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1.
Oncologist ; 27(3): 236-243, 2022 03 11.
Article in English | MEDLINE | ID: mdl-35274714

ABSTRACT

BACKGROUND: Amid continued uncertainty about the management of cancer patients during the pandemic, this study sought to obtain real-world data on the use of immune checkpoint inhibitors (ICIs) before COVID-19 diagnosis and its association with severity and survival outcomes in cancer patients who contracted COVID-19. METHODS: Cancer patients diagnosed with COVID-19 were identified from a large electronic health record database; those treated with ICIs before COVID-19+ diagnosis were matched in a 1:2 ratio to those not treated with ICIs, using a 2-step matching procedure. A descriptive analysis examined the difference in COVID-19 mortality (30-day and overall) and severity outcomes between the 2 cohorts, and overall survival was compared. RESULTS: Among 17 545 adults ≥18 years with cancer who tested positive for COVID-19 between February 20, 2020, and January 28, 2021, in the US, 228 ICI-treated patients were matched to 456 non-ICI-treated patients, comprising the 2 study cohorts. Clinical characteristics differed significantly between the 2 cohorts before matching, with metastatic disease, lung cancer, a history of smoking, and the presence of pulmonary comorbidities being more common in the ICI-treated cohort; after matching, the 2 cohorts were similar. There were no significant differences between the ICI-treated and non-ICI-treated cohorts for 30-day mortality (12.7% vs. 14.9%, P = .235), overall mortality (22.4% vs. 22.4%, P = 1.000), hospitalization (38.6% vs. 39.0%, P = .912), or emergency department visits (16.7% vs. 14.7%, P = .500). Overall survival was similar between the 2 cohorts. CONCLUSION: This analysis adds to the clinical evidence base that use of ICIs before SARS-CoV-2 infection does not affect COVID-19 severity or survival outcomes, supporting the continued use of ICIs in cancer patients during the pandemic.


Subject(s)
COVID-19 Drug Treatment , Lung Neoplasms , Adult , COVID-19 Testing , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , SARS-CoV-2
2.
Clin Cancer Res ; 18(23): 6509-18, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23032746

ABSTRACT

PURPOSE: Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor-stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR). EXPERIMENTAL DESIGN: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46-1.35]. The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues. CONCLUSIONS: In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected.


Subject(s)
Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Maintenance Chemotherapy , Ovarian Neoplasms/drug therapy , Pyridines/therapeutic use , Adult , Aged , Aged, 80 and over , Anilides/administration & dosage , Anilides/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Biomarkers/metabolism , Female , Humans , Middle Aged , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Pyridines/administration & dosage , Pyridines/adverse effects , Remission Induction , Treatment Outcome
3.
N Engl J Med ; 366(23): 2171-9, 2012 Jun 07.
Article in English | MEDLINE | ID: mdl-22670903

ABSTRACT

BACKGROUND: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. METHODS: In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma. RESULTS: In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted. CONCLUSIONS: Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).


Subject(s)
Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Basal Cell/drug therapy , Hedgehog Proteins/antagonists & inhibitors , Pyridines/therapeutic use , Skin Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Anilides/adverse effects , Antineoplastic Agents/adverse effects , Carcinoma, Basal Cell/pathology , Carcinoma, Basal Cell/secondary , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Pyridines/adverse effects , Signal Transduction/drug effects , Skin Neoplasms/pathology , Treatment Outcome
4.
Clin Cancer Res ; 17(8): 2512-20, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21300760

ABSTRACT

PURPOSE: In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics. EXPERIMENTAL DESIGN: Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance-based microsensor, and AAG levels by ELISA. RESULTS: A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R(2) = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (K(D) = 13 µmol/L) and human serum albumin less strongly (K(D) = 120 µmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination. CONCLUSIONS: GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.


Subject(s)
Anilides/pharmacokinetics , Hedgehog Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Pyridines/pharmacokinetics , Signal Transduction/drug effects , Adult , Aged , Aged, 80 and over , Anilides/metabolism , Anilides/therapeutic use , Binding, Competitive , Biological Availability , Chromatography, Liquid , Dose-Response Relationship, Drug , Female , Hedgehog Proteins/metabolism , Humans , Male , Metabolic Clearance Rate , Middle Aged , Neoplasm Metastasis , Neoplasms/metabolism , Neoplasms/pathology , Orosomucoid/metabolism , Protein Binding , Pyridines/metabolism , Pyridines/therapeutic use , Serum Albumin/metabolism , Tandem Mass Spectrometry , Time Factors , Treatment Outcome
5.
Clin Cancer Res ; 17(8): 2502-11, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21300762

ABSTRACT

PURPOSE: The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed. EXPERIMENTAL DESIGN: Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed. RESULTS: Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin. CONCLUSIONS: GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted.


Subject(s)
Anilides/therapeutic use , Hedgehog Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Pyridines/therapeutic use , Signal Transduction/drug effects , Abdominal Pain/chemically induced , Adult , Aged , Aged, 80 and over , Anilides/adverse effects , Anilides/pharmacokinetics , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Fatigue/chemically induced , Female , Gene Expression Regulation, Neoplastic/drug effects , Hedgehog Proteins/metabolism , Humans , Hyponatremia/chemically induced , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Neoplasms/genetics , Neoplasms/pathology , Pyridines/adverse effects , Pyridines/pharmacokinetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/genetics , Treatment Outcome , Zinc Finger Protein GLI1
6.
N Engl J Med ; 361(12): 1164-72, 2009 Sep 17.
Article in English | MEDLINE | ID: mdl-19726763

ABSTRACT

BACKGROUND: Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug. METHODS: We selected 33 patients with metastatic or locally advanced basal-cell carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day. We assessed tumor responses with the use of Response Evaluation Criteria in Solid Tumors (RECIST), physical examination, or both. Molecular aspects of the tumors were examined. RESULTS: The median duration of the study treatment was 9.8 months. Of the 33 patients, 18 had an objective response to GDC-0449, according to assessment on imaging (7 patients), physical examination (10 patients), or both (1 patient). Of the patients who had a response, 2 had a complete response and 16 had a partial response. The other 15 patients had either stable disease (11 patients) or progressive disease (4 patients). Eight grade 3 adverse events that were deemed to be possibly related to the study drug were reported in six patients, including four with fatigue, two with hyponatremia, one with muscle spasm, and one with atrial fibrillation. One grade 4 event, asymptomatic hyponatremia, was judged to be unrelated to GDC-0449. One patient withdrew from the study because of adverse events. We found evidence of hedgehog signaling in tumors that responded to the treatment. CONCLUSIONS: GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma. (ClinicalTrials.gov number, NCT00607724.)


Subject(s)
Antineoplastic Agents/administration & dosage , Benzimidazoles/administration & dosage , Carcinoma, Basal Cell/drug therapy , Hedgehog Proteins/antagonists & inhibitors , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Anilides , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/secondary , Dose-Response Relationship, Drug , Female , Gene Expression , Humans , Male , Middle Aged , Mutation , Patched Receptors , Patched-1 Receptor , Polymerase Chain Reaction , Pyridines , RNA, Messenger/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Sequence Analysis, DNA , Signal Transduction/drug effects , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Transcription Factors/genetics , Transcription Factors/metabolism , Zinc Finger Protein GLI1
7.
Clin Breast Cancer ; 7(2): 153-7, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16800975

ABSTRACT

BACKGROUND: Women with HER2-overexpressing breast cancer have an unfavorable prognosis. Trastuzumab improves survival when combined with chemotherapy in the first-line treatment of patients with HER2-overexpressing metastatic breast cancer and decreases the rate of disease relapse by 52% and the rate of death by 33% in women with HER2-overexpressing early-stage breast cancer. HER2 testing can be performed using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) and can be performed at local pathology laboratories or at central/reference laboratories. Because of the significant benefit seen with trastuzumab, it is critical to accurately identify women most likely to benefit. The method and the location of HER2 testing contribute to the accuracy of test results. PATIENTS AND METHODS: HER-First, a prospective, community-based, phase IV study of first-line trastuzumab/taxane therapy, enrolled patients with HER2-overexpressing metastatic breast cancer. Retesting of all tumor specimens by HER2 IHC and FISH at a high-volume, experienced laboratory was required. RESULTS: Concordance between local and central laboratory HER2 IHC testing was highest for local IHC 3+ samples (n = 377; 77%) and lowest for IHC 2+ samples (n = 184; 26%). Thirty-three percent of samples testing IHC 2+ at a local laboratory tested FISH-positive at the central laboratory. Concordance between HER2 IHC and FISH results was higher when both tests were performed at the central laboratory. CONCLUSION: Accurate HER2 test results are critical to identify patients who are appropriate candidates for trastuzumab, a therapy with significant clinical benefits in HER2-overexpressing breast cancer. These data show that HER2 testing is most accurate when performed at a high-volume reference laboratory.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , Community Health Services , Laboratories , Receptor, ErbB-2/metabolism , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Breast Neoplasms/pathology , Clinical Trials as Topic , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Neoplasm Metastasis , Patient Selection , Predictive Value of Tests , Reproducibility of Results , Trastuzumab
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