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 May 16 - 31.
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
Autologous T Cell Antigen Coupler Targeting HER2 (TAC01-HER2) in Advanced or Metastatic Solid Tumors
Weiss JA, Schlechter BL
The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. We designed a phase 1 clinical trial of TAC01-HER2, an autologous T cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and a dose-expansion at the recommended phase 2 dose (RP2D). A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events were cytokine release syndrome (n=14, 60.9%), anemia (n=5, 21.7%), and increased alanine aminotransferase (n=5, 21.7%). The RP2D was 6-8 × 106 per kg. No treatment-related deaths or adverse events leading to study discontinuation were reported. Two of 9 patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses, and the disease control rate (stable disease or partial response) was 61.1% in the 18 patients with evaluable assessments. The median progression-free survival was 2.6 months (range 0.8-12.4 months), and the overall survival rate at 6 months was 57.9% (95% CI, 36.3%-76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. In summary, we demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T cell activity through cellular therapy.
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Annals of Oncology
Lorlatinib Versus Crizotinib as First-Line Treatment for Advanced ALK-Positive Non-Small Cell Lung Cancer: 7-Year Update from the Phase 3 CROWN Study
Shaw AT
BACKGROUND: Due to the unprecedented PFS benefit with lorlatinib after 5 years of follow-up in the phase 3 CROWN study, we aimed to quantify long-term outcomes at 7 years.
PATIENTS AND METHODS: 296 treatment-naive patients with advanced ALK-positive NSCLC were randomized 1:1 to receive lorlatinib 100 mg OD (n=149) or crizotinib 250 mg BID (n=147). This post hoc analysis presents investigator-assessed efficacy outcomes, safety, and biomarker analyses.
RESULTS: With median follow-up of 83.0 and 77.2 months, median PFS (95% CI) was not reached (NR; 68.5-NR) with lorlatinib and 9.1 months (7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.26); 7-year PFS was 55% and 3% respectively. With lorlatinib, patients without a PFS event at the end of 24 months had a 79% probability of survival without progression at year 7. No new intracranial progression events occurred after the first 30 months on lorlatinib. Median time to intracranial progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 months (12.7-21.9) with crizotinib (HR, 0.06; 95% CI, 0.03-0.12). Overall survival follow-up is ongoing; the number of events for a protocol-specified analysis has not been met. The safety profile was consistent with the 5-year results. With lorlatinib, treatment-related AEs did not lead to discontinuations after the first 26 months. More genetic alterations were detected in ctDNA samples from early progressors than in long-term responders on lorlatinib; new potential resistance mechanisms were identified.
CONCLUSIONS: With median PFS yet to be reached after 7 years of follow-up in CROWN, lorlatinib continues to show unprecedented long-term benefit in patients with advanced ALK-positive NSCLC. Patients without progression within 24 months on lorlatinib have a low risk of progression or death at year 7 and may continue long-term treatment. Findings suggest that sustained long-term disease control with first-line lorlatinib may enable advanced ALK-positive NSCLC to evolve toward a chronic condition.
GOV IDENTIFIER: NCT03052608.
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Annals of Oncology
Updated Results of the POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) Trial
Niman SM, Gelber RD, Partridge AH
BACKGROUND: In patients with hormone receptor-positive (HR+) early breast cancer (BC), the POSITIVE trial demonstrated that temporary interruption of adjuvant endocrine therapy (ET) for pregnancy is feasible and safe in early follow-up (median 41 months). Here we report updated results from a pre-planned analysis with 2.5 years of additional follow-up.
PATIENTS AND METHODS: POSITIVE, a single-arm prospective trial evaluating temporary interruption of adjuvant ET (after 18-30 months and for up to 2 years) to attempt pregnancy in young BC patients, enrolled 518 eligible women (<42 years of age, stage I-III BC, desiring pregnancy) from 12/2014 to 12/2019. Using the bootstrap-matching method, 5-year breast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) event rates are compared to those of SOFT/TEXT trials as external controls.
RESULTS: At a median follow-up of 71 months in the POSITIVE cohort and 80 months in the SOFT/TEXT cohort, the 5-year cumulative incidence of BCFI events was 12.3% in POSITIVE and 13.2% in SOFT/TEXT (-0.9% difference, 95% CI -4.2% to 2.6%). The 5-year cumulative incidence of DRFI events was 6.2% and 8.3%, respectively, (-2.1% difference, 95% CI -4.5% to 0.4%). Among 497 women followed for non-disease outcomes, 377 (76%) had >1 documented pregnancy on trial, 343/497 (69%) had >1 live birth, with 440 offspring. In an unadjusted analysis comparing the 180 women (36%) who had pre-enrollment embryo/oocyte cryopreservation to those who did not, the 5-year cumulative incidence of BCFI events was 14.0% (95% CI: 9.6% to 20.2%) and 11.5% (95% CI: 8.4% to 15.7%), respectively.
CONCLUSION: Longer-term follow-up of the POSITIVE trial demonstrates that temporary interruption of ET for pregnancy including use of fertility preservation does not increase risk of BC events. Continued follow-up is warranted given the known risk of late recurrence in this population.
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JAMA Oncology
Circulating Tumor DNA in Early Breast Cancer: A Review
Schlam I, Tolaney SM, Lin NU, Morganti S
IMPORTANCE: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker with the potential to detect minimal residual disease (MRD), monitor treatment response, and identify recurrence (e.g., molecular relapse) earlier than conventional clinical or imaging approaches. Although ctDNA-based MRD assays have demonstrated prognostic value in early breast cancer, their optimal clinical utility remains uncertain.
OBSERVATIONS: This review summarizes the current data on ctDNA MRD assays in early breast cancer. Although these assays have established analytical and clinical validity, their clinical utility remains uncertain. Dynamics of ctDNA during neoadjuvant therapy are associated with pathologic complete response and long-term outcomes. Following completion of curative-intent therapy, ctDNA positivity (e.g., presence of MRD) is strongly associated with future distant recurrence. Similarly, the emergence of ctDNA during surveillance precedes the clinical diagnosis of overt metastatic disease. Although observational studies and meta-analyses have supported ctDNA as a complementary biomarker for established risk-stratification tools, evidence that demonstrates improved outcomes with ctDNA-guided management remains limited. Furthermore, the optimal timing and frequency of testing remain unknown, and studies comparing assays are lacking. Multiple ongoing prospective interventional trials are evaluating whether ctDNA-guided treatment escalation or de-escalation can improve patient outcomes and support the routine implementation of ctDNA assays in clinical practice.
CONCLUSIONS AND RELEVANCE: ctDNA-based MRD assays hold promise for refining risk stratification, enabling earlier detection of recurrence, and informing treatment decisions in patients with early breast cancer, but clinical utility has not yet been demonstrated. Prospective trials are essential to determine whether ctDNA-guided interventions improve outcomes beyond standard management. Clinicians should understand the strengths, limitations, and evolving evidence base of ctDNA assays, as well as patient preferences, prior to incorporating them into patient care.
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Journal of Clinical Oncology
Is It Time to Move Beyond Graft-Versus-Host Disease-Free, Relapse-Free Survival as a Primary End Point in Clinical Trials for Hematopoietic Cell Transplantation?
Kelkar AH, Abel GA, Cutler CS, Soiffer RJ
Oncology clinical trials share a common goal: to help patients live longer and better. This principle is especially important in curative-intent settings such as allogeneic hematopoietic cell transplantation (HCT), where the promise is not incremental improvement but potential cure. Graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS)—survival without grade 3 to 4 acute GVHD, chronic GVHD requiring systemic therapy, or relapse—has recently been adopted in many HCT trials. First proposed by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), GRFS gained acceptance because it seemed to represent transplant success: disease control without major morbidity. Yet, because relapse remains the main cause of transplant failure, a composite end point that gives GVHD and relapse equal weight, treats either event as equivalent to death, and excludes other complications may not fully capture meaningful clinical benefit. Herein, we re-examine the role of GRFS as a primary end point in HCT trials and propose a pragmatic realignment of end points to match therapeutic intent while still facilitating accelerated approvals.
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Journal of Clinical Oncology
Treatment Effect Reanalysis of the Randomized Individual Screening Trial of Innovative Glioblastoma Therapy in Newly Diagnosed Glioblastoma with External Control Data
Rudra Gupta T, Redd R, Lee EQ, Arrillaga-Romany I, Tan Y, Chukwueke UN, Beroukhim R, Nayak L, Batchelor TT, Bi WL, Arnaout O, Peruzzi PP, Haas-Kogan D, Tanguturi S, Aizer A, Doherty L, Santagata S, Meredith DM, Chiocca EA, Reardon DA, Ligon KL, Wen PY, Trippa L, Rahman R
PURPOSE: Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data.
METHODS: The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls.
RESULTS: After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data.
CONCLUSION: The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.
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Journal of the National Cancer Institute
Pregnancy History, Recency of Childbirth, and Outcomes in Young Women with Early-Stage Breast Cancer
Nader-Marta G, Zheng Y, Rosenberg SM, Dibble KE, Mayer EL, Poorvu PD, Guzman-Arocho YD, Peppercorn J, Valenza C, Tayob N, Come SE, Polyak K, Partridge AH
BACKGROUND: Breast cancer (bc) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunologic, and tissue remodeling changes. Studies have suggested that postpartum bc may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage bc.
PATIENTS AND METHODS: Patients aged ≤40 years with stage I-III bc enrolled in the Young Women's Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by bc subtype [estrogen receptor-positive [ER+]/HER2-, HER2+, and triple-negative (TNBC)], with distant recurrence-free survival (DRFS) as the primary endpoint.
RESULTS: Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2-, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (<2 vs 2 to 5 years), yielded consistent results.
CONCLUSIONS: Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact.
CLINICAL TRIAL REGISTRATION: NCT01468246.
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Molecular Cell
MRE11 Proximal Polyadenylation Site-Mediated Looping Impacts Transcription and Genomic Stability
Huang K, Brault ME, Cong K, Azazmeh N, Lee S, Lantz GA, Raskind G, Beroukhim R, Chowdhury D
Alternative polyadenylation (APA) generates transcript isoforms with variable 3' untranslated regions (UTR) lengths, yet its role in DNA damage response (DDR) genes is poorly understood. Here, we demonstrate that the proximal polyadenylation site (pPAS) of MRE11 engages in PAS-promoter looping to facilitate RNA polymerase recycling and sustain high promoter activity-a mechanism not well characterized in mammals. Deletion of the MRE11 pPAS disrupts this looping, reduces MRE11 transcription, impairs MRE11-RAD50-NBS1 (MRN) complex levels, and phenocopies hypomorphic MRE11 mutations. MRE11pPAS-/- cells exhibit ectopic DNA replication and reduced viability under overgrowth conditions. 5-ethynyl-2'-deoxyuridine sequencing (EdU-seq) revealed aberrant DNA synthesis occurring primarily at intronic and intergenic regions, where MRE11 chromatin immunoprecipitation sequencing (ChIP-seq) showed decreased binding correlating with elevated replication. Furthermore, multiple DDR genes with several PASs also form PAS-promoter loops, suggesting a broader regulatory mechanism. Together these findings identify the MRE11 pPAS as a critical noncoding element that maintains genome stability through transcriptional regulation via PAS-promoter looping.
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Nature Cancer
Gemcitabine and Nab-Paclitaxel with or without the VDR Agonist Paricalcitol for Metastatic Pancreatic Cancer: A Randomized, Multiarm, Run-In Phase Trial
Perez KJ, Dias Costa A, Jordan A, Elganainy D, Kim S, Yuan C, Gui DY, Tan R, Hong SC, Wang X, Cristea S, Coleman E, Zheng H, Furniss CS, Brais L, Bird A, Remland J, Gocheva V, Thalappillil JS, Anderson M, Cleary JM, Enzinger A, Giannakis M, Ng K, Rubinson DA, Schlechter B, Surana R, Singh H, Abrams T, Allen E, Winter PS, Raghavan S, Aguirre A, Nowak JA, Wolpin BM
Vitamin D receptor (VDR) agonists promote quiescence of cancer-associated fibroblasts and improve efficacy of chemotherapy in preclinical models of pancreatic cancer. We conducted a run-in phase trial with primary endpoint of safety when the VDR agonist paricalcitol is given with first-line gemcitabine and albumin-bound paclitaxel (GA) in patients with metastatic pancreatic cancer. Secondary endpoints included pharmacodynamic analyses. Thirty-six patients were randomized to GA plus placebo, GA plus intravenous paricalcitol or GA plus oral paricalcitol with pretreatment and on-treatment tumor biopsies. Paricalcitol was safely administered with GA, although five patients (42%) receiving oral paricalcitol had grade 2-4 hypercalcemia and required dose reduction. Nuclear VDR protein expression was heterogeneous across patients, and VDR was expressed in tumor, immune and stromal cells. Compared to pretreatment specimens, on-treatment biopsies had decreased proportion of αSMA+ fibroblasts, altered fibroblast VDR activation signature and greater density and spatial colocalization of CD8+ T cells with tumor cells in the GA-plus-paricalcitol arms. VDR expression was predictive of tumor response in the GA-plus-paricalcitol arms. Paricalcitol can be safely administered with chemotherapy to patients with metastatic pancreatic cancer, and on-treatment biopsies indicated favorable modulation of the tumor microenvironment by paricalcitol as predicted by preclinical models. ClinicalTrials.gov identifier: NCT03520790.
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Nature Chemical Biology
Pharmacological Targeting of IRF4 as a Therapeutic Strategy for Multiple Myeloma
Agius MP, Song C, Liu Q, Iemura T, Hevenor L, Payne NC, Pistofidis RS, Pantano L, Zhao H, Seo HS, Heilpern-Mallory D, Heaslip C, Sun ZJ, Bashyal P, Aranha MP, Lightbody E, Mazitschek R, Dhe-Paganon S, Mitsiades CS, Ghobrial IM, Qi J
Interferon regulatory factor 4 (IRF4) is an oncogenic transcription factor (TF) in several hematological malignancies. To date, no pharmacological agents have been developed specifically for IRF4 due to the challenging nature of targeting TFs. Here we first identified (S)-H1, a binder of IRF4, by targeting the SPI1-IRF4 interaction on IRF4's interferon association domain via high-throughput screening. Next, we successfully turned our binder into dIRF4-2, a first-in-class proteolysis-targeting chimera of IRF4, by linking (S)-H1 to E3 ligase ligands of cereblon. dIRF4-2 can induce highly selective proteasomal degradation of IRF4 and has strong cytotoxic effects in all multiple myeloma lines evaluated in vitro. Our study showcases methodology to effectively target the IRF family of TFs and illustrates how to convert an inert binder into a powerful chemical probe for studying the functions of important oncoproteins that are structurally difficult to target.
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Nature Communications
Carboplatin with or without Nivolumab in Metastatic Triple-Negative Breast Cancer: A Randomized Phase II Trial
Garrido-Castro AC, Graham N, Li KX, Bi L, Crowdis J, Bi K, Park J, Pastorello R, Li Y, Gupta H, Kuntz T, Patel A, Lange P, DiLullo M, Attaya V, Frey AM, Sinclair N, Tung N, Faggen M, Block CC, Walsh J, Chen W, Wucherpfennig KW, Tian Y, Schnitt S, Cherniack AD, Barroso R, Ligibel J, Lin NU, Mittendorf EA, Tayob N, Van Allen E, Tolaney SM
This multi-institutional randomized phase II clinical trial (NCT03414684) investigated the efficacy and safety of carboplatin plus nivolumab compared to carboplatin in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was progression-free survival (PFS) in a modified intention-to-treat (mITT) population of patients with chemotherapy-naïve (i.e., first-line) mTNBC. Secondary endpoints included overall survival (OS), confirmed objective response rate, confirmed clinical benefit rate, time to and duration of confirmed objective response, safety, and tolerability. Clinical outcomes were evaluated in the PD-L1-positive subgroup ( ≥ 1% immune cells; SP142 clone) per central review. Biospecimens were collected for correlative analyses. 75 patients were enrolled and treated between 2/2018-9/2020. Among the mITT population (n = 62), median PFS was 4.2 months with carboplatin plus nivolumab vs 5.5 months with carboplatin. Median OS did not significantly differ between arms (16.8 vs 11.1 months, respectively). In PD-L1-positive mTNBC patients (n = 24), median PFS was 8.3 vs 4.7 months; median OS was 17.6 vs 10.7 months. Grade ≥3 adverse events occurred in 56.8% of patients in the combination arm and 65.8% in the carboplatin arm. Carboplatin plus nivolumab did not significantly improve PFS compared to carboplatin in patients overall; however, a trend toward improved outcomes was observed in PD-L1-positive mTNBC patients. High mutational burden, interferon-gamma signaling, early circulating tumor DNA reduction, low baseline serum thymidine kinase activity, and urea cycle dysregulation in the microbiome emerged as potential predictors of response to immune checkpoint inhibitors with platinum.
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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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Nature Medicine
Fibroblast Growth Factor Receptor Inhibition for Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: A Phase 2 Trial
Merriam P, Morrow JJ, Mazzola E, Solimini NL, Gokhale PC, Bothwick N, Eschle BK, Nguyen V, Shapiro GI, Demetri G, Bernstein B, George S
While most gastrointestinal stromal tumors are driven by oncogenic mutations in KIT or PDGFRA, 10-15% exhibit functional loss of the succinate dehydrogenase (SDH) complex and genome-wide DNA hypermethylation. Excess methylation in SDH-deficient gastrointestinal stromal tumors disrupts genomic insulators, inducing aberrant expression of oncogenic ligands FGF3, FGF4, and activating an autocrine signaling loop mediated through FGFR1. We conducted a phase 2 trial of pan-fibroblast growth factor receptor inhibitor rogaratinib in patients with sarcoma and report here on the cohort of patients with advanced SDH-deficient GIST. The primary objective was to estimate objective response rate. Secondary objectives were to estimate progression-free survival (PFS) and assess safety and tolerability. Exploratory objectives were to evaluate serial measurements of FGF3 and FGF4 and fibroblast growth factor receptors in serial biopsies, to perform whole-exome sequencing in serial biopsies and to explore rogaratinib exposure with pharmacodynamic effects. Twenty-four patients received rogaratinib and ten experienced partial responses for an objective response rate of 41.7%. Median PFS was 31.0 months (95% confidence interval 20.2-not reached), and 1-year PFS was 77.4% (95% confidence interval 61.7-97.1). Toxicities were manageable and included hyperphosphatemia, fatigue and diarrhea. Elevations in phosphorous were seen across the cohort, consistent with target engagement of FGFR1. Whole-exome and next-generation sequencing revealed alterations in the SDH subunit coding genes (SDHx) as expected. This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier: NCT04595747.
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Science Translational Medicine
Efficacy and Safety of Durcabtagene Autoleucel in a Phase 1 Trial for Patients with Relapsed/Refractory Multiple Myeloma
Sperling AS, Nikiforow S, Alonso A, Ikegawa S, Nadeem O, Liegel J, Ritz J, Munshi NC
Traditional manufacturing of B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapies is prolonged, leading to reduced patient access, T cell exhaustion, and consequently limiting therapeutic efficacy. To address this issue, we developed durcabtagene autoleucel, a BCMA-directed CAR T cell therapy manufactured using a rapid platform aimed at preserving T cell stemness. Here, we present the primary findings of part A of a phase 1 study (NCT04318327) of durcabtagene autoleucel in patients with relapsed/refractory multiple myeloma (r/r MM). The primary objective was safety; secondary objectives included response rates, cellular kinetics, immunogenicity, and manufacturing feasibility. Durcabtagene autoleucel was successfully manufactured for all 55 patients (median vein-to-vein time, 24 days) and given as a single infusion at one of four flat target doses (2.5 × 106 to 20 × 106 CAR T cells). Among all patients, the overall response rate was 98%, and the stringent complete response rate was 55%. Eighty percent of evaluable patients (35 of 44) achieved minimal residual disease negativity. There were no unexpected safety findings and no reports of delayed neurotoxicity. Immunophenotyping and transcriptomic analyses confirmed preservation of a stem-like phenotype in the manufactured final product. On the basis of the safety, efficacy, and cellular expansion results from the phase 1 trial, a phase 2 trial (NCT05172596) was initiated to further explore the efficacy and safety of durcabtagene autoleucel in heavily pretreated patients with aggressive r/r MM.
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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
A First-in-Pediatric Study of ALRN-6924, a Novel Stapled-Peptide Dual MDM2/MDMX Inhibitor, for Children with Advanced Hematologic and Solid Malignancies
Shulman DS, Place AE, Chi SN, Kamihara J, O'Neill AF, Church AJ, Crompton BD, Klega K, Tanhaemami M, Armant M, Pikman Y, Stegmaier K, Ezrre S, Czaplinski J, Walensky LD, Bhushan K, Kao PC, London WB, Dubois SG
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Clinical Cancer Research
Clinical Outcomes and Predictors of Response to PD-(L)1 Blockade in Patients with NSCLC without Actionable Genomic Alterations Who Never Used Tobacco
Gariazzo E, Santo V, Pecci F, Garbo E, Alessi JV, LoPiccolo J, Paoloni F, Nishino M, Sholl LM, Florez N, Rotow J, Frumm SM, Wang X, Rakaee M, Awad MM, Ricciuti B
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Clinical Cancer Research
Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A Phase 1 Dose-Escalation Study of Navitoclax, Venetoclax, and Decitabine
Chen EC, Liu Y, Bell HL, Ryan J, Wu J, Minihane EJ, Luskin MR, Winer ES, Vedula R, Volpe V, Roberts D, Galinsky I, Gerard M, Hersch M, Lee J, Neuberg D, Stone RM, DeAngelo DJ, Lane AA, Garcia JS
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Haematologica
A Phase I/II Study of Twice-Weekly Ixazomib Plus Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma
Nadeem O, Redd RA, Laubach JP, Bianchi G, Mo CC, Midha S, Sperling AS, Liu Y, Hartley-Brown MA, Chuma MP, Nicholson T, Benjamin EJ, Distaso A, Regan E, Hof AMV, Dahill AJ, Goldbaum R, Mohammadi K, Lewis A, Poda R, Munshi NC, Anderson KC, Ghobrial IM, Richardson PG
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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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JNCI Cancer Spectrum
Outcomes and Treatment Patterns in Germline BRCA1/2 Carriers from Two Matched Cohort
Morganti S, Kim SE, Jin Q, Cha J, Zeigler JE, Newman AB, Kirkner GJ, Snow C, Zheng Y, Vincuilla J, Parker T, Buehler RM, Bychkovsky BL, Dibble KE, Sella T, Rosenberg SM, Peppercorn J, Guzman-Arocho YD, Come SE, Poorvu PD, Hughes ME, Mittendorf EA, King TA, Lin NU, Garber JE, Tayob N, Tolaney SM, Partridge AH, Lynce F
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Lancet Digit Health
Artificial Intelligence Analysis of Temporalis Muscle Thickness for Monitoring Sarcopenia and Clinical Outcomes in Individuals with Paediatric Brain Tumours: A Retrospective Cohort Study
Zapaishchykova A, Zielke J, Tak D, Climent Pardo JC, Mojahed-Yazdi R, Soto-Rivera CL, Liu KX, Saraf A, Ye Z, Wang W, Chen YH, Vajapeyam S, Mak RH, Wilson RL, Dieli-Conwright CM, Ligon KL, Haas-Kogan DA, Aerts HJWL, Poussaint TY, Benitez V, Chi SN, Kann BH
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