ABSTRACT
Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Neoplasm Recurrence, Local/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Benzamides/adverse effects , Female , Humans , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Pyrazines/adverse effects , Treatment OutcomeABSTRACT
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Gefitinib/therapeutic use , Lung Neoplasms/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/therapeutic use , Triazines/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Dose-Response Relationship, Drug , ErbB Receptors/genetics , Female , Gefitinib/administration & dosage , Gefitinib/adverse effects , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Proto-Oncogene Proteins c-met/biosynthesis , Pyrazines/administration & dosage , Pyrazines/adverse effects , Triazines/administration & dosage , Triazines/adverse effectsABSTRACT
B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Adenine/analogs & derivatives , Benzamides , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Piperidines , Protein Kinase Inhibitors/adverse effects , PyrazinesABSTRACT
Double-hit diffuse large B-cell lymphoma (DH-DLBCL) is an aggressive, and often refractory, type of B-cell non-Hodgkin lymphoma (NHL) characterized by rearrangements in MYC and BCL2. Cyclin-dependent kinase 9 (CDK9) regulates transcriptional elongation and activation of transcription factors, including MYC, making it a potential targeted approach for the treatment of MYC+ lymphomas. Enitociclib is a well-tolerated and clinically active CDK9 inhibitor leading to complete metabolic remissions in 2 of 7 patients with DH-DLBCL treated with once weekly 30 mg intravenous administration. Herein, we investigate the pharmacodynamic effect of CDK9 inhibition in preclinical models and in blood samples from patients [DH-DLBCL (n = 10) and MYC+ NHL (n = 5)] treated with 30 mg i.v. once weekly enitociclib. Enitociclib shows significant regulation of RNA polymerase II Ser2 phosphorylation in a MYC-amplified SU-DHL-4 cell line and depletion of MYC and antiapoptosis protein MCL1 in SU-DHL-4 and MYC-overexpressing SU-DHL-10 cell lines in vitro. Tumor growth inhibition reaching 0.5% of control treated SU-DHL-10 xenografts is achieved in vivo and MYC and MCL1 depletion as well as evidence of apoptosis activation after enitociclib treatment is demonstrated. An unbiased analysis of the genes affected by CDK9 inhibition in both cell lines demonstrates that RNA polymerase II and transcription pathways are primarily affected and novel enitociclib targets such as PHF23 and TP53RK are discovered. These findings are recapitulated in blood samples from enitociclib-treated patients; while MYC downregulation is most robust with enitociclib treatment, other CDK9-regulated targets may be MYC independent delivering a transcriptional downregulation via RNA polymerase II. SIGNIFICANCE: MYC+ lymphomas are refractory to standard of care and novel treatments that downregulate MYC are needed. The utility of enitociclib, a selective CDK9 inhibitor in this patient population, is demonstrated in preclinical models and patients. Enitociclib inhibits RNA polymerase II function conferring a transcriptional shift and depletion of MYC and MCL1. Enitociclib intermittent dosing downregulates transcription factors including MYC, providing a therapeutic window for durable responses in patients with MYC+ lymphoma.
Subject(s)
Cyclin-Dependent Kinase 9 , Lymphoma, Large B-Cell, Diffuse , RNA Polymerase II , Humans , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Down-Regulation , Homeodomain Proteins/genetics , Lymphoma, Large B-Cell, Diffuse/drug therapy , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Proto-Oncogene Proteins c-myc/genetics , RNA Polymerase II/geneticsABSTRACT
The emerging field of small-molecule-drug conjugates (SMDCs) using small-molecule biomarker-targeted compounds for tumor homing may provide new perspectives for targeted delivery. Here, for the first time, we disclose the structure and the synthesis of VIP236, an SMDC designed for the treatment of metastatic solid tumors by targeting αvß3 integrins and extracellular cleavage of the 7-ethyl camptothecin payload by neutrophil elastase in the tumor microenvironment. Imaging studies in the Lewis lung mouse model using an elastase cleavable quenched substrate showed pronounced elastase activity in the tumor. Pharmacokinetics studies of VIP236 in tumor-bearing mice demonstrated high stability of the SMDC in plasma and high tumor accumulation of the cleaved payload. Studies in bile-duct-cannulated rats showed that biliary excretion of the unmodified conjugate is the primary route of elimination. Treatment- and time-dependent phosphorylation of H2AX, a marker of DNA damage downstream of topoisomerase 1 inhibition, verified the on-target activity of the payload cleaved from VIP236 in vivo. Treatment with VIP236 resulted in long-lasting tumor regression in subcutaneous patient-derived xenograft (PDX) models from patients with non-small-cell lung, colon, and renal cancer as well as in two orthotopic metastatic triple-negative breast cancer PDX models. In these models, a significant reduction of brain and lung metastases also was observed.
ABSTRACT
Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Positive Transcriptional Elongation Factor B , Animals , Mice , Positive Transcriptional Elongation Factor B/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Cyclin-Dependent Kinase 9 , Cyclin T/metabolism , Phosphorylation , Cell Nucleus/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
The polarised distribution of signals downstream from receptor tyrosine kinases (RTKs) regulates fundamental cellular processes that control cell migration, growth and morphogenesis. It is poorly understood how RTKs are involved in the localised signalling and actin remodelling required for these processes. Here, we show that the Gab1 scaffold is essential for the formation of a class of polarised actin microdomain, namely dorsal ruffles, downstream from the Met, EGF and PDGF RTKs. Gab1 associates constitutively with the actin-nucleating factor N-WASP. Following RTK activation, Gab1 recruits Nck, an activator of N-WASP, into a signalling complex localised to dorsal ruffles. Formation of dorsal ruffles requires interaction between Gab1 and Nck, and also requires functional N-WASP. Epithelial cells expressing Gab1DeltaNck (Y407F) exhibit decreased Met-dependent Rac activation, fail to induce dorsal ruffles, and have impaired cell migration and epithelial remodelling. These data show that a Gab1-Nck signalling complex interacts with several RTKs to promote polarised actin remodelling and downstream biological responses.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Surface Extensions/enzymology , Oncogene Proteins/metabolism , Phosphoproteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Adaptor Proteins, Signal Transducing/chemistry , Amino Acid Sequence , Animals , Binding Sites , Cell Line , Cell Surface Extensions/drug effects , Enzyme Activation/drug effects , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , ErbB Receptors/metabolism , Hepatocyte Growth Factor/pharmacology , Humans , Mice , Models, Biological , Molecular Sequence Data , Oncogene Proteins/chemistry , Protein Binding/drug effects , Protein Transport/drug effects , Proto-Oncogene Proteins c-crk/metabolism , Receptors, Platelet-Derived Growth Factor/metabolism , Tyrosine/metabolism , Wiskott-Aldrich Syndrome Protein, Neuronal/metabolism , rac GTP-Binding Proteins/metabolismABSTRACT
BACKGROUND: Papillary renal cell carcinoma (PRCC) represents 15% of RCCs but has no indicated therapies, with limited biomarker-based data to inform targeted treatment. MET alterations may be key; > 80% of PRCC tumours show MET upregulation. The objective of this study was to assess MET status in PRCC and its impact on clinical outcomes. METHODS: This retrospective, observational study included patients with locally advanced/metastatic PRCC from three international registries. MET status was determined retrospectively by next generation sequencing (NGS) of archival tissue. MET-driven was defined as MET and/or hepatocyte growth factor amplification, chromosome 7 gain, and/or MET kinase domain mutations. Objectives included progression-free survival (PFS) and overall survival (OS) by MET status using a Cox proportional hazards model. RESULTS: Of 308 patients, 305 received first-line treatment; most commonly sunitinib (n = 208; 68%), then everolimus (n = 40; 13%). Of 179 patients with valid NGS results, 38% had MET-driven and 49% MET-independent tumours (13% unevaluable). In the MET-driven versus MET-independent subgroups, respectively, of sunitinib-treated patients, median PFS was numerically longer, though not statistically significantly; PFS: 9.2 months (95% confidence interval [CI]: 5.4-13.2) versus 5.7 months (95% CI: 4.3-7.4), hazard ratio (HR) = 0.67; 95% CI: 0.41-1.08. There was no difference between the OS of each subgroup. CONCLUSIONS: MET-driven PRCC may respond to targeted agents. However, the presence of MET alterations did not appear to be predictive for outcomes in response to current therapies, which are not biomarker-driven, compared with MET-independent tumours.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Observational Studies as Topic , Retrospective Studies , Sunitinib/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. PATIENTS AND METHODS: Adults with solid tumors or aggressive non-Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined. RESULTS: Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in > 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). CONCLUSIONS: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.
Subject(s)
Neoplasms , Neutropenia , Adult , Cyclin-Dependent Kinase 9 , Dose-Response Relationship, Drug , Humans , Maximum Tolerated Dose , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Kinase Inhibitors/adverse effects , Treatment OutcomeABSTRACT
Analysis of biomarkers in peripheral blood is becoming increasingly important in clinical trials to establish proof of mechanism to evaluate effects of treatment, and help guide dose and schedule setting of therapeutics. From a single blood draw, peripheral blood mononuclear cells can be isolated and processed to analyze and quantify protein markers, and plasma samples can be used for the analysis of circulating tumor DNA, cytokines, and plasma metabolomics. Longitudinal samples from a treatment provide information on the evolution of a given protein marker, the mutational status and immunological landscape of the patient. This can only be achieved if the processing of the peripheral blood is carried out effectively in clinical sites and samples are properly preserved from the bedside to bench. Here, we present an optimized general-purpose protocol that can be implemented at clinical sites for obtaining PBMC pellets and plasma samples in multi-center clinical trials, that will enable clinical professionals in hospital laboratories to successfully provide high quality samples, regardless of their level of technical expertise. Alternative protocol variations are also presented that are optimized for more specific downstream analytical methods. We apply this protocol for studying protein biomarkers against DNA damage response (DDR) on X-ray irradiated blood to demonstrate the suitability of the approach in oncology settings where DDR drugs and/or radiotherapy have been practiced as well as in preclinical stages where mechanistic hypothesis testing is required.
Subject(s)
Biomarkers/blood , Leukocytes, Mononuclear/immunology , Plasma/immunology , HumansABSTRACT
Mutations in the STK11 (LKB1) gene regulate resistance to PD-1/PD-L1 blockade. This study evaluated this association in patients with nonsquamous non-small cell lung cancer (NSCLC) enrolled in three phase I/II trials. STK11 mutations were associated with resistance to the anti-PD-L1 antibody durvalumab (alone/with the anti-CTLA4 antibody tremelimumab) independently of KRAS mutational status, highlighting STK11 as a potential driver of resistance to checkpoint blockade. Retrospective assessments of tumor tissue, whole blood, and serum revealed a unique immune phenotype in patients with STK11 mutations, with increased expression of markers associated with neutrophils (i.e., CXCL2, IL6), Th17 contexture (i.e., IL17A), and immune checkpoints. Associated changes were observed in the periphery. Reduction of STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical STK11 knockout models. These results suggest that STK11 mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy. SIGNIFICANCE: Patients with nonsquamous STK11-mutant (STK11mut) NSCLC are less likely than STK11 wild-type (STK11wt) patients to respond to anti-PD-L1 ± anti-CTLA4 immunotherapies, and their tumors show increased expression of genes and cytokines that activate STAT3 signaling. Preclinically, STAT3 modulation reverses this resistance, suggesting STAT3-targeted agents as potential combination partners for immunotherapies in STK11mut NSCLC.This article is highlighted in the In This Issue feature, p. 2659.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , AMP-Activated Protein Kinase Kinases , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Protein Serine-Threonine Kinases/genetics , Retrospective Studies , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Tumor MicroenvironmentABSTRACT
In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.
Subject(s)
Neoplasm Recurrence, Local , Protein Kinase Inhibitors , B-Lymphocytes , Benzamides , Humans , Morpholines , Protein Kinase Inhibitors/therapeutic use , Pyrazines , PyrimidinesABSTRACT
Importance: Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell RCC. Because some cases of PRCC are MET-driven, MET inhibition could be a targeted treatment approach. In previous studies, savolitinib (AZD6094, HMPL-504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in this patient group. Objective: To determine whether savolitinib is a better treatment option for this patient population, vs standard of care, sunitinib. Design, Setting, and Participants: The SAVOIR phase 3, open-label, randomized clinical trial was a multicenter study carried out in 32 centers in 7 countries between July 2017 and the data cutoff in August 2019. Overall, 360 to 450 patients were to be screened to randomize approximately 180 patients. Patients were adults with MET-driven (centrally confirmed), metastatic PRCC, with 1 or more measurable lesions. Exclusion criteria included prior receipt of sunitinib or MET inhibitor treatment. Overall, 254 patients were screened. Interventions: Patients received 600 mg of savolitinib orally once daily (qd), or 50 mg of sunitinib orally qd for 4 weeks, followed by 2 weeks without treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS, assessed by investigator and confirmed by blinded independent central review). Secondary end points included overall survival (OS), objective response rate (ORR), duration of response, and safety/tolerability. Results: At data cutoff, 60 patients were randomized (savolitinib n = 33; sunitinib n = 27); most patients had chromosome 7 gain (savolitinib, 30 [91%]; sunitinib, 26 [96%]) and no prior therapy (savolitinib, 28 [85%]; sunitinib, 25 [93%]). For savolitinib and sunitinib, 4 (12%) and 10 (37%) patients were women, and the median (range) age was 60 (23-78) and 65 (31-77) years, respectively. Following availability of external data on PFS with sunitinib in patients with MET-driven disease, study enrollment was closed. Progression-free survival, OS, and ORR were numerically greater with savolitinib vs sunitinib. Median PFS was not statistically different between the 2 groups: 7.0 months (95% CI, 2.8-not calculated) for savolitinib and 5.6 months (95% CI, 4.1-6.9) for sunitinib (hazard ratio [HR], 0.71; 95% CI, 0.37-1.36; P = .31). For savolitinib and sunitinib respectively, grade 3 or higher adverse events (AEs) were reported in 14 (42%) and 22 (81%) of patients and AE-related dose modifications in 10 (30%) and 20 (74%). After discontinuation, 12 (36%) and 5 (19%) of patients on savolitinib and sunitinib respectively, received subsequent anticancer therapy. Conclusions and Relevance: Although patient numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy vs sunitinib, with fewer grade 3 or higher AEs and dose modifications. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03091192.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrazines/therapeutic use , Sunitinib/therapeutic use , Triazines/therapeutic use , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/adverse effects , Female , Humans , Male , Protein Kinase Inhibitors/adverse effects , Pyrazines/adverse effects , Single-Blind Method , Sunitinib/adverse effects , Treatment Outcome , Triazines/adverse effectsABSTRACT
Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2-6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL. SIGNIFICANCE: Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity-enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.This article is highlighted in the In This Issue feature, p. 327.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/genetics , Antibodies, Monoclonal, Humanized/administration & dosage , Benzamides/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Pyrazines/administration & dosage , Adult , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides/adverse effects , Cell Proliferation/drug effects , Drug Administration Schedule , Female , Humans , Interleukin-2/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Pyrazines/adverse effects , Rituximab/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS: Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS: Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION: We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.
ABSTRACT
Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells. We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
Subject(s)
Glioblastoma/drug therapy , Glioblastoma/pathology , Molecular Targeted Therapy , Precision Medicine , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bortezomib/pharmacology , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p15/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Gene Regulatory Networks/drug effects , Genetic Heterogeneity , Genome, Human , Glioblastoma/genetics , Humans , Mice, Inbred BALB C , Mutation/genetics , Proteasome Inhibitors/pharmacology , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolismABSTRACT
BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Acerta Pharma.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazines/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Benzamides/adverse effects , Benzamides/pharmacology , Female , Gastrointestinal Diseases/chemically induced , Humans , Male , Middle Aged , Myeloid Differentiation Factor 88/genetics , Neoplasm Proteins/antagonists & inhibitors , Neutropenia/chemically induced , Pain/chemically induced , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Pyrazines/adverse effects , Pyrazines/pharmacology , Quality of Life , Recurrence , Respiratory Tract Infections/etiology , Salvage Therapy , Treatment Outcome , Waldenstrom Macroglobulinemia/enzymology , Waldenstrom Macroglobulinemia/geneticsABSTRACT
PURPOSE: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). PATIENTS AND METHODS: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. RESULTS: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. CONCLUSIONS: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
Subject(s)
Neoplasms/drug therapy , Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrazines/therapeutic use , Triazines/therapeutic use , Biomarkers, Tumor , Drug Monitoring , Female , Humans , Male , Molecular Targeted Therapy , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Neoplasms/etiology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/adverse effects , Pyrazines/pharmacokinetics , Treatment Outcome , Triazines/administration & dosage , Triazines/adverse effects , Triazines/pharmacokineticsABSTRACT
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Among 33 treated patients (61% men; median age, 64 years; range, 50-82 years), median duration of prior ibrutinib treatment was 11.6 months (range, 1-62 months); median time from ibrutinib discontinuation to acalabrutinib start was 47 days (range, 3-331 days). After a median of 19.0 months (range, 0.2-30.6 months), 23 patients remained on acalabrutinib; 10 had discontinued (progressive disease, n = 4; AEs, n = 3). No acalabrutinib dose reductions occurred. During acalabrutinib treatment, the most frequent AEs included diarrhea (58%), headache (39%), and cough (33%). Grade 3/4 AEs occurred in 58%, most commonly neutropenia (12%) and thrombocytopenia (9%). Of 61 ibrutinib-related AEs associated with intolerance, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. Overall response rate was 76%, including 1 complete and 19 partial responses and 5 partial responses with lymphocytosis. Among 25 responders, median duration of response was not reached. Median progression-free survival (PFS) was not reached; 1-year PFS was 83.4% (95% confidence interval, 64.5%-92.7%). Acalabrutinib was well tolerated with a high response rate in patients who were previously intolerant to ibrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02029443.