Therapy alteration of solid tumors based on FoundationOne comprehensive genome profiling assay.

e14742 Background: Molecular profiling assays are becoming widely available and provide valuable information on tumor characteristics, which can identify targeted therapies or immunotherapies for cancer patients. However, the clinical utility of such tests remains unclear. Within our institution, we analyzed the clinical utility and subsequent treatment alterations of the FoundationOne Comprehensive Genome Profiling Test (FOne). Methods: We conducted a retrospective cohort review (2017 - 2018) of patients with solid tumors under standard diagnostic care who received FOne testing. We reviewed the therapies that were proposed by FOne and studied whether they led to a therapeutic alteration. Results: 71 patients were identified, of which the majority presented a progressive disease state (80%). Among the cancer types most frequently tested were adenocarcinoma of the colon (14%), prostate (8%), lung (4%), intrahepatic cholangiocarcinoma (8%) and breast invasive ductal carcinoma (4%). In 16 cases (22%), therapies suggested by FOne were approved in patient’s tumor type while in 30 cases (42%) therapies were approved in another tumor type. For an additional 13 cases (18%) only therapies tested in clinical trials were reported. 4 patients (6%) received a new therapy based on the FOne result: cancer of unknown primary (Everolimus due to a TSC1 mutation), cutaneous angiosarcoma (Pembrolizumab due to a high tumor mutational burden (TMB)), gastrointestinal neuroendocrine carcinoma (Ipilimumab and Nivolumab due to an intermediate TMB) and mucinous adenocarcinoma of the appendix (Talazoparib due to an ATM mutation). For 11 cases (15%), a new therapy option was identified by FOne, which due to the current treatment plan might be considered for later use. 3 cases (4%) were evaluated for potential clinical trial enrollment. Note that for an additional 6 patients (8%), the therapies proposed by FOne were already established on the basis of previous testing (e.g. smaller genomic panels, IHC, FISH). Conclusions: Overall, 18 (25%) patients received a new therapy option by FOne after standard of care diagnostics. Therapeutic alterations were observed particularly in patients with a rare or unknown tumor type.

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Druggable fusion gene landscape in solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13517 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13517-e13517

Author(s):

Gareth Haydn Williams ◽

Robert Paul Thatcher ◽

Borja Nevado Polo ◽

Tiffany Eira Haddow ◽

Keeda-Marie Hardisty ◽

...

Keyword(s):

Targeted Therapy ◽

Solid Tumors ◽

Fusion Gene ◽

Real Life ◽

Rare Event ◽

Unknown Primary ◽

Precision Oncology ◽

Tumor Type ◽

Fusion Genes ◽

Fda Approval

e13517 Background: Kinases activated by gene fusions represent an important class of oncogenes in solid tumors highlighted by the unique site agnostic FDA approval of larotrectinib for NTRK gene rearrangements. However, the frequency and types of druggable fusions in solid tumors are not well characterized from the clinical perspective. Methods: Oncofocus is a clinically validated precision oncology platform that includes analysis of 399 druggable driver-partner oncogenic fusion genes linked to 140 unique targeted therapy protocols. A retrospective analysis of Oncofocus trending data in a real-life cohort of 1111 patients has been used to determine the actionable fusion gene landscape in solid tumors. Results: Eighty nine actionable fusion genes were identified in 1111 samples of solid tumors linked to 73 targeted therapy protocols. Seven of the samples harbored multiple fusion genes. Eighty two of the 1111 samples tested had at least one actionable fusion gene representing a frequency of 7.38%. The highest frequency of actionable fusions were observed in glioblastoma (23%), head and neck (12%), kidney (11%) and prostate (10%) cancers. Four of the seven samples with multiple actionable fusions were found in glioblastoma. Pancreatic, lung and endometrial cancers and cancer of unknown primary (CUPs) had an actionable fusion gene frequency ranging from 7-9%. TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 and EGFR VIII fusions were identified as the most common druggable fusions. All actionable fusion genes were found to interact with one or more of the following pathways RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT. Although a targeted agent for TRK fusions now has FDA approval, this rearrangement appears to be a rare event. In contrast, inhibitors targeting the TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 fusions and linked downstream signalling pathways appear to offer much broader clinical utility. Conclusions: Druggable fusions were identified at an unexpectedly high frequency and should therefore be included as part of routine comprehensive precision oncology testing. Notably, many of the actionable fusions are not tumor type specific reinforcing the “site agnostic” approach to profiling and supporting the concept of “molecular basket” clinical trials. Precision oncology trending data also provides actionable mutational landscapes which can be used to refine precision oncology testing, patient selection for targeted therapy protocols and enhancement of clinical trial design.

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Metastatic Adenocarcinoma to the Breast arising from a Mediastinal Mature Teratoma with Somatic Malignancy: A Case Report with a Review of the Literature

10.21203/rs.3.rs-135224/v1 ◽

2020 ◽

Author(s):

Gwenaëlle ARHANT ◽

Dahlia Mirdad ◽

Anca Berghian ◽

Nicolas PITON ◽

Jean-Cristophe Sabourin

Keyword(s):

Malignant Transformation ◽

Breast Biopsy ◽

Ductal Carcinoma ◽

Mature Teratoma ◽

Subsequent Treatment ◽

Exceptional Case ◽

Pathological Examination ◽

Unknown Primary ◽

Anterior Mediastinal Mass ◽

Metastatic Adenocarcinoma

Abstract Background Malignant transformation in mature teratomas, especially somatic-type malignancies, are extremely rare phenomena with few cases described in the literature. In the mediastinum, these lesions are often accompanied by metastases, ultimately unmasking them. Case presentation We report an exceptional case of metastatic adenocarcinoma to the breast arising from a mediastinal mature teratoma with malignant transformation in a 31-year-old female. The patient initially presented with a breast lesion that was later diagnosed as either a triple negative ductal carcinoma or a metastatic adenocarcinoma of unknown origin. Extensive clinical workup and radiological imagining revealed an anterior mediastinal mass. Subsequent pathological examination of the mass showed a mature teratoma with malignant transformation equivalent to that found in the breast biopsy. Conclusion Mediastinal teratomas with malignant transformation (TMTs) are rare entities; however these tumors should be suspected in cases of suspicious mediastinal masses presenting with unusual clinical and radiological signs, such as metastasis of unknown primary origin. Pathological corroboration of extensive sampling and meticulous microscopic examination is crucial for the diagnosis in order to tailor subsequent treatment.

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Clinical activity and safety of the RET inhibitor pralsetinib in patients with RET fusion-positive solid tumors: Update from the ARROW trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3079 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3079-3079

Author(s):

Vivek Subbiah ◽

Philippe A. Cassier ◽

Salvatore Siena ◽

Guzman Alonso ◽

Luis G. Paz-Ares ◽

...

Keyword(s):

Thyroid Cancer ◽

Solid Tumors ◽

Phase 1 ◽

Driver Mutations ◽

Unknown Primary ◽

Clinical Activity ◽

Tumor Type ◽

Multiple Tumor ◽

Duration Of Response ◽

Tumor Types

3079 Background: RET fusions are targetable oncogenic drivers in multiple solid tumor types. ARROW study (NCT03037385) data supported the US FDA approval of pralsetinib, a once-daily (QD) oral highly potent and selective RET inhibitor, for RET-altered metastatic non-small cell lung cancer (NSCLC) and advanced/metastatic thyroid cancer. Here we provide an update on the clinical activity of pralsetinib in patients (pts) with advanced RET fusion-positive solid tumors other than NSCLC and thyroid cancer (“other” RET fusion–positive solid tumors). Methods: The global ongoing ARROW study (84 sites in 13 countries) includes phase 1 dose-escalation (30–600 mg [QD or twice daily]) and phase 2 expansion cohorts (400 mg QD) defined by tumor type and RET alteration status. Primary objectives are overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off) for 21 pts with other RET fusion–positive solid tumors enrolled by May 22, 2020 (enrollment cut-off) (lung other than NSCLC, n = 4; pancreatic, n = 3; colon, n = 3; cholangiocarcinoma, n = 3; unknown primary [UP], n = 2; other, n = 6). Overall, 11 (52%) pts received ≥2 prior lines of therapy for metastatic disease. The most common RET fusion partners were CCDC6 and KIF5B (24% each), NCOA4 (19%), other (10%), and unknown (24%). Two pts with colon cancer were excluded from efficacy analyses due to other driver mutations ( KRAS, PIK3CB). In 19 evaluable pts, ORR was 53% (95% CI, 29–76) with 2 (11%) complete responses (CR) and 8 (42%) partial responses (PR). Responses occurred across multiple tumor types including 3/3 pts with pancreatic cancer (including a CR ongoing at 20.8 months on treatment), 2/2 pts with UP, 2/3 pts with cholangiocarcinoma, and in pts with mesenchymal, salivary duct, and lung carcinoid tumors. Median duration of response was 19.0 months (95% CI, 5.5–not estimable). Clinical benefit rate (proportion with CR, PR, or stable disease persisting ≥16 weeks) was 68% (95% CI, 43–87). Tumor shrinkage was observed in 89% of 18 evaluable pts with post-baseline tumor assessment. In all pts enrolled in ARROW who received pralsetinib 400 mg QD irrespective of tumor type (n = 471) the most common (≥25%) treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (39%), anemia (35%), increased alanine aminotransferase (28%), constipation (26%), and hypertension (25%). Overall, 6% of pts discontinued treatment due to TRAEs. Conclusions: Pralsetinib showed robust, durable antitumor activity in patients with multiple RET fusion‒positive, heavily pre-treated, advanced solid tumors, and was well tolerated. These data highlight the need for broad RET testing to identify candidates who could benefit from treatment with pralsetinib. Enrollment of patients with other RET fusion–positive solid tumors in ARROW is ongoing. Clinical trial information: NCT03037385.

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Pan-cancer analysis of CD274 (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002558 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002558

Author(s):

Richard S.P. Huang ◽

Brennan Decker ◽

Karthikeyan Murugesan ◽

Matthew Hiemenz ◽

Douglas A. Mata ◽

...

Keyword(s):

Protein Expression ◽

Checkpoint Inhibitors ◽

Endometrial Adenocarcinoma ◽

Primary Melanoma ◽

B Cell Lymphoma ◽

Unknown Primary ◽

Future Research ◽

Tumor Type ◽

Missense Mutations ◽

L1 Protein

BackgroundThe effects of non-amplification short variant (SV) mutations in CD274 (programmed death-ligand 1 (PD-L1)) on PD-L1 protein expression and immune checkpoint inhibitors (ICPIs) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1.MethodsCGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer-related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n=58,341) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS).ResultsOverall, the prevalence of CD274 SV mutations was low (0.3%, 1081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n=51), R260C (n=18), R125Q (n=12), C272fs*13 (n=11), R86W (n=10), and R113H (n=10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. In addition, we saw a significantly lower level of PD-L1 expression in samples with a clonal truncating variant (nonsense or frameshift indel) when compared with samples with a subclonal truncating variants (mean: TPS=1 vs TPS=38; p<0.001), and also in clonal versus subclonal missense mutations (mean: TPS=11 vs TPS=22, respectively; p=0.049)ConclusionsWe defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.

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Extrapolation of pharmacokinetics and pharmacodynamics of sunitinib in children with gastrointestinal stromal tumors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-020-04221-x ◽

2021 ◽

Author(s):

Reza Khosravan ◽

Steven G. DuBois ◽

Katherine Janeway ◽

Erjian Wang

Keyword(s):

Body Size ◽

Solid Tumors ◽

Gastrointestinal Stromal Tumors ◽

Drug Exposure ◽

Tumor Type ◽

Plasma Drug ◽

Safety And Efficacy ◽

Stromal Tumors ◽

Mixed Effects Modeling ◽

Starting Dose

Abstract Purpose The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors. Methods Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure–response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored. Results Two-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure. Conclusion Based on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.

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Reply to: “Real-world prevalence across 159,872 patients with cancer supports the clinical utility of TMB-H to define metastatic solid tumors for treatment with pembrolizumab.” by D. Fabrizio et al.

Annals of Oncology ◽

10.1016/j.annonc.2021.06.017 ◽

2021 ◽

Author(s):

D.J. McGrail ◽

P.G. Pilié ◽

N.U. Rashid ◽

L. Voorwerk ◽

M. Slagter ◽

...

Keyword(s):

Solid Tumors ◽

Real World ◽

Clinical Utility ◽

Patients With Cancer

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Suboptimal clinician awareness of appropriate NTRK fusion testing and TRK inhibitor use in solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.229 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 229-229

Author(s):

Ryan P. Topping ◽

Krista Marcello ◽

Terrence Fagan ◽

Timothy A. Quill ◽

Todd Michael Bauer ◽

...

Keyword(s):

Solid Tumors ◽

Progressive Disease ◽

Inhibitor Therapy ◽

Tumor Type ◽

Advanced Solid Tumors ◽

Educational Activities ◽

Time Period ◽

Trk Inhibitors ◽

Therapeutic Alternatives ◽

Selection Of

229 Background: Since late 2018, 2 TRK inhibitors—larotrectinib and entrectinib—have been approved by the EMA and FDA for treating patients with advanced solid tumors harboring an NTRK fusion and progressive disease or no therapeutic alternatives. It is recommended that testing for NTRK fusions occur as early as possible after a diagnosis of advanced disease in patients with solid tumors to inform potential use of TRK inhibitors. Methods: Between April 2018 and April 2021, we conducted multiple live and online educational activities for oncology healthcare professionals (HCPs) on NTRK fusion testing and/or TRK inhibitor treatment for varied solid tumors. Each activity included polling questions designed to assess HCP knowledge and practice patterns. In this analysis, we assessed HCP responses to these questions to evaluate awareness of expert recommendations on NTRK fusion testing and the selection of TRK inhibitor therapy for appropriate patients. Results: In 6 live and online activities with data from April 2018 to April 2021, 29% of HCPs (n = 844) indicated that they ordered molecular profiling to test for NTRK fusions in all solid tumors in their current practice. Of note, low rates of testing were reported in TRK inhibitor/ NTRK testing-focused activities throughout this time period, with no significant increase over time. In assessing different patient cases across 8 activities where experts recommended TRK inhibitor therapy as optimal, many HCPs did not select a TRK inhibitor, with considerable variance by tumor type (Table). *For all cases, experts selected larotrectinib and/or entrectinib as optimal treatment. †HCP respondents. GBM, glioblastoma; GI, gastrointestinal; MSI-H, microsatellite instability-high; PD, progressive disease; PTC, papillary thyroid cancer.Conclusions: The rate of broad testing for NTRK fusions across patients with solid tumors remains low, and many HCPs lack awareness of when to consider a TRK inhibitor. Educational activities designed to address these deficiencies would be of clear benefit to HCPs treating patients with advanced solid tumors. A detailed analysis of HCP trends will be presented.[Table: see text]

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Trial in progress: Phase 1a/b study of PF-07284890 (brain-penetrant BRAF inhibitor) with/without binimetinib in patients with BRAF V600-mutant solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps3152 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS3152-TPS3152

Author(s):

Vivek Subbiah ◽

Martin Gutierrez ◽

Carey K. Anders ◽

George Ansstas ◽

Taofeek K. Owonikoko ◽

...

Keyword(s):

Disease Progression ◽

Solid Tumors ◽

Dose Level ◽

Solid Tumor ◽

Human Study ◽

Tumor Type ◽

Overall Response ◽

Secondary Endpoints ◽

Phase 1B ◽

Brain Involvement

TPS3152 Background: BRAF inhibitors have transformed treatment (Tx) for patients (pts) with BRAF V600-mutant cancers, but long-term efficacy is limited by disease progression in the brain, due to poor brain penetration. PF-07284890 is a potent, selective, highly brain-penetrant, small-molecule inhibitor of BRAF V600 mutations. This first in human study will assess the PK, safety, and preliminary clinical activity of PF-07284890, as monotherapy and in combination with binimetinib (MEK inhibitor), in pts with BRAF V600-mutated advanced solid tumors with/without brain metastases. Methods: Phase 1a/1b open-label, multicenter, dose-finding study (NCT04543188). Pts will be ≥18 y with a histologically confirmed advanced/metastatic solid tumor including primary brain tumor (PBT), confirmed BRAF V600 mutation, and presence/absence of brain involvement. Pts will have disease progression despite prior Tx without alternative Tx options. Pts with brain metastasis/PBT > 4 cm and/or symptomatic brain disease will be excluded initially, but allowed based on emerging PK. Phase 1a is a dose escalation study of PF-07284890 (monotherapy and combination). ̃35 pts will be enrolled to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of PF-07284890 (monotherapy and combination). Cohorts of 2-4 pts will be treated at each dose level of PF-07284890 until MTD/RDE determination (PF-07284890 starting dose: 50 mg QD; binimetinib 45 mg BID). Bayesian Logistic Regression Model will be used to inform dose level decisions. At least 6 pts each for monotherapy and combination will be treated at MTD/RDE. Phase 1a primary endpoints: Cycle 1 dose-limiting toxicities; MTD/RDE; AEs; lab abnormalities; and dose interruptions, modifications and discontinuations due to AEs. Secondary endpoints include PK parameters and overall response (RECIST; overall and intracranial; RANO for PBT). Phase 1b is a dose expansion and drug-drug interaction study to further evaluate PF-07284890 + binimetinib. Cohorts 1-4 (̃40 pts each) will enroll pts based on tumor type, brain involvement (asymptomatic/symptomatic), and prior Tx. Cohort 5 (̃20 pts) will include pts with any solid tumor including leptomeningeal metastases. Cohort 6 (̃10 pts) will assess the effect of PF-07284890 + binimetinib on CYP3A activity using midazolam as a substrate. Phase 1b primary endpoint: overall response (RECIST; overall and intracranial; RANO for PBT). Secondary endpoints: duration of response; progression-free survival; disease control rate; time to response; overall survival; AEs; lab abnormalities; and dose interruptions, modifications and discontinuations due to AEs; and PK parameters. For both Phase 1a and 1b, Tx will continue until disease progression, unacceptable toxicity or patient refusal. Study began enrolling pts in January 2021 and is ongoing. Clinical trial information: NCT04543188.

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Uptake and Clinical Utility of Multibiomarker Disease Activity Testing in the United States

The Journal of Rheumatology ◽

10.3899/jrheum.180071 ◽

2018 ◽

Vol 46 (3) ◽

pp. 237-244 ◽

Cited By ~ 1

Author(s):

Jeffrey R. Curtis ◽

Fenglong Xie ◽

Shuo Yang ◽

Maria I. Danila ◽

Justin K. Owensby ◽

...

Keyword(s):

United States ◽

Disease Activity ◽

Clinical Utility ◽

The United States ◽

Routine Care ◽

Subsequent Treatment ◽

Janus Kinase ◽

Jak Inhibitor ◽

Medicare Data ◽

Multivariable Adjustment

Objective.The clinical utility of the multibiomarker disease activity (MBDA) test for rheumatoid arthritis (RA) management in routine care in the United States has not been thoroughly studied.Methods.Using 2011–2015 Medicare data, we linked each patient with RA to their MBDA test result. Initiation of a biologic or Janus kinase (JAK) inhibitor in the 6 months following MBDA testing was described. Multivariable adjustment evaluated the likelihood of adding or switching biologic/JAK inhibitor, controlling for potential confounders. For patients with high MBDA scores who added a new RA therapy and were subsequently retested, lack of improvement in the MBDA score was evaluated as a predictor of future RA medication failure, defined by the necessity to change RA medications again.Results.Among 60,596 RA patients with MBDA testing, the proportion adding or switching biologics/JAK inhibitor among those not already taking a biologic/JAK inhibitor was 9.0% (low MBDA), 11.8% (moderate MBDA), and 19.7% (high MBDA, p < 0.0001). Similarly, among those already taking biologics/JAK inhibitor, the proportions were 5.2%, 8.3%, and 13.5% (p < 0.0001). After multivariable adjustment, referent to those with low disease MBDA scores, the likelihood of switching was 1.51-fold greater (95% CI 1.35–1.69) for patients with moderate MBDA scores, and 2.62 (2.26–3.05) for patients with high MBDA scores. Among those with high MBDA scores who subsequently added a biologic/JAK inhibitor and were retested, lack of improvement in the MBDA score category was associated with likelihood of future RA treatment failure (OR 1.61, 95% CI 1.27–2.03).Conclusion.The MBDA score was associated with both biologic and JAK inhibitor medication addition/switching and subsequent treatment outcomes.

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