bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of cancer in pulmonary embolism presentation and outcomes: A large academic center study.
Authors: Au Cherry , Gupta Ena , Khaing Phue , DiBello Joseph , Chengsupanimit Tayoot , Mitchell Edith P. , West Frances , Baram Michael , Awsare Bharat K. , Kane Gregory C.
Published: May 2019

6613

Background: The risk of venous thromboembolism is increased 4- to 7-fold in patients with malignancy, emphasizing the need to identify and treat these patients early to improve outcomes. We aimed to study the clinical presentation and outcomes of pulmonary embolism (PE) in patients with and without cancer. Methods: We performed a retrospective analysis of consecutive patients diagnosed with PE via CT scan from 2014-2016 at Jefferson Hospital. We compared patient characteristics, presentation, PE characteristics and mortality of patients with and without cancer. Cox proportional regression hazards model was used for survival-time analysis. Results: Our study included 581 patients, of which 187 (32.1%) had active cancer. Cancer patients were less likely to have chest pain (18.2% vs 37.4% p < 0.01), syncope (2.7% vs 6.6% p = 0.05), bilateral PEs (50% vs 60% p = 0.025), and right heart strain (RHS) (48% vs 58% p = 0.024). Indwelling catheters (IC) were present in 41.2% (n = 77) of cancer patients. However, presence of IC was not associated finding of incidental PEs (26% vs 18.2% p = 0.201). There was no difference in hospital length of stay (8.9 vs 9.4 days p = 0.61) or intensive care unit admission (31.9% vs 33.3% p = 0.75). There were fewer massive PE (3.2% vs 7.1% p = 0.06) in patients with cancer, but this difference was not statistically significant. Cancer patients elected comfort care at higher rates (15.2% vs 5.4% p = 0.01). Cancer patients had higher 1-year mortality as compared to non-cancer (adj HR 6.9, 95% CI 3.3- 14.7, p < 0.01). Among cancer patients, 52.7% had metastasis with a higher 1-year mortality (adj HR 2.5, 95% CI 1.8- 4.9, p < 0.1) and 35.8% were on active chemotherapy with no difference in 1-year survival (adj HR 1.1, 95% CI 0.6-1.8, p = 0.79). The most represented cancers were genitourinary, lung and head and neck (35.3%, 23.0%, 13.4%, respectively). Conclusions: Cancer patients presented with less severe pulmonary emboli which may be due to increased health care contact and pre-clinical suspicion. The presence of IC did not affect the size, location of PE or incidental PEs among cancer patients. Although cancer patients have higher 1-year mortality, PE may not be as large as a contributor as previously perceived.
Quality control system of Watson for oncology: Artificial intelligence for supporting clinical decisions in oncology.
Authors: Fang Juemin , Guo Xianling , Zhu Zhongzheng , Wang Hui , Hu Fei , Chen Jianhua , Yuan Min , Zhao Yu , Wu Jianguo , Gao Song , Xu Qing
Published: May 2019

6616

Background: Watson for Oncology (WFO) is an artificial intelligent clinical decision-support system (AI-CDSS) developed by IBM and trained by Memorial Sloan Kattering Cancer Center to assist in cancer care by providing evidence-based treatment options with priority. However, there are disagreements argue that WFO recommends “unsafe and incorrect” cancer treatments. Also, guidelines and drug availability in China are different from USA. Therefore, a quality control system of WFO is urgently needed to help oncologists better use WFO in China. Methods: Experts from medical oncology, surgical oncology, radiology, intervention, radiology and pathology etc. forming a Multiple Disciplinary Team (MDT) to score Watson recommendations in 6 aspects (shown in the table). Results: With this quality control system, the value of WFO was carefully evaluated by MDT. Recommendations with higher score(especially more than 80) were more standardized, reasonable and evidence-based thus more likely to be chosen. Localization and drug availability problem was solved by taking Chinese guidelines and drug approval into evaluation within this scoring system. Treatment options unsuitable or unavailable for patients by the system will be removed and replaced by the advices of MDT. Conclusions: Reliability and security are the top concerns of applying new technology in healthcare. With the MDT quality control system, AI-CDSS can be used safely and efficiently before it is fully mature. Also, the accuracy and advancement are assessed in this system to help oncologists better use WFO in China in the future. Indicators evaluating the WFO recommendations. [Table: see text]
Combination of statin/vitamin D and metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of two randomized clinical trials.
Authors: de Velasco Guillermo , Lora David , Carretero-Gonzalez Alberto , Martin Soberón Maria Cruz , Sepulveda Sanchez Juan Manuel Manuel , Lorente David , Castellano Daniel E.
Published: May 2019

6617

Background: Retrospective database studies have suggested that statins and vitamin D have a positive impact on prostate cancer survival and specifically in mCRPC patients (pt). Methods: We conducted a post-hoc analysis of individual pt data of mCRPC pts treated with abiraterone (AA) and/or Prednisone (P) on two randomized phase III clinical trials COU -AA-301 and COU-AA-302 to analyze the impact of statins and vitamin D in overall survival (OS). Statistical analyses were performed using the Kaplan Meier method and Independent predictors were investigated using Cox regression analysis. This study, carried out under YODA Project #2016-1136, used data obtained from the Yale University Open Data Access Project. Results: These two studies included 2280 patients (1340 treated with AA/P and 640 with P). Use of Statin + vitamin D was associated with a 38% reduction in mortality in the postdocetaxel setting and 32% in the predocetaxel setting in patients treated with abiraterone (Table 1 and 2). No significant reduction in the rate of skeletal-related events was seen in patients treated with vitamin D or statins. Conclusions: To our knowledge this is the first report suggesting the impact of vitamin D+statin in mCPRC treated with abiraterone. The potential benefits of vitamin D do not seem to be secondary to concomitant statin use in this population. Further studies are needed to confirm these results. [Table: see text][Table: see text]
Impact of Oncology Care Model (OCM) reporting requirements on quality of care.
Authors: Castellanos Emily , Orlando Abigail , Hamrick James , Ma Xinran , O'Connell Gillian , Meropol Neal J. , Adamson Blythe J.S.
Published: May 2019

6620

Background: The OCM is a voluntary Center for Medicare and Medicaid Innovation alternative payment model pilot program. As of Oct 2017, OCM practices are required to report the biomarker status for NSCLC pts. Our objective was to assess the effect of OCM reporting on quality of care in aNSCLC. Methods: We developed a decision-analytic model to compare the likelihood of receiving biomarker testing and corresponding appropriate therapy. We populated the model using real-world data from pts (n=7,075) at OCM sites (n=45) and non-OCM sites (n=105) in the Flatiron Health electronic health record (EHR)-derived database. The pre-period control included pts diagnosed with aNSCLC from Jan 1, 2011 - Dec 31, 2015; the post-period included pts diagnosed Oct 2017 - Nov 2018. For OCM vs non-OCM sites, we estimated probabilities and unadjusted odds ratio (OR) of biomarker testing (EGFR, ROS1, or ALK) and subsequent delivery of appropriate therapy, defined as use of a biomarker-guided tyrosine kinase inhibitor (TKI) for positive pts, or non-TKI therapy for negative pts. Results: No differences in rates of biomarker testing or delivery of appropriate therapy were detected between OCM and non-OCM practices prior to the reporting requirement. In the post-period, OCM was associated with higher odds of biomarker testing and appropriate therapy (Table). Conclusions: To our knowledge, this is the first study of the association of OCM reporting requirements with downstream quality of care. Our results suggest that OCM documentation and reporting requirements are associated with modestly higher quality of care for pts with aNSCLC. Ongoing sensitivity analyses will determine the relative contribution of provider and practice characteristics to these findings. Careful measurement of the impact of reporting requirements is essential to measure the impact of payment reform interventions and inform policy. [Table: see text]
Virtual visits for children, adolescents, and young adults with cancer.
Authors: Anderson Peter Meade , Zahler Stacey , Harter Lynn , Hanna Rabi
Published: May 2019

6622

Background: Children, adolescents, and young adults have rare cancers and standard-of-care treatment is commonly very aggressive. Virtual visits provide include many of the nuances of face-to face communication. These are much friendlier than phone calls or email and can be scheduled and structured to provide a large amount of information efficiently. Methods: Cleveland Clinic uses HIPPA-compliant software from American Well (Boston, MA) that allows the health care provider and patient to use a phone, tablet, or desktop computer for video visits. Our intake process involves obtaining a Medical Record Number (MRN), sending a brief summary, uploading or sending a CD with images in DICOM, and having an administrative assistant schedule the virtual visit. Telemedicine sessions typically last <60 minutes. During the visit a summary is updated, images are reviewed, and this and other information shared via email after the visit. Results: In 2017+ 2018 we conducted 223 virtual visits; 85% were <30 years old (table). The summary has been a key to efficient and effective organization and includes not only contact information and past medical history, but also an “Opportunities to Improve Health" section (problem list /action plan). Topics discussed in solid tumor patients include: 1) local control, 2) medical therapy (chemotherapy), 3) imaging and tumor markers, 4) control of side effects and nutrition, 5) social issues and goals of care (which can include palliative care and hospice), and 6) follow-up. A power point with key images and the updated summary and articles are emailed at the end of the visit to the patient & caregivers and often referring physician, NP, or PA . Visit diagnoses have included osteosarcoma and Ewing sarcoma (73%), but also other rare cancers such as rhabdomyosarcoma, DSRCT, paraganglioma, and adrenal cortical carcinoma. Survivorship and cGVHD have also been discussed. Conclusions: A structured virtual visit to help young people and their caregivers understand complex multi-disciplinary cancer care is now possible for all regions of North America. A major source of satisfaction has been two-way sharing of information to improve not only cancer control, but also improved nutrition, communication, and proactive toxicity reduction. [Table: see text]
Evaluating the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) value frameworks for Food and Drug Administration (FDA) approved checkpoint inhibitors (CIs).
Authors: Feng Sophie , Cao Yanshuo , Amir Eitan , Chen Eric Xueyu
Published: May 2019

6624

Background: Although the development of CIs has led to a dramatic change in the oncology landscape, these agents are associated with significant costs and toxicity. ASCO and ESMO have developed separate frameworks to define the value of emerging cancer treatments in order to encourage cost-effective therapies. We apply these frameworks to trials supporting FDA approvals of CIs and explore the correlation between these two scoring systems. Methods: We searched the FDA database for CIs and indications approved between January 1, 2011 and January 1, 2019. Only randomized phase II/III trials for solid tumors were included. Data on survival, toxicity and quality of life were extracted from the most recent publications by two reviewers independently. A trial showing a substantial benefit was defined as an ASCO score of ≥ 45, or ESMO Grade 4-5 (palliative setting) or Grade A/B (curative setting). Concordance for substantial benefit was assessed using Cohen’s Kappa while Spearman coefficients were used to determine the degree of correlation in individual scores. Results: We identified 40 FDA indications for 7 CIs. Of these, 18 indications based on Phase I/II single-arm trials were excluded. The remaining 22 indications were based on 21 randomized phase II/III trials (3 adjuvant, 18 metastatic). In the palliative setting, 73% and 86% trials showed substantial benefit based on ASCO and ESMO frameworks respectively [median ASCO score: 54.8, interquartile range (IQR) 46.2-64.0; median ESMO score: 5, IQR: 4-5]. 27% of trials were scored intermediate or low benefit by ASCO, while 9% were ineligible for ESMO scoring. Weighted kappa was 0.719 between the two frameworks. Spearman rho was 0.84. All 3 adjuvant trials were assigned ESMO grade A but low benefit with ASCO (median 37.7, IQR 20.5-40.9). Conclusions: In the palliative setting, the majority of trials supporting FDA approved CI indications demonstrated substantial benefit using both ASCO and ESMO frameworks. There was a strong correlation between the two frameworks. However, in the curative setting scores were discordant. The ASCO framework may require further refinement for adjuvant trials.
Followup mammography after breast conservation therapy: Is 3D Tomosynthesis(3DT) worth it?
Authors: Hasan Shaakir , Gresswell Steven , Colosimo Brittany , Weinberger Kevin , Anderson Sidney , Bigbey Matthew , Wegner Rodney E , Shindel Beth , Julian Thomas B. , Trombetta Mark G.
Published: May 2019

6628

Background: Screening three-dimensional tomosynthesis mammography (3DT) is more cost-effective than two-dimensional mammography (2DM) for detecting breast cancer, however cost-effectiveness as a follow-up for treated breast cancer is unknown. We retrospectively analyzed the downstream workup and costs associated with 3DT compared to 2DM when employed as initial follow-up imaging in breast conservation therapy (BCT). Methods: Between the years 2015-2017, 450 consecutive BCT patients ages 32 – 89 with a follow-up 3DT (n = 162) or 2DM (n = 288) were reviewed in this IRB-approved study. The primary endpoint was further workup after follow-up mammogram and associated healthcare costs at 1 year. Downstream workup was secondarily tested for correlation with clinical and treatment-related variables. A single 3DT cost an estimated $149 compared to $111 for a 2DM, based on Centers for Medicare claims data Oncology Care Model. Results: Patient clinical characteristics were : 6% DCIS, 10% T1a, 29% T1b, 35% T1c, 19% T2, 88% N0, 9% N1, 3% N2, 76% ER+/PR+/HerNeu2-, 12% TNBC, and 14% Her2Neu+. Whole breast radiation was given with conventional (59%) and hypo (39%) fractionation (81% with a boost), and 10% received accelerated partial breast irradiation. First post-treatment mammogram was received within 3 months (20%), 3-6 months (32%), and after 6 months (48%) following RT. There were no differences in breast density, patient age, T/N stage, receptor status, type of RT, or mammogram timing between those in the 2DM and 3DT groups. The following downstream workup ensued for 3DT compared to 2D imaging: 18% vs 29% short-interval (6-month) mammogram (OR = 1.83, P = 0.01), 6% vs 11% breast MRI (OR = 1.90, P = 0.08), 4% ultrasound for each, and 3% biopsy for each (1 positive in the 2D group). Including downstream workup, the estimated cost per patient in the 3DT group = $249.00 compared to $253.64 in the 2D group. With multivariable analysis the independent predictors for reduced downstream workup was the use of 3DT and follow-up mammogram at least 6 months after radiation (P < 0.05). Conclusions: Excess workup was reduced with 3DT compared to 2DM in the post-treatment setting. A single 3DT costs approximately 34% more than 2DM, however in this study the associated reduction in downstream workup with 3DT actually made it more cost-effective.
The effect of guideline-concordant novel therapy use on meeting cost targets in OCM: Results from a large community oncology network.
Authors: Schleicher Stephen Matthew , Chaudhry Basit , Waynick Christopher A. , Crouse Cheryl A. , Shipley Johnathan D. , Dickson Natalie R. , Patton Jeffrey , Supalla Susanna N. , Soudek Daniel , Lyss Aaron J.
Published: May 2019

6635

Background: The Oncology Care Model (OCM) is intended to incentivize physicians to improve the quality and reduce the cost of cancer care. In OCM, providers are accountable for all costs during six month episodes of care relative to target costs (TC) derived from a baseline spending period (BSP; 2013-2015). This accountability is intended to foster care coordination to reduce preventable emergency department visits and hospitalizations (EDH). Benefits of reducing EDH may be diluted when new treatment indications for costly immunotherapies (IO) are introduced into clinical practice after BSP. Methods: We identified all non-small cell lung cancer (NSCLC) and bladder cancer (BC) OCM episodes attributed to Tennessee Oncology (TO), a large community oncology network of over 90 oncologists, during performance period 2 (PP2; the most recent PP with available data). We selected NSCLC and BC because both diseases have IO indications that became standard of care after BSP. Using claims data analytics software, we identified all NSCLC and BC episodes with spending above TC, and found a subset of these above target episodes (ATEs) without any EDH that remained above TC due to IO use. Two medical oncologists reviewed these cases in duplicate to assess guideline concordance of IO. Results: During PP2 there were 2,623 OCM episodes attributed to TO, including 240 NSCLC and 31 BC episodes. Spending was above TC in 118 (49%) and 13 (42%) of NSCLC and BC episodes, respectively. For these NSCLC and BC ATEs, EDH was prevented in 62 (53%) and 5 (38%) of cases, respectively. In NSCLC and BC ATEs without EDH, 43 (69%) and 5 (100%) of episodes included IO, respectively. Clinician review in duplicate (S.M.S.; C.A.W.) found that the use of IO was NCCN guideline concordant in 33 (77%) and 4 (80%) of these NSCLC and BC cases, respectively (K = 0.87). Conclusions: Guideline-concordant use of expensive IO as its treatment indications expand poses substantial challenges to meeting cost targets in OCM, even when practices prevent EDH. [Table: see text]
Burden of cytokine release syndrome (CRS) and neurologic events (NE) in patients (Pts) with relapsed/refractory non-Hodgkin lymphoma (NHL) receiving lisocabtagene maraleucel (Liso-cel; JCAR017) in TRANSCEND NHL 001.
Authors: Abramson Jeremy S. , Siddiqi Tanya , Garcia Jacob , Dehner Christine , Nguyen Andy , Snyder Sophie , Gitlin Matthew , Chung Karen C.
Published: May 2019

6637

Background: We assessed incidence, healthcare resource utilization (HCRU), and costs of CRS and NE in pts in TRANSCEND receiving liso-cel, an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells. Methods: HCRU within the dates of onset and resolution of CRS and NE was identified from case report forms and trial management guidelines. Costs associated with grade (G) of CRS or NE were applied using public databases and literature on national average costs from a provider perspective. Results: Of 102 pts, 21 (21%) had CRS only (no G≥3), 6 (6%) had NE only (no G≥4), 6 (6%) had nonconcurrent CRS and NE, and 11 (11%) had concurrent CRS and NE (including 1 G4 CRS). Most pts had G≤2 events (31/44, 70%). Of pts with both CRS and NE, 16/17 (94%) had CRS first. Of pts with nonconcurrent events, NE developed a median of 2 days after CRS resolved. Of 10/11 pts with concurrent events and CRS before NE, NE developed a median of 3.5 days after CRS onset. 11/38 pts with CRS (29%) received tocilizumab and 21/44 with CRS and/or NE (48%) received dexamethasone. Overall median costs for G≤2 vs G≥3 CRS and/or NE were $16,479 vs $70,549. Management costs for CRS and/or NE were largely driven by hospitalizations (Table), and ranged $177–24,947 for G≤2 CRS or NE only, $30,749 for G≤2 concurrent CRS and NE, and $43,974–264,149 for G≥3 CRS and/or NE. Conclusions: In TRANSCEND, incidences of G≥3 CRS and NE were low. G≥3 events resulted in a 328% increase in overall median costs vs G≤2 events. Clinical trial information: NCT02631044. [Table: see text]
Clinical benefit and prices of cancer drugs in the United States and Europe.
Authors: Vokinger Kerstin Noëlle , Hwang Thomas J , Tibau Martorell Ariadna , Rosemann Thomas J , Kesselheim Aaron S
Published: May 2019

6638

Background: Given rising cancer drug costs, Medicare recently proposed to tie some US drug prices to average prices paid by comparable countries. To understand the potential scope of this policy, we assessed differences in cancer drug prices in the US and selected European countries. We also evaluated the correlation between drug prices and their clinical benefit, as measured by two value frameworks: the American Society of Clinical Oncology Value Framework v2 (ASCO VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale v1.1 (ESMO-MCBS). Methods: We identified all new drugs for adult solid and hematologic cancers, approved by the FDA from 2009-2017 and that have also been approved by the EMA by December 31, 2018. US average sales prices (and if not available, wholesale acquisition costs) were extracted as of February 1, 2019, and compared to comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland. ASCO VF and ESMO-MCBS scores were assessed for pivotal trials supporting solid tumor drugs; in case of multiple trials, we focused on the highest score. Consistent with the developers of the rating scales, “high benefit” was defined as scores of A-B (neo/adjuvant setting) and 4-5 (palliative setting) on the ESMO-MCBS scale and scores≥45 on the ASCO VF. Linear regression models and non-parametric Kruskal-Wallis test and were used to assess the association between drug prices and benefit scores. Results: The study cohort included 63 drugs approved by the FDA and the EMA during the study period. 46 (73%) were approved for solid tumors, and 17 (27%) were approved for hematologic malignancies. Overall, median cancer drug prices in included European countries were 52% (interquartile range: 37-72%) lower than US prices. There was no statistically significant association between monthly treatment cost and ASCO-VF or ESMO-MCBS scores in any country. There was also no association between price differential between US and median European drug prices and either ASCO-VF (P = 0.599) or ESMO-MBCS (P = 0.321) scores. Conclusions: Cancer drug prices in the US were significantly higher than in the compared European countries. Drug prices of cancer drugs were not associated with clinical benefit in the US or in European countries.
A cost-utility analysis of atezolizumab in the second-line treatment of metastatic urothelial carcinoma.
Authors: Parmar Ambika , Richardson Marina , Sander Beate , Cheng Susanna Y. , Chan Kelvin K.
Published: May 2019

6639

Background: Despite early promising results, IMvigor211 failed to demonstrate an overall survival benefit for atezolizumab, compared to chemotherapy, in the second-line treatment of metastatic urothelial carcinoma. However, given improvements in adverse events (AE) and quality of life with atezolizumab, there may still be investment value. We conducted a cost-utility analysis (CUA) of atezolizumab compared to chemotherapy from a public-payer healthcare perspective. Methods: We developed a partitioned survival model to evaluate atezolizumab versus chemotherapy (i.e. docetaxel, paclitaxel or vinflunine). IMvigor211 informed rates of treatment receipt (initial and subsequent), AE, effectiveness and utility estimates. Cost for treatment, AE and death were based on published literature (adjusted to 2018 Canadian dollars). Per health state, cost of treatment (initial and subsequent) and AE were incorporated. Outcomes included quality-adjusted life-years (QALY), cost per treatment, and incremental cost-effectiveness ratio (ICER). QALY and cost were discounted at 1.5% (Canadian guidelines). Parameter uncertainty was assessed through one-way and scenario analyses. Time horizons of 2 (within trial) and 5 years (extrapolated lifetime) were evaluated. Results: QALY of atezolizumab and chemotherapy over 2 years (lifetime) were 0.65 (0.93) and 0.58 (0.64), respectively. Cost of atezolizumab and chemotherapy over 2 years (lifetime) was $77,614.64, ($92,484.34), and $62,212.35 ($67,606.65), respectively. ICER over 2 years and lifetime was $220,032.71/QALY and $85,785.14/QALY. Scenario analysis from a North American perspective with only taxane chemotherapy with and without third line immunotherapy (IO) revealed an ICER of $80,144.90/QALY, $125,332.76/QALY over a lifetime horizon, respectively. Conclusions: The difference in ICER dependent on time horizon, driven by extrapolated survival benefits, highlights the importance of long-term follow-up to examine whether early evidence for durable response translates into long-term survival and improvements in cost-effectiveness. Thus, CUA of IO require careful interpretation and warrant dynamic assessment as new data becomes available.
Cost-effectiveness of CHOP in treating DLBCL in Malawi.
Authors: Painschab Matthew , Kohler Racquel Elizabeth , Wheeler Stephanie B. , Gopal Satish
Published: May 2019

6644

Background: DLBCL is common in Africa, and often curable, but treatment costs and cost-effectiveness are key considerations. WHO defines extremely cost-effective interventions as having an incremental cost-effectiveness ratio (ICER) < GDP per capita. Methods: We used a decision tree model to conduct a cost-effectiveness and budget impact analysis from a health systems perspective in Malawi (2017 GDP per capita $340). Comparisons were made between CHOP vs. palliative care with diagnosis (PC+D), and palliative care without diagnosis (PC-D). Microcosting and clinical outcomes were derived from published prospective data. Costs reflect treatment and 2 years of follow-up. Outcomes reflect a lifetime time horizon. Life expectancies were derived from UNdata, and disability-adjusted life year (DALY) weights from the Global Burden of Disease Study. Costs were analyzed in 2017 US $, and costs and outcomes were discounted at 3% annually. Annual estimates for new DLBCL cases (n=161) were used as input incidence. Probablistic sensitivity analysis was conducted using Crystal Ball software over 1000 simulations. Results: For the base case, the ICER of CHOP versus PC+D is $150/DALY averted, and versus PC-D is $200/DALY averted (Table). The ICER was stable across a wide range of sensitivity analyses. The ICER varied most across the range of progression-free survival estimates ($117-209), and range of costs for CHOP plus follow-up ($71-308). CHOP was extremely cost-effective by the WHO definition in 99% of simulations versus PC+D, and 94% of simulations versus PC-D. In the base case, total annual cost of DLBCL treatment with CHOP in Malawi was $306,221. Conclusions: This is one of the first rigorous cost-effectiveness and budget impact analyses for cancer treatment in a low-income country. CHOP is extremely cost-effective compared to palliative care, with ~$300,000 needed annually to treat all DLBCL cases in Malawi. These findings merit external validation, and support continued regional investments in cancer care. [Table: see text]
United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.
Authors: Tarhini Ahmad A. , Lee Sandra J. , Hodi F. Stephen , Rao Uma N. M. , Cohen Gary Irvin , Hamid Omid , Hutchins Laura Fulper , Sosman Jeffrey Alan , Kluger Harriet M. , Sondak Vernon K. , Koon Henry B. , Lawrence Donald P. , Kendra Kari Lynn , Minor David R. , Lee Carrie B. , Albertini Mark R. , Flaherty Lawrence E. , Petrella Teresa M. , Kirkwood John M.
Published: May 2019

9504

Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.
Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.
Authors: Papadopoulos Kyriakos P. , Autio Karen A. , Golan Talia , Dobrenkov Konstantin , Chartash Elliot , Li Xiaoyun Nicole , Wnek Richard , Long Georgina V.
Published: May 2019

9509

Background: Ligation of GITR on immune cells decreases Treg-mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cellinflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points  primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( > 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754.
Circulating tumor DNA (ctDNA) kinetics to predict survival in patients (pts) with unresectable or metastatic melanoma treated with dabrafenib (D) or D + trametinib (T).
Authors: Syeda Mahrukh M , WIGGINS JENNIFER M , Corless Broderick , Long Georgina V. , Flaherty Keith , Schadendorf Dirk , Nathan Paul D. , Robert Caroline , Ribas Antoni , Davies Michael A. , Grob Jean Jacques , Gasal Eduard , Squires Matthew , Marker Mahtab , Brase Jan C. , Polsky David
Published: May 2019

9510

Background: There are no validated blood-based biomarkers to monitor efficacy in pts with advanced melanoma. Lactate dehydrogenase (LDH) is an established prognostic factor; however, it is not normally used to inform treatment decisions. ctDNA at baseline (BL) is associated with a poor prognosis in pts treated with BRAF inhibitors, but no studies have examined the association between serial changes in ctDNA and survival after BRAF and/or MEK inhibitor therapy. Methods: We measured BRAF V600E/K ctDNA at BL and wk 4 in plasma samples from a pooled population of pts with unresectable or metastatic melanoma treated with D or D+T in the phase 3 COMBI-d trial (NCT01584648). We used mutation-specific droplet digital PCR assays; ctDNA results were categorized as positive/negative (pos/neg) using an analytically validated detection threshold of 0.25 copies/mL. Progression-free (PFS) and overall survival (OS) were analyzed in all pts and by BL LDH level (> or < upper limit of normal). Results: BL ctDNA was detectable in 320/345 pts (92.7%) and was not associated with survival. Nearly all pts had a considerable drop in ctDNA after 4 wks of therapy; 201 pts had paired samples (BL and wk 4) and detectable ctDNA at BL. In 80/201 pts (40%) whose ctDNA changed from pos at BL to neg at wk 4, PFS and OS were prolonged vs in 121/201 (60%) whose ctDNA remained pos (median PFS, 12.9 [95% CI, 9.2-20.2] mo vs 7.1 [5.5-8.9] mo; HR, 0.55 [0.39-0.76]; P = .0003; median OS, 28.2 [20.5-48.8] mo vs 14.6 [11.8-18.7] mo; HR, 0.56 [0.40-0.79]; P = .0007). Undetectable ctDNA at wk 4 was associated with prolonged PFS and OS, especially in pts with high BL LDH (Table). Conclusions: Particularly in pts with high LDH, on-treatment ctDNA monitoring may be helpful for early identification of pts likely to benefit from D or D+T. All ctDNA Samples at Wk 4. Clinical trial information: NCT01584648. [Table: see text]
Responders to anti-PD1 therapy: Long-term outcomes and responses to retreatment in melanoma (mel).
Authors: Betof Warner Allison , Palmer Jessica S. , Shoushtari Alexander Noor , Goldman Debra A , Panageas Katherine , Callahan Margaret K. , Wolchok Jedd D. , Postow Michael A. , Chapman Paul B.
Published: May 2019

9513

Background: Little is known about patients (pts) who discontinue anti-PD1 therapy after a complete response (CR) outside of clinical trials. There are also limited data about retreatment with a second course of anti-PD1 upon disease progression. Methods: We retrospectively studied pts (n = 398) at MSKCC with unresectable mel (non-uveal) who received ≥1 dose of single-agent anti-PD1 and were followed ≥3 months (mos) after treatment cessation. CR was defined radiographically or by a negative biopsy of residual tissue. Overall survival (OS) and time to treatment failure (TTF, time until next therapy or death) were calculated from time of CR. When to stop therapy and whether to retreat after progressive disease (PD) were at the discretion of the treating oncologist. A subset of pts received a second course of single-agent anti-PD1 ≥3 months after initial discontinuation; retreated pts were evaluable if they had radiographic or clinical evaluation to assess retreatment efficacy. Results: 102 pts (25.6%) achieved CR (n = 89 radiographic, n = 13 pathologic). Median follow-up was 22.6 mos for survivors who had a CR. Estimated 3-year OS from time of CR was 82.5% (95% CI 67.4-91.0). For pts who had a CR, therapy was discontinued due to CR (n = 72), toxicity (n = 24), or other reasons (n = 6). The median duration of treatment for CR pts was 9.4 mos (range 1.6-36.1). 20 CR pts later had progressive disease (PD). Median TTF has not been reached; at 3-years the estimated treatment-free survival for CR pts was 72.3% (95% CI 60.2-81.3). 34 pts received a second course of anti-PD1 for PD after a median of 11.6 mos off treatment (range 3.5-28.6). Best responses to the second course of treatment were: 2 CRs (5.9%), 3 with tumor shrinkage (8.8%), 9 (26.5%) with SD, and 20 with PD (58.8%). Of these pts who had had a CR (n = 8) or some lesser degree of tumor shrinkage (n = 13) to the initial course of anti-PD1 treatment, only 1 and 2 pts responded, respectively, to retreatment. Median duration of retreatment was 10.9 wks. Conclusions: In this largest dataset to knowledge of mel pts treated with a second course of anti-PD1, response rate was low, even in pts who had achieved a response initially. Further study is needed into the necessary duration of initial anti-PD1 treatment and optimal strategies for initial responders who discontinue and later develop PD.
Standard-dose pembrolizumab (pembro) plus alternate-dose ipilimumab (ipi) in advanced melanoma: Initial analysis of KEYNOTE-029 cohort 1C.
Authors: Long Georgina V. , Robert Caroline , Butler Marcus O. , Couture Felix , Carlino Matteo S. , O'Day Steven , Atkinson Victoria , Cebon Jonathan S. , Brown Michael Paul , Dalle Stéphane , Hill Andrew Graham , Gibney Geoffrey Thomas , McCune Steven L. , Menzies Alexander M. , Niu Cuizhen , Ibrahim Nageatte , Homet Moreno Blanca , Diab Adi
Published: May 2019

9514

Background: KEYNOTE-029 cohort 1B showed substantial efficacy for standard-dose pembro + 4 doses of ipi 1 mg/kg with lower rate of grade 3-5 toxicity than reported for standard-dose nivolumab + ipi in patients (pts) with advanced melanoma. In KEYNOTE-029 cohort 1C, we assessed the toxicity and antitumor activity of standard-dose pembro plus 2 alternate ipi doses (NCT02089685). Methods: Eligible pts with previously untreated stage III/IV melanoma, ECOG PS 0-1, and no active CNS metastases were randomized 1:1 to pembro 200 mg Q3W for 24 mo + 4 doses of ipi 50 mg Q6W (arm A) or pembro 200 mg Q3W for 24 mo + 4 doses of ipi 100 mg Q12W (arm B). Primary endpoints were the grade 3-5 treatment-related AE (TRAE) rate and ORR (RECIST v1.1, central review). With 50 pts per arm and compared with other anti–PD-1 + ipi regimens, a grade 3-5 TRAE rate ≤26% would suggest a meaningful reduction in toxicity and an ORR ≥48% would suggest no decrease in efficacy. Data cutoff date was Jul 17, 2018, and will be updated. Results: 102 pts were randomized: 51 to each arm. Median age was 63.5 y, 70% were male, 15% had ECOG PS 1, 34% had BRAF mutation, and 30% had elevated LDH at baseline. With 9.4 mo median follow-up, 69% of pts in arm A and 71% in arm B remained on treatment. All pts in arm A and 96.1% in arm B had ≥1 TRAE; grade 3-5 TRAE rates were 22% in arm A and 33% in arm B. 1 pt had a grade 5 TRAE (autoimmune myocarditis; arm A). ORR was 49% (95% CI 35-63) in arm A, including 7 CRs and 18 PRs, and 53% (95% CI 39-67) in arm B, including 6 CRs and 21 PRs. An additional 16 pts in each arm had SD or non-CR/non-PD, leading to a DCR of 80% and 84%, respectively. Median response duration was not reached in either arm (range 1.4+ to 9.6+ in arm A, 1.4+ to 9.8+ in arm B). Updated data based on longer follow-up will be presented. Conclusions: Standard-dose pembro + ipi 50 mg Q6W and standard-dose pembro + ipi 100 mg Q12W showed robust antitumor activity in this initial analysis. Both regimens appeared to have a lower rate of grade 3-5 TRAEs than previously observed. Longer follow-up and randomized studies are needed to confirm that these regimens reduce toxicity without compromising efficacy compared with other anti–PD-1 and ipi combinations. Clinical trial information: NCT02089685.
Tumor microenvironment (TME), longitudinal biomarker changes, and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma treated with first-line spartalizumab (S) + dabrafenib (D) + trametinib (T).
Authors: Dummer Reinhard , Gusenleitner Daniel , Campbell Catarina D. , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Ana , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Gasal Eduard , Brase Jan C. , Long Georgina V.
Published: May 2019

9515

Background: Although pts with both low tumor mutation burden (TMB) and T-cell–inflamed gene expression profiles (TI-GEPs) usually have poor outcomes with anti–PD-1 therapy, an analysis in the adjuvant melanoma setting suggested that these pts benefited from adjuvant D+T therapy. Here we analyze TMB/TI-GEPs and other biomarkers in pts receiving a combination of anti–PD-1 and D+T therapy. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating S in combination with D+T in previously untreated pts with BRAF V600–mutant unresectable/metastatic melanoma. In the safety run-in (part [p] 1) and biomarker (p2) cohorts, blood/tissue samples were collected at baseline (BL), after 2-3 and 8-12 wk of treatment, and at disease progression. TMB/circulating tumor DNA (ctDNA) and TI-GEPs were examined by targeted DNA-seq and RNA-seq, respectively. Results: At data cutoff, 6 of 22 pts with DNA- and RNA-seq data available had a PFS event. At BL, these pts had low TMB, low TI-GEPs (4 of 6), or high levels of immunosuppressive TME signatures (eg, fibroblast, M2 macrophages) vs pts without a PFS event. Elevated BL ctDNA was significantly associated with PFS events ( P< .001). Pts with a complete response (CR) on S+D+T had significantly lower levels of BL immunosuppressive TME signatures (eg, M2 macrophages; P< .01) than pts without a CR. We observed a consistent increase in TI-GEPs and decrease in MAPK pathway activity score (MPAS) from BL to biopsy at 2-3 wk in all pts regardless of subsequent progression. Pts with a PFS event and available longitudinal biomarker data were characterized by a subsequent decrease in TI-GEPs and an increase in MPAS per the 8- to 12- wk biopsy sample. Conclusions: These results suggest that S+D+T had an early impact on tumor cells and the TME, potentially promoting antitumor activity. The majority of PFS events occurred in the TMB-low/TI-GEP-low subgroup. An immunosuppressive TME might preclude early CRs. The predictive implications of coupling TMB/GEP subgroups with other TME marker subgroups need further validation. The randomized placebo-controlled p3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Circulating PD-L1-exosomes to monitor tumor response in melanoma patients.
Authors: Nardin Charlee , Cordonnier Marine , Chanteloup Gaetan , Derangere Valentin , Algros Marie Paule , Marcion Guillaume , Arnould Laurent , Garrido Carmen , Aubin Francois , Gobbo Jessica
Published: May 2019

9517

Background: In the era of effective molecular targeted treatments and immunotherapies, there is an urgent need to implement the use of circulating biomarkers in the clinic to facilitate personalized therapy and predict treatment response. We conducted a retrospective study to demonstrate the involvement of circulating PD-L1 exosomes in melanoma patients. Methods: One hundred melanoma patients were included. Exosomes were isolated by ultracentrifugation and evaluated by nanoparticle tracking analysis using a NS300 Instrument (Nanosight, Amesbury, UK). Isolated exosomes were tested for the expression of exosomes markers such as TSG101. PD-L1 expression in plasma and in melanoma plasma-derived exosomes (ExoPD-L1) was measured using an enzyme-linked immunosorbent assay (PD-L1 Human ELISA Kit, Invitrogen). Results: First, ExoPD-L1 was assessed in melanoma cell lines. Exosomes may have a role in cancer immunosuppression mediated by T-cells since they were as efficient as cancer cells to inhibit T-cells activation. In melanoma patients, ExoPD-L1 (median 64,26 pg/mL) was significantly higher than free PD-L1 in the plasma which was barely detectable (0,1 pg/mL). Furthermore, ExoPD-L1 was detected in all patients whereas only 67 % were PD-L1 positive in tumor. Although baseline ExoPD-L1 levels were not associated with clinicopathologic characteristics and tumour burden, ExoPD-L1 variations (ΔExoPD-L1) after treatment correlated with tumor response and survival. A ΔExoPD-L1 cut-off of > 100 was defined, yielding a 83% sensitivity, a 70% specificity, a 91% positive predictive value and a 54% negative predictive values for disease progression. The use of this cut-off allowed stratification in two groups of patients statistically different in terms of overall survival and progression free survival. Conclusions: PD-L1 level in circulating exosomes may be a more reliable marker than PD-L1 expression in the tumor tissue. Monitoring of circulating exosomal PD-L1 may be a promising biomarker to predict tumor response and correlate with survival.
One-year (yr) recurrence-free survival (RFS) from a randomized, open label phase II study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surgx) versus surgx for resectable stage IIIB-IVM1a melanoma (MEL).
Authors: Dummer Reinhard , Gyorki David E. , Hyngstrom John Robert , Berger Adam C. , Conry Robert Martin , Demidov Lev V. , Sharma Anjali , Treichel Sheryl , Faries Mark B. , Ross Merrick I.
Published: May 2019

9520

Background: We previously reported that neo T-VEC + surgx resulted in a pathologic CR rate of 21% and an OR rate of 14.7% in a randomized trial of neo T-VEC + surgx vs upfront surgx in pts with resectable stage IIIB/C/IVM1a MEL (Andtbacka et al, ASCO 2018; NCT02211131). Here, we present results from an interim 1-yr analysis of RFS. Methods: Patients (pts) with resectable stage IIIB/C/IVM1a MEL, ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm, and no systemic tx 3 mos prior were randomized 1:1 to 6 doses/12 wks of T-VEC followed by surgx during wks 13-18 (Arm 1) vs upfront surgx during wks 1-6 (Arm 2). T-VEC was given at standard dosing until surgx, no injectable tumors, or intolerance. This analysis conducted on the ITT set estimated a between-group difference in 1-yr RFS per protocol. An RFS event was defined as the first of local, regional or distant recurrence or death due to any cause after surgx. Pts without a R0 surgical outcome or withdrew prior to surgx were considered an event at randomization for RFS. In a sensitivity analysis, RFS was calculated from randomization to the date of the first post-surgx event regardless of surgical outcome. Results: 150 pts were randomized (76 Arm 1, 74 Arm 2). Median (range) follow-up time was 20.6 (0.1, 38.5) mos in Arm 1 and 20.0 (0.1, 35.3) mos in Arm 2. 75% in Arm 1 and 93% in Arm 2 had surgx as planned. R0, R1, and R2 rates, respectively, for Arm 1 were 42.1%, 31.6%, and 1.3% and for Arm 2 were 37.8%, 51.4%, and 4.1%. At 1 yr, 33.5% of pts in Arm 1 and 21.9% of pts in Arm 2 remained recurrence free (HR 0.73, P= 0.048). From the sensitivity analysis, 55.8% of pts in Arm 1 and 39.3 % in Arm 2 remain recurrence free at 1 yr (HR 0.63, P= 0.024). OS rates at 1 yr were 95.9% in Arm 1 and 85.8% in Arm 2 (HR 0.47, P= 0.076). Pts receiving subsequent adjuvant tx was 8 (11%) in Arm 1 and 20 (29%) in Arm 2- most common was immunotherapy 6 (8.2%) and 8 (11.6%), respectively. Conclusions: In the largest randomized neo trial to date in resectable stage IIIB-IVM1a MEL, the following outcomes were improved with neo T-VEC monotherapy vs surgx: R0 surgical resections, 1-yr RFS, and OS. Primary analysis of RFS at 2 yrs is expected. Clinical trial information: NCT02211131.