Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors.
To evaluate the antitumor activity of ...pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received.
This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively.
Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062.
Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing.
At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months 95% CI, 2.0-9.8 months for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy.
Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received.
ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.
Purpose: To evaluate serum 25-hydroxyvitamin D 25(OH)D concentrations and factors related to vitamin D inadequacy in postmenopausal North American women receiving therapy to treat or prevent ...osteoporosis.
Methods: Serum 25(OH)D and PTH were obtained in 1536 community-dwelling women between November 2003 and March 2004. Multivariate logistic regression was used to assess risk factors for suboptimal (<30 ng/ml) 25(OH)D.
Results: Ninety-two percent of study subjects were Caucasian, with a mean age of 71 yr. Thirty-five percent resided at or above latitude 42° north, and 24% resided less than 35° north. Mean (sd) serum 25(OH)D was 30.4 (13.2) ng/ml: serum 25(OH)D was less than 20 ng/ml in 18%; less than 25 ng/ml in 36%; and less than 30 ng/ml in 52%. Prevalence of suboptimal 25(OH)D was significantly higher in subjects who took less than 400 vs. 400 IU/d or more vitamin D. There was a significant negative correlation between serum PTH concentrations and 25(OH)D. Risk factors related to vitamin D inadequacy included age, race, body mass index, medications known to affect vitamin D metabolism, vitamin D supplementation, exercise, education, and physician counseling regarding vitamin D.
Conclusions: More than half of North American women receiving therapy to treat or prevent osteoporosis have vitamin D inadequacy, underscoring the need for improved physician and public education regarding optimization of vitamin D status in this population.
Introduction: KEYNOTE-240 investigated the efficacy and safety of pembrolizumab plus best supportive care (BSC) in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). Results for ...the subgroup of patients from Asia are described. Methods: Adults with advanced HCC previously treated with sorafenib were randomized 2:1 to pembrolizumab or placebo plus BSC. Here, the Asian subgroup comprised patients enrolled in Hong Kong, Japan, Korea, the Philippines, Taiwan, and Thailand. Primary endpoints were progression-free survival (PFS) per blinded central imaging review and overall survival (OS). Secondary endpoints included objective response rate (ORR) per blinded central imaging review, duration of response (DOR), and safety. Results: The Asian subgroup included 157 patients. As of January 2, 2019, the median follow-up in this subgroup was 13.8 months for pembrolizumab and 8.3 months for placebo. The median PFS was 2.8 months for pembrolizumab (95% confidence interval CI 2.6–4.1) versus 1.4 months (95% CI 1.4–2.4) for placebo (hazard ratio HR 0.48; 95% CI 0.32–0.70). The median OS was 13.8 months (95% CI 10.1–16.9) for pembrolizumab versus 8.3 months (95% CI 6.3–11.8) for placebo (HR 0.55; 95% CI 0.37–0.80). ORR was 20.6% (95% CI 13.4–29.5) for pembrolizumab versus 2.0% (95% CI 0.1–10.6) for placebo (difference: 18.5%; 95% CI 8.3–27.6). The median DOR was 8.6 and 2.8 months for pembrolizumab and placebo, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 63 patients (58.9%) receiving pembrolizumab and 24 patients (48.0%) receiving placebo; 14 (13.1%) and 2 (4.0%) patients experienced grade 3–5 TRAEs, respectively. No treatment-related deaths occurred. Conclusion: Pembrolizumab demonstrated antitumor activity and was well tolerated in the Asian subgroup of KEYNOTE-240. A trend toward greater benefit with pembrolizumab in the Asian subgroup was observed compared with the overall cohort, supporting further evaluation of pembrolizumab treatment in this population.
Abstract only
4004
Background: Pembro received accelerated approval based on results of KEYNOTE-224, a phase 2 trial in pts with advanced HCC in the second line setting. KEYNOTE-240 (NCT02702401) was ...a randomized, placebo (Pbo) controlled, phase 3 study of Pembro vs BSC in pts with previously treated advanced HCC. Methods: Eligible pts had a radiographic or pathologic diagnosis of HCC, radiographic progression on/intolerance to sorafenib, Child-Pugh A disease and ECOG PS 0-1. Pts were randomized 2:1 to receive Pembro 200 mg + BSC or Pbo + BSC IV every 3 wk, stratified by geographic region, macrovascular invasion and ɑ-fetoprotein levels for ≤35 cycles or until confirmed PD/unacceptable toxicity. Response was assessed every 6 wk per RECIST v1.1 by central imaging review. Co-primary endpoints were OS and PFS. Secondary endpoints included ORR, DOR and safety. Data cutoff was Jan 2 2019 for OS; Mar 26
2018 for PFS and ORR. Results: 413 patients were randomized; 278 to Pembro and 135 to Pbo. After a median follow up of 13.8 mo, 10.1% of pts remained on Pembro and 3.0% on Pbo. Pembro improved OS (HR: 0.78; one sided p = 0.0238) and PFS (HR: 0.78; one sided p = 0.0209) vs Pbo; these differences did not meet significance per the prespecified statistical plan. ORR was 16.9% (95% CI 12.7-21.8%) for Pembro vs 2.2% (95% CI 0.5-6.4%) for Pbo (nominal one sided p = 0.00001); responses on Pembro were durable (median DOR: 13.8 mo 1.5-23.6+). Off study, new therapy use was 42% for Pembro and 47% for Pbo. The safety profile including incidence of hepatitis and other immune mediated events was generally consistent with that previously reported in Pembro studies; no cases of HBV/HCV flare were identified. Conclusions: Pembro reduced the risk of death by 22% and improved PFS over Pbo in pts with advanced HCC, although significance was not reached per prespecified statistical criteria. ORR in the Pembro arm was consistent with that of KEYNOTE-224. Subsequent anticancer therapy in the Pbo arm likely impacted the OS results. The safety profile was comparable to that established for Pembro monotherapy. These results are overall consistent with those of KEYNOTE-224 further supporting second line therapy with Pembro in HCC pts. Clinical trial information: NCT02702401.
Abstract Background Extended-release niacin/laropiprant (ERN/LRPT) reduces flushing and preserves the lipid-modifying effects of ERN. This study compared the efficacy and safety of ERN/LRPT plus ...simvastatin (ERN/LRPT + SIMVA) with atorvastatin (ATORVA) in patients with mixed hyperlipidemia. Methods After a 4-week placebo run-in, 2340 patients (LDL-C ≥ 130 and ≤ 190 mg/dL, TG ≥ 150 and ≤ 500 mg/dL and above NCEP ATP III risk-based LDL-C goal) were randomized to 1 of 6 treatment arms: ERN/LRPT 1 g/20 mg + SIMVA (10 or 20 mg), or ATORVA (10, 20, 40, or 80 mg) once daily. Results At Week 12, ERN/LRPT + SIMVA was superior to ATORVA in decreasing LDL-C/HDL-C (primary endpoint) at each pre-specified dose comparison: ERN/LRPT + SIMVA 20 mg vs. ATORVA 10 mg (− 13.2%; p < 0.001); ERN/LRPT + SIMVA 40 mg vs. ATORVA 20 mg (− 10.8%; p < 0.001); ATORVA 40 mg (− 5.1%; p < 0.001); and ATORVA 80 mg (− 4.2%; p = 0.007). At Week 12, ERN/LRPT + SIMVA was superior to ATORVA in increasing HDL-C and reducing TG for all pre-specified treatment comparisons, and reducing non-HDL-C and LDL-C for the ERN/LRPT + SIMVA 20 mg versus ATORVA 10 mg and ERN/LRPT + SIMVA 40 mg versus ATORVA 20-mg dose comparisons, but not the ERN/LRPT + SIMVA 40 mg versus ATORVA 40- and 80-mg dose comparisons. Adverse experiences (AEs) typically associated with niacin (flushing, pruritus, increased glucose, increased uric acid) were more common with ERN/LRPT + SIMVA, and hepatic-related laboratory AEs were more common with ATORVA. Conclusion ERN/LRPT + SIMVA was generally superior to ATORVA in improving lipid parameters after 12 weeks and was generally well tolerated in patients with mixed hyperlipidemia.
Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the ...efficacy and safety of pembrolizumab in this population.
This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds,
= .0174 final analysis and
= .002 first interim analysis, respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug.
Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio HR, 0.781; 95% CI, 0.611 to 0.998;
= .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987;
= .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904;
= .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified.
In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.
The care of patients with trauma places a large burden on the health care system
1
,
2
. Trauma is the leading cause of death in people under the age of 40 years, and the care of patients with trauma ...accounts for more hospital days per year than the care of patients with heart disease or cancer
1
–
4
.
It is generally believed that deep-vein thrombosis and pulmonary embolism are common complications of major trauma
5
,
6
. However, there is a paucity of information on the epidemiology of venous thromboembolism in patients with trauma
5
,
6
. An autopsy study found deep-vein . . .
Background: In clinical practice, bone mineral density (BMD) determined by dual-energy x-ray absorptiometry is used to monitor response to osteoporosis therapy. However, 1 to 2 yr are usually ...required to assess patients’ BMD responses. The possibility of earlier indicators of a response or nonresponse to treatment, such as changes in bone turnover markers (BTMs), is of interest to physicians and patients.
Methods: In this post hoc analysis of women treated with once-weekly bisphosphonates, we examined the association of tertile percentage change from baseline in BTMs at 3 or 6 months and association of several baseline clinical characteristics with 24-month percentage change from baseline in BMD and with percentage of patients showing BMD nonresponse (defined as BMD loss at two or more of four sites) at 24 months. Multivariable analysis was performed to determine which factors were independently associated with BMD nonresponse.
Results: Patients in the tertile with the greatest decrease in each of the BTMs had the greatest mean increase in BMD and the lowest percentage of BMD nonresponders at 24 months. Several characteristics were independently associated with BMD nonresponse, including smaller 3-month reductions from baseline in serum C-terminal telopeptide of type 1 collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type 1 procollagen; younger age of menopause; a family history of osteoporosis; and higher baseline trochanteric BMD. Baseline BTMs were not predictive of 24-month BMD response to therapy. The strongest associations were for changes in BTMs with treatment.
Conclusion: In groups of patients, short-term changes in markers of bone turnover appear to be predictors of longer term BMD response and nonresponse to bisphosphonate therapy.
In groups of patients, short-term changes in bone turnover markers were predictive of longer term bone mineral density response and non-response to bisphosphonate therapy.
To compare clinicians' ratings of therapeutic effectiveness when different trial end points were presented as percent reductions in relative compared with absolute risk and as numbers of patients ...treated to avoid one adverse outcome.
Survey, with random allocation of two questionnaires.
Toronto teaching hospitals.
Convenience sample of 100 faculty and housestaff in internal medicine and family medicine.
One questionnaire presented results for three end points of the Helsinki Heart Study as separate drug trials using only absolute differences in events; the other showed the same end points as relative differences. Both questionnaires included a fourth "trial," showing person-years of treatment needed to prevent one myocardial infarction.
The "trials" were each rated on an 11-point scale, from treatment "harmful" to "very effective."
Respondents' ratings of effectiveness varied with the end point. Controlling for end point, ratings of effectiveness by the 50 participants receiving absolute event data were lower than those by 50 participants responding to relative risk reductions (P < 0.001); however, no end-point difference was more than 0.6 scale points. For a "trial" reporting that 77 persons were treated for 5 years to prevent one myocardial infarction, mean ratings were 2.3 or 1.8 scale points lower, respectively (both P < 0.001), than when the same data were shown as relative or absolute risk reductions.
Clinicians' views of drug therapies are affected by the common use of relative risk reductions in both trial reports and advertisements, by end-point emphasis, and, above all, by underuse of summary measures that relate treatment burden to therapeutic yields in a clinically relevant manner.
Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID).
To evaluate elbasvir-grazoprevir in treating HCV infection in PWID.
Randomized, placebo-controlled, double-blind trial. ...(ClinicalTrials.gov: NCT02105688).
Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States.
301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT).
The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks.
The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events.
The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event.
These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID.
Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT.
Merck & Co.
PDF
