Fangdi Sun

All Publications

• Efficacy and Safety of Continuing Next-Generation ALK TKIs With Chemotherapy for Advanced ALK-Positive NSCLC A Multicenter Retrospective Study JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Waliany, S., Roy, S., Pecci, F., Weber, U. M., Sun, F., Arter, Z., Lomibao, M., V. Alessi, J., Nishino, M., Luo, F., Repetto, M., Falcon, C., Do, A., Peterson, J., Liang, J., Liu, A., Nagasaka, M., Ricciuti, B., Drilon, A., Ou, S., Neal, J. W., Patil, T., Awad, M., Yeap, B. Y., Digumarthy, S. R., Lin, J. J. 2025; 23 (12)

  View details for DOI 10.6004/jnccn.2025.7071

  View details for Web of Science ID 001645239700014

• Cisplatin, immunotherapy, and chemoradiation in nasopharyngeal carcinoma: How far should one trial move the needle? Med (New York, N.Y.) Sun, F., Colevas, A. D. 2025; 6 (11): 100917

  Abstract

  In patients with locoregionally advanced, Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma, the DIAMOND trial demonstrated that eliminating the concurrent cisplatin radiosensitizer while maintaining PD-1 inhibition throughout a treatment course anchored by gemcitabine-cisplatin induction resulted in non-inferior three-year failure-free survival and significantly lower all-grade vomiting.1 While such a strategy may be considered for cisplatin-ineligible patients, substitution of immunotherapy for concurrent cisplatin in all-comers remains premature.

  View details for DOI 10.1016/j.medj.2025.100917

  View details for PubMedID 41240897

• Characteristics of Short-Term Survivors With ALK or ROS1-Altered Metastatic NSCLC. JTO clinical and research reports Liu, K. L., Watts, A., Grady, C. B., Liu, G., Patel, D., Balaratnam, K., Liu, S. V., Montenegro, G. B., Nie, Y., Nieva, J., Herrmann, A., Marrone, K., Lam, V., Sun, F., Dowell, J., Schwartzman, W., Velcheti, V., Fankuchen, O., Ullah, T., Villaruz, L., Nguyen, M., Weiss, J., Patel, S., Miller, K., Iams, W., Chandrasekhara, K., Tompkins, W., Patil, T., Aisner, D., Camidge, D. R., Hwang, W. T., Sun, L., Marmarelis, M. E. 2025; 6 (11): 100876

  Abstract

  The prognostic significance of baseline and on-treatment brain and liver metastasis in ALK+ or ROS1+ metastatic NSCLC (mNSCLC) remains unclear. As we consider intensification strategies, it is critical to identify factors that predict high-risk disease.Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with ALK+ or ROS1+ mNSCLC. Baseline characteristics and the cumulative incidence (CI) of brain and liver metastases were compared (≥2-year survivors versus <2-year; pre-2017 versus post-2017). Multivariable Cox proportional hazard models were used to evaluate the association between factors and overall survival, and multivariable logistic regression models were used for the odds of death within 2 years.A total of 310 patients with ALK+ mNSCLC were identified (≥2-y: 229, <2-y: 81). There was no difference in cumulative incidence of brain metastases between survival groups (29% at 21 mo). However, the cumulative incidence of liver metastasis was higher in those who survived less than 2 years (20.9% versus 5.4% at 21 mo). The cumulative incidence of brain but not liver metastases has improved post-2017 with the newer generation of ALK tyrosine kinase inhibitors. There were 69 patients with ROS1+ mNSCLC who were identified (≥2-y: 46, < 2-y: 23). There was no significant difference in the cumulative incidence of brain or liver metastases between less-than-2-year and greater-than-or-equal-to-2-year survivor cohorts (p = 0.664, p = 0.201).Among patients with ALK+ but not ROS1+ mNSCLC, the presence of liver metastases at baseline and on-treatment was associated with worse survival. In the ALK+ population, the cumulative incidence of brain but not liver metastases is improving, highlighting a need for therapies effective at the treatment and prevention of liver metastases.

  View details for DOI 10.1016/j.jtocrr.2025.100876

  View details for PubMedID 41235297

  View details for PubMedCentralID PMC12605057

• The evolving landscape of leptomeningeal metastases from NSCLC: an international, contemporary, multicenter cohort study. Annals of oncology : official journal of the European Society for Medical Oncology Zheng, M. M., Xia, Y., Pan, K., Sun, F., Tan, A. C., Dong, X. R., Tu, H. Y., Tang, L. B., Li, Y. S., Yin, K., Borgeaud, M., Singhal, S., Zhu, E., Zhang, J., Nilsson, M., Wu, J., Gibbons, D. L., Wakelee, H., Neal, J. W., Lee, J., Vaporciyan, A. A., Ringsurongkawong, W., Tran, H. T., Zhang, R. Z., Zhang, T., Zhou, Q., Zhong, W. Z., Li, W., Zhang, Y. C., Riess, J. W., Addeo, A., Heymach, J. V., Myall, N., Tan, D., Wu, Y. L., Le, X. 2025

  Abstract

  Leptomeningeal metastatic disease (LMD) represents a devastating complication of non-small-cell lung cancer (NSCLC) with a poor prognosis. Our understanding of LMD is limited in the era of molecular testing and emerging therapeutic options for lung cancer.We conducted an international, multicenter, retrospective study involving eight institutions across Asia, United States, and Europe. Patients diagnosed with LMD from advanced NSCLC were identified (2007-2024). Clinicopathological characteristics, treatment patterns, and outcomes were analyzed. The primary endpoint was overall survival from the LMD diagnosis (LMOS).A total of 2052 patients with NSCLC and LMD were included and analyzed by molecular subtypes: epidermal growth factor receptor (EGFR) (n = 1610), ALK (n = 141), other actionable genomic alterations (other AGA; n = 137), and non-AGA (n = 164). The cumulative prevalence of LMD by molecular subgroups was EGFR, 11.1%; ALK, 11.2%; ROS1, 16%; ERBB2, 12.3%, non-AGA, 3.6%. A higher proportion of LMD was diagnosed >3 years after initial metastatic diagnosis. By the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) diagnostic criteria, type I (cerebrospinal fluid cytology positive) had significantly shorter LMOS than type II (magnetic resonance imaging and/or symptom positive). Median LMOS was 10.9 months [95% confidence interval (CI) 10.0-11.8 months] in all patients. Compared with historical cohorts, patients demonstrated improved LMOS in contemporary cohorts (7.3 versus 11.5 months, P < 0.0001), across all molecular subtypes. In AGA NSCLC, tyrosine kinase inhibitors (TKIs) were associated with improved LMOS [hazard ratio (HR) 0.39, 95% CI 0.31-0.48, P < 0.0001]. Immune checkpoint inhibitors (ICIs) conferred survival benefit in non-AGA patients (HR 0.45, 95% CI 0.25-0.84, P = 0.012). For the EGFR-mutated cohort, central nervous system (CNS)-penetrant TKI usage delayed LMD onset (P < 0.0001). Continued CNS-penetrant TKIs after LMD diagnosis were associated with longer LMOS (12.4 versus 6.0 months, P < 0.0001).The prevalence of LMD is rising, largely due to prolonged survival in advanced NSCLC. Contemporary systemic treatments, including TKIs and ICIs, were the main contributors to delayed LMD onset and improved LMD survival.

  View details for DOI 10.1016/j.annonc.2025.09.140

  View details for PubMedID 41125209

• Clinical factors and molecular co-alterations impact outcomes in patients receiving first-line osimertinib for EGFR-mutated non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Sun, F., Banwait, M. K., Singhal, S., Herrmann, A., Piotrowska, Z., Yun, K., Bazhenova, L., Ullah, A. T., Guo, E. W., Wakelee, H. A., Neal, J. W., Das, M. S., Ramchandran, K. J., Roy, M., Diehn, M., Myall, N. J. 2025; 208: 108747

  Abstract

  Until recently, osimertinib was the preferred first-line therapy for nearly all patients with EGFR-mutated advanced NSCLC. However, with approval of the FLAURA2 and MARIPOSA regimens, identifying molecular or clinical factors that confer higher risk for inferior outcomes to first-line osimertinib may better inform upfront treatment selection for newly-diagnosed patients.This real-world, multicenter retrospective study across 4 U.S. academic centers included adult patients with metastatic NSCLC and classic sensitizing EGFR mutations (exon 19 deletion, L858R mutation) receiving first-line osimertinib monotherapy who had tissue-based next-generation sequencing performed at diagnosis. Survival analyses for time-to-treatment discontinuation (TTD) on osimertinib and overall survival (OS) were conducted by number of co-alterations, individual gene alterations, previously defined molecular pathways, and clinical factors.A total of 219 patients were included (median age 68, 62 % female, 51 % with baseline CNS metastases). TP53 was most frequently co-altered (58 %), followed by EGFR amplification (13 %), CDKN2A (10 %), RB1 (9 %), and PIK3CA (8 %). Number of de novo co-alterations and presence of co-alterations by molecular pathway did not significantly predict TTD or OS. Co-alteration of both TP53 and PIK3CA, but not TP53 alone, demonstrated significantly shorter median OS compared to the TP53 and PIK3CA wild-type population (21.9 vs 39.5 months, p = 0.046), with similar numerical trend for median TTD. On multivariate analysis, L858R mutation and CNS and bone metastases remained significant predictors for inferior clinical outcomes.Co-alteration of TP53 and PIK3CA may represent a high-risk molecular subgroup of EGFR-mutated NSCLC, however both clinical and molecular features should be considered in risk stratification.

  View details for DOI 10.1016/j.lungcan.2025.108747

  View details for PubMedID 40957338

• Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer. Journal for immunotherapy of cancer Miller, N. J., Baik, C., Neal, J. W., Sun, F., Santana-Davila, R., Lee, S., Eaton, K. D., Martins, R. G., Rodriguez, C., Wakelee, H., Padda, S. K., Sotillo, E., Konnick, E. Q., Camai, A., Pisarenko, T., Nair, V. S., Mackall, C., Houghton, A. M., Chiou, S. H., Tseng, D. 2025; 13 (7)

  Abstract

  Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 HLA-A*02 carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21 to 0.76 univariate; p=0.033, HR 0.45, 95% CI 0.23 to 0.91 multivariate).Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.

  View details for DOI 10.1136/jitc-2025-011907

  View details for PubMedID 40664448

  View details for PubMedCentralID PMC12265838

• FLAURA2: evidence for escalated first-line therapy in EGFR-mutated non-small cell lung cancer with central nervous system metastases. Translational cancer research Sun, F., Neal, J. W., Myall, N. J. 2025; 14 (6): 3295-3301

  View details for DOI 10.21037/tcr-2024-2589

  View details for PubMedID 40687261

  View details for PubMedCentralID PMC12268507

• Update: Immunotherapeutic Strategies in HPV-Associated Head and Neck Squamous Cell Carcinoma. Viruses Sun, F., Colevas, A. D. 2025; 17 (5)

  Abstract

  The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has increased substantially over the past three decades, and since 2017, it has been recognized in the AJCC staging system as distinct from its HPV-negative counterpart. The underlying mechanisms of HPV-associated carcinogenesis, tumor microenvironment, and host immune response represent opportunities for therapeutic development. While anti-PD-1 immunotherapy is now part of standard treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in general, there are no established immunotherapeutic strategies specifically for HPV-related HNSCC. In this context, multiple emerging approaches are being actively studied-among these are therapeutic vaccines with or without anti-PD-(L)1 adjuvants, peptide-HLA-based immunotherapeutic platforms, and adoptive cell therapies including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR) therapy, and chimeric antigen receptor (CAR) T-cell therapy. Beyond further maturation of these novel immunotherapeutic strategies, additional work is needed to delineate the optimal disease state of application (localized versus recurrent/metastatic), as well as in the development of small molecule inhibitors targeting HPV-specific mechanisms of viral oncogenesis.

  View details for DOI 10.3390/v17050712

  View details for PubMedID 40431723

• Osimertinib vs. Afatinib in 1L therapy of atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC): A multi-institution, real-world survival analysis. Lung cancer (Amsterdam, Netherlands) Barsouk, A., Elghawy, O., Watts, A., Reed-Guy, L., Tompkins, W., Chandrasekhara, K., Grady, C. B., Iams, W., Sun, F., Liu, G., Patel, D., Nieva, J. J., Marrone, K. A., Velcheti, V., Liu, S. V., Patil, T., Weiss, J., Schwartzman, W., Villaruz, L. C., Hermann, A., Aisner, D. L., Hwang, W. T., Camidge, D. R., Sun, L., Singh, A. P., Cohen, R. B., Aggarwal, C., Langer, C. J., Marmarelis, M. E. 2025; 203: 108551

  Abstract

  Data are limited on the efficacy of different TKIs for patients with atypical EGFR-mutated (AM) mNSCLC, a heterogeneous group excluding classical mutations (CM) L858R and exon19del. In our previous single-institution analysis, AM patients had longer survival with osimertinib than afatinib, but outcomes for patients with specific mutations could not be compared due to sample size.We performed a multi-institution, retrospective survival analysis of atypical EGFR mutated (AM) mNSCLC patients treated with 1L osimertinib or afatinib between 2015-2021 at 12 US institutions. Time to discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier curves and compared using log rank tests between treatment or mutation groups.Among 52 patients identified, 32 (62 %) were treated with osimertinib and 20 (38 %) with afatinib. 20 had mutations in G719X (38 %), 12 in L861Q (23 %), and 5 in S768I (10 %). 34(65 %) had compound mutations: 20(62 %) had AM + CM, and 14(38 %) had ≥ 2 AMs. Among G719X (n = 20), afatinib was associated with longer time to discontinuation (TTD) (log-rank: p = 0.047) and longer OS (p = 0.043) vs. osimertinib. Median TTD (mTTD) was 20.3 m[95 %CI 7.3-24.2] and 9.4[1.7-14.0], respectively. For L861Q (n = 12), osimertinib was associated with longer TTD vs. afatinib (p = 0.004), with no statistical difference in OS (p = 0.215). mTTD was 7.2 m[2.2-12.3] and 1.3[0-3.1], respectively. In AM + CM (n = 20), osimertinib was associated with longer TTD and OS compared to those receiving afatinib (p = 0.037, p = 0.042, respectively).Patients with G719X alterations experienced longer TTD and OS with afatinib than osimertinib. In contrast, patients with L861Q alterations had longer TTD with osimertinib. In AM + CM pts, TTD and OS with osimertinib were longer than afatinib, suggesting that classical mutations may be driving the outcomes. Atypical EGFR mutations may warrant distinct treatment recommendations based on the specific mutation(s) identified, but more studies are needed.

  View details for DOI 10.1016/j.lungcan.2025.108551

  View details for PubMedID 40262226

• Brief Report: Safety of Pulse-Dose Osimertinib for Treatment of Leptomeningeal Disease or Refractory Brain Metastases in EGFR-Mutated Nonsmall Cell Lung Cancer Clinical Lung Cancer Sun, F., Nagpal, S., Singhal, S., Neal, J. W., Wakelee, H. A., Myall, N. J., Bolan, P., Riess, J. W., Gandara, D. R., Das, M. S. 2025; 26 (7): 603-609.e2

  View details for DOI 10.1016/j.cllc.2025.08.002

• A summary of the 2025 lung cancer summit at Stanford University: understanding lung cancer in people who have never smoked Journal of Asian Health Sun, F., Lin, B., Wakelee, H. A. 2025; 5 (2)
• Recent updates in targeted therapy for advanced non-small cell lung cancer with actionable genomic alterations: a narrative review AME Clinical Trials Review Sun, F., Neal, J. W. 2025; 3
• Highly CNS-penetrant tyrosine kinase inhibitors improve leptomeningeal overall survival in NSCLC patients with leptomeningeal disease AACR Annual Meeting Le, X., Pan, K., Zhang, J., Sun, F., Borgeaud, M., Riess, J., Myall, N., Xia, Y., Addeo, A., Heymach, J. 2025: 1155

  View details for DOI 10.1158/1538-7445.AM2025-1155

• Changing Treatment and Metastatic Disease Patterns in Patients with EGFR Mutated NSCLC: An Academic Thoracic Medical Investigator's Consortium Registry Analysis. JTO clinical and research reports Stalker, M., Grady, C. B., Watts, A., Hwang, W. T., Chandrasekhara, K., Sun, F., Liu, G., Patel, D., Nieva, J., Herrmann, A., Marrone, K., Lam, V. K., Velcheti, V., Liu, S. V., Bravo Montenegro, G. L., Tompkins, W., Patil, T., Weiss, J., Miller, K. L., Schwartzman, W., Dowell, J. E., Shaverdashvili, K., Villaruz, L., Cass, A., Iams, W., Aisner, D., Aggarwal, C., Camidge, D. R., Sun, L., Marmarelis, M. E. 2025; 6 (1): 100765

  Abstract

  Osimertinib is now a standard first-line (1L) therapy for EGFR-mutated (EGFRm) advanced NSCLC. We aimed to characterize patterns of therapy and longitudinal risk of brain and liver metastasis in a cohort of EGFRm NSCLC.Patients with metastatic EGFRm NSCLC who received 1L systemic therapy at sites within the Academic Thoracic Medical Investigator's Consortium were included; demographic and clinical data including treatment patterns were described. Analyses of overall survival, time to next treatment, and incident brain and liver metastasis were performed using the Kaplan-Meier method, Cox regression, and cumulative incidence functions on patients who started 1L therapy in 2015 or later.The full cohort included 1132 patients and the mean age of the participants was 63.4 years; among the participants, 53% were White individuals, 68% were female individuals, and 67% were nonsmokers. Among the participants, 830 patients received 1L systemic therapy in 2015 or later. The predominant first EGFR-tyrosine kinase inhibitor was erlotinib (65%) before 2018 and osimertinib (81%) after 2018. The median time to the next treatment after the start of 1L therapy was 13.9 months overall and the longest in patients receiving 1L osimertinib (28 months). In the post-2015 cohort, the baseline prevalence of brain metastasis (BM) was 54% and among patients without baseline brain metastasis, the probability of incident BM at 12, 24, and 48 months was 8%, 22%, and 44%, respectively. Development of an on-treatment brain metastasis among patients without baseline brain metastasis was associated with a 3.2 times higher risk of death.Even in a contemporary era with prevalent osimertinib use, the baseline and longitudinal risk of BM development was high. The ongoing risk of developing BM, together with the associated survival detriment, argues for routine surveillance of the brain through magnetic resonance imaging for patients with EGFRm NSCLC, which is not currently included in the guidelines.

  View details for DOI 10.1016/j.jtocrr.2024.100765

  View details for PubMedID 39758601

  View details for PubMedCentralID PMC11699429

• Targeting the EZH2-SLFN11 pathway-a lesson in developing molecularly-informed treatments for recurrent small cell lung cancer. Translational cancer research Sun, F., Das, M. S. 2024; 13 (12): 6608-6612

  View details for DOI 10.21037/tcr-24-1755

  View details for PubMedID 39816547

  View details for PubMedCentralID PMC11730446

• Determining Line of Therapy from Real-World Data in Non-Small Cell Lung Cancer. Pharmacoepidemiology and drug safety Grady, C. B., Hwang, W. T., Reuss, J. E., Iams, W., Cass, A., Liu, G., Patel, D., Liu, S. V., Montenegro, G. L., Patil, T., Nieva, J. J., Herrmann, A., Marrone, K. A., Lam, V. K., Schwartzman, W., Dowell, J., Villaruz, L. C., Miller, K. L., Weiss, J., Sun, F., Velcheti, V., Camidge, D. R., Aggarwal, C., Sun, L., Marmarelis, M. E. 2024; 33 (12): e70049

  Abstract

  Determining lines of therapy (LOT) using real-world data is crucial to inform clinical decisions and support clinical research. Existing rules for determining LOT in patients with metastatic non-small cell lung cancer (mNSCLC) do not incorporate the growing number of targeted therapies used in treatment today. Therefore, we propose rules for determining LOT from real-world data of patients with mNSCLC treated with targeted therapies.LOT rules were developed through expert consensus using a real-world cohort of 550 patients with ALK+ or ROS1+ mNSCLC in the multi-institutional, electronic medical record-based Academic Thoracic Oncology Medical Investigators Consortium's (ATOMIC) Driver Mutation Registry. Rules were subsequently modified based on a review of appropriate LOT determination. These resulting rules were then applied to an independent cohort of patients with EGFR+ mNSCLC to illustrate their use.Six rules for determining LOTs were developed. Among 1133 patients with EGFR mutations and mNSCLC, a total of 3168 regimens were recorded with a median of 2 regimens per patient (IQR, 1-4; range, 1-13). After applying our rules, there were 2834 total LOTs with a median of 2 LOTs per patient (IQR, 1-3; range, 1-11). Rules 1-3 kept 11% of regimen changes from advancing the LOT. When compared to previously published rules, LOT assignments differed 5.7% of the time, mostly in LOTs with targeted therapy.These rules provide an updated framework to evaluate current treatment patterns, accounting for the increased use of targeted therapies in patients with mNSCLC, and promote standardization of methods for determining LOT from real-world data.

  View details for DOI 10.1002/pds.70049

  View details for PubMedID 39586662

  View details for PubMedCentralID PMC11588435

• Characteristics of Long-Term Survivors With EGFR-Mutant Metastatic NSCLC. JTO clinical and research reports Tompkins, W., Grady, C. B., Hwang, W. T., Chandrasekhara, K., McCoach, C., Sun, F., Liu, G., Patel, D., Nieva, J., Herrmann, A., Marrone, K., Lam, V. K., Velcheti, V., Liu, S. V., Montenegro, G. L., Patil, T., Weiss, J., Miller, K. L., Schwartzman, W., Dowell, J. E., Shaverdashvili, K., Villaruz, L., Cass, A., Iams, W., Aisner, D., Aggarwal, C., Camidge, D. R., Marmarelis, M. E., Sun, L. 2024; 5 (8): 100669

  Abstract

  Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors.Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively.Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively).Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.

  View details for DOI 10.1016/j.jtocrr.2024.100669

  View details for PubMedID 39157674

  View details for PubMedCentralID PMC11328087

• Combination metronomic chemotherapy and immunotherapy in non-small cell lung cancer remains exploratory: the VinMetAtezo trial AME Clinical Trials Review Sun, F., Neal, J. W. 2024; 2 (12)
• Characteristics of long-term survivors with EGFR mutant (EGFRm) metastatic non-small cell lung cancer (mNSCLC) Marmarelis, M., Grady, C. B., McCoach, C., Sun, F., Liu, G., Patel, D., Nieva, J. J., Marrone, K. A., Velcheti, V., Liu, S. V., Patil, T., Weiss, J., Schwartzman, W., Villaruz, L. C., Cass, A., Aisner, D. L., Hwang, W., Aggarwal, C., Camidge, D., Sun, L. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003783

• Checkpoint Inhibitor Immunotherapy to Treat Temozolomide-Associated Hypermutation in Advanced Atypical Carcinoid Tumor of the Lung. JCO precision oncology Sun, F., Grenert, J. P., Tan, L., Van Ziffle, J., Joseph, N. M., Mulvey, C. K., Bergsland, E. 2022; 6: e2200009

  View details for DOI 10.1200/PO.22.00009

  View details for PubMedID 35737914

  View details for PubMedCentralID PMC9249272

• In Response to: "Comparing Addition of Radiotherapy in EGFR- and ALK-Positive NSCLC With Brain Metastases: Are We Evaluating the Optimal Endpoint?" Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Thomas, N. J., Myall, N. J., Sun, F., Patil, T., Mushtaq, R., Yu, C., Sinha, S., Pollom, E. L., Nagpal, S., Camidge, D. R., Rusthoven, C. G., Braunstein, S. E., Wakelee, H. A., McCoach, C. E. 1800; 17 (2): e12-e14

  View details for DOI 10.1016/j.jtho.2021.11.017

  View details for PubMedID 35074229

• Capturing what matters: A retrospective observational study of advance care planning documentation at an academic medical center during the COVID-19 pandemic. Palliative medicine Sun, F., Lipinsky DeGette, R., Cummings, E. C., Deng, L. X., Hauser, K. A., Kopp, Z., Penner, J. C., Scott, B. S., Raffel, K. E., Kantor, M. A. 2022; 36 (2): 342-347

  Abstract

  Advance care planning allows patients to share their preferences for medical care with the aim of ensuring goal-concordant care in times of serious illness. The morbidity and mortality of the COVID-19 pandemic has increased the importance and public visibility of advance care planning. However, little is known about the frequency and quality of advance care planning documentation during the pandemic.This study examined the frequency, quality, and predictors of advance care planning documentation among hospitalized medical patients with and without COVID-19.This retrospective cohort analysis used multivariate logistic regression to identify factors associated with advance care planning documentation.This study included all adult patients tested for COVID-19 and admitted to a tertiary medical center in San Francisco, CA during March 2020.Among 262 patients, 31 (11.8%) tested positive and 231 (88.2%) tested negative for SARS-CoV-2. The rate of advance care planning documentation was 38.7% in patients with COVID-19 and 46.8% in patients without COVID-19 (p = 0.45). Documentation consistently addressed code status (100% and 94.4% for COVID-positive and COVID-negative, respectively), but less often named a surrogate decision maker, discussed prognosis, or elaborated on other wishes for care. Palliative care consultation was associated with increased advance care planning documentation (OR: 6.93, p = 0.004).This study found low rates of advance care planning documentation for patients both with and without COVID-19 during an evolving global pandemic. Advance care planning documentation was associated with palliative care consultation, highlighting the importance of such consultation to ensure timely, patient-centered advance care planning.

  View details for DOI 10.1177/02692163211065928

  View details for PubMedID 34920691

• Treatment patterns and outcomes in ALK or ROS1 altered NSCLC: An ATOMIC Registry Study ASCO Annual Meeting Marmarelis, M. E., Grady, C. B., Liu, G., Patel, D., Liu, S. V., Montenegro, G. L., Patil, T., Nieva, J. J., Herrmann, A., Marrone, K., Lam, V. K., Sun, F., Dowell, J., Velcheti, V., Nguyen, M., Miller, K. L., Iams, W. T., Hwang, W., Camidge, D. R., C, A. 2022

  View details for DOI 10.1200/JCO.2022.40.16_suppl.907

• Brain Metastases in EGFR- and ALK-positive Non-Small Cell Lung Cancer: Outcomes of CNS Penetrant Tyrosine Kinase Inhibitors (TKIs) Alone versus in Combination with Radiation. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Thomas, N. J., Myall, N. J., Sun, F., Patil, T., Mushtaq, R., Yu, C., Sinha, S., Pollom, E. L., Nagpal, S., Camidge, D. R., Rusthoven, C. G., Braunstein, S. E., Wakelee, H. A., McCoach, C. E. 2021

  Abstract

  INTRODUCTION: Management of central nervous system (CNS) metastases in patients with driver-mutated non-small cell lung cancer (NSCLC) has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next-generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases.METHODS: Data was retrospectively collected from 3 academic institutions. Two treatment groups (CNS-penetrant TKI alone vs TKI+CNS RT) were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy.RESULTS: A total of 147 patients were included (EGFR n=94, ALK n=52, both n=1). In patients receiving radiation, larger metastases, neurological symptoms, and receipt of steroids were more common. There were no significant differences between TKI vs CNS RT+TKI groups for any of the study outcomes, including time to progression (8.5 vs 6.9 months, p=0.13 [EFGR] and 11.4 vs 13.4 months, p=0.98 [ALK]), time to intracranial progression (14.8 vs 20.5 months, p=0.51 [EGFR] and 18.1 vs 21.8 months, p=0.65 [ALK]), or time to treatment failure (13.8 vs 8.6 months, p=0.26 [EGFR] and 13.5 vs 23.2 months, p=0.95 [ALK]).CONCLUSION: These results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively impacting progression.

  View details for DOI 10.1016/j.jtho.2021.08.009

  View details for PubMedID 34455066

• Therapeutic Advances in the Management of Patients with Advanced RET Fusion-Positive Non-Small Cell Lung Cancer. Current treatment options in oncology Sun, F., McCoach, C. E. 2021; 22 (8): 72

  Abstract

  Screening for activating driver gene alterations at the time of diagnosis is the standard of care for advanced non-small cell lung cancer (NSCLC). Activating RET fusions are identified in approximately 1-2% of NSCLCs and have emerged as a targetable driver alteration. Selpercatinib and pralsetinib are RET-selective tyrosine kinase inhibitors (TKIs) with encouraging efficacy, intracranial activity, and tolerability that we recommend as first-line therapy. As with use of TKIs in other oncogene-addicted NSCLCs, development of acquired resistance is pervasive and should be specifically delineated through use of repeat tissue biopsy with genetic profiling at the time of disease progression. If an actionable resistance mechanism emerges for which there is a candidate targeted therapy, combination inhibition should be considered. Alternatively, or in the absence of such findings, platinum doublet chemotherapy or particularly platinum-pemetrexed therapy with or without bevacizumab demonstrates a moderate effect.We would not recommend the routine use of nonselective multi-targeted TKIs such as cabozantinib and vandetanib, which have modest activity but limited tolerability due to predictable off-target effects. Single-agent immunotherapy has minimal activity in RET fusion-positive NSCLC. The role of combination chemotherapy and immunotherapy requires further study but may be considered, particularly in the presence of an activating KRAS alteration. While further development of novel RET-selective TKIs may address common RET-specific resistance mutations, they will not have activity against off-target, RET-independent resistance mechanisms. This again highlights the importance of serial biopsy and next-generation sequencing for the rational choice of sequential therapy in RET fusion-positive NSCLC.

  View details for DOI 10.1007/s11864-021-00867-8

  View details for PubMedID 34165651

• Incidence of peripheral edema in patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer. Breast cancer research and treatment Daniell, K. M., Bardia, A., Sun, F., Roberts, S. A., Brunelle, C. L., Gillespie, T. C., Sayegh, H. E., Naoum, G. E., Juric, D., Isakoff, S. J., Fitzgerald, D. M., Taghian, A. G. 2019; 175 (3): 649-658

  Abstract

  This study evaluated development of edema in patients receiving PI3K/mTOR/CDK4/6 targeted therapy for metastatic breast cancer (MBC).We reviewed medical records of 160 patients receiving targeted therapy with PI3K/mTOR/CDK4/6 inhibitors to treat MBC (n = 160; 185 treatment occurrences). Clinicopathologic data, treatment details, and edema incidence were recorded.Edema incidence was 43.1% (69/160) overall and 25.6% (41/160) in the upper extremity ipsilateral to the treated breast. In 185 therapy regimens administered, 6.8% of patients on a PI3K inhibitor, 8.8% of patients on an mTOR inhibitor, and 9.2% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting upper extremity edema. Further, 9.1% of patients on a PI3K inhibitor, 18.8% of patients on an mTOR inhibitor, and 10.5% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting edema elsewhere in the body. Multivariate logistic regression showed that, beyond the established breast cancer-related lymphedema (BCRL) risk factors [axillary lymph node dissection (Odds Ratio (OR) 2.69, p = 0.020), regional lymph node irradiation (OR 6.47, p < 0.001), and body-mass index ≥ 30 kg/m2 (OR 3.46, p = 0.006)], a relative decrease in serum albumin after 3 months of treatment increased risk of developing edema (OR 2.07, p = 0.062). Neither duration nor type of therapy were significant risk factors for edema.PI3K/mTOR/CDK4/6 inhibitors may influence the development of edema, which may cause or exacerbate progression of BCRL in patients with MBC. The varied incidence of edema between therapeutic regimens warrants vigilant monitoring of patients treated with these therapies, especially those at high risk of developing BCRL.

  View details for DOI 10.1007/s10549-019-05206-y

  View details for PubMedID 30919166

• Upper extremity edema in the at-risk arm among patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer San Antonio Breast Cancer Symposium Daniell, K. M., Bardia, A., Sun, F., Brunelle, C. L., Gillespie, T. C., Sayegh, H. E., Naoum, G. E., Isakoff, S. J., Juric, D., Taghian, A. G. 2019

  View details for DOI 10.1158/1538-7445.SABCS18-P3-14-02

• Perometry versus simulated circumferential tape measurement for the detection of breast cancer-related lymphedema. Breast cancer research and treatment Sun, F., Hall, A., Tighe, M. P., Brunelle, C. L., Sayegh, H. E., Gillespie, T. C., Daniell, K. M., Taghian, A. G. 2018; 172 (1): 83-91

  Abstract

  Despite increasing emphasis on screening and early intervention for breast cancer-related lymphedema (BCRL), there is marked heterogeneity in diagnostic methodology, including for volumetric measures. This retrospective study compared two volumetric modalities, perometry and simulated circumferential tape measurement (anatomic- and interval-based), for BCRL detection.Between 2005 and 2017, 287 female patients with unilateral breast cancer were prospectively screened for BCRL by perometry and the relative volume change (RVC) formula. Circumferential measurement was performed by sampling at five anatomic landmark-based points or 4-cm intervals from pairs of perometer arm diameter measurements. Volumetric conversion was by a frustum model. The Bland-Altman method was used to compare segmental volume differences. Confusion matrix analysis was performed for each circumferential measurement technique against perometry.Median follow-up was 34.7 months over 4 postoperative visits. There was no difference in total arm volume comparing any of the circumferential measurement techniques to perometry. Landmark-based methods significantly underestimated upper arm volume (mean difference - 207 mL [- 336, - 78 mL]) and overestimated forearm volume (mean difference + 170 mL [+ 105, + 237 mL]). Landmark-based methods had greater sensitivity and specificity compared to 4-cm interval methods for detection of both RVC ≥ 10 and 5-10%. Landmark-based methods were comparable to perometry for detection of RVC ≥ 10%, but sensitivity was only 63.2-66.7% for RVC 5-10%.This hypothesis-generating study suggested the superiority of anatomic landmark-based circumferential tape measurement compared to interval-based methods, while generating questions about the underestimation of upper arm volume and overestimation of forearm volume of circumferential tape measurement compared to perometry.

  View details for DOI 10.1007/s10549-018-4902-z

  View details for PubMedID 30062571

  View details for PubMedCentralID PMC6191334

• Letter to the editor of "Current and future perspectives on the evaluation, prevention and conservative management of breast cancer related lymphoedema: A best practice guideline" from N. Gebruers and colleagues. European journal of obstetrics, gynecology, and reproductive biology Sun, F., Brunelle, C. L., Daniell, K. M., Gillespie, T. C., Sayegh, H. E., Taghian, A. G. 2018; 225: 255-256

  View details for DOI 10.1016/j.ejogrb.2018.03.023

  View details for PubMedID 29573838

• Amino Acid Uptake Measured by [18F]AFETP Increases in Response to Arginine Starvation in ASS1-Deficient Sarcomas. Theranostics Prudner, B. C., Sun, F., Kremer, J. C., Xu, J., Huang, C., Sai, K. K., Morgan, Z., Leeds, H., McConathy, J., Van Tine, B. A. 2018; 8 (8): 2107-2116

  Abstract

  Rational: In a subset of cancers, arginine auxotrophy occurs due to the loss of expression of argininosuccinate synthetase 1 (ASS1). This loss of ASS1 expression makes cancers sensitive to arginine starvation that is induced by PEGylated arginine deiminase (ADI-PEG20). Although ADI-PEG20 treatment is effective, it does have important limitations. Arginine starvation is only beneficial in patients with cancers that are ASS1-deficient. Also, these tumors may metabolically reprogram to express ASS1, transforming them from an auxotrophic phenotype to a prototrophic phenotype and thus rendering ADI-PEG20 ineffective. Due to these limitations of ADI-PEG20 treatment and the potential for developing resistance, non-invasive tools to monitor sensitivity to arginine starvation are needed. Methods: Within this study, we assess the utility of a novel positron emission tomography (PET) tracer to determine sarcomas reliant on extracellular arginine for survival by measuring changes in amino acid transport in arginine auxotrophic sarcoma cells treated with ADI-PEG20. The uptake of the 18F-labeled histidine analogue, (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (AFETP), was assessed in vitro and in vivo using human-derived sarcoma cell lines. In addition, we examined the expression and localization of cationic amino acid transporters in response to arginine starvation with ADI-PEG20. Results: In vitro studies revealed that in response to ADI-PEG20 treatment, arginine auxotrophs increase the uptake of L-[3H]arginine and [18F]AFETP due to an increase in the expression and localization to the plasma membrane of the cationic amino acid transporter CAT-1. Furthermore, in vivo PET imaging studies in mice with arginine-dependent osteosarcoma xenografts showed increased [18F]AFETP uptake in tumors 4 days after ADI-PEG20 treatment compared to baseline. Conclusion: CAT-1 transporters localizes to the plasma membrane as a result of arginine starvation with ADI-PEG20 in ASS1-deficient tumor cells and provides a mechanism for using cationic amino acid transport substrates such as [18F]AFETP for identifying tumors susceptible to ADI-PEG20 treatment though non-invasive PET imaging techniques. These findings indicate that [18F]AFETP-PET may be suitable for the early detection of tumor response to arginine depletion due to ADI-PEG20 treatment.

  View details for DOI 10.7150/thno.22083

  View details for PubMedID 29721066

  View details for PubMedCentralID PMC5928874

• Cytosolic delivery of siRNA by ultra-high affinity dsRNA binding proteins. Nucleic acids research Yang, N. J., Kauke, M. J., Sun, F., Yang, L. F., Maass, K. F., Traxlmayr, M. W., Yu, Y., Xu, Y., Langer, R. S., Anderson, D. G., Wittrup, K. D. 2017; 45 (13): 7602-7614

  Abstract

  Protein-based methods of siRNA delivery are capable of uniquely specific targeting, but are limited by technical challenges such as low potency or poor biophysical properties. Here, we engineered a series of ultra-high affinity siRNA binders based on the viral protein p19 and developed them into siRNA carriers targeted to the epidermal growth factor receptor (EGFR). Combined in trans with a previously described endosome-disrupting agent composed of the pore-forming protein Perfringolysin O (PFO), potent silencing was achieved in vitro with no detectable cytotoxicity. Despite concerns that excessively strong siRNA binding could prevent the discharge of siRNA from its carrier, higher affinity continually led to stronger silencing. We found that this improvement was due to both increased uptake of siRNA into the cell and improved pharmacodynamics inside the cell. Mathematical modeling predicted the existence of an affinity optimum that maximizes silencing, after which siRNA sequestration decreases potency. Our study characterizing the affinity dependence of silencing suggests that siRNA-carrier affinity can significantly affect the intracellular fate of siRNA and may serve as a handle for improving the efficiency of delivery. The two-agent delivery system presented here possesses notable biophysical properties and potency, and provide a platform for the cytosolic delivery of nucleic acids.

  View details for DOI 10.1093/nar/gkx546

  View details for PubMedID 28641400

  View details for PubMedCentralID PMC5570165

• The need for preoperative baseline arm measurement to accurately quantify breast cancer-related lymphedema. Breast cancer research and treatment Sun, F., Skolny, M. N., Swaroop, M. N., Rawal, B., Catalano, P. J., Brunelle, C. L., Miller, C. L., Taghian, A. G. 2016; 157 (2): 229-240

  Abstract

  Breast cancer-related lymphedema (BCRL) is a feared outcome of breast cancer treatment, yet the push for early screening is hampered by a lack of standardized quantification. We sought to determine the necessity of preoperative baseline in accounting for temporal changes of upper extremity volume. 1028 women with unilateral breast cancer were prospectively screened for lymphedema by perometry. Thresholds were defined: relative volume change (RVC) ≥10 % for clinically significant lymphedema and ≥5 % including subclinical lymphedema. The first postoperative measurement (pseudo-baseline) simulated the case of no baseline. McNemar's test and binomial logistic regression models were used to analyze BCRL misdiagnoses. Preoperatively, 28.3 and 2.9 % of patients had arm asymmetry of ≥5 and 10 %, respectively. Without baseline, 41.6 % of patients were underdiagnosed and 40.1 % overdiagnosed at RVC ≥ 5 %, increasing to 50.0 and 54.8 % at RVC ≥ 10 %. Increased pseudo-baseline asymmetry, increased weight change between baselines, hormonal therapy, dominant use of contralateral arm, and not receiving axillary lymph node dissection (ALND) were associated with increased risk of underdiagnosis at RVC ≥ 5 %; not receiving regional lymph node radiation was significant at RVC ≥ 10 %. Increased pseudo-baseline asymmetry, not receiving ALND, and dominant use of ipsilateral arm were associated with overdiagnosis at RVC ≥ 5 %; increased pseudo-baseline asymmetry and not receiving ALND were significant at RVC ≥ 10 %. The use of a postoperative proxy even early after treatment results in poor sensitivity for identifying BCRL. Providers with access to patients before surgery should consider the consequent need for proper baseline, with specific strategy tailored by institution.

  View details for DOI 10.1007/s10549-016-3821-0

  View details for PubMedID 27154787