Ramamoorthy Nagasubramanian

All Publications

• Factors Associated With Symptom Burden Among Pediatric Patients With Cancer. JCO oncology practice Yan, A. P., Dupuis, L. L., Aftandilian, C., Agarwal, V., Baggott, C., Beauchemin, M. P., Bradfield, S. M., Cannone, D., Caywood, E. H., Crellin-Parsons, N., Demedis, J., Dickens, D., Esbenshade, A. J., Freyer, D. R., Grimes, A. C., Kelly, K. M., King, A. A., Klesges, L. M., Kyono, W., Nagasubramanian, R., Orgel, E., Orsey, A. D., Roth, M. E., Sherani, F., Vettese, E., Walsh, A., Woods-Swafford, W., Yu, L. C., Tomlinson, G. A., Sung, L. 2025: OP2500244

  Abstract

  PURPOSE: The objective was to identify factors associated with self-reported symptom burden measured using Symptom Screening in Pediatrics Tool (SSPedi) in pediatric patients with cancer.METHODS: This was a secondary analysis of a cluster randomized trial enrolling pediatric patients newly diagnosed with cancer. Twenty sites were randomized to routine symptom screening versus usual care. Intervention included thrice-weekly symptom screening with SSPedi, delivery of severely bothersome scores to health care teams, and implementation of locally adapted symptom management care pathways. Primary outcome was total SSPedi scores, 0 (no bothersome symptoms) to 60 (worst bothersome symptoms), obtained at baseline, week four, and week eight in 430 patients (n = 217 intervention and n = 213 usual care). We created a mixed linear regression model evaluating design (including time point), patient/guardian, and site characteristics for their associations with symptom burden after controlling for treatment assignment.RESULTS: SSPedi scores were significantly lower at weeks 4 and 8 compared with baseline (P < .0001 overall), and at intervention versus control sites (P < .0001). In the full model, males (estimate, -3.3 [95% CI, -4.6 to -2.0]; P < .0001) and sites with higher physician staffing ratios (each physician full-time equivalent per 100 new diagnoses estimate -0.20 [95% CI, -0.5 to 0.0]; P = .024) had significantly lower total SSPedi scores.CONCLUSION: Total symptom burden was reduced by time, intervention (symptom screening and care pathways), and greater physician staffing ratio. Females had higher symptom burden. These data may inform programmatic implementation of routine symptom screening in pediatric patients with cancer.

  View details for DOI 10.1200/OP-25-00244

  View details for PubMedID 40811761

• Factors Associated With Self-Report Symptom Screening Adherence in Pediatric Cancer Patients. Cancer medicine Dupuis, L. L., Vettese, E., Aftandilian, C., Agarwal, V., Baggott, C., Bradfield, S. M., Crellin-Parsons, N., Freyer, D. R., Kelly, K. M., King, A. A., Kyono, W., Nagasubramanian, R., Orgel, E., Roth, M. E., Sherani, F., Yu, L., Grimes, A. C., Beauchemin, M. P., Klesges, L. M., Tomlinson, G. A., Sung, L. 2025; 14 (14): e71053

  Abstract

  Objective was to describe the association between baseline characteristics and the number of Symptom Screening in Pediatrics Tool (SSPedi) assessments completed over an 8-week period.This was a sub-analysis of a cluster randomized controlled trial among 10 sites that were randomized to the intervention group. Participants were English- or Spanish-speaking pediatric patients 8-18 years of age newly diagnosed with cancer. Participants were prompted to complete SSPedi three times weekly for 8 weeks. The outcome was the number of SSPedi assessments completed during the 8-week period. Factors associated with the number of assessments were determined using mixed effects Poisson regression.At the 10 intervention sites, 216 patients were included in the analysis. Among these participants, 129 (59.7%) were male, 112 (51.9%) were white, and 83 (38.4%) were Hispanic. The number of SSPedi assessments was significantly higher for participants 11-14 years (rate ratio (RR) 1.13, 95% confidence interval (CI) 1.02-1.25) and 15-18 years (RR 1.15, 95% CI 1.04-1.27) compared to 8-10 years. Participants completed more SSPedi assessments if they were Asian compared to white (RR 1.27, 95% CI 1.10-1.46), non-Hispanic compared to Hispanic (RR 1.15, 95% CI 1.04-1.28) and from families with a household income ≥$60,000 (RR 1.12, 95% CI 1.03-1.21). Participants completed fewer SSPedi assessments if they had solid tumors compared to leukemia (RR 0.91, 95% CI 0.84-0.99).Adherence to three-times weekly SSPedi varied by age, race, ethnicity, cancer diagnosis, and family income. This information may facilitate interventions to support routine symptom screening in clinical practice.NCT04614662.

  View details for DOI 10.1002/cam4.71053

  View details for PubMedID 40686265

• Care Pathway- and Guideline-Consistent Care in Pediatric Cancer Symptom Management. JCO oncology practice Crellin-Parsons, N., Dupuis, L. L., Vettese, E., Aftandilian, C., Agarwal, V., Baggott, C., Bradfield, S. M., Freyer, D. R., Kelly, K. M., King, A. A., Kyono, W., Nagasubramanian, R., Orgel, E., Roth, M. E., Sherani, F., Yu, L., Grimes, A. C., Beauchemin, M. P., Klesges, L. M., Tomlinson, G. A., Sung, L. 2025: OP2400912

  Abstract

  Ten pediatric cancer treatment sites previously implemented site-specific symptom management care pathways for 15 symptoms, which were based upon clinical practice guidelines (CPGs). The primary objective of this analysis was to describe the prevalence of care pathway- and CPG-consistent care for symptom management. The secondary objective was to identify factors associated with care pathway-consistent care.Participants were patients age 8-18 years diagnosed with cancer within the previous 4 weeks. We identified any intervention to manage each of 15 symptoms during a 3-day period 8 weeks after enrollment. We determined whether the intervention appeared in that site's care pathway and whether it was recommended in the CPG. We determined whether type of symptom (observable v nonobservable) or patient characteristics were associated with care pathway-consistent care.Two hundred twenty participants were analyzed. The prevalence of care pathway-consistent care for each symptom ranged from 0% (problems thinking, body or face changes, and diarrhea) to 52.3% (throwing up) and was <27% for 14 of 15 symptoms. Similarly, the prevalence of CPG-consistent care was <50% across all symptoms. Participants received significantly more care pathway-consistent interventions for observable symptoms compared with nonobservable symptoms (difference 30% [95% CI, 3 to 54]). Factors associated with receipt of at least one care pathway-consistent intervention were age group, race, ethnicity, and cancer type.Care pathway- and CPG-consistent care were surprisingly uncommon. Care pathway-consistent interventions were more common for observable than nonobservable symptoms and were associated with patient characteristics. Future work should identify approaches to improve care pathway-consistent care delivery.

  View details for DOI 10.1200/OP-24-00912

  View details for PubMedID 40267372

• Symptom Screening Linked to Care Pathways for Pediatric Patients With Cancer: A Randomized Clinical Trial. JAMA Dupuis, L. L., Vettese, E., Grimes, A. C., Beauchemin, M. P., Klesges, L. M., Baggott, C., Demedis, J., Aftandilian, C., Freyer, D. R., Crellin-Parsons, N., Orgel, E., Dickens, D., Kelly, K. M., Kyono, W., Walsh, A., Sherani, F., Cannone, D., Orsey, A. D., King, A. A., Yu, L., Woods-Swafford, W., Bradfield, S. M., Roth, M. E., Esbenshade, A. J., Caywood, E. H., Agarwal, V., Nagasubramanian, R., Tomlinson, G. A., Sung, L. 2024

  Abstract

  Pediatric patients with cancer commonly experience severely bothersome symptoms. The effectiveness of routine symptom screening with symptom feedback and symptom management care pathways is unknown.To determine whether thrice-weekly symptom screening with symptom feedback and management care pathways, compared with usual care, improves overall self-reported symptom scores measured by the Symptom Screening in Pediatrics Tool (SSPedi) in pediatric patients with cancer.This cluster randomized trial enrolled participants between July 2021 and August 2023 from 20 pediatric cancer centers in the US. Patients newly diagnosed with cancer aged 8 to 18 years receiving any cancer treatment were included. Twenty sites were randomized to provide symptom screening (n = 10) vs usual care (n = 10); 221 participants were enrolled at intervention sites and 224 participants at control sites. The date of final follow-up was October 18, 2023.Symptom screening included providing thrice-weekly symptom screening prompts to participants, email alerts to the health care team, and locally adapted symptom management care pathway implementation.The primary outcome was self-reported total SSPedi score at week 8 (range, 0-60; higher scores indicate more bothersome). Secondary outcomes were Patient-Reported Outcomes Measurement Information System Fatigue score (mean [SD] score, 50 [10]; higher scores indicate more fatigue), Pediatric Quality of Life 3.0 Acute Cancer Module scores (range, 0-100; higher scores indicate better health), symptom documentation and interventions at week 8, and unplanned health care encounters.A total of 445 participants (median [range] age, 14.8 [8.1-18.9] years; 58.9% males) were enrolled. The mean (SD) 8-week SSPedi score was 7.9 (7.2) in the symptom screening group vs 11.4 (8.7) in the usual care group. Symptom screening was associated with significantly better 8-week total SSPedi scores (adjusted mean difference, -3.8 [95% CI, -6.4 to -1.2]) and less bothersome individual symptoms, with 12 of 15 symptoms being statistically significantly reduced. There was no difference in fatigue or quality of life. The mean (SD) number of emergency department visits was 0.77 (1.12) in the symptom screening group and 0.45 (0.81) in the usual care group. There were significantly more emergency department visits in the symptom screening group (rate ratio, 1.72 [95% CI, 1.03-2.87]).Symptom screening with symptom feedback and symptom management care pathways was associated with improved symptom scores and increased symptom-specific interventions. Future work should integrate symptom screening into routine clinical care.ClinicalTrials.gov Identifier: NCT04614662.

  View details for DOI 10.1001/jama.2024.19585

  View details for PubMedID 39535768

• Symptom management care pathway adaptation process and specific adaptation decisions. BMC cancer Vettese, E., Sherani, F., King, A. A., Yu, L., Aftandilian, C., Baggott, C., Agarwal, V., Nagasubramanian, R., Kelly, K. M., Freyer, D. R., Orgel, E., Bradfield, S. M., Kyono, W., Roth, M., Klesges, L. M., Beauchemin, M., Grimes, A., Tomlinson, G., Dupuis, L. L., Sung, L. 2023; 23 (1): 350

  Abstract

  BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions.METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications.RESULTS: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection.CONCLUSIONS: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes.TRIAL REGISTRATION: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 .

  View details for DOI 10.1186/s12885-023-10835-0

  View details for PubMedID 37069510

• Quality of life of adults and children with TRK fusion cancer treated with larotrectinib compared to the general population. Kummar, S., Van Tilburg, C. M., Albert, C. M., Berlin, J., Farago, A. F., McDermott, R. S., Bielack, S. S., Doz, F. P., DuBois, S. G., Lassen, U., Leyvraz, S., Mascarenhas, L., Nagasubramanian, R., Keating, K. N., Chirila, C., Childs, B. H., Laetsch, T., Drilon, A. E., Hong, D. S. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301504

• Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. The Lancet. Oncology Hong, D. S., DuBois, S. G., Kummar, S. n., Farago, A. F., Albert, C. M., Rohrberg, K. S., van Tilburg, C. M., Nagasubramanian, R. n., Berlin, J. D., Federman, N. n., Mascarenhas, L. n., Geoerger, B. n., Dowlati, A. n., Pappo, A. S., Bielack, S. n., Doz, F. n., McDermott, R. n., Patel, J. D., Schilder, R. J., Tahara, M. n., Pfister, S. M., Witt, O. n., Ladanyi, M. n., Rudzinski, E. R., Nanda, S. n., Childs, B. H., Laetsch, T. W., Hyman, D. M., Drilon, A. n. 2020

  Abstract

  The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.Bayer and Loxo Oncology.

  View details for DOI 10.1016/S1470-2045(19)30856-3

  View details for PubMedID 32105622

• Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi) Hyman, D., Kummar, S., Farago, A., Geoerger, B., Mau-Sorensen, M., Taylor, M., Garralda, E., Nagasubramanian, R., Natheson, M., Song, L., Capra, M., Jorgensen, M., Ho, A., Shukla, N., Smith, S., Huang, X., Tuch, B., Ku, N., Laetsch, T. W., Drilon, A., Hong, D. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-CT127

  View details for Web of Science ID 000488129900113

• Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients. van Tilburg, C., DuBois, S. G., Albert, C., Federman, N., Nagasubramanian, R., Geoerger, B., Orbach, D., Bielack, S. S., Shukla, N., Turpin, B., Casanova, M., Spunt, S. L., Qamoos, H., Nanda, S., Childs, B. H., Cox, M., Pappo, A. S., Laetsch, T., Mascarenhas, L. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.10010

  View details for Web of Science ID 000487345803599

• Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children NEW ENGLAND JOURNAL OF MEDICINE Drilon, A., Laetsch, T. W., Kummar, S., DuBois, S. G., Lassen, U. N., Demetri, G. D., Nathenson, M., Doebele, R. C., Farago, A. F., Pappo, A. S., Turpin, B., Dowlati, A., Brose, M. S., Mascarenhas, L., Federman, N., Berlin, J., El-Deiry, W. S., Baik, C., Deeken, J., Boni, V., Nagasubramanian, R., Taylor, M., Rudzinski, E. R., Meric-Bernstam, F., Sohal, D. S., Ma, P. C., Raez, L. E., Hechtman, J. F., Benayed, R., Ladanyi, M., Tuch, B. B., Ebata, K., Cruickshank, S., Ku, N. C., Cox, M. C., Hawkins, D. S., Hong, D. S., Hyman, D. M. 2018; 378 (8): 731–39

  Abstract

  Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

  View details for PubMedID 29466156

  View details for PubMedCentralID PMC5857389

• Phase 1/2 study of the selective TRK inhibitor larotrectinib in pediatric patients with cancer Federman, N., Albert, C., Turpin, B., Mascarenhas, L., Nagasubramanian, R., Geoerger, B., Casanova, M., Melcon, M., Chisholm, J., Van Tilburg, C. M., Shukla, N., Spunt, S. L., Cox, M., Hawkins, D. S., Pappo, A. S., Bielack, S. S., Doz, F. P., Bisogno, G., Laetsch, T., DuBois, S. G. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.TPS10577

  View details for Web of Science ID 000411932206127