tbuckley/cabot-search huggingface dataset:
Use of single-arm trials to support malignant hematology and oncology drug and biologic approvals: A 20-year FDA experience.
Authors: Sundeep Agrawal, Shaily Arora, Jonathon Joseph Vallejo, Thomas Gwise, Meredith Kathleen Chuk, Laleh Amiri-Kordestani, Richard Pazdur, Paul Gustav Kluetz, Julia A. Beaver
Journal: Journal of Clinical Oncology (2021)

e13572 Background: Improved understanding of the underlying biology of cancer has led to a paradigm shift in cancer drug development and has paved the way for many products to receive accelerated or regular approval based on non-randomized/single arm trials (SATs). Given the high unmet medical need of cancer patients, challenges with lengthy and confounded survival endpoints, and difficulty enrolling rare biomarker-defined subsets of disease, SATs have been used to evaluate a variety of cancer therapies. Unlike time to event endpoints, the objective and clinically relevant endpoint of response rate (RR) and duration of response is interpretable in SATs, as spontaneous tumor shrinkage is not expected. Methods: A search of FDA databases identified all drugs and biologics approved for malignant hematology and oncology indications from January 1, 2001, to December 31, 2020 based on SATs. Data sources included approval letters, U.S. prescribing information, and clinical review documents. The definition of response varied by setting and time period (e.g. RECIST, WHO, IWG, etc.). Results: Between January 1, 2001 and December 31, 2020, FDA granted 153 new indications based on SATs, including 102 accelerated approvals (AAs) and 51 regular approvals (RAs). Overall, 69 approvals (45%) were for new molecular entities and 84 (55%) were expanded indications. Response rate was the most common endpoint used in the trial providing substantial evidence of efficacy to support approval [120/153, (78%)]. The durability of response was also considered to support evidence of clinical benefit. Of the 102 AAs, 38 (37%) have fulfilled their post-marketing requirement (PMR) to verify clinical benefit, 59 (58%) are pending verification of benefit, and 5 (5%) have been withdrawn from the market. Of note, 88% (52/59) of AAs pending verification of benefit occurred in the last 5 years alone (22 AAs in 2020, 8 in 2019, 8 in 2018, 12 in 2017, and 2 in 2016). Between 2001-2020, 58 (38%) new indications were granted for kinase inhibitors, 34 (22%) for immune checkpoint inhibitors (CPIs), and 61 (40%) for drugs with other mechanisms of action including but not limited to antibody-drug conjugates, cytotoxic drugs, and non-CPI monoclonal antibodies. Conclusions: In the last two decades, SATs have been effectively used to study anti-cancer therapies in well-defined patient populations using durable RR as an objective and interpretable clinical endpoint. Although randomized clinical trials remain the gold standard in clinical research, SATs have allowed for rapid advancements in oncology drug development and will continue to serve an important role in bringing new therapies to patients with unmet need.
PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer
Authors: Yoon-Koo Kang, Jeong Hwan Yook, Young-Kyu Park, Jong Seok Lee, Young-Woo Kim, Jin Young Kim, Min-Hee Ryu, Sun Young Rha, Ik Joo Chung, In-Ho Kim, Sang Cheul Oh, Young Soo Park, Taeil Son, Mi Ran Jung, Mi Hwa Heo, Hark Kyun Kim, ChoHyun Park, Chang Hak Yoo, Jin-Hyuk Choi, Dae Young Zang, You Jin Jang, Ji Young Sul, Jong Gwang Kim, Beom Su Kim, Seung-Hoon Beom, Sang Hee Cho, Seung Wan Ryu, Myeong-Cherl Kook, Baek-Yeol Ryoo, Hyun Ki Kim, Moon-Won Yoo, Nam Su Lee, Sang Ho Lee, Gyunji Kim, YeonJu Lee, Jee Hyun Lee, Sung Hoon Noh
Journal: Journal of Clinical Oncology (2021)

PURPOSE Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748 ) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m 2 , oxaliplatin 100 mg/m 2 intravenously day 1, S-1 40 mg/m 2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.
Mir-34a as predictor of immunotherapy efficacy in NSCLC patients.
Authors: Alexia Monastirioti, Chara Papadaki, Konstantinos Rounis, Despoina Kalapanida, Dimitrios Makrakis, Nikolaos Vardakis, Dimitrios Mavroudis, Sofia Agelaki
Journal: Journal of Clinical Oncology (2021)

e21191 Background: MicroRNAs are critical modulators of the immune response and regulate the expression of various immune checkpoints during immunotherapy. In the present study we evaluated the predictive significance of immune related miRNAs in the plasma of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. Methods: Plasma was obtained from 62 NSCLC patients before the initiation of immunotherapy, administered as second- or third-line treatment. The expression profile of immune-related miR-34a, miR-146a, miR-155, miR-200b, miR-202 and miR-223 was assessed by RT-qPCR. Patients were classified in high and low expression groups according to the median value of each miRNA. Patients that had achieved partial response (PR) or stable disease (SD) were classified as responders, whereas patients with progressive disease (PD) were classified as non-responders. Results: No statistical correlations were observed among miRNA expression and clinical outcomes in the whole group of patients (N = 62). However, in the non-squamous subgroup (N = 36) lower miR-34a expression levels were observed in non-responders compared to responders (80% vs 20%; p = 0.029). Univariate binary logistic regression analysis revealed that only low miR-34a expression (HR: 8.000, 95% CI: 1.215-52.693; p = 0.031) was correlated with the probability of developing progressive disease as best response to immunotherapy. Patients with low miR-34a expression levels were associated with shorter progression free survival (PFS) and overall survival (OS) compared to patients with high 34a expression (1.97 vs 6.33 months; p = 0.042 and 2.93 vs 9,60 months; p = 0.012, respectively). Furthermore, low miR-34a expression emerged as an independent predictor of shorter PFS and OS (HR: 2.449; p = 0.049 and HR: 3.203; p = 0.016, respectively). No other correlations were observed among the rest of the miRNAs and clinical outcomes. Conclusions: Our findings suggest that circulating miR-34a may serve as a potential predictive biomarker in NSCLC patients treated with immunotherapy. These observations need to be further validated in a larger cohort of patients.
Incidence of SARS-CoV-2 infection according to baseline antibody status in staff and residents of 100 long-term care facilities (VIVALDI): a prospective cohort study
Authors: Maria Krutikov, Tom Palmer, Gokhan Tut, Chris Fuller, Madhumita Shrotri, Haydn Williams, Daniel Davies, Aidan Irwin-Singer, James Robson, Andrew Hayward, Paul Moss, Andrew Copas, Laura Shallcross
Journal: The Lancet Healthy Longevity (2021)

SummaryBackgroundSARS-CoV-2 infection represents a major challenge for long-term care facilities (LTCFs) and many residents and staff are seropositive following persistent outbreaks. We aimed to investigate the association between the SARS-CoV-2 antibody status at baseline and subsequent infection in this population.MethodsWe did a prospective cohort study of SARS-CoV-2 infection in staff (aged <65 years) and residents (aged >65 years) at 100 LTCFs in England between Oct 1, 2020, and Feb 1, 2021. Blood samples were collected between June and November, 2020, at baseline, and 2 and 4 months thereafter and tested for IgG antibodies to SARS-CoV-2 nucleocapsid and spike proteins. PCR testing for SARS-CoV-2 was done weekly in staff and monthly in residents. Cox regression was used to estimate hazard ratios (HRs) of a PCR-positive test by baseline antibody status, adjusted for age and sex, and stratified by LTCF.Findings682 residents from 86 LCTFs and 1429 staff members from 97 LTCFs met study inclusion criteria. At baseline, IgG antibodies to nucleocapsid were detected in 226 (33%) of 682 residents and 408 (29%) of 1429 staff members. 93 (20%) of 456 residents who were antibody-negative at baseline had a PCR-positive test (infection rate 0·054 per month at risk) compared with four (2%) of 226 residents who were antibody-positive at baseline (0·007 per month at risk). 111 (11%) of 1021 staff members who were antibody-negative at baseline had PCR-positive tests (0·042 per month at risk) compared with ten (2%) of 408 staff members who were antibody-positive staff at baseline (0·009 per month at risk). The risk of PCR-positive infection was higher for residents who were antibody-negative at baseline than residents who were antibody-positive at baseline (adjusted HR [aHR] 0·15, 95% CI 0·05–0·44, p=0·0006), and the risk of a PCR-positive infection was also higher for staff who were antibody-negative at baseline compared with staff who were antibody-positive at baseline (aHR 0·39, 0·19–0·82; p=0·012). 12 of 14 reinfected participants had available data on symptoms, and 11 of these participants were symptomatic. Antibody titres to spike and nucleocapsid proteins were comparable in PCR-positive and PCR-negative cases.InterpretationThe presence of IgG antibodies to nucleocapsid protein was associated with substantially reduced risk of reinfection in staff and residents for up to 10 months after primary infection.FundingUK Government Department of Health and Social Care.
Age-based disparities in clinical trials supporting FDA approval of therapies for solid tumors.
Authors: Ajeet Gajra, Marjorie E. Zettler
Journal: Journal of Clinical Oncology (2021)

e18534 Background: Cancer of any site is most frequently diagnosed among adults age 65 years and older, however older adults have historically been under-represented in clinical trials for oncology drugs (difference in median age [DMA] −6.49 years among clinical trials for breast, prostate, lung and colorectal cancer from 1994-2015 [Ludmir et al, JAMA Oncology 2019]). Representation in registrational trials, which are the basis for drug approval and inform the prescribing information, is of particular importance as age‐related differences may affect response and toxicity. We conducted an analysis of the trials supporting recent Food and Drug Administration approvals of new therapies for the treatment of solid tumors to assess the median age of participants and compare it to the median age of patients in the real world for each malignancy. Methods: Prescribing information for novel therapies that received primary approval for solid tumor indications between 2015 and 2019 was reviewed, and the median age in the evaluable population of the supporting clinical trials was abstracted. Median age estimates among adults for each indication in the general population were obtained from the Surveillance, Epidemiology and End Results database or the published literature. The DMA was calculated for each trial by subtracting the median age in the real-world population from the median age in the trial. Characteristics of trial protocols were obtained from approval packages accessed in the Drugs@FDA database. Data are presented using descriptive statistics. Results: A total of 35 solid tumor drugs were approved based on 38 trials, with 15859 patients in the evaluable populations. Less than half of the trials were phase 3 (16; 42%) or were randomized with a control group (18; 47%). On average, the median age of the trial participants was 2.6 years younger than the median age of the disease populations (95% CI: -1.4, -3.9 years; p &lt; 0.01). For indications with &gt; 1 trial, those with the greatest disparities were in melanoma (mean DMA -6.5), urothelial carcinoma (-5.8), and lung cancer (-4.1). The DMA among phase 3 trials was -1.8, vs. -3.2 among phase 1 and 2 trials. None of the protocols for the trials specified upper age limits, however 23 (61%) required an ECOG performance status (PS) ≤1, and all trials had eligibility restrictions related to organ function or comorbidities. Conclusions: In this contemporary analysis of registrational trials across all solid tumor indications, we found that the median age of clinical trial participants was nearly 3 years younger than their real-world counterparts. No trial protocols had upper age limits, however most restricted PS, organ impairment or the presence of comorbidities, which may have impacted older patients’ eligibility to participate. Although inclusion of older adults in clinical trials appears to have improved in recent years, changes to trial design may help to ensure adequate representation.
Preoperative chemotherapy combined with PD-1 inhibitor in locally advanced operable or potentially resectable esophageal squamous cell carcinoma: A real world study.
Authors: Puyuan Wu, Tao Wang, Baojun Chen, Minke Shi, Yong Zhou, Bin Huang, Nandie Wu, Liang Qi, Lifeng Wang, Jia Wei, Baorui Liu, Wei Ren
Journal: Journal of Clinical Oncology (2021)

e16010 Background: Preoperative therapy of esophageal squamous cell carcinoma (ESCC) is stepping into the era of combined therapy with PD-1 inhibitor after the success of PD-1 antibodies in the first-line and second-line treatment for advanced ESCC. This single center study retrospectively analyzed the efficacy and safety of preoperative chemotherapy combined with PD-1 antibody in patients with locally advanced operable or potentially resectable ESCC in the real world. Methods: The study enrolled operable or potentially resectable locally advanced ESCC patients treated with preoperative chemotherapy combined with PD-1 inhibitor in our center from April 2020 to December 2020. The treatment regimen were 2 to 4 cycles of paclitaxel liposome (135̃175 mg/m 2 ) or albumin paclitaxel (180mg/m 2 ) plus nedaplatin (75mg/m 2 ) or lobaplatin (30mg/m 2 ) combined with PD-1 inhibitors (toripalimab 13/20, sintilimab 3/20, pembrolizumab 2/20, camrelizumab 1/20, tislelizumab 1/20) with standard therapeutic dose followed by tumor response assessment and surgery. The primary end point were safety, tumor response and complete pathological response (pCR) rate. Results: A total of 20 patients including 17 males and 3 females, of which median age was 65 and 85% were stage III-IVA (AJCC 8 th ), were included in the study. Of all the patients, 18 patients accomplished 2 cycles of therapy and had safety assessment, 13 patients underwent surgery, 2 patients were waiting for operations and 2 patients achieving partial response rejected surgery and were prepared for radical chemoradiotherapy. Treatment-related adverse events exceeding grade 3 levels included leukopenia 5.6% (1/18), neutropenia 16.7% (3/18), thrombocytopenia 5.6% (1/18), and immune hepatitis 5.6% (1/18). There was no severe surgery-related complication. Objective response rate (ORR) was 70.6% (12/17), and disease control rate (DCR) was 100% (17/17). R0 resection rate was 92.3% (12/13), the pCR rate was 15.4% (2/13), and 61.5% (8/13) of the patients had downstaged to the ypT1-2N0M0 I stage. One patient finally reached a pCR after switching to preoperative chemoradiotherapy because of progression after treatment of chemotherapy and PD-1 inhibitor. Conclusions: Preoperative chemotherapy combined PD-1 inhibitor treatment was well tolerated and had high efficacy in locally advanced operable and potential resectable ESCC. Since the study included some potentially resectable patients with late staging, the pCR rate may be lowered. The further study aims to find the efficient biomarker including PD-L1 expression and CD8 + T cell infiltration. Moreover, well-designed randomized prospective trials for better evidence are required.
Utilization of preoperative breast MRI among women with newly diagnosed breast cancer.
Authors: I-Wen Pan, Tina W.F. Yen, Isabelle Bedrosian, Ya-Chen T. Shih
Journal: Journal of Clinical Oncology (2021)

1546 Background: The use of preoperative (pre-op) breast MRI remains controversial. Current practice may rely on patient characteristics and providers’ clinical judgment. This national study examined factors associated with pre-op breast MRI among women with newly diagnosed breast cancer (BC) and explored sources of variations. Methods: We applied the Nattinger algorithm to identify women with incident BC diagnosed between Mar 2008 and Dec 2018 from OPTUM Clinformatics database. Patients who had 26 months of full enrollment, 14 months before and 12 months after the first (index) BC surgery, and no pre-op radiotherapy were included. We defined pre-op MRI as patients who had an MRI between the date of BC diagnosis and date of index surgery. We conducted multivariable logistic regression models to examine factors associated with pre-op MRI and performed separate analyses for elderly (age &gt; = 65) and non-elderly (age &lt; 65) women. Results: 61,865 women (non-elderly: 27,309, elderly: 34,556) were included in the analysis. The crude rate of pre-op MRI increased from 7.4% in 2008 to 14.6% in 2018 (p-value &lt;.001). For the non-elderly, women who were older (adjusted rates: 60-64, 10% vs 20-49, 12.1%), had no distant metastasis (10.6% vs. 12.3% with metastasis), no neoadjuvant chemotherapy (9.9% vs 15.0% with neoadjuvant), and 2 or more comorbidities (9.0% vs. 11.1% with zero comorbidity) were less likely to undergo pre-op MRI (all p-value &lt;.001). Compared to white women (adjusted rate 10.6%), African Americans were more likely to have pre-op MRI (12.7%, p &lt;.001) and Hispanics were less likely (8.14%, P &lt;.001). There was no association between Health Management Organization (HMO) status and receipt of pre-op MRI among non-elderly. For elderly women, older age, more comorbidities, no distant metastasis, and no neoadjuvant chemotherapy were similarly associated with less pre-op MRI use. There was no significant association between race and receipt of pre-op MRI. Moreover, elderly women with HMO insurance were less likely to receive pre-op MRI. In both age groups, we observed wide geographic variations, with significant interaction between census division and HMO enrollment among elderly group only (Table). Conclusions: The use of pre-op MRI nearly doubled from 2008 and 2018. In addition to demographic and clinical characteristics, regional practice pattern variations and insurance type played a key role in the receipt of pre-op MRI among newly diagnosed breast cancer patients. Future study to understand this phenomenon is warranted.[Table: see text]
A Text-Book of the Practice of Medicine.
Journal: JAMA (1897)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
The frequency and predictors of end-of-life symptom in patients with advanced cancer.
Authors: Shuji Hiramoto, Ayako Kikuchi, Tomohiko Taniyama, Hori Tetsuo, Akira Yoshioka, Toshihiko Kirishima
Journal: Journal of Clinical Oncology (2021)

e24061 Background: Advanced cancer patients complain of highly distressing symptom at the end-of-life, and important reasons for palliative intervention to relive symptoms. Methods: We analyzed 1282 patients who died of advanced cancer from August 2011 to August 2019 retrospectively. We divided into patients who complain of symptom include fatigue, dyspnea, nausea and vomiting, and cancer pain, or didn’t for 3 days prior to death, and analyzed predictors by multiple logistics method. The primary endpoint of this study was to identify frequency and predictors of end-of-life symptoms in advanced cancer patients. Results: As a background, the median age is 73 years old, 690 males, 592 females, 227 gastroesophageal cancers, 250 biliary pancreatic cancers, 54 hepatocellular carcinomas, 189 colorectal cancer, 251 lung cancers, 71 breast cancers, 58 urological malignancies, 60 gynecological malignancies, 47 head and neck cancer, 31 hematological malignancies, and 22 sarcomas. Number of patients who complained of dyspnea, fatigue, nausea and vomiting, and cancer pain were 235 (18.3%), 318 (24.8%), 81 (6.3%), and 322 (25.1%) at the end-of-life. In a multivariate analysis, peritoneal metastasis (ORs 1.812), with mental (ORs 0.549), palliative referral (ORs 0.680), Eastern Cancer Organization Group Performance Status (ECOG-PS) (OR0.679) and consciousness level (ORs 0.610) was independent predictors in patients with fatigue at the end-of-life. Chest cancer (Odds Ratio 2.635), lung (ORs 2.159), brain (ORs 0.431) and peritoneal metastasis (ORs 0.602), with mental (ORs 0.429), respiratory (ORs 1.960) and metabolic disorder (ORs 0.520), palliative referral (ORs 0.645) and consciousness level (ORs 0.468) was independent predictors in patients with dyspnea. Lung metastasis (ORs 0.480, peritoneal metastasis (ORs 1.812), with anti-cancer therapy (OR 2.244) and consciousness level (ORs 0.610) was independent predictors in patients with nausea and vomiting. Brain metastasis (ORs 0.435, liver metastasis (ORs 1.374), and consciousness level (ORs 0.599) was independent predictors in patients with cancer pain. Conclusions: We reported frequency and independent predictors of end-of-life symptoms in advanced cancer patients. Information on these predictors be useful to explaining about their end-of-life in advance.