Welcome to Dana-Farber's Research News
September 15, 2023
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.
Annals of Oncology
Parsons HA, Blewett T, Chu X, Sridhar S, Santos K, Xiong K, Patel A, Cheng J, Rhoades J, Liu R, Burstein HJ, Winer EP, Tayob N, Krop IE, Makrigiorgos GM, Golub TR, Mayer EL, Adalsteinsson VA
BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAT).
PATIENTS AND METHODS: We identified responders (RCB-0/1) and matched non-responders (RCB-2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel vs. cisplatin in TNBC. We collected plasma samples at baseline, three weeks, and twelve weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.
RESULTS: Of 139 patients, 68 had complete samples and no additional NAT. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3, and 55% at week 12. Median tumor fraction (TFx) was 3.7 x 10-4 (range: 7.9 x 10-7 to 4.9 x 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10/11 patients with RCB-0, 3/8 with RCB-1, 4/15 with RCB-2, and 0/4 with RCB-3. Among 6 patients with known recurrence five had persistent ctDNA at week 12.
CONCLUSION: NAT for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine if ctDNA-guided approaches can improve outcomes.
Blood
Merrill MH, Redd RA, McDonough MM, Chen YB, DeFilipp Z, Fisher DC, LaCasce AS, Odejide OO, Ng SY, Jacobson CA, Merryman RW, Kim AI, Armand P, Jacobsen ED
Autologous stem cell transplantation (ASCT) is often used as consolidation for several subtypes of peripheral T-cell lymphoma (PTCL) in first remission. However, many patients relapse after ASCT and have a very poor prognosis. There are no approved treatment options for posttransplantation maintenance or consolidation in PTCL. PD-1 blockade has demonstrated some efficacy for patients with PTCL. We, therefore, conducted a phase 2 multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab after ASCT in patients with PTCL in first remission. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles within 21 days from post-ASCT discharge (and within 60 days of stem cell infusion). The primary end point was progression-free survival (PFS) at 18 months after ASCT. Twenty-one patients were treated in this study and 67% (n = 14) completed 8 cycles of treatment. Among all patients who were evaluable, 13 of 21 were alive and achieved PFS at 18 months after ASCT, meeting the study's primary end point. The estimated 18-month PFS was 83.6% (95% confidence interval [CI], 68-100), and overall survival 94.4% (95% CI, 84-100). The toxicity profile was consistent with the known toxicity profile of pembrolizumab, with no grade 5 toxicities. In conclusion, PD-1 blockade after ASCT with pembrolizumab is feasible with a favorable safety profile and promising activity, supporting further confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
Blood
Takahashi T, Bratrude B, Betz K, Yu A, Neuberg DS, Duncan C, Horan JT, Kean LS
In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough_1 (9 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 www.clinicaltrials.gov as #NCT01743131.
Blood
Two to Tango! IL-13 and TGF-b Drive Myelofibrosis
Jutzi JS, Mullally A
In this issue of Blood, Melo-Cardenas et al explore the role of interleukin-13 (IL-13)/IL-4 signaling in myelofibrosis as an important pathway driving fibrotic progression through megakaryocyte expansion and increased transforming growth factor-? (TGF-?) production.
Cell
Modeling Epigenetic Lesions that Cause Gliomas
Rahme GJ, Javed NM, Puorro KL, Xin S, Hovestadt V, Johnstone SE, Bernstein BE
Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.
Journal of Clinical Oncology
Versluis J, Tsai HK, Gibson CJ, Cutler C, Lindsley RC
PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study.
METHODS: We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity).
RESULTS: The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). Among those with a TP53 mutation, OS was similar between TP53single versus TP53multihit (22% ± 8% v 20% ± 6% at 3 years; P = .31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P = .001).
CONCLUSION: HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.
Lancet
Author Gender Representation of Journal Reviews and Editorials on Lymphoma
LaCasce A
Gender inequity in academic medicine is a well recognised problem that marginalises a crucial talent pool and ultimately diminishes innovation, collaboration, and progress. The international Women in Lymphoma (WiL) alliance, founded in 2019, consists of over 930 members globally from more than 50 countries. WiL is led by a steering committee of 23 members representing nine countries from five global regions. Recognising gender parity in lymphoma practice despite the under-representation of women in lymphoma leadership, WiL is committed to advocacy and promotion of equal gender representation in all lymphoma academic and clinical leadership settings. A key priority is to analyse gender data related to academic presentations and publishing.
Journal of Clinical Oncology
Tolaney SM
PURPOSE: Amcenestrant (oral selective estrogen receptor degrader) demonstrated promising safety and efficacy in earlier clinical studies for endocrine-resistant, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (aBC).
PATIENTS AND METHODS: In AMEERA-3 (ClinicalTrials.gov identifier: NCT04059484), an open-label, worldwide phase II trial, patients with ER+/HER2- aBC who progressed in the (neo)adjuvant or advanced settings after not more than two previous lines of endocrine therapy (ET) were randomly assigned 1:1 to amcenestrant or single-agent endocrine treatment of physician's choice (TPC), stratified by the presence/absence of visceral metastases, previous/no treatment with cyclin-dependent kinase 4/6 inhibitor, and Eastern Cooperative Oncology Group performance status (0/1). The primary end point was progression-free survival (PFS) by independent central review, compared using a stratified log-rank test (one-sided type I error rate of 2.5%).
RESULTS: Between October 22, 2019, and February 15, 2021, 290 patients were randomly assigned to amcenestrant (n = 143) or TPC (n = 147). PFS was numerically similar between amcenestrant and TPC (median PFS [mPFS], 3.6 v 3.7 months; stratified hazard ratio [HR], 1.051 [95% CI, 0.789 to 1.4]; one-sided P = .643). Among patients with baseline mutated ESR1; (n = 120 of 280), amcenestrant numerically prolonged PFS versus TPC (mPFS, 3.7 v 2.0 months; stratified HR, 0.9 [95% CI, 0.565 to 1.435]). Overall survival data were immature but numerically similar between groups (HR, 0.913; 95% CI, 0.595 to 1.403). In amcenestrant versus TPC groups, treatment-emergent adverse events (any grade) occurred in 82.5% versus 76.2% of patients and grade 3 events occurred in 21.7% versus 15.6%.
CONCLUSION: AMEERA-3 did not meet its primary objective of improved PFS with amcenestrant versus TPC although a numerical improvement in PFS was observed in patients with baseline ESR1 mutation. Efficacy and safety with amcenestrant were consistent with the standard of care for second-/third-line ET for ER+/HER2- aBC.
Journal of Clinical Oncology
Mack JW, Cernik C, Uno H, Fisher L, Lakin JR
PURPOSE: Adolescents and young adults (AYAs) with cancer receive high rates of medically intensive measures at the end of life. This study aimed to characterize the prevalence and timing of conversations about goals of care and advance care planning among AYAs at the end of life as one potential influence on care received.
METHODS: This was a review of electronic health data and medical records for 1,929 AYAs age 12-39 years who died after receiving care at one of three sites between 2003 and 2019, including documented conversations about goals of care and advance care planning, and care received.
RESULTS: A majority of AYAs were female (54%) and White (61%); 12% were Asian, 8% Black, and 27% Hispanic. Most patients had documented discussions about prognosis (86%), goals of care (83%), palliative care (79%), hospice (79%), and preferred location of death (64%). When last documented goals of care were evaluated, 69% of patients wanted care focused on palliation; however, 29% of those with palliative goals spent time in the intensive care unit (ICU) in the last month of life, and 32% had multiple emergency room (ER) visits. When goals-of-care discussions happened earlier, >30 days before death, AYAs were less likely to receive chemotherapy in the last 14 days of life (P = .001), ICU care (P < .001), ER visits (P < .001), and hospitalizations in the last month (P < .001).
CONCLUSION: High rates of medically intensive measures among AYAs near the end of life do not appear to be the result of a lack of discussions about goals of care and advance care planning. Although some interventions may be used to support palliative goals, earlier discussions have potential to reduce late-life intensive measures.
Journal of Clinical Oncology
Sarosiek S, Treon SP, Branagan AR, Castillo JJ
In the recent publication “Bortezomib-Dexamethasone, Rituximab, and Cyclophosphamide as First-Line Treatment for Waldenström's Macroglobulinemia: A Prospectively Randomized Trial of the European Consortium for Waldenström's Macroglobulinemia” by Buske et al, 202 patients with Waldenström's macroglobulinemia (WM) were randomly assigned to receive dexamethasone-rituximab-cyclophosphamide (DRC) versus bortezomib-DRC (B-DRC). Buske et al should be commended on successfully conducting this large, randomized trial in a rare disease. The effort to focus on the development of a finite, combination therapy with the goal of achieving a prolonged progression-free survival (PFS) is greatly appreciated.
JAMA Oncology
Miscommunication in Cancer Care-Do You Hear What I Hear?
Rosenberg AR
Effective communication is central to patient-centered cancer care. Although tools to improve and refine communication approaches are well described, few address the causes or consequences of miscommunication. Generally understood as a failure to communicate clearly, we focus specifically on how (and why) clinicians and patients hear different things in the same encounter. This is important because miscommunication between cancer clinicians and patients translates to divergent expectations, intentions, and outcomes.
Lancet
Bardia A, Tolaney SM
BACKGROUND: Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables.
METHODS: In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339.
FINDINGS: At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12¬?5-month (IQR 6¬?4-18¬?8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14¬?4 months [95% CI 13¬?0-15¬?7] vs 11¬?2 months [10¬?1-12¬?7]; hazard ratio [HR] 0¬?79, 95% CI 0¬?65-0¬?96; p=0¬?020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1¬?63 [95% CI 1¬?03-2¬?56]; p=0¬?035), as was time to deterioration of global health status and quality of life (median 4¬?3 months vs 3¬?0 months; HR 0¬?75 [0¬?61-0¬?92]; p=0¬?0059) and fatigue (median 2¬?2 months vs 1¬?4 months; HR 0¬?73 [0¬?60-0¬?89]; p=0¬?0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment.
INTERPRETATION: Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3¬?2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer.
FUNDING: Gilead Sciences.
Molecular Cell
A Sweet Way to Regulate Cellular Growth: OGT and mTOR Join Forces
Latorre-Muro P, Puigserver P
In this issue, Xu and Pan et al report a glucose-sensing and activation mechanism of mTORC1 through the glycosyltransferase OGT, which activates Raptor, allowing lysosomal targeting of mTORC1 to promote cell proliferation.
Nature
Epitope Editing Enables Targeted Immunotherapy of Acute Myeloid Leukaemia
Casirati G, Cosentino A, Mucci A, Salah Mahmoud M, Ugarte Zabala I, Zeng J, Ficarro SB, Klatt D, Brendel C, Ritz J, Marto JA, Pellin D, Bauer DE, Armstrong SA, Genovese P
Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia1,2, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens3-5. Acute myeloid leukaemia immunotherapies target genes expressed by haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells, resulting in intolerable on-target/off-tumour toxicity. Here we show that epitope engineering of donor HSPCs used for bone marrow transplantation endows haematopoietic lineages with selective resistance to chimeric antigen receptor (CAR) T cells or monoclonal antibodies, without affecting protein function or regulation. This strategy enables the targeting of genes that are essential for leukaemia survival regardless of shared expression on HSPCs, reducing the risk of tumour immune escape. By performing epitope mapping and library screenings, we identified amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT, and optimized a base-editing approach to introduce them into CD34+ HSPCs, which retain long-term engraftment and multilineage differentiation ability. After CAR T cell treatment, we confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts. Furthermore, we show that multiplex epitope engineering of HSPCs is feasible and enables more effective immunotherapies against multiple targets without incurring overlapping off-tumour toxicities. We envision that this approach will provide opportunities to treat relapsed/refractory acute myeloid leukaemia and enable safer non-genotoxic conditioning.
Nature Biotechnology
Lareau CA, Ludwig LS, Muus C, Gohil SH, Zhao T, Chiang Z, Pelka K, Verboon JM, Luo W, Christian E, Rosebrock D, Getz G, Boland GM, Chen F, Buenrostro JD, Hacohen N, Wu CJ, Aryee MJ, Regev A, Sankaran VG
In the version of this article initially published, due to a coding error, cell clonotypes and allele frequencies were permuted, impacting the visualization of panels in Fig. 6i, j, k, and o. Corrected panels appear as Fig. 1 below, and the software and documentation listed in the Code availability section have been updated. Interpretations of the data or text in the paper were not impacted by this issue. The figure has been corrected in the HTML and PDF versions of the article.
Nature Cancer
Clinical and Translational Advances in Ovarian Cancer Therapy
Konstantinopoulos PA, Matulonis UA
Ovarian cancer is an aggressive disease that is frequently detected at advanced stages and is initially very responsive to platinum-based chemotherapy. However, the majority of patients relapse following initial surgery and chemotherapy, highlighting the urgent need to develop new therapeutic strategies. In this Review, we outline the main therapeutic principles behind the management of newly diagnosed and recurrent epithelial ovarian cancer and discuss the current landscape of targeted and immune-based approaches.
Nature Cell Biology
KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer
Duplaquet L, Li Y, Booker MA, Xie Y, Olsen SN, Hong D, Hatton C, Denize T, Walton E, Laimon YN, Li R, Jiang Y, Bronson RT, Southard J, Li S, Signoretti S, Qiu X, Cejas P, Armstrong SA, Long HW, Tolstorukov MY, Oser MG
Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
Nature Communications
Spisak S, Tisza V, Nuzzo PV, Seo JH, Sztupinszki Z, Bell C, Rohanizadegan M, Stillman DR, Alaiwi SA, Bartels AB, Shetty A, Pomerantz M, Baca S, Szallasi Z, Gusev A, Freedman ML
To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.
New England Journal of Medicine
Mezigdomide Plus Dexamethasone in Relapsed and Refractory Multiple Myeloma
Richardson PG
BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.
METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1.
RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9).
CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).
ACS Central Science
Manipulating Tyrosine Phosphorylation by Heterobifunctional Small Molecules
Meng X, Qi J
Annals of Surgical Oncology
Great Debate: The Surgeon's Role in Locoregional Management of Stage IV Breast Cancer
King TA
Blood Advances
Feraco AM, Friedmann AM, Weinstein HJ, Flerlage JE
Blood Advances
Fillmore NR, La J, Corrigan JK, Branch-Elliman W, Monach P, Brophy MT, Do NV, Munshi NC
Blood Advances
Hacken ET, Yin S, Redd R, Clement K, Hoffmann GB, Regis FF, Witten E, Li S, Neuberg D, Pinello L, Livak KJ, Wu CJ
Blood Advances
Monoallelic Deletion of BCMA is a Frequent Feature in Multiple Myeloma
Samur MK, Aktas Samur A, Anderson KC, Munshi NC
Blood Advances
Wobma H, Kapadia M, Kim HT, Alvarez-Calderon F, Baumeister SHC, Duncan C, Forrest S, Gorfinkel L, Huang J, Lehmann LE, Li H, Schwartz M, Koreth J, Ritz J, Kean LS, Whangbo JS
Bone Marrow Transplantation
Gray TF, Amonoo HL
British Journal of Haematology
Ryan CE, Zon RL, Redd R, Fisher DC, Crombie JL, Sadrzadeh H, Kim AI, Nayak L, Chukwueke UN, Jacobson CA, Frigault MJ, Armand P, Merryman RW
Cancer
Lost in the Shadow of Giants: The Neglected Treatment Modalities in Oncologic Trials
Mohammadi H, Schoenfeld JD
Cancer
Physical Activity in Recurrent Colon Cancer: Cancer and Leukemia Group B/SWOG 80702 (Alliance)
Ma C, Meyerhardt JA
Cell Reports
Genome-Guided Discovery of Cancer Therapeutic Targets
Konda P, Garinet S, Van Allen EM, Viswanathan SR
Haematologica
Richardson PG, Raje N, Munshi N, Laubach JP, O'Donnell E, Anderson KC
Journal of Adolescent and Young Adult Oncology
Carroll BR, Zheng Y, Emmons KM, Partridge AH
Journal of General Internal Medicine
Rosenberg AR
Journal of Palliative Medicine
Mendoza K, Killeen K, Lakin JR, Leiter RE, Sciacca KR, Gelfand SL
JAMA Dermatology
Larocca CA, Fay CJ, Meyerhardt JA, Cleary JM, LeBoeuf NR
Oncologist
Choueiri TK
Pediatric Blood and Cancer
Olsen HE, Liu KX, Frazier AL, O'Neill AF, Janeway KA, DuBois SG, Shulman DS
Pediatric Blood and Cancer
Ward A, Li YY, Lazo de la Vega L, Nag A, Forrest SJ, Gupta HV, Thorner AR, Meyerson M, Kamihara J, Cherniack AD, Janeway KA
Science Advances
Jurkunas UV, Yin J, Johns LK, Li S, Negre H, Shaw KL, Kheirkhah A, Katikireddy K, Gauthier A, Ong Tone S, Kaufman AR, Ellender S, Hernandez Rodriguez DE, Daley H, Dana R, Armant M, Ritz J
Transplantation and Cellular Therapy
Sarosiek S, Quillen K