Christopher T Chen, MD

All Publications

• Phase I Clinical Trial Evaluating Safety, Tolerability, and Early Activity of Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF-Altered Solid Tumors or NRAS-Mutant Melanoma JCO Oncology Advances Gambardella, V., et al 2026
• Phase 1 Study of [177Lu]Lu-NeoB in Patients with Advanced Solid Tumors Overexpressing Gastrin-Releasing Peptide Receptor: Preliminary Safety and Dosimetry Results. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Mittra, E. S., Solnes, L. B., van der Veldt, A. A., Wong, J., Aloj, L., Heinrich, M. C., Chen, C. T., Rowe, S. P., Brabander, T., Pacey, S., Aimone, P., Pathak, D., Blumenstein, L., Liu, Y., Iagaru, A. 2025

  Abstract

  Gastrin-releasing peptide receptor (GRPR) is overexpressed in a range of tumor types, making it an attractive candidate for novel treatment approaches. NeoB binds to GRPR with high affinity and can be radiolabeled with 68Ga ([68Ga]Ga-NeoB) for imaging or 177Lu ([177Lu]Lu-NeoB, hereafter 177Lu-NeoB) for therapy, making it suitable for theranostics. Methods: NeoRay is a prospective, phase 1/2a, open-label, multicenter, first-in-human study of 177Lu-NeoB. Patients with selected advanced solid tumors with GRPR expression (confirmed by [68Ga]Ga-NeoB lesion uptake) were enrolled. Here, we report preliminary data (cutoff, April 29, 2024) from phase 1, which aimed to identify the maximum tolerated dose and/or recommended phase 2 dose of 177Lu-NeoB. Patients were scheduled to receive at least 3 cycles of 177Lu-NeoB at an interval of at least 6 wk. A Bayesian optimal interval design was used, with dose-escalation decisions based on dose-limiting toxicities (DLTs) during cycle 1 of each dose level. The primary endpoint was the incidence and nature of DLTs. Safety was assessed before and throughout each cycle. Dosimetry was assessed after the first administration. Results: Seventeen patients (median age, 65 y; 71% male) with advanced gastrointestinal stromal tumors, prostate cancer, glioblastoma, or breast cancer received 177Lu-NeoB activities of 1.85 GBq (cycle 1) and then 5.55 GBq (cycles 2-4) (n = 3), 9.25 GBq (n = 9), or 11.1 GBq (n = 5). Four DLTs were observed in 3 patients who received 11.1 GBq: grade 3 anemia (n = 2), grade 4 neurologic decline (n = 1), and grade 3 encephalopathy (n = 1). No DLTs were observed at lower administered activities. Overall, 4 of 17 patients (23.5%) had treatment-related adverse events of grade 3 or higher. Among patients with at least 1 evaluable dosimetry measurement (n = 16), the mean absorbed dose coefficient was 0.10 Gy/GBq (SD, 0.056 Gy/GBq) in the kidneys, 0.055 Gy/GBq (SD, 0.039 Gy/GBq) in the pancreas, and 0.018 Gy/GBq (SD, 0.0076 Gy/GBq) in the red marrow. Conclusion: 177Lu-NeoB has a favorable organ dosimetry profile in patients with advanced solid tumors expressing GRPR, with a large safety margin compared with accepted external beam radiation therapy thresholds for organ toxicity. The maximum tolerated dose of 177Lu-NeoB was identified as 9.25 GBq, and the recommended phase 2 dose for the phase 2a dose expansion is 9.25 GBq.

  View details for DOI 10.2967/jnumed.125.270411

  View details for PubMedID 41344852

• p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program. Cancer discovery Wang, M., Bieging-Rolett, K. T., Kaiser, A. M., Brady, C. A., Lockhart, J. H., Ferreira, S., Nguyen, K. T., Rajeevan, A., Evans, S. A., Zhao, T., Raj, N., Elkrief, A., Tischfield, S. E., Ladanyi, M., Ozawa, M. G., Bui, N. Q., Chen, C. T., Flores, E. R., Attardi, L. D. 2025

  Abstract

  Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

  View details for DOI 10.1158/2159-8290.CD-25-0525

  View details for PubMedID 41115251

• Durable response to an anti-CD25 antibody-drug conjugate and anti-PD-1 antibody in ovarian carcinoma: a case report. Immunotherapy Bekheet, F., Ashland, M., Reyes, R., Dorigo, O., Karam, A., Chen, C. T. 2025: 1-5

  Abstract

  Although PD-1 checkpoint inhibition has improved outcomes for some cancer types, a substantial proportion of solid tumors still do not respond, in part due to inadequate cytotoxic CD8+ T-cell infiltration and survival within the tumor microenvironment (TME). CD25+ regulatory T-cells (Tregs) are a subset of T-cells that play a key role in suppressing CD8+ T-cell activity. Depletion of Tregs in the TME could thus enhance anti-cancer immune responses. Here, we present the experience of a patient with platinum-resistant ovarian carcinoma who achieved a durable partial response on a phase 1 clinical trial of an anti-CD25 antibody-drug conjugate combined with pembrolizumab. Notably, her tumor response correlated with a reduction in CD25+ Tregs on paired tumor biopsies and further deepened after treatment discontinuation. This case provides early proof-of-concept that Treg depletion combined with PD-1/PD-L1 inhibitors can lead to anti-cancer efficacy in refractory diseases and offers key lessons to guide future development of anti-Treg therapeutics.

  View details for DOI 10.1080/1750743X.2025.2561398

  View details for PubMedID 40970869

• Immunotherapy Efficacy in Mismatch Repair-Proficient Colorectal Cancer Patients With and Without Liver Metastases. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Beiter, E. R., Patel, S. R., Chen, C. T. 2025: JCO2501044

  View details for DOI 10.1200/JCO-25-01044

  View details for PubMedID 40934442

• Milademetan in advanced solid tumors with MDM2 amplification and wild-type TP53: pre-clinical and phase 2 clinical trial results. Clinical cancer research : an official journal of the American Association for Cancer Research Dumbrava, E. E., Stinchcombe, T. E., Gounder, M., Cote, G. M., Hanna, G. J., Sumrall, B., Wise-Draper, T. M., Kanaan, M., Duffy, S., Sumey, C., Cobb, P., Forbes, A., Beckmann, A., Schadt, E., Ku, N., Tirunagaru, V. G., Singh, K., Pei, X., Xu, F., Doebele, R. C., Chen, C. T. 2025

  Abstract

  MDM2 is an E3 ubiquitin ligase that degrades the tumor suppressor p53. In cancers, MDM2 amplification (MDM2amp) leads to overexpression of MDM2, inducing p53 degradation and a p53-null phenotype even in the absence of TP53 mutations. We report here the pre-clinical and clinical activity of milademetan, a potent and selective oral small molecule inhibitor of the MDM2-p53 interaction, in MDM2amp, TP53-wildtype (wt) solid tumors.Milademetan was tested against a variety of cell-line and xenograft tumor models. This supported a phase II basket study (MANTRA-2) in patients with advanced MDM2amp, TP53-wt solid tumors. The primary endpoint was objective response rate (ORR), and key secondary endpoints included progression-free survival (PFS) and adverse events.Milademetan showed potent activity against MDM2amp, TP53-wt laboratory models. In the phase II trial, 40 patients received milademetan, of whom 31 had centrally confirmed molecular testing. The best overall response was 19.4% (6/31) with 1 confirmed response (3.2%) and 5 unconfirmed partial responses, including a patient with endometrial stromal sarcoma who achieved 100% target lesion reduction. The median PFS was 3.5 months (95% CI:1.8, 3.7). Grade 3 or 4 adverse events observed included thrombocytopenia, neutropenia, anemia, leukopenia, and diarrhea.Milademetan had a manageable safety profile and achieved responses against a variety of refractory MDM2amp, TP53 -wt solid tumors, but tumor reductions were short-lived. Subsequent MDM2 inhibitor efforts should focus on combination strategies or treatment in earlier lines of therapy to achieve more durable clinical benefit.

  View details for DOI 10.1158/1078-0432.CCR-25-0762

  View details for PubMedID 40788172

• Completed phase 1a dose escalation study of the first oral ENPP1 inhibitor RBS2418 immunotherapy in subjects with metastatic solid tumors. Marron, T., Wainberg, Z. A., Spira, A. I., Gordon, M. S., Chen, C. T., Segar, J., Scott, A. J., Boccia, R. V., Johnson, D. H., Berlin, J., Ho, W., Schanzer, J., Sengupta, D., Huang, N., Glenn, J. S., Csiki, I., Klumpp, K., Misleh, J. LIPPINCOTT WILLIAMS & WILKINS. 2025

  View details for DOI 10.1200/JCO.2025.43.16_suppl.2577

  View details for Web of Science ID 001534380500001

• Leveraging advanced practice providers in a clinical research program to provide trial prescreening and counseling increases clinic volume and trial accruals. Reyes, R., Arrieta, K., Shah, D., Janchenko, L., Chen, C. T., Breudecheck, K. LIPPINCOTT WILLIAMS & WILKINS. 2025: e13529

  View details for DOI 10.1200/JCO.2025.43.16_suppl.e13529

  View details for Web of Science ID 001609079900001

• Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX): Two-Year primary outcome analysis. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Klebaner, D., Brown, E., Fisher, G. A., Shelton, A., Johnson, T. P., Shaheen, S., Chen, C., Heestand, G., Holden, T., Bien, J., King, D. A., Dawes, A. J., Morris, A. M., Kirilcuk, N., Kin, C., Gahagan, J., Sheth, V., Ghanouni, P., Richter, S., Vitzthum, L., Rahimy, E., Chang, D. T., Pollom, E. L. 2025; 207: 110884

  Abstract

  As patients with rectal cancer with clinical complete response (cCR) after neoadjuvant therapy may be safely spared Total Mesorectal Excision (TME), strategies to maximize cCR are needed.We conducted a single-arm phase II study to determine whether dose-escalated short-course radiotherapy (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by eight cycles of FOLFOXIRI increased cCR rates among adult patients with > T2N0M0 or low T2N0 rectal cancer.Between 2020 and 2023, we enrolled 37 patients, of whom 27 (73 %) had at least one high-risk feature (cT4, extramural vascular invasion [EMVI], N2, threatened circumferential resection margin, positive lateral node). At primary endpoint assessment, nine (24 %) patients had cCR on both endoscopy and MRI, and pursued organ preservation (OP). Fourteen (38 %) patients had cCR only on endoscopy, nine of whom pursued OP. Of the 18 patients who pursued OP, nine had local regrowth at two years from radiotherapy start, with two-year TME-free survival of 26 %. Baseline factors significantly associated with not achieving OP included age < 50 years and T4 disease. At mid-treatment restaging, patients who achieved OP were significantly less likely to have persistent node positivity, EMVI, and endoscopically visible tumor. Grade 3+ adverse events at least possibly attributed to chemotherapy and radiotherapy occured in 51% and 43% of patients, respectively.Short-course radiotherapy with a boost followed by FOLFIXIRI results in OP in one-quarter of patients with high-risk rectal cancer, with poorer response among younger patients and T4 disease. Mid-treatment response may help guide timely decision-making regarding treatment.

  View details for DOI 10.1016/j.radonc.2025.110884

  View details for PubMedID 40209856

• Unveiling the Anti-Tumor Activity of Exarafenib in BRAF-Mutated NSCLC Through Genomic Analysis and Combined Preclinical, Clinical Outcomes Manabe, T., Wang, T., Severson, P., Miller, N., Lee, C., Donderici, E., Zhang, N., Bergo, H. C., Chou, Y., Kerr, D. L., Wu, W., Grandinetti, K. B., Soroceanu, L., Pelham, R. J., Martin, E. S., Murphy, E. A., Khanna, V., Neal, J. W., Chen, C. T., Kato, S., Williams, R., Bivona, T. G. ELSEVIER SCIENCE INC. 2025: S1-S2

  View details for Web of Science ID 001469705500002

• Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer. The New England journal of medicine Schram, A. M., Goto, K., Kim, D. W., Macarulla, T., Hollebecque, A., O'Reilly, E. M., Ou, S. I., Rodon, J., Rha, S. Y., Nishino, K., Duruisseaux, M., Park, J. O., Neuzillet, C., Liu, S. V., Weinberg, B. A., Cleary, J. M., Calvo, E., Umemoto, K., Nagasaka, M., Springfeld, C., Bekaii-Saab, T., O'Kane, G. M., Opdam, F., Reiss, K. A., Joe, A. K., Wasserman, E., Stalbovskaya, V., Ford, J., Adeyemi, S., Jain, L., Jauhari, S., Drilon, A. 2025; 392 (6): 566-576

  Abstract

  Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. The efficacy and safety of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion-positive solid tumors are unclear.In this registrational, phase 2 clinical study, we assigned patients with advanced NRG1 fusion-positive cancer involving any tumor type to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary end point was overall response (complete or partial response) according to investigator assessment. Secondary end points included duration of response, progression-free survival, and safety.A total of 204 patients with 12 tumor types were enrolled and treated. Among 158 patients who had measurable disease and were enrolled at least 24 weeks before the data-cutoff date, a response occurred in 30% (95% confidence interval [CI], 23 to 37). The median duration of response was 11.1 months (95% CI, 7.4 to 12.9); 19% of responses were ongoing at the data-cutoff date. Responses were observed in multiple tumor types - including in 27 of 93 patients (29%; 95% CI, 20 to 39) with non-small-cell lung cancer (NSCLC) and 15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer - and across multiple NRG1 fusion partners. The median progression-free survival was 6.8 months (95% CI, 5.5 to 9.1). Adverse events were primarily grade 1 or 2. The most common adverse events that were considered by the investigator to be related to zenocutuzumab were diarrhea (in 18% of the patients), fatigue (in 12%), and nausea (in 11%). Infusion-related reactions (composite term) were observed in 14% of the patients. One patient discontinued zenocutuzumab owing to a treatment-related adverse event.Zenocutuzumab showed efficacy in patients with advanced NRG1 fusion-positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events. (Funded by Merus; eNRGy ClinicalTrials.gov number, NCT02912949.).

  View details for DOI 10.1056/NEJMoa2405008

  View details for PubMedID 39908431

  View details for PubMedCentralID PMC11878197

• MDM2 inhibition is associated with the emergence of TP53-altered clonal hematopoiesis. NPJ precision oncology Khanna, V., Eslami, G., Reyes, R., Diep, R., Fernandez-Pol, S., Stehr, H., Suarez, C. J., Pinto, H., Ford, J. M., Zhang, T. Y., Chen, C. T. 2025; 9 (1): 34

  Abstract

  Murine double minute 2 (MDM2) inhibitors have shown promising activity in TP53-wild type tumors and are under active investigation across a spectrum of malignancies. Herein, we report a 51-year-old female with MDM2-amplified, TP53-wild type adenoid cystic carcinoma who was treated with a MDM2 inhibitor and developed persistent pancytopenia despite drug discontinuation. Her pancytopenia was associated with 20 distinct pathogenic TP53 mutations in peripheral blood and bone marrow not present in drug-resistant tumor tissue. Plasma TP53 mutations were similarly detected among 4 other patients treated at our institution, with the number of mutations correlating strongly with duration of treatment. This case suggests that MDM2 inhibitors are associated with TP53 clonal hematopoiesis, which may confer a risk of subsequent myeloid malignancy. As multiple MDM2 inhibitor trials are ongoing, our findings underscore the need for further investigation into the potential long-term deleterious effects of these inhibitors in the hematopoietic stem and progenitor compartment.

  View details for DOI 10.1038/s41698-025-00823-x

  View details for PubMedID 39900989

  View details for PubMedCentralID PMC11790943

• Unveiling Exarafenib's Role in BRAF-Mutated NSCLC Through Genomic Analysis and Combined Preclinical, Clinical Outcomes Manabe, T., Severson, P., Wang, T., Miller, N., Zhang, N., Donderici, E., Soroceanu, L., Lee, C., Pelham, R., Chou, Y., Khanna, V., Neal, J., Chen, C., Kato, S., Williams, R., Bivona, T. WILEY. 2025: 1293

  View details for Web of Science ID 001401044103145

• A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma. Annals of oncology : official journal of the European Society for Medical Oncology Goyal, L., DiToro, D., Facchinetti, F., Martin, E. E., Peng, P., Baiev, I., Iyer, R., Maurer, J., Reyes, S., Zhang, K., Majeed, U., Berchuck, J. E., Chen, C. T., Walmsley, C., Pinto, C., Vasseur, D., Gordan, J. D., Mody, K., Borad, M., Karasic, T., Damjanov, N., Danysh, B. P., Wehrenberg-Klee, E., Kambadakone, A. R., Saha, S. K., Hoffman, I. D., Nelson, K. J., Iyer, S., Qiang, X., Sun, C., Wang, H., Li, L., Javle, M., Lin, B., Harris, W., Zhu, A. X., Cleary, J. M., Flaherty, K. T., Harris, T., Shroff, R. T., Leshchiner, I., Parida, L., Kelley, R. K., Fan, J., Stone, J. R., Uboha, N. V., Hirai, H., Sootome, H., Wu, F., Bensen, D. C., Hollebecque, A., Friboulet, L., Lennerz, J. K., Getz, G., Juric, D. 2024

  Abstract

  Fibroblast growth factor receptor (FGFR) inhibitors have significantly improved outcomes for patients with FGFR-altered cholangiocarcinoma, leading to their regulatory approval in multiple countries. However, as with many targeted therapies, acquired resistance limits their efficacy. A comprehensive, multimodal approach is crucial to characterizing resistance patterns to FGFR inhibitors.This study integrated data from six investigative strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology. We characterized the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care across 10 institutions.Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared to those without clinical benefit (65% vs 10%, p<0.0001). We identified 26 distinct FGFR2 kinase domain mutations, with 63% of patients harboring multiple. While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.Our multimodal analysis led to a model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrated approach offers a blueprint for advancing drug resistance research across cancer types.

  View details for DOI 10.1016/j.annonc.2024.12.011

  View details for PubMedID 39706336

• Redefining Available Therapy in Oncology Accelerated Approval Decisions. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Patel, S. R., Ramachandran, M., Ai, A., Chen, C. T. 2024: JCO2400892

  Abstract

  When weighing rapid approval for follow-on drugs, should @FDAOncology recognize the drugs that came before?

  View details for DOI 10.1200/JCO.24.00892

  View details for PubMedID 39454117

• NCCN Guidelines Insights: Colorectal Cancer Screening, Version 1.2024. Journal of the National Comprehensive Cancer Network : JNCCN Ness, R. M., Llor, X., Abbass, M. A., Bishu, S., Chen, C. T., Cooper, G., Early, D. S., Friedman, M., Fudman, D., Giardiello, F. M., Glaser, K., Gurudu, S., Hall, M., Huang, L. C., Issaka, R., Katona, B., Kidambi, T., Lazenby, A. J., Maratt, J., Markowitz, A. J., Marsano, J., May, F. P., Mayer, R. J., Olortegui, K., Patel, S., Peter, S., Porter, L. D., Shafi, M., Stanich, P. P., Terdiman, J., Vu, P., Weiss, J. M., Wood, E., Cassara, C. J., Sambandam, V. 2024; 22 (7): 438-446

  Abstract

  The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.

  View details for DOI 10.6004/jnccn.2024.0047

  View details for PubMedID 39236750

• ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors. Cancer research communications Chen, C. T., Khanna, V., Kummar, S., Abdul-Karim, R. M., Sommerhalder, D., Tolcher, A. W., Ueno, N. T., Davis, S. L., Orr, D. W., Hamilton, E., Patel, M. R., Spira, A. I., Jauhari, S., Florou, V., Duff, M., Xu, R., Wang, J., Barkund, S. R., Zhou, H., Pankov, A., Kong, W., Jahchan, N. S., Jackson, E. L., Sun, J. D., Junttila, M. R., Multani, P. S., Daemen, A., Chow Maneval, E., Munster, P. N. 2024

  Abstract

  PURPOSE: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of anti-apoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial.PATIENTS AND METHODS: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel.RESULTS: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naive and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, 5 objective responses were observed. A pre-planned futility analysis in dose expansion showed a 3.2% (95% CI 0.4, 11.2) ORR with a median PFS of 2 months (95% CI 1.8, 2.8) across all 4 cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1.CONCLUSIONS: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play.

  View details for DOI 10.1158/2767-9764.CRC-24-0115

  View details for PubMedID 39177285

• Reflections and Roadmaps: Career Development Beyond the FDA-AACR Oncology Educational Fellowship. Clinical cancer research : an official journal of the American Association for Cancer Research Patel, T., Chen, C., Al Hadidi, S., Kadry, Y., Sridhara, R., Purcell, E., Wisch, L., Retzlaff, J., Foti, M., Pazdur, R., Kluetz, P., Gao, J. 2024

  Abstract

  In 2020, the U.S. Food and Drug Administration's Oncology Center of Excellence, in collaboration with the American Association for Cancer Research, launched a novel educational partnership known as the FDA-AACR Oncology Educational Fellowship. This year-long program is aimed for hematology/oncology fellows, scientists, and early-career investigators, offering an in-depth exploration of the regulatory review process by blending didactic learning with practical cases discussing oncology drug approvals. The fellowship has been met with enthusiastic feedback, with participants lauding its role in demystifying the regulatory landscape and enhancing their professional careers. This paper reflects on the experiences of four alumni, showcasing the program's transformative impact across diverse oncology career paths in government, academia, and industry.

  View details for DOI 10.1158/1078-0432.CCR-24-1444

  View details for PubMedID 38856702

• Correlation of baseline ENPP1 and cGAS expression in advanced solid tumors with intratumoral immune activation and clinical outcomes after treatment with the first-in-class oral ENPP1 inhibitor RBS2418, alone or in combination with pembrolizumab Marron, T., Wainberg, Z. A., Spira, A. I., Gordon, M. S., Chen, C., Segar, J., Boccia, R. V., Berlin, J., Csiki, I., Schanzer, J., Huang, N., Glen, J., Klumpp, K., Misleh, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400539

• Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 (trastuzumab imbotolimod) plus /- pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan (T-DXd) Pegram, M. D., Calfa, C., Chen, C., Salgado, A., Heeke, A., Kang, I., Pistilli, B., Pohlmann, P. R., Rugo, H. S., Saura, C., Vicier, C., Pearson, C., Mangeshkar, M., Yu, T., Alonso, M. N., Colburn, D. E., Perez, E. A., Drago, J. Z. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557406026

• A phase 1/2 study of BDC-3042, a novel dectin-2 agonistic antibody, in patients with advanced cancers. Salkeni, M., Vandross, A. L., Dumbrava, E., Giordano, A., Chen, C., Kenkel, J., Cai, D., Xu, L., Alonso, M. N., Ackerman, S., Yu, T., Colburn, D. E., Perez, E. A., Wilks, S. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557406116

• Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX). Pollom, E. L., Fisher, G. A., Shelton, A., Johnson, T., Chen, C., Jackson, S., Shaheen, S., Holden, T., Bien, J., King, D., Morris, A. M., Kin, C., Dawes, A., Kirilcuk, N., Gahagan, J., Vitzthum, L., Sheth, V., Brown, E., Pratapneni, A., Chang, D. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400852

• A phase 1, open-label, dose escalation, and expansion study of CUE-102, a novel WT1-pHLA-IL2-Fc fusion protein, in patients with HLA-A*0201-positive disease and WT1-positive recurrent/metastatic cancers Uboha, N., Saenger, Y. M., Alese, O. B., Kim, D., Zheng, L., Chaves, J., Fu, S., Gong, J., Jin, Z., Powderly, J. D., Gabrail, N., Bekaii-Saab, T. S., Alistar, A., Chen, C., Agensky, L., Goel, A., Margossian, S., Quayle, S. N., Levisetti, M., Selfridge, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400808

• Toward Precision Perioperative Therapy in GI Malignancies. JCO precision oncology Glover, M. J., Bien, J., Chen, C. T. 2023; 7: e2200381

  Abstract

  The term precision oncology typically refers to molecularly guided therapies against cancer. Less appreciated but also critically important is molecular identification of patients with resectable disease who are most likely to benefit from perioperative drugs, and tailored selection of such drugs. We call this idea precision perioperative therapy. Over the past several years, use of precision perioperative approaches for patients with localized GI cancers has expanded in clinical trials and practice. Here, we summarize the status of the field and highlight areas of future innovation.Using PubMed, we reviewed articles published from 2017 to 2023 in English. We used search terms "adjuvant," "perioperative," "neoadjuvant," and "precision medicine" for various types of GI malignancies. Information about ongoing clinical trials was accessed through ClinicalTrials.gov, accessed January 2023.Paradigms such as minimal residual disease detection via circulating tumor DNA and perioperative immunotherapy in lieu of chemotherapy for mismatch repair-deficient disease may lead to reduced toxicity and improved long-term outcomes in select populations. Molecularly targeted drugs that have shown activity against metastatic disease may also hold promise in the curable setting.The field is very much in development, but emerging data demonstrate early promise. We are optimistic that ongoing research efforts will increasingly bring precision perioperative therapy to patients with resectable GI malignancies.

  View details for DOI 10.1200/PO.22.00381

  View details for PubMedID 37625103

• Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. The Lancet. Oncology Strickler, J. H., Cercek, A., Siena, S., André, T., Ng, K., Van Cutsem, E., Wu, C., Paulson, A. S., Hubbard, J. M., Coveler, A. L., Fountzilas, C., Kardosh, A., Kasi, P. M., Lenz, H. J., Ciombor, K. K., Elez, E., Bajor, D. L., Cremolini, C., Sanchez, F., Stecher, M., Feng, W., Bekaii-Saab, T. S. 2023; 24 (5): 496-508

  Abstract

  HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer.MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing.Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47-64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7-49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression.Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer.Seagen and Merck & Co.

  View details for DOI 10.1016/S1470-2045(23)00150-X

  View details for PubMedID 37142372

• Trials in progress: a global phase 1/1b clinical trial evaluating exarafenib (KIN-2787), a highly selective pan-RAF inhibitor, in adult patients with BRAF-altered solid tumors and NRAS mutant melanoma Spira, A., Gambardella, V., Kato, S., Perez, C., Mckean, M., Cao, M., Kim, R., Chen, C. T., Italiano, A., Cassier, P., Mehnert, J., Chmielowski, B., Lee, G., Severson, P., Unger, C., Guan, X., Williams, R., Long, G. AMER ASSOC CANCER RESEARCH. 2023

  View details for DOI 10.1158/1538-7445.AM2023-CT032

  View details for Web of Science ID 001018089900022

• GLIMMER-01: initial results from a phase 1 dose escalation trial of a first-in-class bi-sialidase (E-602) in solid tumors Luke, J. J., Johnson, M., Tolcher, A., Chen, C. T., Dai, T., Curti, B. D., El-Khoueiry, A., Sznol, M., Henick, B. S., Horak, C., Jayaraman, P., Cole, C. B., Wilson, D., Cao, L., Peng, L., Feltquate, D., Lathers, D., Sharma, M. R. AMER ASSOC CANCER RESEARCH. 2023

  View details for DOI 10.1158/1538-7445.AM2023-CT034

  View details for Web of Science ID 001018089900024

• Results of a phase 1 study investigating camidanlumab tesirine as monotherapy and in combination with pembrolizumab in patients with selected advanced solid tumors Chen, C. 2023

  View details for DOI 10.1136/jitc-2023-SITC2023.0608

• A PHASE 1/2 DOSE ESCALATION/EXPANSION STUDY EVALUATING THE SAFETY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTITUMOR ACTIVITY OF E-602, A BI-SIALIDASE FUSION PROTEIN, IN ADVANCED CANCER (GLIMMER-01) Sharma, M., Lathers, D., Johnson, M., Luke, J., Puzanov, I., Curti, B., Chen, C., El-Khoueiry, A., Henick, B., Callahan, M., Sznol, M., Patel, S., Wilson, D., Ricker, M., Cao, L., Jayaraman, P., Che, J., Peng, L., Feltquate, D., Tolcher, A. BMJ PUBLISHING GROUP. 2022: A803

  View details for DOI 10.1136/jitc-2022-SITC2022.0772

  View details for Web of Science ID 000919423400728

• The Clinical Landscape of Cell-Free DNA Alterations in 1,671 Patients with Advanced Biliary Tract Cancer. Annals of oncology : official journal of the European Society for Medical Oncology Berchuck, J. E., Facchinetti, F., DiToro, D. F., Baiev, I., Majeed, U., Reyes, S., Chen, C., Zhang, K., Sharman, R., Junior, P. L., Maurer, J., Shroff, R. T., Pritchard, C. C., Wu, M., Catenacci, D. V., Javle, M., Friboulet, L., Hollebecque, A., Bardeesy, N., Zhu, A. X., Lennerz, J. K., Tan, B., Borad, M., Parikh, A. R., Kiedrowski, L. A., Kelley, R. K., Mody, K., Juric, D., Goyal, L. 2022

  Abstract

  BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2,068 cfDNA samples from 1,671 patients with advanced BTC generated with Guardant360. We performed clinical annotation on a multi-institutional subset (n=225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes.RESULTS: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. FGFR2 fusions, IDH1 mutations, and BRAF V600E were clonal in majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%).CONCLUSIONS: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.

  View details for DOI 10.1016/j.annonc.2022.09.150

  View details for PubMedID 36089135

• Rectosigmoid Cancer-Rectal Cancer or Sigmoid Cancer? American journal of clinical oncology Hui, C., Baclay, R., Liu, K., Sandhu, N., Loo, P., von Eyben, R., Chen, C., Sheth, V., Vitzthum, L., Chang, D., Pollom, E. 2022

  Abstract

  OBJECTIVES: We aimed to determine the optimal treatment for patients with locally advanced rectosigmoid cancers, and to determine whether this can be guided by distance from anal verge (AV) and/or anatomic landmarks such as the sacral promontory and peritoneal reflection (PR).MATERIALS AND METHODS: We retrospectively reviewed patients with T3-T4 and/or node-positive rectosigmoid cancers who underwent surgery from 2006 to 2018 with available pelvic imaging. We included tumors at 9 to 20cm from the AV on either staging imaging, or colonoscopy. Patients were stratified into those who received neoadjuvant therapy, and those who underwent upfront surgery. Comparisons of characteristics were performed using chi2 test and Fischer exact test. Locoregional failure (LRF) and overall survival were compared using Cox regressions and Kaplan-Meier analysis.RESULTS: One hundred sixty-one patients were included. Ninety-seven patients had neoadjuvant therapy, and 64 patients had upfront surgery. Median follow-up time was 45.1 months. Patients who had neoadjuvant therapy had tumors that were higher cT stage (P<0.01) with more positive/close circumferential resection margins seen on imaging by radiologists (28.9% vs. 1.6%, P=0.015). The 2-year rate of LRF, distant metastases, or overall survival was not significantly different between the 2 groups. None of 15 patients with tumors below the PR treated with neoadjuvant therapy had LRF, but 1 (25%) of 4 patients with tumors below the PR treated with adjuvant therapy experienced LRF (P=0.05).CONCLUSIONS: Patients with tumors below the PR may benefit more from neoadjuvant therapy. The PR on imaging may be a reliable landmark in addition to the distance from the AV to determine the most appropriate treatment option.

  View details for DOI 10.1097/COC.0000000000000931

  View details for PubMedID 35848736

• Phase 1b/2 trial of tucatinib plus trastuzumab plus /- chemotherapy or pembrolizumab in patients with metastatic HER2+GI cancers Shitara, K., Park, H., Bekaii-Saab, T., Kim, S. S., Kamath, S., Pishvaian, M. J., Chen, C., Zhen, D. B., Mayor, J., Tan, Q., Strickler, J. H. ELSEVIER. 2022: S502

  View details for DOI 10.1016/j.annonc.2022.05.183

  View details for Web of Science ID 000834940400283

• Effect of camidanlumab tesirine (Cami) as monotherapy and in combination with pembrolizumab ( PEM) on the immune cell profile in patients with selected advanced solid tumors Puzanov, I., Chen, C. T., LoRusso, P., Papadopoulos, K. P., Kummar, S., Hamilton, E., LeBruchec, Y., Havenith, K., Pantano, S., Toukam, M., Wuerthner, J., Boni, J. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509508531

• Chromatin modifier alterations confer resistance to endocrine deprivation and CDK4/6 inhibitors in ER plus breast cancer and drive convergent evolution in patient autopsy lesions Leshchiner, E., Leshchiner, I., Martin, E. E., Chen, C. T., Zhang, T., Pinto, C., Rhrissorrakrai, K., Utro, F., Levovitz, C., Jacobs, R. A., Danysh, B. P., Slowik, K., Broudo, M., Parida, L., Juric, D., Getz, G. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509505471

• A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2) Dumbrava, E., Hanna, G. J., Cote, G., Stinchcombe, T., Johnson, M., Chen, C., Devarakonda, S., Shah, N., Xu, F., Doebele, R., Gounder, M. M. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680304881

• Severe Lactic Acidosis Complicated by Insulin-Resistant Hyperosmolar Hyperglycemic Syndrome in a Patient With Metastatic Breast Cancer Undergoing AKT-Inhibitor Therapy. JCO precision oncology Stamou, M. I., Chen, C., Wander, S. A., Supko, J. G., Juric, D., Bardia, A., Wexler, D. J. 2022; 6: e2100428

  View details for DOI 10.1200/PO.21.00428

  View details for PubMedID 35700410

• A Novel Framework for the Next Generation of Precision Oncology Targets. JAMA oncology Chen, C. T., Ford, J. M. 2022

  View details for DOI 10.1001/jamaoncol.2022.0760

  View details for PubMedID 35587343

• Phase II trial of organ preservation program using short-course radiation and folfoxiri for rectal cancer (SHORT-FOX) Pollom, E. L., Shelton, A., Fisher, G. A., Bien, J., King, D., Johnson, T., Chen, C., Shaheen, S., Chong, C., Vitzthum, L., Kirilcuk, N., Morris, A. M., Kin, C., Dawes, A., Sheth, V., Sundaram, V., Brown, E., Chang, D. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1200/JCO.2022.40.4_suppl.TPS218

  View details for Web of Science ID 000770995900213

• Phase 1b/2, open-label, dose-escalation and expansion trial of tucatinib in combination with trastuzumab with and without oxaliplatin-based chemotherapy or pembrolizumab in patients with unresectable or metastatic HER2+gastrointestinal cancers (trial in progress) Park, H., Bekaii-Saab, T. S., Kim, S. S., Kamath, S., Pishvaian, M. J., Chen, C., Zhen, D., Mayor, J., Tan, Q., Strickler, J. H. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1200/JCO.2022.40.4_suppl.TPS376

  View details for Web of Science ID 000770995900364

• Proteogenomic characterization of CDK4/6 inhibitor-resistant ER plus breast cancer Chen, C. T., Leshchiner, I., Martin, L., Kane, H., Rhrissorrakrai, K., Utro, F., Levovitz, C., Gillette, M., Satpathy, S., Pinto, C., McLoughlin, D., Allen, R., Danysh, B. P., Slowik, K., Jacobs, R. A., Carr, S., Parida, L., Getz, G., Juric, D. AMER ASSOC CANCER RESEARCH. 2021

  View details for DOI 10.1158/1535-7163.TARG-21-P065

  View details for Web of Science ID 000776028100117

• Paving a pathway for drug development in HER2-positive biliary tract cancer. The Lancet. Oncology Chen, C. T., Goyal, L. 2021; 22 (9): 1204-1206

  View details for DOI 10.1016/S1470-2045(21)00465-4

  View details for PubMedID 34478661

• A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors. Puzanov, I., LoRusso, P., Papadopoulos, K. P., Chen, C. T., LeBruchec, Y., He, X., Cousin, T., Havenith, K., Boni, J., Bendell, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.2556

  View details for Web of Science ID 000708120601077

• Case 8-2021: A 34-Year-Old Woman with Cholangiocarcinoma. The New England journal of medicine Goyal, L. n., Chen, C. T., Pierce, T. T., Deshpande, V. n. 2021; 384 (11): 1054–64

  View details for DOI 10.1056/NEJMcpc2027092

  View details for PubMedID 33730458

• Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer. Nature communications Pereira, B., Chen, C. T., Goyal, L., Walmsley, C., Pinto, C. J., Baiev, I., Allen, R., Henderson, L., Saha, S., Reyes, S., Taylor, M. S., Fitzgerald, D. M., Broudo, M. W., Sahu, A., Gao, X., Winckler, W., Brannon, A. R., Engelman, J. A., Leary, R., Stone, J. R., Campbell, C. D., Juric, D. 2021; 12 (1): 3199

  Abstract

  In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

  View details for DOI 10.1038/s41467-021-23394-4

  View details for PubMedID 34045463

• Characterization of spatial and temporal heterogeneity of ER positive metastatic breast cancer using serial biopsies Allen, R. K., Pinto, C. J., Fitzgerald, D. M., Huynh, T. G., Chen, C. T., Juric, D. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.SABCS19-PD8-08

  View details for Web of Science ID 000527012503342

• Plasma sequencing demonstrates that breast cancer patients have a higher prevalence of clonal and multiple PIK3CA mutations than other solid tumor patients Chen, C., Sahu, A., Price, K., Pinto, C., Allen, R., Wang, X., Szabolcs, A., Goyal, L., Ting, D., Liu, S., Juric, D. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.SABCS19-P4-10-34

  View details for Web of Science ID 000527012502173

• Overcoming Resistance to Targeted Therapies in Gastrointestinal Cancers: Progress to Date and Progress to Come. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Chen, C. n., Di Bartolomeo, M. n., Corallo, S. n., Strickler, J. H., Goyal, L. n. 2020; 40: 161–73

  Abstract

  Targeted therapies have transformed the treatment paradigm in diseases such as non-small cell lung cancer and melanoma but have shown relatively modest clinical benefit in gastrointestinal malignancies. Anti-EGFR therapy in RAS wild-type colorectal cancer, anti-HER2 therapy in HER2- amplified esophagogastric cancer, and FGFR and isocitrate dehydrogenase 1 (IDH1) inhibitors in FGFR2 fusion-positive and IDH1-mutant biliary tract cancers offer antitumor efficacy, but the clinical benefit and durability of response in each case are typically limited. We review targeted therapies in each of these therapeutic areas and discuss their clinical efficacy, mechanisms of primary and acquired resistance, and strategies to overcome this resistance. We discuss lessons learned that we hope will lead to an expanded role for molecularly targeted therapy options for patients with gastrointestinal cancers.

  View details for DOI 10.1200/EDBK_280871

  View details for PubMedID 32421451

• Response rates and lesion-level progression patterns of solid tumor patients in an academic phase I program: implications for tumour heterogeneity Chen, C., Pinto, C., Walmsley, C., Allen, R., Muzikansky, A., Henderson, L., Broudo, M., Wolfgang, J., Fitzgerald, D. M., Hong, T., Juric, D. OXFORD UNIV PRESS. 2019

  View details for Web of Science ID 000491295501307

• Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating Treg cells. Science advances Feng, M., Jin, J. Q., Xia, L., Xiao, T., Mei, S., Wang, X., Huang, X., Chen, J., Liu, M., Chen, C., Rafi, S., Zhu, A. X., Feng, Y. X., Zhu, D. 2019; 5 (5): eaau5240

  Abstract

  The Wnt/β-catenin (β-cat) pathway plays a critical role in cancer. Using hydrocarbon-stapled peptide technologies, we aim to develop potent, selective inhibitors targeting this pathway by disrupting the interaction of β-cat with its coactivators B-cell lymphoma 9 (BCL9) and B-cell lymphoma 9-like (B9L). We identified a set of peptides, including hsBCL9CT-24, that robustly inhibits the activity of β-cat and suppresses cancer cell growth. In animal models, these peptides exhibit potent anti-tumor effects, favorable pharmacokinetic profiles, and minimal toxicities. Markedly, these peptides promote intratumoral infiltration of cytotoxic T cells by reducing regulatory T cells (Treg) and increasing dendritic cells (DCs), therefore sensitizing cancer cells to PD-1 inhibitors. Given the strong correlation between Treg infiltration and APC mutation in colorectal cancers, it indicates our peptides can reactivate anti-cancer immune response suppressed by the oncogenic Wnt pathway. In summary, we report a promising strategy for cancer therapy by pharmacological inhibition of the Wnt/β-cat signaling.

  View details for DOI 10.1126/sciadv.aau5240

  View details for PubMedID 31086813

  View details for PubMedCentralID PMC6506245

• Efficacy, Safety, and Regulatory Approval of Food and Drug Administration-Designated Breakthrough and Nonbreakthrough Cancer Medicines. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Hwang, T. J., Franklin, J. M., Chen, C. T., Lauffenburger, J. C., Gyawali, B., Kesselheim, A. S., Darrow, J. J. 2018; 36 (18): 1805-1812

  Abstract

  Purpose The breakthrough therapy program was established in 2012 to expedite the development and review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough-designated versus non-breakthrough-designated cancer drugs approved by the US Food and Drug Administration (FDA). Methods We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial efficacy end point, novelty of mechanism of action) were compared between breakthrough-designated and non-breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not attributed to disease progression. Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non-breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough-designated and non-breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy-designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non-breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non-breakthrough-designated drugs.

  View details for DOI 10.1200/JCO.2017.77.1592

  View details for PubMedID 29688832

• Medicare Spending for Breast, Prostate, Lung, and Colorectal Cancer Patients in the Year of Diagnosis and Year of Death. Health services research Chen, C. T., Li, L. n., Brooks, G. n., Hassett, M. n., Schrag, D. n. 2018; 53 (4): 2118–32

  Abstract

  To characterize spending patterns for Medicare patients with incident breast, prostate, lung, and colorectal cancer.2007-2012 data from the Surveillance, Epidemiology, and End Results Program linked with Medicare fee-for-service claims.We calculate per-patient monthly and yearly mean and median expenditures, by cancer type, stage at diagnosis, and spending category, over the years of diagnosis and death.Over the year of diagnosis, mean spending was $35,849, $26,295, $55,597, and $63,063 for breast, prostate, lung, and colorectal cancer, respectively. Over the year of death, spending was similar across different cancer types and stage at diagnosis.Characterization of Medicare spending according to clinically meaningful categories may assist development of oncology alternative payment models and cost-effectiveness models.

  View details for DOI 10.1111/1475-6773.12745

  View details for PubMedID 28748564

  View details for PubMedCentralID PMC6051983

• Walk-in clinics versus physician offices and emergency rooms for urgent care and chronic disease management. Cochrane database of systematic reviews Chen, C. E., Chen, C. T., Hu, J., Mehrotra, A. 2017; 2: CD011774-?

  Abstract

  Walk-in clinics are growing in popularity around the world as a substitute for traditional medical care delivered in physician offices and emergency rooms, but their clinical efficacy is unclear.To assess the quality of care and patient satisfaction of walk-in clinics compared to that of traditional physician offices and emergency rooms for people who present with basic medical complaints for either acute or chronic issues.We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers on 22 March 2016 together with reference checking, citation searching, and contact with study authors to identify additional studies. We applied no restrictions on language, publication type, or publication year.Study design: randomized trials, non-randomized trials, and controlled before-after studies.standalone physical clinics not requiring advance appointments or registration, that provided basic medical care without expectation of follow-up. Comparisons: traditional primary care practices or emergency rooms.We used standard methodological procedures expected by Cochrane and the Cochrane Effective Practice and Organisation of Care (EPOC) Group.The literature search identified 6587 citations, of which we considered 65 to be potentially relevant. We reviewed the abstracts of all 65 potentially relevant studies and retrieved the full texts of 12 articles thought to fit our study criteria. However, following independent author assessment of the full texts, we excluded all 12 articles.Controlled trial evidence about the mortality, morbidity, quality of care, and patient satisfaction of walk-in clinics is currently not available.

  View details for DOI 10.1002/14651858.CD011774.pub2

  View details for PubMedID 28211045

• Journey of Generic Imatinib: A Case Study in Oncology Drug Pricing. Journal of oncology practice Chen, C. T., Kesselheim, A. S. 2017; 13 (6): 352–55

  View details for DOI 10.1200/JOP.2016.019737

  View details for PubMedID 28445102

• Transforming healthcare delivery: Why and how accountable care organizations must evolve. Journal of hospital medicine Chen, C. T., Ackerly, D. C., Gottlieb, G. n. 2016; 11 (9): 658–61

  Abstract

  Accountable care organizations (ACOs) have shown promise in reducing healthcare spending growth, but have proven to be financially unsustainable for many healthcare organizations. Even ACOs with shared savings have experienced overall losses because the shared savings bonuses have not covered the costs of delivering population health. As physicians and former ACO leaders, we believe in the concept of accountable care, but ACOs need to evolve if they are to have a viable future. We propose the novel possibility of allowing ACOs to bill fee-for-service for their population health interventions, a concept we call population health billing. Journal of Hospital Medicine 2016;11:658-661. © 2016 Society of Hospital Medicine.

  View details for DOI 10.1002/jhm.2589

  View details for PubMedID 27596543

• Disruptive innovation in academic medical centers: balancing accountable and academic care. Academic medicine : journal of the Association of American Medical Colleges Stein, D. n., Chen, C. n., Ackerly, D. C. 2015; 90 (5): 594–98

  Abstract

  Numerous academic medicine leaders have argued that academic referral centers must prepare for the growing importance of accountability-driven payment models by adopting population health initiatives. Although this shift has merit, execution of this strategy will prove significantly more problematic than most observers have appreciated. The authors describe how successful implementation of an accountable care health strategy within a referral academic medical center (AMC) requires navigating a critical tension: The academic referral business model, driven by tertiary-level care, is fundamentally in conflict with population health. Referral AMCs that create successful value-driven population health systems within their organizations will in effect disrupt their own existing tertiary care businesses. The theory of disruptive innovation suggests that balancing the push and pull of academic and accountable care within a single organization is achievable. However, it will require significant shifts in resource allocation and changes in management structure to enable AMCs to make the inherent difficult choices and trade-offs that will ensue. On the basis of the theories of disruptive innovation, the authors present recommendations for how academic health systems can successfully navigate these issues as they transition toward accountability-driven care.

  View details for DOI 10.1097/ACM.0000000000000606

  View details for PubMedID 25517702

• Readmission penalties and health insurance expansions: a dispatch from Massachusetts. Journal of hospital medicine Chen, C., Scheffler, G., Chandra, A. 2014; 9 (11): 681-7

  Abstract

  Payers are penalizing hospitals for high readmission rates. It is unknown whether major changes in population insurance coverage can affect readmission rates, despite the Affordable Care Act's coverage expansions coming into effect this year.To evaluate the impact of a large-scale insurance expansion on hospital readmissions, using Massachusetts' 2006 health reform as a natural experiment.Difference-in-difference time-series design.All Massachusetts acute-care hospitals.Inpatient visits from 2004 to 2010.Primary outcome was the hospital 30-day readmission rate. Readmissions to any Massachusetts hospital were tracked.Decreases in uninsurance rates during and after reform were largely limited to the hospital quartile with the highest prereform uninsurance rates (from 14% uninsured at the start of the reform to 2.9% by the end of the study period). The other hospitals collectively experienced a smaller decline in their uninsured admissions (5.9% at the start of reform to 2.5% by the end of the study period). According to difference-in-difference regression analysis, the highest uninsured hospital quartile experienced a modest increase in their unadjusted readmission rate of 0.6 percentage points (95% confidence interval: 0.1%-1.1%) during the reform period as compared to the other hospital quartiles (P = 0.01). This represents a relative increase of 4.5% in the readmission rate. Risk-adjusted readmission rates showed no corresponding change.The Affordable Care Act's insurance expansion may be associated with an increase in unadjusted readmission rates among hospitals that cared for disproportionate numbers of uninsured patients. Risk-adjustment appears to take this effect into account.

  View details for DOI 10.1002/jhm.2213

  View details for PubMedID 24945696

• Beyond ACOs and bundled payments: Medicare's shift toward accountability in fee-for-service. JAMA Chen, C. n., Ackerly, D. C. 2014; 311 (7): 673–74

  View details for DOI 10.1001/jama.2014.11

  View details for PubMedID 24549543

• Massachusetts' health care reform and emergency department utilization. The New England journal of medicine Chen, C., Scheffler, G., Chandra, A. 2011; 365 (12): e25

  View details for DOI 10.1056/NEJMp1109273

  View details for PubMedID 21899444