The addition of pembrolizumab, an anti–PD-1 antibody, to a platinum–taxane chemotherapy combination significantly prolonged progression-free and overall survival among patients with untreated ...squamous cell lung cancer, regardless of the level of tumor PD-L1 expression.
In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified ...exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data.
PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis.
At date cut-off of 24 March 2017, median follow-up was 31 months (range 23–41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 95% confidence interval (CI): 0.57, 0.77. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival 0.63 (95% CI: 0.45, 0.89) and newly collected samples 0.53 (95% CI: 0.38, 0.72). In patients with TPS ≥1%, PFS HRs were similar across archival 0.82 (95% CI: 0.66, 1.02) and newly collected samples 0.83 (95% CI: 0.68, 1.02).
Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.
ClinicalTrials.gov: NCT01905657.
Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer ...(NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy.
In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS).
Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%–49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18–37) and median overall survival was 22.1 months (95% CI 17.1–27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher 14/27 (51.9%; 95% CI 32%–71%), 54%, and 85%, respectively than the overall population 27/101 (26.7%; 95% CI 18.4%–36.5%), 35%, 71%. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths.
Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%.
KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).
In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship ...between pembrolizumab dose, exposure, and response to define an effective dose for these patients.
Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration–time curve at steady state over 6 weeks (AUCss–6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure–safety relationship was assessed by logistic regression of pembrolizumab AUCss–6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology.
Overall response rates were 15% 95% confidence interval (CI) 7%–28% at 2 mg/kg Q3W, 25% (18%–33%) at 10 mg/kg Q3W, and 21% (95% CI 14%–30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss–6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure–response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure–safety analysis showed the AE incidence to be similar among the clinically tested doses.
No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2–10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.
NCT01295827.
In a randomized trial involving patients with previously untreated advanced non–small-cell lung cancer, pembrolizumab was associated with a higher response rate, longer progression-free and overall ...survival, and fewer adverse events than was platinum-based chemotherapy.
Approximately 23 to 28% of patients with advanced non–small-cell lung cancer (NSCLC) have a high level of programmed death ligand 1 (PD-L1) expression, which is defined as membranous PD-L1 expression on at least 50% of tumor cells, regardless of the staining intensity (i.e., a PD-L1 tumor proportion score of 50% or greater).
1
,
2
Data from the phase 1 KEYNOTE-001 and phase 3 KEYNOTE-010 studies indicated that patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater were more likely than those with lower tumor proportion scores to have a response to pembrolizumab, a highly selective, humanized . . .
In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell ...lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs).
In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4–6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1–3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients.
Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and −0·9 (−4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 31% of 151 patients vs 58 39% of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached 95% CI 8·5 to not reached vs 5·0 months 3·6 to not reached; hazard ratio 0·66, 95% CI 0·44–0·97; two-sided nominal p=0·029).
Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC.
Merck & Co.
Combinations of cytotoxic chemotherapy with estramustine phosphate (EMP), a nornitrogen mustard-estrogen conjugate, are used to treat patients with hormone-refractory prostate carcinoma (HRPC). ...However, thromboembolic events (TE), including deep venous thrombosis (DVT), pulmonary embolism, stroke, myocardial infarction, and arterial thrombosis, are significant toxicities of these regimens. The current study sought to establish the rate of TE and to determine risk factors for TE.
A MEDLINE-based search identified EMP-based clinical trials published in the English-language peer-reviewed literature after 1990 in which > or = 20 patients with HRPC were enrolled and TE were clearly documented. Patient characteristics and the dose of EMP given were analyzed to determine their association with the rate of TE.
Twenty-three studies, enrolling a total of 896 patients, were included in the analysis. The overall risk of TE was 0.07 (95% confidence interval 95% CI, 0.05-0.11). The risk of DVT was 0.06 (95% CI, 0.04-0.09). The risks of all other types of TE were <0.01. Using univariate logistic regression analysis, the dose of EMP administered, baseline patient age, and baseline prostate-specific antigen level were not found to be associated with the total risk of TE. The rates of total TE and DVT may be inflated because one of the analyzed studies initially had a very high rate of DVT (25%) when compared with the others.
The rate of TE in men with HRPC who are treated with EMP-based regimens is significant, but it does not appear to be related to the dose of EMP. Whether TE can be prevented with anticoagulant prophylaxis remains to be determined.
PDF
