tbuckley/cabot-search huggingface dataset:
Why do industry and payers disagree on the value of novel pharmaceuticals?
Authors: Henry Jacob Conter
Journal: Journal of Clinical Oncology (2018)

e18886 Background: Industry-related bias may exist in economic analyses of new drugs. We sought to characterize and quantify discrepancies in cost-effectiveness (CE) analyses between sponsors and a payer and determine the relationship between drug price, incremental cost (IC), and CE. Methods: The pan-Canadian Oncology Drug Review (pCODR) is systematic cancer drug review process that guides formulary decision-making. All submissions include a CE analysis submitted by the sponsor that is reviewed by the Economic Guidance Panel and modified, where appropriate. Final economic guidance reports from 1/1/2016 to 1/28/2018 were reviewed. Data on cost per quality adjusted life year gained (QALY), life-year gained (LYG), IC, and drug price were abstracted. Coefficients of determination (CD) were calculated. Results: 40 of 42 reviews were incorporated into the final analysis, encompassing 26 distinct drugs across 18 disease sites, submitted by 13 sponsors. pCODR recommended 1 for funding, 30 for funding conditional on CE being improved, and 9 for rejection. Of those rejected, 8 submitted single-arm phase 2 data as their primary source and 1 used a non-validated surrogate endpoint. Excluding 2 outliers, pCODR revised the sponsor’s estimate by a median of $66,326/QALY (range -$7,755-$385,140) or 51% (IQR 74%). pCODR revised the gains in QALY and LYG by a median of -24% (IQR 24%) and -28% (IQR 20%). Total costs were adjusted by a median of 1% (IQR 22%) and total dollar value of $1,514 (IQR $15,793). The sponsors’ estimate of CE was weakly correlated with pCODR’s, R² = 0.55. Estimates for QALY gains, life-year gains, and cost were more closely correlated R² = 0.78, 0.67, 0.94, respectively. No sponsor demonstrated superior CE accuracy (one-way ANOVA, p = 0.76). The price per 28-day cycle for continuous agents was $8,213 (IQR $1,426). The correlation of price to CE was R² < 0.01 for both pCODR and the sponsor. The CD of price to IC was R² = 0.01. Conclusions: Price is uncorrelated with IC or value for new pharmaceuticals. Industry and payers generally agree on the cost, but less on effectiveness. These disagreements exacerbate the difference in calculated value. Registry clinical trials should be refined to reduce uncertainty in the estimates for effectiveness of new agents.
Bringing Pancreas Cancer into the Lab
Authors: Eric A. Collisson
Journal: Cancer Discovery (2018)

Abstract Summary: Two articles in this issue of Cancer Discovery show that deep profiling of advanced pancreatic cancer is feasible and identify many clinically actionable features with surprising frequency. Cancer Discov; 8(9); 1062–3. ©2018 AACR. See related article by Aguirre et al., p. 1096. See related article by Tiriac et al., p. 1112.
Treatable traits in bronchiectasis
Authors: Rita Boaventura, Oriol Sibila, Alvar Agusti, James D. Chalmers
Journal: European Respiratory Journal (2018)

The diagnostic label "bronchiectasis" describes the existence of localised and permanent airway dilation, but when used to describe a disease it includes a heterogeneous group of disorders that differ significantly in terms of aetiological, clinical, radiological, functional and microbial features \[1]. Using cluster analysis, some previous studies have attempted to identify distinct "clinical phenotypes" in patients with bronchiectasis [2–4\] (defined as "a single or combination of disease attributes that describe differences between patients that are related to clinically meaningful outcomes" [5]). By and large, however, these studies did not consider the underlying biology or response to therapy ( i.e. the underlying endotype(s) [6]). Potential endotypes in bronchiectasis include immunodeficiency, ciliary dyskinesia, infection (with typical bacteria and non-tuberculous mycobacteria (NTM)), hypersensitivity to fungi and autoimmunity. Importantly, all of them can potentially become therapeutic targets [7]. A treatment approach based on "treatable traits" may provide better outcomes in the treatment of bronchiectasis <http://ow.ly/ywaF30l71OG>
Microarray analysis of cytokine expression in the gastrointestinal stromal tumors with different malignant potential.
Authors: Bo Zhang
Journal: Journal of Clinical Oncology (2017)

e15701 Background: Nowadays, a variety of prognostic criteria, which established merely based on clinicopathologic features, have been proposed, validated and widely used in practice. Numerous studies have confirmed tumor location, size and mitotic index were closely associated with the prognoses of GISTs. However, no method has yet been proven sufficient power to discriminate malignant potential and to predict biological behavior in all cases. In fact, the changes in cytokine level may result in alteration of tumor's microenvironment, which is considered to be related in the course of malignization for many tumors. Methods: The expression profile of cytokine in 4 patients with gastric GISTs (low malignant potential in 2 cases: 2x2cm, 3/50HPF; 2x1.8cm, 2/50HPF. high malignant potential in 2 cases: 12x10cm, 14/50HPF; 15x12cm, 16/50HPF), along with matched normal gastric tissue was evaluated by microarray. Results: The majority of cytokines expression between adjacent tissue of low and high malignant potential GISTs was similar. The high malignant potential GISTs exhibiting a notable upregulation of 41 cytokines, whereas a total of 23 cytokines with decreased expression in comparison to those with low malignant potential, after considering the expression level of cytokines among matched normal tissue. The cytokines expressed differentially including SPARCL1, MMP13 and FAP have been proven enormously valuable for assessing the prognoses of many tumors. Conclusions: Abnormally expressed cytokines in GISTs may play a vital role in promoting tumor progression, and detection of these cytokines proteins is useful to understand GISTs- malignization mechanisms and is also helpful to evaluate risk of recurrence in the treatment of GISTs patients.
Topical immunotherapy with diphencyprone (DPCP) for in-transit and other melanoma cutaneous lesions: Canadian single-institution case series.
Authors: Carrie Yeung, Teresa M. Petrella, Wadid Abadir, Frances Catriona Wright, Nicole Jannelle Look Hong
Journal: Journal of Clinical Oncology (2016)

e21071 Background: In-transit melanoma metastases can have severe morbidity and poor survival. Preferred treatment is surgical resection but is limited by site and extent of disease. Diphencycprone (DPCP) cream is a cost effective and accessible immune contact sensitizer that can be directly applied to in-transit lesions. Studies show favorable, and durable, clinical efficacy and toxicity. Mean time to complete response is 8 months. We present the first North American series of patients with in-transit and other melanoma cutaneous lesions treated with DPCP. Methods: From a prospective database with demographic and clinical data at a tertiary care cancer center, a single center retrospective study of 15 consecutive patients with in-transit, unresectable, or other cutaneous melanoma lesions treated with DPCP for ≥ 1 month from December 1, 2014 to December 31, 2015 was done. Primary objectives were response rate and toxicity. Patients were sensitized with 2% DPCP followed by initial applications of 0.1% - 0.01% DPCP to the lesions. Concentration and duration were titrated weekly for optimal contact hypersensitivity response. Toxicity was graded with CTCAE v.4.03. Descriptive statistics were performed. Results: Mean patient age was 75 (range 43-92). 73% of patients had prior treatment, mainly surgery and intralesional Interleukin-2. 67% of treated lesions were on the lower limb. 2 patients (13%) had a complete response after 25 and 27 weeks on 0.05% and 0.01% DPCP. 4 patients (27%) had a partial response with a mean treatment time of 30 weeks (6-51 weeks). 6 (40%) had stable disease. 6 patients stopped DPCP: 3 from systemic progression and 3 from toxicity. 1 had CTACE 3/4 skin ulceration but resolved on stopping DPCP. The most common toxicity was blisters. Most blisters resolved with dose reduction and topical steroid. Conclusions: 80% of patients had either complete, partial response or stable disease and tolerable toxicity. DPCP is a simple, feasible, and low-cost option for in-transit and other melanoma cutaneous lesions ineligible/refractory to surgery. Future study should refine response rates, limit toxicity and create a sequential treatment map for locoregional disease.
Clinical outcomes according to ethnicity in patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeted therapy (TT).
Authors: Dominick Bosse, Wanling Xie, Connor Wells, Aly-Khan A. Lalani, Frede Donskov, Alisha Bent, Hao-Wen Sim, Benoit Beuselinck, Aristotelis Bamias, Camillo Porta, Ulka N. Vaishampayan, Sumanta K. Pal, Neeraj Agarwal, Sandy Srinivas, Brian I. Rini, Ajjai Shivaram Alva, Lori Wood, Anil Kapoor, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2017)

e16065 Background: Discrepancies in clinical outcomes between different ethnic groups are well known in cancer patients. Differences in mRCC patients receiving VEGF-TT are less well characterized. We thought to report on baseline characteristics and treatment outcomes in African-Americans (AA) and Hispanic patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Methods: Caucasians, AA and Hispanics with mRCC treated with 1 st line VEGF-TT were identified from the IMDC. We created 2 matched cohorts: 1) AA vs. Caucasians and 2) Hispanics vs. Caucasians, both matched for age (&lt;50; 50-59; 60-69; &lt;70-year-old), gender, years of treatment (2003-07; 2008-12; 2013-16) and geography (Canada, USA, Europe). Weighted Cox and logistic regressions were used to compare OS, time-to-treatment failure (TTF) and best response, adjusted for nephrectomy status, IMDC risk groups, number of metastatic sites (1 v. &gt;1) and histology (clear-cell vs. else). Results: 73 AA and 71 Hispanics met eligibility criteria and were matched with 1236 and 901 eligible Caucasians, respectively. AA had more non-clear cell histology (26% v. 11%), time from diagnosis to therapy&lt;1 year (67% v. 55%) and anemia (75% v. 54%) vs. Caucasians. Differences were not significant for Hispanics. Clinical outcomes are presented in Table. Conclusions: Adjusted for clinical prognostic factors, Hispanics with mRCC have statistically shorter TTF and survival than Caucasians. AA had a trend toward shorter TTF (not significant) but similar survival than Caucasians. Underlying genetic/biological differences, along with potential cultural variations, may impact survival in Hispanic mRCC patients. [Table: see text]
Immune checkpoint inhibitor efficacy and safety in elderly non-small cell lung cancer patients.
Authors: Hiromi Watanabe, Toshio Kubo, Kiichiro Ninomiya, Daisuke Minami, Kenichiro Kudo, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2018)

e21034 Background: Immune checkpoint inhibitors (ICIs) offer longer survival than chemotherapy in advanced non-small cell lung cancer (NSCLC). In subset analyses, ICIs extended survival compared to chemotherapy in patients aged ≥65 years, but the effects in patients aged ≥75 years are controversial. We performed multicenter, collaborative, and retrospective analyses of ICI efficacy and safety in NSCLC patients aged ≥75 years. Methods: We retrospectively studied 434 advanced NSCLC patients who received ICIs from December 2015 to December 2017 at seven centers, and retrospectively applied the G8 screening tool from medical records. Results: Of 434 patients who received ICIs, 89 were aged ≥75 years (median: 79 years; range: 75–90 years). Five patients with PS 3 were omitted. The histological diagnoses were non-squamous cell carcinoma in 49 (58.3%), squamous cell carcinoma in 35 (41.7%). ICIs were given as a first-line treatment to 19 patients, and as a second- or later-line treatment to 65; 58 (69.0%) patients received nivolumab, and 26 (31.0%) pembrolizumab. The PD-L1 tumor proportion scores (TPS) were < 1% in 5 (6.0%), 1-49% in 8 (9.5%), and ≥50% in 25 (29.8%) and unknown in 45 (53.6%). The objective response rate (ORR) was 36.8% (CR: 0, PR: 7, SD: 6, PD: 4, NE: 2), the median progression-free survival (PFS) was 6.1 months [95% confidence interval (CI): 1.9–7.7], and the median survival time (MST) was 8.6 months [95% CI: 7.9–not reached (NR)] for first-line treatment in patients with TPS ≥50%. The ORR was 21.5% (CR: 0, PR: 14, SD: 13, PD: 28, and NE: 10), the PFS was 2.9 months [95% CI: 1.6–4.6], and the MST was 17.8 months [95% CI: 5–NR] for second- or later-line treatment. The median G8 score was 11.5 (range: 5.5–15.5). The MST was longer in the G8 high ( > 11.5) group than the low (≤11.5) group (NR vs. 7.9 months) (p = 0.01). Likewise, the MST was NR (PS 0–1) vs. 3.1 months (PS 2) (p < 0.01). The grade ≥2 immune-related adverse events incidence was 15.5% (thyroid disease: 2.4%; interstitial lung disease: 6.0%). Conclusions: Although the observation period is short and the data is immature, ICIs were effective and tolerable for patients aged ≥75 years. PS is a simple and exact parameter, but G8 screening is also useful in judging ICI adequacy for the elderly.
Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial.
Authors: Ming-Yuan Chen, Su-Mei Cao, Qi Yang, Ling Guo, Hai-Qiang Mai, Hao-Yuan Mo, Ka-Jia Cao, Chao-Nan Qian, Chong Zhao, Xiang Yanqun, Xiu-Ping Zhang, Zhi-Xiong Lin, Wei-Xiong Li, Xiang Guo, Ming-Huang Hong
Journal: Journal of Clinical Oncology (2017)

6005 Background: The role of neoadjuvant chemotherapy (NACT) for locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. We aimed to evaluate the feasibility and efficacy of NACT followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced NPC. Methods: Patients with stage III-IVB (excluding T3N0-1) NPC were randomly assigned to receive NACT followed by CCRT (investigational arm) or CCRT alone (control arm). Both arms were treated with 80 mg/m² cisplatin every three weeks concurrently with radiotherapy. The investigational arm received cisplatin (80 mg/m² d1) and fluorouracil (800 mg/m² civ d1-5) every three weeks for two cycles before CCRT. The primary endpoint was disease-free survival (DFS) and distant metastasis-free survival (DMFS). Secondary endpoint was overall survival (OS). Results: 476 patients were randomly assigned to the investigational (n = 238) and control arms (n = 238). The investigational arm achieved higher 3-year DFS rate (82.0%, 95% CI = 0.77-0.87) than the control arm (74.1%, 95% CI = 0.68-0.80, P = 0.028). The 3-year DMFS rate was 86.0% for the investigational arm versus 82.0% for the control arm, with marginal statistical significance (P = 0.056). However, there were no statistically significant differences in OS or locoregional relapse-free survival (LRRFS) rates between two arms (OS: 88.2% vs 88.5%, P = 0.815; LRRFS: 94.3% vs 90.8%, P = 0.430). The most common grade 3–4 toxicity during NACT was neutropenia (16.0%). During CCRT, the investigational arm experienced statistically significantly more grade 3–4 toxicities (P &lt; 0.001). Conclusions: NACT improved tumor control compared with CCRT alone in locoregionally advanced NPC, particularly at distant sites. However, there was no early gain in overall survival. Longer follow-up is needed to determine the eventual therapeutic efficacy. Clinical trial information: NCT00705627.
The association of polymorphism in gonadotropin releasing hormone with serum testosterone level during androgen-deprivation therapy and prognosis in metastatic prostate cancer.
Authors: Masaki Shiota, Naohiro Fujimoto, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Takeshi Uchiumi, Masatoshi Eto
Journal: Journal of Clinical Oncology (2017)

e16570 Background: Serum testosterone suppression during androgen-deprivation therapy (ADT) have been reported to affect ADT efficacy. However, the factor affecting hormonal variations during ADT was less explored. Therefore, in this study, we investigated the missense polymorphisms in gonadotropin releasing hormone (GNRH) and hormonal variations during ADT as well as the prognosis among men treated with primary ADT for metastatic prostate cancer. Methods: This study included 80 Japanese patients with metastatic prostate cancer, whose serum testosterone levels during ADT were available. The association of the GNRH1 gene polymorphism (rs6185, S20W) and the GNRH2 gene polymorphism (rs6051545, A16V) with clinicopathological parameters including serum testosterone levels during ADT as well as the prognosis including progression-free survival and overall survival was examined. Results: The CT allele and the CT/TT alleles in the GNRH2 gene (rs6051545) were associated with higher serum testosterone levels during ADT compared with the CC allele. Consequently, the CT alleles was associated with higher progression risk after adjustment with age and serum testosterone levels during ADT [hazard ratio (95% confidence interval), 1.73 (1.00-3.00), P = 0.049]. Conclusions: Taken together, these findings suggested that genetic variation in rs6051545 ( GNRH2) may result in the inadequate suppression of on serum testosterone during ADT, which may lead to detrimental effect of ADT on prognosis among men with metastatic prostate cancer.
Novel formulation of abiraterone acetate with significantly higher bioavailability and eliminated food effect might allow higher abiraterone exposure and better patient outcome.
Authors: Hristos Glavinas, Tamás Solymosi, Zsolt Otvos, Réka Angi, Betti Ordasi, Tamás Jordán, László Molnár, John McDermott, Vanessa Zann, Ann Church, Stuart Mair, Genoveva Filipcsei, Gabor Heltovics
Journal: Journal of Clinical Oncology (2018)

e17036 Background: Zytiga (Abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect. This is attributed to the inadequate and variable dissolution of the compound in the gastrointestinal tract in the fasted state (Geboers, 2016). Recent clinical studies show that abiraterone trough concentration correlates with PSA response and PFS (Carton, 2015), while administration of Zytiga with food resulted in the reversal of PSA progression (Stover, 2015). Doubling the dose of Zytiga at the time of acquired resistance was not effective (Friedlander, 2017) most likely because Zytiga exposure is not linear above 1,000 mg resulting in only a little improvement in drug exposure. To resolve the low bioavailability and food effect we developed a novel AA formulation with improved solubility and dissolution characteristics (Solymosi, 2017) and evaluated its clinical pharmacokinetics and safety in healthy volunteers. Methods: The study was conducted in 11 healthy men aged 47–57 years. All subjects received 3 consecutive single doses of the novel formulation of AA (100 and 200 mg in the fasted state and 200 mg in the fed state). Data was compared with pharmacokinetic and safety data reported for 1,000 mg Zytiga, the marketed drug. Results: The novel formulation of AA allows rapid absorption of the compound with tmax values within one hour. Based on AUC values, a ~250 mg dose of the novel formulation is predicted to give the same exposure as 1,000 mg Zytiga in the fasted state. The significant positive food effect was also eliminated and the variability of exposure was significantly reduced when compared to published Zytiga data. AA administered in the novel formulation was well tolerated with no IMP related safety AEs reported. Conclusions: The novel formulation has two potentially advantageous properties: (1) allows 75% dose reduction with significant reduction of inter-individual variability and no significant positive food effect, and (2) the improved bioavailability could allow increased doses and drug exposures for patients and thereby improve the outcome of abiraterone acetate therapy. Clinical trial information: 2015-002759-83.
Preoperative prealbumin level as an independent predictor of long-term outcomes after hepatectomy of hepatocellular carcinoma: A multi-institution study of 1,483 patients.
Authors: Ju-Dong Li, Jiong-Jie Yu, Xin-Fei Xu, Li-Yang Sun, Wen-Tao Yan, Jia-He Wang, Bing Quan, Zheng Wang, Jun Han, Han Wu, Hao Xing, Chao Li, Ya-Hao Zhou, Wei-Min Gu, Hong Wang, Ting-Hao Chen, Meng-Chao Wu, Feng Shen, Tian Yang
Journal: Journal of Clinical Oncology (2018)

e16110 Background: Serum prealbumin is more sensitive to profile nutritional status and liver function than albumin, which could hardly be affected by infusion supplement. This study aims to identify the relationship between preoperative prealbumin level and the long-term outcomes after hepatectomy of hepatocellular carcinoma (HCC). Methods: Patients treated with hepatectomy of HCC between 2001 and 2014 at six institutions in China were enrolled. By using 170 mg/dl as cut-off value of serum prealbumin level, these patients were divided into the low and normal preoperative prealbumin groups. The overall survival (OS) and recurrence-free survival (RFS) were analyzed and compared. Univariable and multivariable Cox-regression analyses were performed to identify predictive factors of OS and RFS. Results: Among 1,483 patients, 437 (29.5%) had a low prealbumin level within a week before surgery. The 1-, 3-, and 5-year OS and RFS rates of patients in the low prealbumin group were 83.8, 57.0, and 31.1%, and 67.0, 39.8, and 19.9%, respectively, which was significantly poorer than those in the normal prealbumin group (93.0, 75.5, and 42.6%, and 77.0, 56.4, and 28.4%, both P < 0.001). Multivariable analyses revealed that preoperative prealbumin level, but not albumin level, was an independent predictor of OS (HR, 1.789; 95% CI: 1.544 -2.072, P < 0.001) and RFS (HR, 1.420; 95% CI: 232-1.636, P < 0.001). Conclusions: Preoperative prealbumin level is useful for predicting long-term outcomes in patients undergoing liver resection for HCC. Prealbumin may be suitable to displace albumin, yielding to an updated Child-Pugh grade for accessing liver function.