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Phase II Trial of Response-Based Radiation Therapy for Patients With Localized CNS Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study

Fangusaro, Jason; Wu, Shengjie; MacDonald, Shannon; Murphy, Erin; Shaw, Dennis; Bartels, Ute; Khatua, Soumen; Souweidane, Mark; Lu, Hsiao-Ming; Morris, David; Panigrahy, Ashok; Onar-Thomas, Arzu; Fouladi, Maryam; Gajjar, Amar; Dhall, Girish
PURPOSE/OBJECTIVE:Stratum 1 of ACNS1123 (ClinicalTrials.gov identifier: NCT01602666), a Children's Oncology Group phase II trial, evaluated efficacy of reduced-dose and volume of radiotherapy (RT) in children and adolescents with localized nongerminomatous germ cell tumors (NGGCTs). The primary objective was to evaluate the impact of reduced RT on progression-free survival (PFS) with a goal of preserving neurocognitive function. PATIENTS AND METHODS/METHODS:Patients received six cycles of chemotherapy with carboplatin and etoposide alternating with ifosfamide and etoposide, as used in the Children's Oncology Group predecessor study (ACNS0122; ClinicalTrials.gov identifier: NCT00047320). Patients who achieved a complete response (CR) or partial response (PR) with or without second-look surgery were eligible for reduced RT, defined as 30.6 Gy whole ventricular field and 54 Gy tumor-bed boost, compared with 36 Gy craniospinal irradiation plus 54 Gy tumor-bed boost used in ACNS0122. RESULTS:A total of 107 eligible patients were enrolled. Median age was 10.98 years (range, 3.68 to 21.63) and 75% were male. Sixty-six of 107 (61.7%) achieved a CR or PR and proceeded to reduced RT. The 3-year PFS and overall survival and standard error values were 87.8% ± 4.04% and 92.4% ± 3.3% compared with 92% and 94.1%, respectively, in ACNS0122. There were 10 recurrences, prompting early study closure; however, after a retrospective central review, only disease in eight of 66 (12.1%) patients eligible for reduced RT subsequently progressed; six patients had distant spinal relapse alone and two had disease with combined local plus distant relapse. Serum and CSF α-fetoprotein and β-human chorionic gonadotropin levels were not associated with PFS. CONCLUSION/CONCLUSIONS:Patients with localized NGGCT who achieved a CR or PR to chemotherapy and received reduced RT had encouraging PFS similar to patients in ACNS0122 who received full-dose craniospinal irradiation. However, the patterns of failure were distinct, with all patients having treatment failure in the spine.
PMID: 31545689
ISSN: 1527-7755
CID: 4107402

Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy

Cristescu, Razvan; Mogg, Robin; Ayers, Mark; Albright, Andrew; Murphy, Erin; Yearley, Jennifer; Sher, Xinwei; Liu, Xiao Qiao; Lu, Hongchao; Nebozhyn, Michael; Zhang, Chunsheng; Lunceford, Jared K; Joe, Andrew; Cheng, Jonathan; Webber, Andrea L; Ibrahim, Nageatte; Plimack, Elizabeth R; Ott, Patrick A; Seiwert, Tanguy Y; Ribas, Antoni; McClanahan, Terrill K; Tomassini, Joanne E; Loboda, Andrey; Kaufman, David
Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
PMID: 30309915
ISSN: 1095-9203
CID: 4276732