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Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer

Long, G V; Tykodi, S S; Schneider, J G; Garbe, C; Gravis, G; Rashford, M; Agrawal, S; Grigoryeva, E; Bello, A; Roy, A; Rollin, L; Zhao, X
Background/UNASSIGNED:A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure-response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen. Patients and methods/UNASSIGNED:Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials. Results/UNASSIGNED:Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grades 3-4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified. Conclusions/UNASSIGNED:The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care. Clinical trial numbers/UNASSIGNED:NCT01721772, NCT01668784, NCT01673867, NCT01642004.
PMCID:6290887
PMID: 30215677
ISSN: 1569-8041
CID: 3646902

Painless Jaundice: A Rare Presentation of Uterine Leiomyosarcoma With Pancreatic Metastasis [Meeting Abstract]

Ali, Mohammad; Sticco, Kristen; Shah, Rakesh; Schneider, Jeffrey; Allendorf, John; Widmer, Jessica
ISI:000464611003104
ISSN: 0002-9270
CID: 3897702

A Retrospective Review of CyberKnife Stereotactic Body Radiotherapy for Adrenal Tumors (Primary and Metastatic): Winthrop University Hospital Experience

Desai, Amishi; Rai, Hema; Haas, Jonathan; Witten, Matthew; Blacksburg, Seth; Schneider, Jeffrey G
The adrenal gland is a common site of cancer metastasis. Surgery remains a mainstay of treatment for solitary adrenal metastasis. For patients who cannot undergo surgery, radiation is an alternative option. Stereotactic body radiotherapy (SBRT) is an ablative treatment option allowing larger doses to be delivered over a shorter period of time. In this study, we report on our experience with the use of SBRT to treat adrenal metastases using CyberKnife technology. We retrospectively reviewed the Winthrop University radiation oncology data base to identify 14 patients for whom SBRT was administered to treat malignant adrenal disease. Of the factors examined, the biological equivalent dose (BED) of radiation delivered was found to be the most important predictor of local adrenal tumor control. We conclude that CyberKnife-based SBRT is a safe, non-invasive modality that has broadened the therapeutic options for the treatment of isolated adrenal metastases.
PMID: 26347852
ISSN: 2234-943x
CID: 3498022

Commercial laboratory testing of excision repair cross-complementation group 1 expression in non-small cell lung cancer

Schneider, Jeffrey G; Farhadfar, Nosha; Sivapiragasam, Abirami; Geller, Matthew; Islam, Shahidul; Selbs, Elena
Excision repair cross-complementation group 1 (ERCC1) expression by non-small cell lung cancer (NSCLC) has been reported to predict resistance to platinum-based therapies. On this basis, several commercial laboratories have offered ERCC1 testing to facilitate clinical decision making, but the reliability of such assays has recently been called into question. Methods. First, three large commercial laboratories were queried for their cumulative ERCC1 test results in NSCLC patients to compare their independent rates of ERCC1 expression. Second, identical tumor blocks from individual NSCLC patients underwent round-robin analysis to evaluate interlaboratory concordance for ERCC1 expression. Third, a retrospective review of medical records from NSCLC patients identified those who were both highly responsive and resistant to platinum-based chemotherapies. Tumor blocks from these patients were then used in a gold standard analysis to determine individual laboratory sensitivity and specificity for ERCC1 results. Results. Significant differences were observed in independent laboratory ERRC1 expression rates (Clarient 70% vs. Genzyme 60% vs. Third Laboratory 44%, p < .0001 for all two-way comparisons). Only 4 of 18 tumors examined in round-robin analysis were fully concordant (κ ≤ 0.222 for all two-way comparisons). In preselected platinum responsive and resistant specimens, none of these three commercially marketed laboratory assays achieved a specificity of greater than 50%. Conclusion. The results of commercial laboratory testing for ERCC1 are inconsistent and unreliable. Better validation and postmarketing surveillance should be mandated before tumor biomarker assays are allowed to enter the clinical arena.
PMID: 24705979
ISSN: 1549-490x
CID: 3465672

Stereotactic body radiation therapy for stage I non-small cell lung cancer: a small academic hospital experience

Factor, Oren B; Vu, Charles C; Schneider, Jeffrey G; Witten, Matthew R; Schubach, Scott L; Gittleman, Alicia E; Catell, Donna T; Haas, Jonathan A
PURPOSE/OBJECTIVE(S)/OBJECTIVE:Stereotactic body radiation therapy (SBRT) has been shown to have increased local control and overall survival relative to conventional external beam radiation therapy in patients with medically inoperable stage I non-small cell lung cancer (NSCLC). Excellent rates of local control have been demonstrated both in clinical trials and in single-center studies at large academic institutions. However, there is limited data on the experiences of small academic hospitals with SBRT for stage I NSCLC. The purpose of this study is to report the local control and overall survival rates in patients treated with SBRT for stage I NSCLC at Winthrop-University Hospital (WUH), a small academic hospital. MATERIALS/METHODS/METHODS:This is a retrospective review of 78 stage I central and peripheral NSCLC tumors treated between December 2006 and July 2012 with SBRT at WUH. Treatment was given utilizing fiducials and a respiratory tracking system. If the fiducials were not trackable, a spine tracking system was used for tumor localization. CT-based planning was performed using the ray trace algorithm. Treatment was delivered over consecutive days to a median dose of 4800 cGy delivered in four fractions. The Kaplan-Meier method was used to calculate local control and overall survival. RESULTS:The median age was 78.5 years. Fifty-four percent of the patient population was female. Sixty seven percent of the tumors were stage IA, and 33% of the tumors were stage IB. Fifty-three percent of the tumors were adenocarcinomas and 29% were squamous cell carcinomas, with the remainder being of unknown histology or NSCLC, not otherwise specified The 2-year local control rate was 87%, and the 2-year overall survival was 68%. CONCLUSION/CONCLUSIONS:Our findings support that local control and overall survival at a small academic hospital are comparable to that of larger academic institutions' published experiences with SBRT for stage I NSCLC.
PMID: 25368843
ISSN: 2234-943x
CID: 3490162

Why does Oncotype DX recurrence score reduce adjuvant chemotherapy use?

Schneider, Jeffrey G; Khalil, Danny N
The Oncotype DX recurrence score (RS) reduces breast cancer adjuvant treatment utilization, but the reasons for this effect are not straightforward. We performed a retrospective chart review of 89 consecutive node-negative breast cancer patients for whom RS was ordered to facilitate adjuvant treatment decisions. By subtracting the relapse rate predicted by RS from that calculated using the Adjuvant! Online (AOL) web-based instrument, a "prognostic delta" (P∆) was determined, reflecting the difference between prognoses predicted by these two indices. Clinician interviews were conducted to evaluate the actual effect of RS on treatment decisions and its relation to P∆. Adjuvant chemotherapy use decreased from 61 to 26 % as a consequence of RS results (p < 0.0001). In multivariate analysis, RS was the only factor significantly associated with the final adjuvant treatment choice. Surprisingly, RS caused chemotherapy to be withheld even when P∆ was negative (i.e., cases in which RS predicted a less favorable outcome than AOL). The prognostic and chemotherapy predictive utilities of the RS do not fully account for its effect in reducing adjuvant chemotherapy use. Further studies are required to more fully elucidate other factors that may be responsible for this effect, including the possibility of unintended influence.
PMID: 22723033
ISSN: 1573-7217
CID: 3510112