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1.
J Thorac Oncol ; 16(4): 665-676, 2021 04.
Article in English | MEDLINE | ID: mdl-33485960

ABSTRACT

INTRODUCTION: In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs). METHODS: Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted. RESULTS: PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy. CONCLUSIONS: Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression.


Subject(s)
Lung Neoplasms , Nivolumab , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/therapeutic use , Humans , Ipilimumab/therapeutic use , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Nivolumab/therapeutic use , Patient Reported Outcome Measures , Quality of Life
2.
N Engl J Med ; 381(21): 2020-2031, 2019 11 21.
Article in English | MEDLINE | ID: mdl-31562796

ABSTRACT

BACKGROUND: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more. RESULTS: Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy. CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).


Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Ipilimumab/administration & dosage , Lung Neoplasms/drug therapy , Nivolumab/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Female , Humans , Ipilimumab/adverse effects , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Male , Middle Aged , Nivolumab/adverse effects , Survival Analysis
3.
Eur J Cancer ; 116: 137-147, 2019 07.
Article in English | MEDLINE | ID: mdl-31195357

ABSTRACT

BACKGROUND: In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). AIM: To evaluate patient-reported outcomes (PROs) in this population. METHODS: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. RESULTS: In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. CONCLUSION: First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. CLINICAL TRIAL REGISTRATION: NCT02477826.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Patient Reported Outcome Measures , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Health Status , Humans , Ipilimumab/administration & dosage , Male , Middle Aged , Nivolumab/administration & dosage , Quality of Life
4.
J Clin Oncol ; 34(25): 2980-7, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27354485

ABSTRACT

PURPOSE: Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved survival over docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC). First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate 012 trial. METHODS: Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity; postprogression treatment was permitted per protocol. The primary objective was to assess safety; secondary objectives included objective response rate (ORR) and 24-week progression-free survival (PFS) rate; overall survival (OS) was an exploratory end point. RESULTS: Any-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. The confirmed ORR was 23% (12 of 52), including four ongoing complete responses. Nine of 12 responses (75%) occurred by first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+ months) at the time of data lock. ORR was 28% (nine of 32) in patients with any degree of tumor PD-ligand 1 expression and 14% (two of 14) in patients with no PD-ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was 41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively. CONCLUSION: First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Cohort Studies , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Nivolumab
5.
J Clin Oncol ; 34(25): 2969-79, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27354481

ABSTRACT

PURPOSE: Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC). PATIENTS AND METHODS: Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression. RESULTS: No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression. CONCLUSION: The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Aged , B7-H1 Antigen/biosynthesis , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cohort Studies , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Dose-Response Relationship, Drug , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Male , Middle Aged , Nivolumab , Pemetrexed/administration & dosage , Pemetrexed/adverse effects , Proto-Oncogene Proteins p21(ras)/genetics , Survival Rate , Gemcitabine
6.
J Clin Oncol ; 31(14): 1740-7, 2013 May 10.
Article in English | MEDLINE | ID: mdl-23569308

ABSTRACT

PURPOSE As part of the ENTHUSE (Endothelin A Use) program, the efficacy and safety of zibotentan (ZD4054), an oral specific endothelin A receptor antagonist, has been investigated in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS In this randomized, double-blind, placebo-controlled, phase III study, patients received intravenous docetaxel 75 mg/m(2) on day 1 of 21-day cycles plus oral zibotentan 10 mg or placebo once daily. The primary end point was overall survival (OS). Secondary end points included time to pain and prostate-specific antigen (PSA) progression, pain and PSA response, progression-free survival, health-related quality of life, and safety. Results A total of 1,052 patients received study treatment (docetaxel-zibotentan, n = 524; docetaxel-placebo, n = 528). At the time of data cutoff, there had been 277 and 280 deaths, respectively. There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P = .963). No significant differences were observed on secondary end points, including time to pain progression (median 9.3 v 10.0 months, respectively) or pain response (odds ratio, 0.84; 95% CI, 0.61 to 1.16; P = .283). The median time to death was 20.0 and 19.2 months for the zibotentan and placebo groups, respectively. The most commonly reported adverse events in zibotentan-treated patients were peripheral edema (52.7%), diarrhea (35.4%), alopecia (33.9%), and nausea (33.3%). CONCLUSION Docetaxel plus zibotentan 10 mg/d did not result in a significant improvement in OS compared with docetaxel plus placebo in patients with metastatic CRPC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms/drug therapy , Aged , Aged, 80 and over , Disease Progression , Disease-Free Survival , Docetaxel , Double-Blind Method , Drug Administration Schedule , Humans , Kaplan-Meier Estimate , Male , Orchiectomy , Prostate-Specific Antigen/blood , Prostatic Neoplasms/immunology , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Pyrrolidines/administration & dosage , Taxoids/administration & dosage , Treatment Failure
7.
J Urol ; 188(1): 103-9, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22583636

ABSTRACT

PURPOSE: Understanding the extent of disease in asymptomatic patients with castration resistant prostate cancer is important when making treatment decisions and designing clinical trials. The ENTHUSE M0 (ENdoTHelin A USE) trial (NCT00626548) was a large phase III study comparing the endothelin A receptor antagonist zibotentan with placebo in patients with nonmetastatic, castration resistant prostate cancer. The study was stopped prematurely after early efficacy review indicated that it was unlikely to meet its co-primary objectives of improved overall and progression-free survival vs placebo. Screening failed in an unexpectedly high number of patients. We investigated this screening failure rate to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials in this setting. MATERIALS AND METHODS: The number of patients enrolled in and subsequently excluded from study was analyzed by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients. RESULTS: Of 2,577 patients enrolled in a total of 350 hospital based centers in 39 countries screening failed in 1,155 (45%). The most common reason for screening failure was the detection of metastatic disease in 32% of all screened patients and in 71% of those in whom screening failed. The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region. CONCLUSIONS: The high frequency of asymptomatic metastasis in men thought to have nonmetastatic, castration resistant prostate cancer highlights the importance of periodic staging assessments for the condition. Optimal treatment modalities may differ for metastatic and nonmetastatic disease.


Subject(s)
Mass Screening , Orchiectomy , Prostatic Neoplasms/secondary , Pyrrolidines/administration & dosage , Adult , Aged , Aged, 80 and over , Disease Progression , Disease-Free Survival , Dose-Response Relationship, Drug , Double-Blind Method , Endothelin A Receptor Antagonists , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Metastasis , Prostate/pathology , Prostate-Specific Antigen/blood , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/therapy , Survival Rate/trends
8.
Clin Cancer Res ; 15(11): 3866-71, 2009 Jun 01.
Article in English | MEDLINE | ID: mdl-19458055

ABSTRACT

PURPOSE: The study aimed to assess the pharmacokinetic behavior of satraplatin under fasted and fed conditions, and its safety and preliminary antitumor activity in adults with advanced solid tumors. EXPERIMENTAL DESIGN: Satraplatin was administered orally at 80 mg/m(2) once daily with prophylactic antiemetics for 5 consecutive days every 5 weeks. Patients were randomized to receive day 1 and day 5 doses of satraplatin in either the fed or fasted state, the order being reversed for cycle 2. Pharmacokinetic sampling was done during the first two cycles. For all subsequent cycles, patients received satraplatin in the fasted state. RESULTS: Seventeen patients were treated with 60 total cycles of satraplatin. There was no dose-limiting toxicity during cycle 1. Severe hematologic toxicity was rare and the hematologic nadir occurred during week 4. Nausea, vomiting, and diarrhea were grade 1/2. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The hypothesis that food decreased ultrafiltrate platinum bioavailability could not be rejected, as the lower limit of the 90% confidence intervals for peak plasma concentration and area under the concentration-time curve from time 0 to 24 hours were 56.14% and 73.53%, respectively, both below the 80% bioequivalence acceptance criterion. One partial response (hormone refractory prostate cancer) and four durable stable diseases (breast, ovarian, parotid, and hormone refractory prostate cancer) were confirmed. CONCLUSIONS: There is an effect of food on the pharmacokinetics of satraplatin, the clinical significance of which is unclear. It is recommended that satraplatin be administered in the fasting state. This 5-week interval schedule of satraplatin was well tolerated in heavily pretreated patients.


Subject(s)
Food-Drug Interactions , Neoplasms/metabolism , Organoplatinum Compounds/pharmacokinetics , Abdominal Pain/chemically induced , Administration, Oral , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Biological Availability , Diarrhea/chemically induced , Drug Administration Schedule , Eating , Fasting , Female , Humans , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Neoplasms/drug therapy , Neoplasms/pathology , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Vomiting/chemically induced
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