Wide Association Studies of Acute Myeloid Leukemia (AML) Patients Identifies Variants Associated with Risk of 11q23/KMT2A-Translocated and Core-Binding Factor (CBF) AML and Suggests a Role for Transcription Elongation in Leukemogenesis

A Mechanistic Physiologically Based Pharmacokinetic (PBPK) Drug Interaction Model for the Mouse Double Minute 2 (MDM2) Inhibitor KRT-232

Background: KRT-232 is a potent, selective, orally available, targeted inhibitor of human MDM2 homolog interactions with tumor suppressor protein 53 (p53). KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia and Merkel cell carcinoma. KRT-232 is a highly permeable 568.6 g/mol, monoprotic carboxylic acid (pKa 4.35); elimination involves primarily biliary-fecal excretion of an acyl glucuronide metabolite (M1) and enteric glucuronide hydrolysis with enterohepatic recirculation of parent drug. M1 is a 744.7 g/mol monoprotic acid with pKa 3.32 and 1/5th the MDM2 inhibitory potency of KRT-232. Plasma protein binding (fup) of KRT-232 and M1 were ~0.026 and ~0.006, respectively. Static model drug-drug interaction (DDI) calculations (FDA-CDER. 2020) indicated a potential minor DDI with substrates of cytochrome P450s (CYP) CYP3A4 and CYP2C8, UGT1A1, P-glycoprotein 1 (P-gp) and OATP1B1/3. Here, a 'fit-for-purpose' PBPK model for KRT-232 was developed using physicochemical, preclinical (in vitroandin vivo) and clinical pharmacokinetic (PK) data (KartosData on file; Ye et al.Xenobiotica. 2015; Gluck et al.Invest New Drugs. 2020 [Study A]). Methods:Simcyp Simulator V17 (release 1; 27/11/2017; 17.0.90.0) was used. In vitro kinetic parameters: In vitroKi for competitive inhibition of CYP2C8 was 3.8 and 0.17 µM for KRT-232 and M1, respectively.In vitroKI and kinact for mechanism-based inhibition of CYP3A4 by KRT-232 were 28 µM and 4.14 h-1, respectively. Estimatedin vitroKi values for KRT-232-mediated inhibition of UGT1A1, P-gp, OATP1B1 and OATP1B3, were 1.9, 14.8, 4.9 and 6.9 µM. For M1-mediated inhibition of UGT1A1, OATP1B1 and OATP1B3, values were 2.3, 0.393 and 0.606 µM. Model development and verification:KRT-232 absorption was described by a first-order process; fraction absorbed was assumed to be 100% and the absorption rate constant was manually optimized using observed mean plasma concentration data from Part 1 of Study A. KRT-232 clearance was based onin vitroformation clearance of M1 in human liver microsomes, scaled up 4-fold based on observed oral clearance of KRT-232 (Wood et al.Drug Metab Dispos. 2017). KRT-232 distribution volume was described by a minimal PBPK model. KRT-232 and M1 DDI parameters were based onin vitrodata. M1 clearance was manually optimized using mean observed data from Study A (Part 1, 240 mg dose), and distribution volume was predicted by the Simulator using Method 1 and a full PBPK model. PBPK simulated data were compared with patient PK data collected during Part 2 of Study A. Model application:The model predicted potential DDI after steady state (SS) 240 mg once daily KRT-232 administration with substrates of CYP3A4, CYP2C8, UGT1A1, P-gp and OATP1B1/3. DDI simulations included 100 virtual subjects assigned to 10 virtual trials (N=10 each). Population estimates of geometric mean and median Cmax and AUC0-∞ ratios were generated. A "worst case" sensitivity analysis was performed by using a 10-fold increase inin vitroCYP3A4 interaction potency (KI, EC50) relative to the measuredin vitrovalue. Results:Figure 1shows simulated SS mean and individual observed KRT-232 and M1 concentration data from Part 2 of Study A. SS KRT-232 Cmax, AUC0-24h and t1/2 were predicted within 0.80-1.25-fold of observed PK data and tmax was under-predicted (0.36-fold) by the model (Table 1). M1 Cmax and AUC0-24h were within 0.80-1.25-fold of observed PK data on Day 1 (not shown). M1 Cmax on Day 7 was within 0.80-1.25-fold of observed PK data and SS AUC0-24h, t1/2, and tmax were underpredicted (0.72, 0.79 and 0.61-fold) relative to observed PK data. In all simulated DDIs, no clinically significant interaction was predicted for SS 240 mg doses of KRT-232 since predicted Cmax and AUC0-∞ geometric mean ratio (GMR) changes were less than 1.25-fold (Table 2). The CYP3A4 DDI simulation gave a population GMR (90% CI) for Cmax and AUC0-∞ of 1.07 (1.06, 1.09) and 1.15 (1.12, 1.17), respectively. In a sensitivity check, predicted midazolam Cmax and AUC0-∞ after a 10-fold reduction ofin vitroKI and EC50 were 1.44-fold and 2.18-fold, respectively. Although unlikely, a weak CYP3A4 DDI could not be definitively excluded. Conclusions: Mean plasma exposure of KRT-232 and M1 and inter-individual variability were adequately described by the PBPK model. No clinically significant DDI were predicted based on Cmax and AUC0-∞ GMR changes of less than 1.25-fold. Disclosures Templeton: Certara UK, LTD.:Current Employment.Podoll:IV/PO, LLC:Consultancy.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Slatter:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Amgen:Divested equity in a private or publicly-traded company in the past 24 months.

Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis

Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis

Dose-Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) Is Highly Active for Second Line Treatment in Relapsed/Refractory Classical Hodgkin Lymphoma: Final Results of a Phase I/II Study

Dose-Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) Is Highly Active for Second Line Treatment in Relapsed/Refractory Classical Hodgkin Lymphoma: Final Results of a Phase I/II Study

The Burkitt Lymphoma International Prognostic Index (BL-IPI)

The Burkitt Lymphoma International Prognostic Index (BL-IPI)

Predictors of Cytopenia after Treatment with Axicabtagene Ciloleucel in Patients with Large Cell Lymphoma

Predictors of Cytopenia after Treatment with Axicabtagene Ciloleucel in Patients with Large Cell Lymphoma

Pembrolizumab with R-CHOP in Previously Untreated Diffuse Large B-Cell Lymphoma: Long Term Follow up and Analysis of the Mechanism of Pdl-1 Tumor Expression

Pembrolizumab with R-CHOP in Previously Untreated Diffuse Large B-Cell Lymphoma: Long Term Follow up and Analysis of the Mechanism of Pdl-1 Tumor Expression

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial

Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia. ELEVATE TN is a global, phase 3, multicentre, open-label study in patients with treatment-naive chronic lymphocytic leukaemia done at 142 academic and community hospitals in 18 countries. Eligible patients had untreated chronic lymphocytic leukaemia and were aged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30-69 mL/min (calculated by use of the Cockcroft-Gault equation) or Cumulative Illness Rating Scale for Geriatrics score greater than 6. Additional criteria included an Eastern Cooperative Oncology Group performance status score of 2 or less and adequate haematologic, hepatic, and renal function. Patients with significant cardiovascular disease were excluded, and concomitant treatment with warfarin or equivalent vitamin K antagonists was prohibited. Patients were randomly assigned (1:1:1) centrally via an interactive voice or web response system to receive acalabrutinib and obinutuzumab, acalabrutinib monotherapy, or obinutuzumab and oral chlorambucil. Treatments were administered in 28-day cycles. To reduce infusion-related reactions, acalabrutinib was administered for one cycle before obinutuzumab administration. Oral acalabrutinib was administered (100 mg) twice a day until progressive disease or unacceptable toxic effects occurred. In the acalabrutinib-obinutuzumab group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3-7. In the obinutuzumab-chlorambucil group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 1 and on day 1 (1000 mg) of cycles 2-6. Oral chlorambucil was given (0·5 mg/kg) on days 1 and 15 of each cycle, for six cycles. The primary endpoint was progression-free survival between the two combination-therapy groups, assessed by independent review committee. Crossover to acalabrutinib was allowed in patients who progressed on obinutuzumab-chlorambucil. Safety was assessed in all patients who received at least one dose of treatment. Enrolment for this trial is complete, and the study is registered at ClinicalTrials.gov, NCT02475681. Between Sept 14, 2015, and Feb 8, 2017, we recruited 675 patients for assessment. 140 patients did not meet eligibility criteria, and 535 patients were randomly assigned to treatment. 179 patients were assigned to receive acalabrutinib-obinutuzumab, 179 patients were assigned to receive acalabrutinib monotherapy, and 177 patients were assigned to receive obinutuzumab-chlorambucil. At median follow-up of 28·3 months (IQR 25·6-33·1), median progression-free survival was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil (median not reached with acalabrutinib and obinutuzumab vs 22·6 months with obinutuzumab, hazard ratio [HR] 0·1; 95% CI 0·06-0·17, p<0·0001; and not reached with acalabrutinib monotherapy vs 22·6 months with obinutuzumab, 0·20; 0·13-0·3, p<0·0001). Estimated progression-free survival at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87-96%), 87% with acalabrutinib monotherapy (81-92%), and 47% with obinutuzumab-chlorambucil (39-55%). The most common grade 3 or higher adverse event across groups was neutropenia (53 [30%] of 178 patients in the acalabrutinib-obinutuzumab group, 17 [9%] of 179 patients in the acalabrutinib group, and 70 [41%] of 169 patients in the obinutuzumab-chlorambucil group). All-grade infusion reactions were less frequent with acalabrutinib-obinutuzumab (24 [13%] of 178 patients) than obinutuzumab-chlorambucil (67 [40%] of 169 patients). Grade 3 or higher infections occurred in 37 (21%) patients given acalabrutinib-obinutuzumab, 25 (14%) patients given acalabrutinib monotherapy, and 14 (8%) patients given obinutuzumab-chlorambucil. Deaths occurred in eight (4%) patients given acalabrutinib-obinutuzumab, 12 (7%) patients given acalabrutinib, and 15 (9%) patients given obinutuzumab-chlorambucil. Acalabrutinib with or without obinutuzumab significantly improved progression-free survival over obinutuzumab-chlorambucil chemoimmunotherapy, providing a chemotherapy-free treatment option with an acceptable side-effect profile that was consistent with previous studies. These data support the use of acalabrutinib in combination with obinutuzumab or alone as a new treatment option for patients with treatment-naive symptomatic chronic lymphocytic leukaemia. Acerta Pharma, a member of the AstraZeneca Group, and R35 CA198183 (to JCB).

Histological Subtypes and Response to PD-1/PD-L1 Blockade in Advanced Urothelial Cancer: A Retrospective Study.

Urinary tract cancer can be pure urothelial carcinoma, pure nonurothelial carcinoma or variant urothelial carcinoma (defined here as mixed urothelial carcinoma). Little is known regarding outcomes for patients with variant urothelial carcinoma receiving immune checkpoint inhibitors. We hypothesized that variant urothelial carcinoma does not compromise immune checkpoint inhibitor efficacy in patients with advanced urothelial carcinoma. We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathological, treatment and outcomes data were collected for patients with advanced urothelial carcinoma who received immune checkpoint inhibitors. Patients were divided into pure vs variant urothelial carcinoma subgroups, with variant urothelial carcinoma further divided by type of variant (ie squamous, neuroendocrine etc). We compared overall response rate using univariate and multivariate logistic regression and progression-free survival and overall survival using Kaplan-Meier and univariate and multivariate Cox proportional hazards. Overall 519 patients were identified, with 395, 406 and 403 included in overall response rate, overall survival and progression-free survival analyses, respectively. Overall response rate to immune checkpoint inhibitors between patients with pure vs variant urothelial carcinoma was comparable (28% vs 29%, p=0.90) without significant differences for individual subtypes vs pure urothelial carcinoma. Median overall survival for patients with pure urothelial carcinoma was 11.0 months vs 10.1 months for variant urothelial carcinoma (p=0.60), but only 4.6 months for patients with neuroendocrine features (9 patients, HR 2.75, 95% CI 1.40-5.40 vs pure urothelial carcinoma, p=0.003). Median progression-free survival was 4.1 months for pure vs 5.2 months for variant urothelial carcinoma (p=0.43) and 3.7 months for neuroendocrine features (HR 1.87, 95% CI 0.92-3.79 vs pure urothelial carcinoma, p=0.09). Overall response rate to immune checkpoint inhibitors was comparable across histological types. However, overall survival was worse for patients with tumors containing neuroendocrine features. Variant urothelial carcinoma should not exclude patients from receiving immune checkpoint inhibitors.

Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study

Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. Acerta Pharma.