Ramamoorthy Nagasubramanian

All Publications

• 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among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision.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