Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall ...survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials.
Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m
once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated.
After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.
At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.
Objectives/Hypothesis
The effect of smoking and human papillomavirus (HPV) on overall survival (OS) of oropharyngeal squamous cell carcinoma (OPSCC) patients undergoing concurrent chemotherapy (CCRT) ...remains unclear.
Study Design
Retrospective review.
Methods
Clinical characteristics of OPSCC patients treated between 2008 and 2015 with CCRT were ed from medical records. OS curves and multivariate cox proportional hazard ratios (HRs) were examined.
Results
Of 120 evaluable patients, 71% had HPV+ tumors. Median follow‐up duration for the entire cohort was 41.5 months (range = 6–88 months). HPV+ current smokers experienced significantly worse 5‐year OS (73% alive vs. 36% alive, P = .01) and there was a similar trend in HPV− current smokers (66% alive vs. 31% alive, P = .28) compared to former/never smokers undergoing CCRT. In a multivariate cox proportional hazard model adjusted for age, gender, and overall tumor stage, HPV+ current smokers experienced nearly a fourfold increase in overall mortality in comparison to HPV+ never/former smokers (HR = 3.68, 95% CI = 1.35‐10.0). Similarly, current smokers with HPV− tumors (HR = 6.80, 95% CI = 1.11‐41.67) had increased mortality compared to never/former smokers.
Conclusions
Current smoking is associated with poor prognosis, independent of HPV status, in CCRT‐treated OPSCC patients. Current smoking produced an approximately four‐ to sevenfold increase in risk of mortality for HPV+ and HPV− patients, respectively. Regardless of pack years and HPV status, efforts should be made to achieve smoking cessation before CCRT.
Level of Evidence
4. Laryngoscope, 126:2733–2738, 2016
Although generic drugs constitute approximately 88% of drugs prescribed in the US, there are no reliable methods to identify generic drugs in the US FDA Adverse Event Reporting System (FAERS).
The ...aim of this study was to develop an algorithm for identifying generic drugs in the FAERS.
We used 1237 adverse event reports for tamsulosin, levothyroxine, and amphetamine/dextroamphetamine from the publicly available FAERS from 2011-2013, and 277 source case narratives obtained from the FDA.
Two reviewers independently and in duplicate used a three-item algorithm including the following criteria: manufacturer name, New Drug Application (NDA) number/abbreviated NDA (ANDA), and specific use of the term 'generic' or 'brand' to classify the focal drug of each case report as definitely generic (two of three criteria), probably generic (one of three criteria), brand, and cannot be assessed. Inter-rater reliability was estimated using kappa coefficients, and internal consistency was estimated using Cronbach's alpha. We compared the classification of the drugs as generic versus non-generic in publicly available FAERS compared with the original case reports (reference).
The focal drug was classified as generic (definite or probable) in 15.8% (39/234), 9% (67/742), and 16.7% (42/261) of tamsulosin, levothyroxine and amphetamine/dextroamphetamine cases, respectively (overall kappa 0.89, 95% confidence interval 0.85-0.93), while 37% of reports could not be classified due to incomplete information. Among the drugs classified as generics using the publicly available FAERS, we categorized 95.3% as generic drugs using the original case reports. Among those drugs that did not meet the algorithm-based definition of generic in the publicly available data, 20.9% were reclassified as generics using the original case reports.
The algorithm demonstrated high inter-rater reliability with moderate internal consistency for identifying generic drugs in the FAERS, in our sample. Future efforts should focus on improving the reliability and validity of identifying generics through improving the completeness of reporting in the FAERS.
Socioeconomic factors and the risk for sarcoma Hampras, Shalaka S.; Moysich, Kirsten B.; Marimuthu, Sathiya P. ...
European journal of cancer prevention,
11/2014, Letnik:
23, Številka:
6
Journal Article
Recenzirano
Sarcomas are a heterogeneous group of rare malignancies arising from mesenchymal tissue. Although several occupational exposures have been evaluated in association with sarcoma, little is known about ...the role of socioeconomic indicators such as education. Socioeconomic status has been found to be associated with risk of development of several types of cancers, primarily lung, gastric, and cervical cancers. We conducted a hospital-based case–control study to evaluate the association of socioeconomic level with the risk for sarcoma. A total of 371 incident cases of sarcoma were matched in terms of age, sex, and year of enrollment in the study with 742 cancer-free controls. Education and income levels were evaluated as the indicators of socioeconomic status. Higher education (college level) was associated with a significantly lower risk for sarcoma odds ratio (OR)=0.48, 95% confidence interval (CI)=0.29–0.80, even after adjusting for important confounders. After stratifying by sex, significantly lower risk for sarcoma was observed among men who had college level education compared with men with a level of education of eighth grade or lower (OR=0.38, 95% CI=0.19–0.74). A significant association between education and the risk for sarcoma remained after stratifying by income (OR=0.49, 95% CI=0.28–0.86, among the low income group). When analyzed as a composite exposure, individuals with high education and high income status had significantly lower risk for sarcoma compared with those with low income and low education status (OR=0.41, 95% CI=0.23–0.71). Thus, socioeconomic factors may play a significant role in determining the risk for sarcoma and should be explored further to elucidate the underlying factors that may explain these sociodemographic inequalities related to sarcoma.
Diabetes mellitus (DM) has been associated with the risk of several gastrointestinal cancers including liver, pancreas, colon and rectum. However, the evidence is inconclusive for gastric ...adenocarcinoma (GC). In the current review, we summarize 20 population-based cohort studies that compared GC incidence and mortality between diabetic and non-diabetic population. We discuss the shared risk factors and provide qualitative and quantitative (meta-analytic) summary of the current evidence evaluating the association by high-risk subgroups. The overall risk-estimate based on all studies did not show an increased risk of GC in diabetics. However, 2 cohort studies conducted in East Asian countries, where Helicobacter pylori infection and GC rates are higher, showed a higher risk of GC in diabetics. Additionally, high plasma glucose levels in the presence of Helicobacter pylori infection increased the risk of GC by over four times, suggesting a multiplicative effect. Results from the meta-analysis show that, the risk of GC was also higher in populations with greater prevalence of type 1 DM (relative risk = 1.60), suggesting an insulin-independent carcinogenic process in this subgroup. The risk of mortality due to GC was higher in diabetics compared to non-diabetics (relative risk = 1.62). Although the overall risk estimates do not show an association between DM and GC, complex interactions between infectious, molecular, demographic and host factors may convey a higher risk in certain subgroups. Future studies should be sufficiently powered for detailed subgroup analysis to elucidate the causative and mechanistic association between DM and GC.
TPS278
Background: The standard of care (SoC) for first-line management of non-microsatellite instability-high/deficient mismatch repair (non-MSI-H/dMMR; also referred to as ...microsatellite-stable/proficient MMR) mCRC includes systemic chemotherapy and targeted agents that improve overall survival (OS). However, in patients (pts) with later-line disease, current SoC treatments (including regorafenib and TAS-102) are associated with poor responses (objective response rates ORR < 2%) that are not durable, limited OS (6.4-7.1 months) and substantial toxicity. Immunotherapies targeting programmed death (PD)-1 show promising efficacy in pts with MSI-H mCRC; however, single-agent immunotherapy does not provide benefit for pts with non-MSI-H/dMMR mCRC. Therefore, additional treatment options with an improved benefit-risk profile in pts with later-line non-MSI-H/dMMR mCRC are needed. Emerging data suggest that dual inhibition of LAG-3 and PD-1 has the potential to boost immune surveillance and elicit durable responses in non-MSI-H/dMMR mCRC. RELA is a human immunoglobulin G4 lymphocyte-activation gene 3 (LAG-3)-blocking antibody that enhances the antitumor immune response. Here we describe the RELATIVITY-123 study investigating NIVO + RELA FDC in later-line mCRC. Methods: RELATIVITY-123 (NCT05328908) is a phase 3, randomized (1:1), open-label study to assess NIVO + RELA FDC versus regorafenib or TAS-102 in adult pts with later lines of non-MSI-H/dMMR mCRC. Inclusion criteria include metastatic or recurrent unresectable CRC, recent progression following 1–4 prior lines of treatment (or documented intolerance of prior systemic chemotherapy regimens), ECOG performance status ≤ 1, and measurable disease per RECIST version (v) 1.1. Exclusion criteria include confirmed MSI-H/deficient mismatch repair, prior treatment with an immunotherapy, regorafenib, or TAS-102 and history of significant cardiovascular disease, interstitial lung disease/pneumonitis, or autoimmune disease. Dual primary endpoints are OS in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. Secondary endpoints include ORR, progression-free survival, and duration of response by blinded independent central review and investigator per RECIST v1.1, safety, and time until definitive deterioration-physical function and -quality of life in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. The study initiated in April 2022 and is enrolling globally. Clinical trial information: NCT05328908 .
Abstract only
9000
Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), ...progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 95% CI, 0.61–0.86); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 95% CI, 0.56–0.79); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. Table: see text
Patient-reported outcomes associated with adverse events (AEs) reported with generics have not been evaluated. To map AEs associated with generics to the NIH Patient-reported Outcomes Measurement ...Information System.
We mapped 381 AEs from 148 case reports of generic tamsulosin, levothyroxine and amphetamine/dextroamphetamine to the physical, mental and social domain of the NIH Patient-Reported Outcomes Measurement Information System after reviewing 1237 case reports in the US FDA's Adverse Event Reporting System (FAERS; 2011-2013).
75%, 76% and 71% reports were classified under the physical domain for tamsulosin, levothyroxine and amphetamine/dextroamphetamine, while 9%, 9% and 18% reports were classified under the mental domain, respectively.
FAERS reveals several domains of patient-relevant concerns associated with generic drugs.
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