This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from June 1 - 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing [email protected].
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Annals of Oncology
Cabozantinib Plus Nivolumab and Ipilimumab in Previously Untreated, Advanced Renal Cell Carcinoma: Final Results and Biomarker Analyses from the Phase III COSMIC-313 Study
Choueiri TK
BACKGROUND: Primary results from COSMIC-313 demonstrated significantly longer progression-free survival (PFS) with first-line cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in patients with advanced renal cell carcinoma. Final efficacy and safety results, as well as data from exploratory biomarker analyses, are reported here.
PATIENTS AND METHODS: The design, participants, and primary-endpoint PFS outcomes have been reported previously for this phase III, double-blind, randomized (1 : 1) study of cabozantinib or placebo plus nivolumab and ipilimumab in adults with previously untreated, advanced clear cell renal cell carcinoma. The secondary endpoint was overall survival (OS) in the intention-to-treat population. Exploratory biomarker analyses investigated the potential association between immune cell types and gene signatures with clinical outcomes.
RESULTS: After a median follow-up of 45.0 months, the updated median PFS in the cabozantinib (triplet) arm was longer than in the placebo (doublet) arm (16.6 versus 11.2 months; hazard ratio 0.82, 95% confidence interval 0.69-0.98). There was no significant difference in median OS (hazard ratio 1.02, 95% confidence interval 0.85-1.23, P = 0.84), and the safety profile was consistent with the earlier analysis (grade 3/4 treatment-related adverse events occurred in 75% and 43% of patients in the triplet and doublet arms, respectively). In patients with higher levels of M2-like macrophages, the triplet regimen was associated with significantly improved PFS and OS compared with the doublet regimen. Responders in the triplet arm exhibited elevated angiogenic signatures and reduced immune-related pathways, while responders in the doublet arm had robust immune activation.
CONCLUSIONS: Long-term results from COSMIC-313 continue to demonstrate a PFS benefit with the addition of cabozantinib to nivolumab and ipilimumab. There was no OS benefit and no new safety signals were observed. Exploratory biomarker analyses suggest adding cabozantinib to nivolumab and ipilimumab improves survival in patients with high levels of M2-like macrophages.
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Annals of Oncology
Final Outcomes of the SOFT and TEXT Phase III Trials in Premenopausal Hormone Receptor-Positive Early Breast Cancer
Burstein HJ, Gelber RD, Goldhirsch A, Regan MM
BACKGROUND: The SOFT trial found adding ovarian function suppression (OFS) to tamoxifen (T) reduced breast cancer recurrence, and exemestane (E)+OFS further reduced recurrence. SOFT and TEXT combined analysis showed a significant reduction in distant recurrence with E+OFS versus T+OFS. We now report final 15-year outcomes.
PATIENTS AND METHODS: Premenopausal women with hormone receptor-positive early breast cancer were enrolled, with 3047 in SOFT and 2660 in TEXT intention-to-treat populations. SOFT randomized to 5 years of T versus T+OFS versus E+OFS. TEXT randomized to 5 years of T+OFS versus E+OFS. Chemotherapy was optional, prior to SOFT entry with subsequent premenopausal oestradiol, or concurrent with OFS in TEXT. Endpoints included disease-free survival, breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI) and overall survival. 15-year Kaplan-Meier estimates, hazard ratios (HR) and 95% confidence intervals (CI) are reported.
RESULTS: In SOFT, escalating endocrine therapy (ET) continued to reduce recurrence with 15-year BCFI 78.6% for E+OFS, 75.7% for T+OFS and 72.1% for T; T+OFS versus T, HR 0.82 (CI 0.69-0.98) P=0.03. In the SOFT no-chemotherapy cohort, OFS reduced breast cancer events at 15 years, while DRFI and overall survival remained high regardless of ET assignment. After prior chemotherapy for HER2-negative tumours (n=1257), SOFT 15-year overall survival was 81.0% with E+OFS versus 77.1% with T+OFS versus 76.8% with T. In women under age 35 with HER2-negative tumours (n=241), 15-year overall survival was 82.5% with E+OFS, 77.9% with T+OFS and 68.1% with T. In combined SOFT and TEXT analysis, among those with HER2-negative tumours (n=4035), E+OFS versus T+OFS reduced distant recurrence HR 0.75 (CI 0.63-0.90), with a smaller reduction in deaths HR 0.89 (CI 0.74-1.06), with absolute survival benefits largest with high-risk features, particularly young age or high-grade tumours.
CONCLUSION: Meaningful overall survival benefit in hormone receptor-positive, HER2-negative breast cancer from adjuvant exemestane and/or OFS compared with tamoxifen alone is limited to high-risk premenopausal subgroups. Tamoxifen-based ET may not result in optimal outcomes in premenopausal high-grade HER2-negative tumours.
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Blood
How Does NSD2 Fuel Multiple Myeloma?
Samur MK
In this issue of Blood, Wang et al identify the transcriptional targets dysregulated by NSD2 in t(4;14) multiple myeloma (MM) and revealed an epigenetic process, with competing histone mark antagonism at remote regulatory elements, that drives transcriptional regulation in MM.The t(4;14) translocation identifies a high-risk, poor-prognosis subgroup in MM. The rearrangement places the NSD2 gene (also known as MMSET [multiple myeloma SET] domain) under the control of the immunoglobulin heavy chain enhancer, leading to NSD2 overexpression in patients.NSD2 produces histone H3 lysine 36 dimethyltransferase (H3K36me2), a chromatin mark usually associated with gene activation, and activating translocations are recognized to contribute to t(4;14) MM, B-cell acute lymphoblastic leukemia, mantle cell lymphoma, and some solid tumors such as prostate cancer. But the specific transcriptional mechanisms involved remained unknown. Previous studies used a number of knockout approaches, stable isotope labeling by amino acids in cell culture mass spectrometry, or genome-wide CRISPR screens to identify probable targets and partners of NSD2 in MM; however, prior research was limited by a reliance on continual knockout models, which likely allow cells to adapt to the alteration over time or on contrasting t(4;14)-positive and -negative MM cases which possess numerous genetic differences beyond just NSD2.
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Blood
PKMYT1 is a Targetable Vulnerability in del(17p) High-Risk Multiple Myeloma
Cui J, Encinas J, Talluri S, Shammas MA, Anderson KC, Aktas Samur A, Samur MK, Avet-Loiseau H, Corre J, Munshi NC, Fulciniti M
Deletion of 17p is among the most adverse cytogenetic abnormalities in multiple myeloma (MM). By integrating RNA-seq data from patient MM cells with genetic dependency data from MM cell lines, we identified the protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) kinase, a member of the Wee family, as a potential therapeutic target in MM cells harboring del(17p). Genetic suppression or pharmacological inhibition of PKMYT1 activity with the selective inhibitor RP-6306 triggered accumulation of DNA damage, micronucleus formation and mitotic catastrophe, resulting in preferential cell death in del(17p) MM cells while largely sparing del(17p)-negative MM cells and healthy cells. RP-6306 also reduced tumor burden and extended survival in vivo in both xenograft and TP53-deficient syngeneic models. Collectively, our findings nominate PKMYT1 as an actionable target and support PKMYT1 inhibition as a biomarker-driven therapeutic strategy for patients with del(17p)/TP53-deficient MM.
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Cancer Cell
Identification of Cycling Regulatory T Cell Precursors as Conductors of Immune Escape During Breast Carcinoma Progression
Bui TM, Jimenez ER, Li Z, Foidart P, Puleo J, Yan P, Jhaveri A, Yang L, Nishida J, Seehawer M, Cai X, Parker KA, Sumer OE, Huang XY, Patel A, Dillon D, Dranoff G, Cristea S, Polyak K
Immune escape during the ductal carcinoma in situ (DCIS)-to-invasive breast cancer (IBC) transition shapes tumor evolution. Through transcriptomic mapping of the immune landscapes of normal breast, DCIS, and IBC from large patient cohorts, we identified T and myeloid cells as the primary distinguishing features between DCIS and IBC. We discovered cycling regulatory T cells (cycTreg) as an orchestrator of immunosuppression in IBC. cycTreg frequency predicts cytotoxic CD8+, TCR diversity, disease-specific survival in IBC, and recurrence in DCIS. In a rat model of breast cancer, we demonstrated that cycTreg act as precursors to mature Treg and are inducible by tumor-localized type 2 dendritic cells. Profiling of tumors subjected to αOX40 and αPD-L1 therapies revealed an IL-33-mediated fibroblast-cycTreg signaling loop, the disruption of which enhances intratumoral antigen-experienced CD8+ effectors and systemic immunosurveillance. Our study defines cycTreg as critical inducers of immune escape and promising immuno-oncology targets in breast cancer.
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Cancer Discovery
The Rising Burden of Early-Onset Cancer: Challenges and Opportunities
Rebbeck TR
Early-onset cancers are increasing globally, yet traditional research frameworks have yet to inform the epidemiologic and biological underpinnings of this trend. This perspective summarizes the current state of knowledge and prospects for a research agenda spanning epidemiology, exposure science, mechanistic studies, and federated infrastructures to address this emerging challenge.
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Cell
Biodiversity and Biogeography of the Multi-Kingdom Cancer Microbiome
Dohlman AB, Jiang K, Shumate A, Lee I, Yakubu AR, Huttenhower C, Meyerson M
Microorganisms represent an important component of the tumor microenvironment, but conflicting reports have left the extent of microbial prevalence across cancer types unclear, necessitating more robust methods for characterizing tumor-associated microbiomes. We built and benchmarked a host-subtraction and classification pipeline to identify microbiota in whole-genome sequencing data and applied it to 16,369 high-depth tumor whole genomes from the UK 100,000 Genomes Project. After decontamination, microbial signatures were indistinguishable from the background in most cancer types. However, in orodigestive tumors, we detected multi-kingdom polymicrobial communities, including bacteria, fungi, viruses, archaea, and, in some cases, Trichomonas, a protozoan parasite. These communities varied by tumor site and subtype, with increased microbial colonization of microsatellite-instable and polymerase ε (POLE)/polymerase δ (POLD1)-mutated tumors, supported by a correlation between microbial load and tumor mutation burden observed across orodigestive cancers. This analysis helps to resolve pan-cancer microbial structure and links the tumor microbiome to host phenotype and tumor genomic context.
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JAMA Oncology
Durable Gains and Persistent Questions From the ASTRUM-005 Trial
Florez N
The final analysis of ASTRUM-005, published in this issue of JAMA Oncology, provides long-term data supporting serplulimab as a therapeutic option in extensive-stage small cell lung cancer (ES-SCLC). In a cancer characterized by transient treatment responses and poor long-term survival, the reported 4-year overall survival rate of 21.9% with serplulimab plus chemotherapy, compared with 7.2% for chemotherapy alone, represents a clinically meaningful improvement and expands the role of immune checkpoint inhibition in the frontline setting. Importantly, the addition of serplulimab demonstrated benefit in patients with brain or liver metastases, subgroups that closely mirror the typical ES-SCLC population.
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JAMA Oncology
PD-(L)1 Inhibitor Monotherapy vs Chemoimmunotherapy for Advanced NSCLC with High PD-L1 Expression: A Systematic Review and Meta-Analysis
Pecci F, Wang X, Ricciuti B
IMPORTANCE: For patients with advanced non-small cell lung cancer (NSCLC) and programmed cell death 1 ligand 1 (PD-L1) expression of 50% or higher, programmed cell death 1 protein or PD-L1 (PD-[L]1) inhibitor monotherapy is commonly used as first-line therapy; however, whether adding chemotherapy improves outcomes in this population remains unknown.
OBJECTIVE: To compare overall survival (OS) and progression-free survival (PFS) associated with PD-(L)1 inhibitor monotherapy vs chemoimmunotherapy in treatment-naive patients with advanced NSCLC and high PD-L1 expression.
DATA SOURCES: PubMed, Embase, and major oncology conference proceedings were searched for phase 3 randomized clinical trials (RCTs) published before August 3, 2025.
STUDY SELECTION: Eligible studies were phase 3 RCTs that enrolled patients with untreated advanced NSCLC, evaluated PD-(L)1 inhibitor monotherapy or chemoimmunotherapy vs chemotherapy alone, and reported outcomes in patients with high PD-L1 expression.
DATA EXTRACTION AND SYNTHESIS: Hazard ratios (HRs) for OS and PFS were extracted from published studies and synthesized using inverse variance methods. Additional analyses included meta-regression, network meta-analysis, and reconstructed individual patient data from published Kaplan-Meier curves.
MAIN OUTCOMES AND MEASURES: Primary outcome was OS; secondary outcome was PFS.
RESULTS: Among 24 trials including 5546 patients with PD-L1-high NSCLC, 16 evaluated chemoimmunotherapy and 8 PD-(L)1 inhibitor monotherapy. Compared with chemotherapy, survival was improved by both chemoimmunotherapy (OS: HR, 0.63 [95% CI, 0.56-0.72]; P < .001; PFS: HR, 0.44 [95% CI, 0.39-0.49]; P < .001) and PD-(L)1 inhibitor monotherapy (OS: HR, 0.74 [95% CI, 0.69-0.80]; P < .001; PFS: HR, 0.70 [95% CI, 0.65-0.76]; P < .001). Tests for subgroup differences suggested improved benefit with chemoimmunotherapy compared to PD-(L)1 inhibitor monotherapy (OS: χ21 = 4.1; P = .04; I2 = 75.8%; PFS: χ21 = 48.1; P < .001; I2 = 97.9%), consistent with meta-regression analyses (OS: HR, 0.85 [95% CI, 0.72-1.00]; P = .048; PFS: HR, 0.61 [95% CI, 0.50-0.75]; P < .001) and network meta-analyses (OS: HR, 0.85 [95% CI, 0.73-0.99]; PFS: HR, 0.61 [95% CI, 0.50-0.75]). In the reconstructed individual patient data analysis, median OS was longer with chemoimmunotherapy (n = 704 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (29.2 months [95% CI, 25.2-35.4] vs 19.8 months [95% CI, 18.3-21.7]; HR, 0.74 [95% CI, 0.66-0.82]; P < .001). Similarly, median PFS was significantly longer with chemoimmunotherapy (n = 701 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (11.3 months [95% CI, 10.3-13.5] vs 6.8 months [95% CI, 6.2-7.1]; HR, 0.67 [95% CI, 0.60-0.75]; P < .001).
CONCLUSIONS AND RELEVANCE: In this meta-analysis of phase 3 RCTs, chemoimmunotherapy was associated with significantly improved OS and PFS compared with PD-(L)1 inhibitor monotherapy in patients with advanced NSCLC and high PD-L1 expression. Prospective trials are needed to confirm these findings.
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Journal of Clinical Oncology
Bridging the Gap: Advancing First-Line Therapy for Patients with Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer
Valenza C, Tolaney SM
In the rapidly changing field of oncology, advances in care typically start in an academic environment and then are implemented in various clinical settings with diverse patient populations. By Bridging the Gap between the highly monitored and controlled clinical trial environment and the heterogeneous, complex, and fluid settings in which patients receive care, we aim to improve understanding and raise the bar for a wider patient population, placing original research published in Journal of Clinical Oncology into a practical clinical context.
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Journal of Clinical Oncology
Ethical Design and Implementation of Monetary Transfer Interventions in Clinical Cancer Research
Hantel A, Hanson E, Abel GA, Bona K
Monetary transfer interventions (MTIs) are payments provided to recipients to meet specific needs. MTIs originated in the 1980s to combat the impacts of several South and Central American debt crises. Since that time, MTIs have been designed, implemented, and evaluated as a public health or welfare mechanism to improve social and economic outcomes driven by poverty or related vulnerabilities. Monetary incentives have also been studied in cancer control research to promote specific health behaviors, such as smoking cessation. Now, however, MTIs are being tested in clinical research as therapeutic interventions intended to modify the economic conditions that may causally contribute to health outcomes. The first oncology studies using this approach are now emerging, such as one evaluating the impact of an MTI on childhood cancer survival. Unlike reimbursement, compensation, or appreciation payments for participating in research testing other interventions, payments in MTIs are the intervention. This raises a distinct set of ethical and practical challenges with which cancer researchers and institutional review boards may be less familiar. In this article, we assess the types, purposes, and challenges of MTIs in clinical cancer research and provide guidance on their ethical design and practical conduct.
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Journal of Clinical Oncology
Randomized, Placebo-Controlled Trial of B-Cell Depletion for Prevention of Corticosteroid-Requiring Chronic Graft-Versus-Host Disease
Cutler C, Kim HT, El Banna H, Halloran E, Matozel E, Ho VT, Koreth J, Gooptu M, Shapiro R, Kelkar A, Gibson C, Nikiforow S, Nageshwar P, Reynolds C, Ansuinelli M, Tamada R, Au C, Panaro K, Gervais C, DeFilipp Z, El-Jawahri A, Chen YB, Soiffer R, Antin JH, Ritz J
PURPOSE: Chronic graft-versus-host disease (cGVHD) is a multisystem alloimmune disorder associated with abnormal B-cell biology and aberrant antibody responses. As B-cell-directed therapy can effectively treat established cGVHD, we tested whether prophylactic B-cell depletion could prevent the development of corticosteroid-requiring cGVHD following allogeneic transplantation.
METHODS: We performed a randomized, placebo-controlled, and blinded trial comparing four doses of the B-cell-depleting antibody obinutuzumab (1,000 mg once on days 90, 180, 270, and 365 after transplantation) with placebo in transplant recipients receiving tacrolimus-based GVHD prevention at higher risk of cGVHD. The primary end point was the 1-year incidence of corticosteroid-requiring cGVHD. We measured antibody responses against Y chromosome-encoded minor histocompatibility (H-Y) antigens and correlated their occurrence with corticosteroid-requiring cGVHD incidence.
RESULTS: One hundred seventy-eight participants were analyzed. The prophylactic administration of obinutuzumab resulted in profound B-cell depletion, a significant reduction in the incidence of steroid-requiring cGVHD at 1 year (13.3% v 35.2%; P = .0005), and an improvement in immunosuppression-free, relapse-free survival (48% v 34% at 2 years; P = .02). Neutropenia was more common in the obinutuzumab arm, but nonrelapse mortality was not different. In participants without preformed H-Y antibodies at the time of study intervention, obinutuzumab resulted in the most significant reduction in steroid-requiring cGVHD at 12 months (8.6%) compared with obinutuzumab participants with H-Y antibodies (40%) or placebo participants regardless of antibody status (41% with antibodies, 57% without antibodies).
CONCLUSION: In allogeneic transplant recipients at higher risk of cGVHD, early B-cell depletion results in a significant reduction in the incidence of corticosteroid-requiring cGVHD.
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Journal of Clinical Oncology
Rethinking Cardiovascular Events, End Points, and Surveillance in Oncology Trials
Nohria A, LaCasce AS
Advances in cancer therapeutics have transformed cancer into a curable or chronic disease for many patients. Consequently, long-term morbidity and competing risks have become increasingly relevant. Cardiovascular disease is the leading cause of non–cancer-related mortality among cancer survivors, prompting increased interest in the assessment of cardiovascular safety in oncology trials. The accompanying scientific statement, cosponsored by the American Heart Association and ASCO, calls for standardized definitions of cardiovascular adverse events, cardiovascular specialist involvement, and incorporation of cardiovascular end points in oncology clinical trials to promote better understanding of cancer therapy-related cardiac toxicities with the goal of improving outcomes for cancer survivors. However, translating these recommendations into practice requires careful consideration of both historical precedents and the unintended consequences of increased surveillance.
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Journal of the National Cancer Institute
Racial and Ethnic Differences in Opioid Fills Following Cancer-Directed Surgery Among Older and Younger Medicare Beneficiaries
Odai-Afotey A, Wang X, Keating NL, Landrum MB, Wright AA, Enzinger A
BACKGROUND: Opioid receipt differs by race and ethnicity across multiple settings, yet few studies have examined disparities after cancer-directed surgery.
METHODS: Using fee-for-service Medicare claims, we identified cancer-directed surgeries between 2012 to 2021. Multivariable linear regression models estimated racial and ethnic differences in postoperative opioid fills and doses within 30-days, adjusting for demographic and clinical factors. We ran separate models among older (age ≥ 65) and younger (age < 65) Medicare beneficiaries (who typically qualify based on disability), and further models by preoperative opioid use (opioid-naïve vs not).
RESULTS: We identified 958,593 surgical episodes. Overall 84.9% were non-Hispanic White (White), 8.1% non-Hispanic Black (Black), 4.4% Hispanic, and 2.2% Asian. Among older beneficiaries, Black and Hispanic patients were 4.7 [95%CI : 4.3,5.1] and 3.1 [95%CI : 2.6,3.6] percentage points more likely to fill ≥1 opioid than White patients. Mean 30day doses were similar between Black and White patients; whereas Hispanic and Asian patients filled modestly lower doses (-22 MME [95%CI:-27,-16], -53 MME [95%CI:-61,-46]). Among younger beneficiaries, opioid fill rates were relatively similar across racial and ethnic groups. However, mean 30-day doses were substantially lower among Black (-135 MME [95%CI:-154,-115]), Hispanic (-167 MME [95%CI:-198,-136]), and Asian (-259 MME [95%CI:-327,-191]) vs White patients, particularly those with prior opioid use.
CONCLUSIONS: We observed modest racial and ethnic differences in opioid fills following cancer-directed surgeries among older Medicare beneficiaries. However, among younger beneficiaries, Black, Hispanic, and Asian patients filled substantially lower 30-day doses than White patients, primarily among those with prior opioid use. Cancer pain equity efforts should target populations experiencing meaningful disparities.
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Lancet
Mezigdomide, Carfilzomib, and Dexamethasone Versus Carfilzomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (SUCCESSOR-2): A Phase 3, Open-Label, Randomised Controlled Trial
Hartley-Brown MA, Richardson PG
BACKGROUND: A growing number of patients with multiple myeloma are anti-CD38 antibody-exposed and lenalidomide-exposed at first relapse, subsequently limiting their treatment options. Mezigdomide, a potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs. The SUCCESSOR-2 trial evaluates the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone versus carfilzomib plus dexamethasone.
METHODS: This phase 3, open-label, randomised controlled trial was conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design. Eligible adult patients had measurable multiple myeloma, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment. Interactive response technology was used to randomly assign patients, stratified by age (≤70 years or >70 years), number of previous lines of therapy (≤2 or >2), and International Staging System stage (I, II, or III). Patients received oral mezigdomide (days 1-21 of each 28-day cycle) plus intravenous carfilzomib (56 mg/m2 weekly) and oral or intravenous dexamethasone (40 mg weekly) or carfilzomib (56 mg/m2 twice weekly or 70 mg/m2 weekly) and dexamethasone (20 mg twice weekly or 40 mg weekly). In stage 1, mezigdomide dosing across three levels was optimised. In stage 2, patients were randomly assigned to the selected mezigdomide dose (1·0 mg) plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone. The primary endpoint was progression-free survival (PFS) evaluated in patients who received 1·0 mg mezigdomide plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone across both study stages. No imputation was planned for missing efficacy endpoint values or missing safety evaluations. The trial is registered with ClinicalTrials.gov (NCT05552976) and EUClinicalTrials.eu (EUCT number 2022-500861-29-00). The trial is active but not recruiting.
FINDINGS: Between Feb 3, 2023, and Nov 28, 2025, 762 patients were assessed for eligibility, of which 606 patients were enrolled and 479 were included in the analyses (288 patients in the mezigdomide-carfilzomib-dexamethasone group and 191 patients in the carfilzomib-dexamethasone group). 252 (53%) patients were male, 411 (86%) were anti-CD38 antibody-refractory, and 363 (76%) were lenalidomide-refractory, with a median of two previous lines of therapy (IQR 2-4). At 10·6 months median follow-up, mezigdomide-carfilzomib-dexamethasone significantly improved PFS compared with carfilzomib-dexamethasone (median 18·0 months vs 8·3 months; hazard ratio 0·48 [95% CI 0·36-0·63]; p<0·0001). Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide-carfilzomib-dexamethasone versus 105 (56%) patients receiving carfilzomib-dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]). Eight (3%; 95% CI 1-5) and one (1%; 95% CI 0-3) treatment-related grade 5 adverse events were reported with mezigdomide-carfilzomib-dexamethasone and with carfilzomib-dexamethasone, respectively (rate difference 2%; 95% CI -1 to 5). Deaths occurred in 62 (22%) patients in the mezigdomide-carfilzomib-dexamethasone group and 51 (27%) patients in the carfilzomib-dexamethasone group, mainly due to disease progression.
INTERPRETATION: Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need.
FUNDING: Bristol Myers Squibb.
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Molecular Oncology
Tumor B-Cell Infiltration in Platinum-Treated Advanced Muscle-Invasive Urothelial Carcinoma
Stawiski K, Lee J, Michaud DE, Guerriero JL, Mouw KW, Carvalho FLF, Bellmunt J
Platinum chemotherapy is a standard therapeutic choice for advanced urothelial cancer, but biomarkers demonstrating its benefits are limited. We tested whether the tumor microenvironment, particularly B-cell infiltration, could predict overall survival after platinum chemotherapy. Pretreatment tumors from 189 patients in three cohorts treated with cisplatin- or carboplatin-based regimens underwent bulk transcriptome profiling. Immune cell infiltration and multicellular communities were inferred from gene expression and associated with overall survival using cohort-specific multivariable models and meta-analysis. Higher lymphocyte infiltration was associated with longer overall survival (hazard ratio 0.34, 95% confidence interval 0.16-0.72), driven by B cells and memory B cells (hazard ratio 0.19, 95% confidence interval 0.05-0.75). These associations were confined to cisplatin-treated patients and were strongest in tumors with a pro-inflammatory B-cell-rich community and concordant B-cell gene expression signatures. In contrast, higher myeloid infiltration was associated with shorter overall survival. Pretreatment B-cell enrichment in the tumor microenvironment identified a subset associated with improved overall survival among patients receiving platinum chemotherapy, particularly cisplatin, supporting B-cell-focused biomarker development and spatial characterization of tertiary lymphoid structures in urothelial cancer.
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Nature Cancer
Tumor Transcriptional State Predicts Survival in Immune-Checkpoint-Blockade-Treated Glioblastoma
Ghannam JY, Bryan J, Weiss J, Merrell D, Messer C, Schlueter-Kuck K, Fell GG, Youssef G, Rahman R, Qin L, Young GS, Janes JT 3rd, Van Orden M, Pfaff KL, Gans A, Lin ES, Huang RY, Danysh BP, Li S, Wen PY, Chiocca EA, Neuberg D, Ligon KL, Reardon DA, Getz G, Wu CJ
The determinants of immune checkpoint blockade (ICB) response in glioblastoma (GBM) with wild-type isocitrate dehydrogenase remain poorly understood. Here we profiled 181 ICB-treated GBM cases using bulk DNA sequencing, bulk RNA sequencing and single-nucleus RNA sequencing to investigate the genomic features associated with ICB outcomes. Baseline tumor transcriptional subtype was predictive of overall survival following ICB, with mesenchymal (MES) GBM associated with improved outcomes to ICB but not standard chemoradiation. Non-MES-associated genetic lesions, including those in PDGFRA and CDKN2A, were associated with worse survival following ICB but not standard therapy. Tumor mutational burden was not predictive of outcomes. Survival was associated with pre-ICB enrichment for MES-like malignant cells, marked by high human leukocyte antigen class I expression and greater T cell infiltration. Paired tumor analyses linked ICB exposure to outgrowth of subclones harboring lesions associated with non-MES subtypes, supporting MES-to-non-MES transition as a common trajectory of acquired resistance to ICB, distinct from standard chemoradiation.
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Nature Immunology
Inhibition of Salt-Inducible Kinases Reprograms T Cells and Antitumor Immunity in Ovarian Cancer
Dong H, Ray A, Rotter LK, Wang J, Grabski I, Mewada H, Wang L, Huang K, Tian Y, Meylan M, Barlow G, Yu C, Raundhal M, Yoon SH, Nakhawa S, Ding L, Zhao JJ, Matulonis UA, Wucherpfennig KW, Irizarry RA, Wein MN, Glimcher LH
Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, whereas SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant high-grade serous ovarian carcinoma, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2 and -3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-γ, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.
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Science Immunology
Let Your Light Shine Down
Coffey JM, Griffin GK
The canonical human proteome is currently thought to contain ~20,000 protein-coding genes. However, recent work has begun characterizing protein sequences encoded by thousands of unannotated noncanonical open reading frames (ncORFs) in the genome, often referred to as the “dark proteome.” Because of the lack of reference annotations for these elements, they are frequently absent from proteomics and immunopeptidomics analyses, including efforts focused on finding previously unknown disease-associated antigens or immunotherapeutic targets.
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Advances in Radiation Oncology
Acute Toxicity from Short-Course Radiation Therapy for Rectal Cancer: A Single-Institution Experience
Neibart SS, Chen YH, Droznin A, Huynh MA, Guthier C, Martin N, Mancias JD, Lam MB, Shiloh R, Peng L, Ng K, Surana R, Enzinger PC, Meyerhardt JA, Mamon HJ
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American Journal of Hematology
Final Report of a Phase II Study of Ibrutinib and Venetoclax in Previously Untreated Waldenström Macroglobulinemia
Castillo JJ, Branagan AR, Guijosa A, von Keudell G, Ramirez-Gamero A, Chory H, Kobs M, Budano N, Nguyen J, Eurell A, Boyajian C, Meid K, Guerrera ML, Kofides A, Liu S, Liu X, Tsakmaklis N, Hunter ZR, Patterson CJ, Treon SP, Sarosiek S
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Blood Advances
A Phase 1/2 Study of Duvelisib Plus Venetoclax in Patients with Relapsed/Refractory CLL/SLL or Richter Transformation
Crombie JL, Ryan CE, Ren Y, Tyekucheva S, Carey C, Zou A, Normilus S, Montegaard J, Soumerai JD, Arnason JE, Kim AI, Parry EM, Armand P, Fisher DC, Brown JR, Davids MS
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Blood Advances
A Pilot Randomized Clinical Trial of a Peer Support Intervention for Hematopoietic Stem Cell Transplantation
Amonoo HL, Keane EP, Guo M, Gudenkauf LM, Boardman AC, Larizza IS, Mate-Kole MN, Healy BC, Cutler C, Greer JA, Huffman JC, El-Jawahri A
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Blood Advances
Live-Cell Pick-Seq (LiP-Seq): Interrogating Ultra-Rare Mantle Cell Lymphoma Persistent Cells After CART19 Therapy
Xu R, Wu G, Rice S, Booker M, Weekes J, Bell H, Nirmal AJ, Liu H, Ciantra Z, Luo Q, Fortune A, Whalen K, Guanci T, Wan Y, Louissaint A Jr, Lin JR, Manalis SR, Armand P, Smith E, Jacobson CA, Tolstorukov M, Murakami MA, Sorger PK, Weinstock DM, Lane AA
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Breast
Impact of Pathologic Response and Individual Prognosis After Neoadjuvant Treatment in Patients with Early HER2+ and Triple-Negative Breast Cancer
Corti C, Li T, Martin AR, Hughes ME, Parker T, Duporte TS, King TA, Mittendorf EA, Lin NU, Tayob N, Tolaney SM
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Cancer Research
Cancer Susceptibility to Stapled Oncolytic Peptides Is Dictated by Membrane Cholesterol and Inflammatory Signaling
Adhikary U, Tesar B, Patel K, Schmidt MJ, Levy HR, Zacharakis E, Godes M, Gokhale PC, Hebert KM, Neuberg DS, Bird GH, Walensky LD
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Cell Host and Microbe
Long-Lasting Gut Microbiome and Fecal Metabolome Alterations After Colorectal Adenoma Removal and Their Relationship to Colorectal Cancer
Nogal A, Wang K, Thompson KN, Kim H, Bhosle A, Maharjan S, Upreti C, Nguyen LH, Rimm EB, Garrett WS, Chan AT, Huttenhower C, Song M
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Clinical Cancer Research
Association of Tumor-Infiltrating Lymphocyte Subtypes with Clinical Characteristics and Prognosis in Young Women with Hormone Receptor-Positive Breast Cancer
Tesch ME, Zheng Y, Guzman-Arocho YD, Collins LC, Heng YJ, Tayob N, Peppercorn J, Come SE, Snow C, Mittendorf EA, Partridge AH
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Clinical Genitourinary Cancer
Radiation and Avelumab in Cisplatin-Ineligible Patients with Muscle-Invasive Bladder Cancer
Mouw KW, Shin KY, Parisi J, Zhai B, Spicer B, Mann E, Sathiyamoorthy O, Mossanen M, Ravi P, Ravi A, McGregor B, Fein D, Berg S, Mantia C, Preston M, Baghian A, Bellmunt J
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ESMO Open
Scalp Cooling Outcomes in Patients Receiving Trastuzumab Deruxtecan for Metastatic Breast Cancer
Salehi E, Chu X, Mayer EL, Singer S, Augdahl G, Stalteri M, Li T, Dibble KE, Sinclair N, Faggen M, Walsh J, Sammons S, Sendrick K, Hanna S, Mostaghimi A, Tayob N, LeBoeuf NR, Tolaney SM
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Immunity
Dietary Sulfur Amino Acids Enhance Anti-Tumor Immunity in Colon Cancer Via an NKT Cell-XCL1-cDC1 Circuit
Lobel L, Fonseca-Pereira D, Nakatsu G, Michaud M, Cao YG, Bae S, Krabak C, Oren Y, Clay SL, El Tekle G, Chun E, Chan AT, Clardy J, Glickman JN, Huttenhower C, Garrett WS
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JCO Precision Oncology
Germline Whole-Genome Sequencing in Early-Onset Pediatric Solid Tumors Implicates Novel Risk Factors
Nagy M, Bhattacharjee A, Cinelli A, Kamihara J, Schienda J, Hamilton K, Cibulskis C, Fields N, Sun B, Collins R, Parad RB, Diller L, Gillani R
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Journal of Cardiac Failure
Implementing HeartPal: Design and Early Results of a Specialized Care Delivery Model for Advancing Palliative Care in Advanced Heart Disease Populations
Jain N, Santo EC, Lehto HR, Schaefer KG, Manning KA, Landzberg MJ, Warraich HJ, Givertz MM, Mehra MR, Tulsky JA, Desai AS
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Journal of the American Geriatrics Society
Research Letter: Frailty Within a Cohort of Older Adults with Breast Cancer: Groundwork for Future Geriatric-Specific Outcomes Data
Minami CA, Heiling HM, Tayob N, Hughes ME, Snow C, Ryan S, Elfman S, Lima RF, Cunniff E, Kline D, Faggen M, Constantine M, Walsh J, Sinclair N, McAllister SS, Freedman RA
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Journal of the National Comprehensive Cancer Network
Pathways to Advance Targeted and Helpful Serious Illness Conversations (PATH-SIC): A Randomized Clinical Trial
Manz CR, Cotner CE, Tramontano AC, Awan S, Gwynne N, Voligny E, Siegel J, Post A, Finn B, Rice M, Brain J, Lindvall C, Jackman DM, Jacobson JO, Tulsky JA, Wright AA
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Leukemia and Lymphoma
Allogeneic Transplant Outcomes in T-Cell Prolymphocytic Leukemia: A Single-Center Retrospective Study
Merrill M, Kim HT, Kelkar AH, Panaro K, Tamada R, Au C, Singh S, Vicks A, Jain S, Ritz J, Ho VT, Jacobsen E
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Molecular Cancer Research
Epigenetic Atlas of Bladder Cancer Reveals Master Transcription Factors and Risk-Associated Regulatory Elements in Luminal and Basal-Squamous Molecular Subtypes
Adib E, Baca SC, Hanlon T, Bou Farhat E, Tang Y, Seo JH, El Zarif T, Losko M, Zhang Z, Hirsch MS, Gusev A, Mouw KW, Choueiri TK, Kwiatkowski DJ, Freedman ML
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Supportive Care in Cancer
Food Insecurity, Dietary Quality, and Cardiovascular Risk Among Early Childhood Cancer Survivors
Aziz-Bose R, Paul MA, Lokko L, Jones E, Meng J, Fry C, Kelly CA, Duhaney L, Kenney LB, Bona K
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Transplantation and Cellular Therapy
Caring for the Hematopoietic Stem Cell Transplantation Population: Clinician Perspectives on Challenges and Opportunities in Psychosocial Care Delivery
Keane EP, Adri FN, Larizza IS, Monahan JA, Song MT, Boardman AC, Schaefer DA, Wu JH, Conway S, Gudenkauf LM, Amonoo HL
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