tbuckley/cabot-search huggingface dataset:
SOLO1 versus SOLO2: Cost-effectiveness of olaparib as maintenance therapy for newly diagnosed and platinum-sensitive recurrent ovarian carcinoma among women with germline BRCA mutations (<i>gBRCAmut</i>).
Authors: Juliet Elizabeth Wolford, Krishnansu Sujata Tewari, Su-Ying Liang, Jiaru Bai, Amandeep Kaur Mann, Kathleen N. Moore, Eric Pujade-Lauraine, Jonathan A. Ledermann, Bradley J. Monk, John K. Chan
Journal: Journal of Clinical Oncology (2019)

5545 Background: With the December 19, 2018 regulatory approval by the US FDA of olaparib tablets as maintenance therapy for women with deleterious or suspected deleterious germline or somatic BRCAmut advanced ovarian carcinoma, it becomes important to clarify the role of PARP inhibitors in this disease. We evaluated cost-effectiveness of olaparib in the upfront (SOLO1) versus the recurrent maintenance setting (SOLO2). Methods: Data were obtained from SOLO1, the phase 3 placebo-controlled randomized upfront maintenance study among gBRCAmut patients [median PFS greater than 49.8 vs 13.8m: HR 0.30; 95% CI, 0.23-0.41; p &lt; 0.001, NCT01844986] and SOLO2, the phase 3 placebo-controlled randomized maintenance study among gBRCAmut patients with platinum-sensitive recurrence and at least two prior lines of therapy [median PFS 19.1 vs 5.5m: HR 0.30; 95% CI, 0.22-0.41; p &lt; 0.0001, NCT01874353]. Investigator-assessed median PFS and toxicity data from the trials were incorporated in a Markov model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2015, the costs of pre-treatment testing (eg. gBRCAmut), medications, and management of adverse effects were analyzed. Incremental cost-effectiveness ratios (ICERs) per month of life gained and individual PFS-life year saved (PFS-LYS) were also calculated and compared. Results: In SOLO1, cost prior to progression was 1.7x that of SOLO2 ($937,440 vs $564,451). With the extended, estimated median PFS of at least 49.8m for SOLO1 and 19.1m for SOLO2, upfront maintenance therapy was more cost-effective. SOLO 1 was associated with $312,480 PF-LYS per individual patient, while SOLO2 demonstrated $498,045 PF-LYS. Maintenance olaparib was found to be more cost-effective in the 1st-line setting, with an ICER of $12,149 per month of life gained when compared directly to SOLO2. Conclusions: Although the higher cost associated with olaparib in SOLO1 reflects the longer time patients stay on drug due to extended PFS, the ICER supports early use in the disease course as first-line maintenance therapy among women with gBRCAmut advanced ovarian carcinoma.
Patient reported outcomes in cancer patients: Psychological, physical and functional importance.
Authors: Shiva Shrotriya, Bassam N. Estfan, Mukta Sharma, Supratik Rayamajhi, Declan Walsh
Journal: Journal of Clinical Oncology (2019)

e18209 Background: Patient-reported outcomes (PROs) allow consistent monitoring of patients’ symptoms and quality of life. We evaluated their prevalence among cancer patients. We also evaluated the association of PROs, Emotional Thermometer (ET) distress with demographic and disease characteristics. Methods: PROs were prospectively collected as cross sectional data. This was later combined with retrospectively obtained clinical data from the EMR. Predictors of ET component (Distress, Anxiety, Anger, Depression) was determined by linear regression analysis. The predictors of those who required Help with tablet computers was determined by logistic regression. Results: The mean age was 58 (±14) years; 54% male. The common cancer diagnoses were breast 17%, hematological (leukemia) 17% and lymphoma 12%. Few (7%) participants required help (N = 1076) with the tablet-based surveys. Age ≤ 30 and 51–70 years scored lower in mean depression ET. African Americans had higher ET Anger scale. African Americans scored higher in need of Help –ET. Age 31-50 years was at 13% lower risk and 51–70 years was at 72% lower risk of requiring help. Those with self-care problems were at higher risk of requiring Help with tablet computer. Conclusions: Many cancer patients visiting the cancer center had high pain/discomfort, anxiety/depression, problems with usual activities and mobility problems. Younger patients (31-50 years) had more distress and depression (ET). African Americans reported more problems with mobility, self-care, usual activities, pain/discomfort and anxiety/depression (EQ5D). Those with self-care problems were at risk to require help with tablet-based surveys.
Feasibility study of microbial ecosystem therapeutics (MET-4) to evaluate effects of fecal microbiome in patients on immunotherapy (MET4-IO).
Authors: Tira Jing Ying Tan, Marcus O. Butler, Aaron Richard Hansen, David Hogg, Adrian G. Sacher, Philippe L. Bedard, Kendra Ross, Helen Chow, Aida Al-Kindy, Sarah Boross-Harmer, Wei Xu, Bryan Coburn, Lillian L. Siu, Anna Spreafico
Journal: Journal of Clinical Oncology (2019)

TPS2664 Background: Differences in microbiome diversity and composition in immune checkpoint inhibitor (ICI)-responders vs non-responders have been demonstrated. Transplantation of responder feces in mouse models recapitulated the ICI-responsive phenotype. MET-4 is an oral alternative to fecal transplant consisting a well-defined mixture of intestinal bacteria isolated from healthy donor stool sample. We hypothesize that co-administration of MET-4 with ICI is safe and results in alterations of the gut microbiota. Methods: Three cohorts (n = 65) of subjects with any advanced solid tumor type treated with monotherapy anti- PD1/PD-L1 antibody outside of a therapeutic clinical trial will be enrolled. Group A: safety cohort of 5 subjects already on ICI will receive MET-4 in addition to standard of care (SOC) ICI. If &lt; 2 subjects report adverse events of CTCAE grade ≥3 within 4 weeks at least possibly related to MET-4, this dose will be declared safe and groups B/C may start enrolling. Group B (n = 40): subjects with advanced solid tumors starting on ICI, randomized 3:1 to MET-4 plus SOC vs. SOC. Group C (n = 20): subjects with advanced solid tumors already on ICI with first unconfirmed disease progression randomized 1:1 to MET-4 plus ICI continuation vs. continuing ICI. Serial stool samples will be collected for taxonomic composition, diversity, metagenomics content and MET-4 species abundance. We anticipate the following analyses: 16S rRNA sequencing, shotgun metagenomics sequencing, qPCR, Nanostring nucleic acid detection and metabolomics profiling. Serial blood sampling for flow cytometry/CyTOF. Immune microenvironment of tumor specimen will be examined using immunohistochemistry. Other major inclusion criteria: willingness to provide correlative samples, RECIST v1.1 measurable disease and ECOG 0-2. Subjects unable to swallow oral medications are excluded. For the primary objective of cumulative relative abundance and changes of ICI-responsiveness associated species between baseline and day 12 MET-4, assuming a change of 0.5 standard deviation (SD) of microbial alpha diversity, our study will have ≥84% power to identify a significant difference given a significance level at 0.05 in group B. Assuming a change of 0.9 SD of microbial alpha diversity, we will have ≥83% power to identify a significant difference in group C. Response rates and progression free survival will be assessed per RECIST v1.1 and compared with historical data. Clinical trial information: NCT03686202.
Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma.
Authors: E. Antonio Chiocca, Rimas Vincas Lukas, Ganesh Rao, John A. Barrett, Jill Y. Buck, Nathan Demars, Amy Smith, John Miao, Qiang (John) Zhou, Arnold Bruce Gelb, Laurence Cooper
Journal: Journal of Clinical Oncology (2019)

2020 Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate conditionally expressing IL-12 under the control of veledimex (V) acting via the proprietary RheoSwitch Therapeutic System (RTS) gene switch with a therapeutic window. Intratumoral Ad + oral V monotherapy (Phase 1 study, NCT02026271 ) resulted in a new sustained intra-tumor influx of activated cytotoxic T cells, consistent with an immune-mediated anti-tumor effect improving median overall survival (mOS) of subjects with recurrent glioblastoma (rGBM). This correlated with an increased circulating CD8 + /FoxP3 + T cell ratio (“cytoindex”), an emerging biomarker for mOS. PD-1 expression on infiltrating T cells at biopsy after Ad+V, supports combining controlled IL-12 with a PD-1 inhibitor to further augment T-cell-mediated anti-tumor effects. The rationale is also supported by increased OS (100% combo vs 63% for Ad+V vs 40% for anti-PD-1) in mice bearing GL-261 glioma. Methods: An ongoing open label, dose-escalation Phase 1 trial (NCT03636477) is evaluating safety and tolerability of local, controlled IL-12 with nivolumab (nivo) in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 10 11 viral particles, Day 0) plus V (10-20 mg) PO QD x 15 with nivo (1-3mg/kg) IV on Days -7, 15, then Q2W. Results: Safety data revealed a similar profile as Ad +V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with anti-PD-1 reports. ARs were manageable and reversible with no synergistic toxicities. Nivo alone did not alter peripheral IL-12 levels (median baseline (before anti-PD-1) 0.9 pg/mL; Day 0 1 pg/mL) increasing to 5.5 pg/mL on Day 3. Nivo alone increased peripheral T cells (CD3 + CD8 + median baseline 23%; Day 0 26%) and Ad+V elevated peripheral CD3 + CD8 + to 31% at Day 14. Nivo alone decreased regulatory T cells (FoxP3 baseline 1.5% vs Day 0 0.8%). Ad+V decreased these to 0.3% (Day 14). Combination therapy improved the cytoindex (baseline 15; Day 0 29; Day 14 80). Conclusions: Controlled IL-12 production using Ad + V with nivo is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile, warranting continued investigation in rGBM. Clinical trial information: NCT03636477.
Treatment (tx) characteristics of patients (pts) with locally advanced or metastatic urothelial cancer (mUC) receiving checkpoint inhibitor (CPI) monotherapy in a US clinical practice.
Authors: Alicia K. Morgans, Osama E. Rahma, Shivani K. Mhatre, Ching-Yi Chuo, Jessica Davies, Jorge Martinalbo, Nicole N. Davarpanah, Russell Pachynski
Journal: Journal of Clinical Oncology (2019)

4526 Background: Approval of anti–PD-L1/anti–PD-1 CPI agents has changed the mUC tx landscape, but real-world (RW) tx patterns are not well described. Here, we describe pt characteristics, time on tx (TOT), tx-cycle distribution, relative dose intensity (RDI) and subsequent tx for pts receiving atezolizumab (atezo), nivolumab (nivo) or pembrolizumab (pembro) monotherapy. Methods: Pts diagnosed with mUC who completed atezo, nivo or pembro in the first-line (1L) or prior-platinum second-line and beyond (2L+) settings by April 30, 2018, were identified from the US-based Flatiron Health electronic health record–derived database. TOT was defined as time from first to last CPI administration + 1 cycle, tx cycles as number of CPI doses received during TOT and RDI as ratio of actual to planned dose per week to reflect any dose interruption. Results: RW data from pts receiving atezo, nivo and pembro were analyzed (Table). Up to 38% of pts had ECOG PS &gt; 1. Median TOT ranged from 2.1-2.8 mo, with overlapping 95% CIs; mean TOT ranged from 2.7-4.1 mo. Over 50% of pts had ≤ 4 tx cycles. 21%-38% of pts did not have RDI within 95%-105% of the labeled dose. Most common subsequent txs were platinum-based chemotherapy combinations with gemcitabine or taxanes (post–1L CPI) and taxane monotherapy or other CPI monotherapy/combinations (post–2L+ CPI). Conclusions: Here, we present the largest analysis of RW CPI use in mUC to date. Overall, this unadjusted descriptive analysis showed relative comparability of pt and tx characteristics and TOT across CPI-treated groups. Insights into RW tx allow for an understanding of how clinical trial data translate to broader pt populations, including those with ECOG PS &gt; 1, and may be useful for practitioners. [Table: see text]
Visualizing real-world outcomes through the lens of a molecular tumor board: Persona-typing pancreatic cancers for clinical decision support.
Authors: Emanuel Petricoin, Daniel Barg, Patricia Miren de Arbeloa, Michael J. Pishvaian, Edik Matthew Blais
Journal: Journal of Clinical Oncology (2019)

e18100 Background: Despite the molecular diversity of pancreatic adenocarcinoma, standard therapy options remain largely molecularly-untailored except in the context of DNA damage response alterations such as BRCA mutations, NTRK fusions, or microsatellite instability. Methods: To broaden the utility of molecular profiling, we analyzed real-world outcomes and established 12 molecularly-driven clusters, or “persona types” (PTs), across a cohort of 1280 pancreatic cancers with CLIA-grade genomic/proteomic data (commercially available NGS/IHC panels). Patients were consented into Perthera’s precision oncology platform via referrals from advocacy programs and hospital partnerships for case review by a molecular tumor board (MTB). Persona types were generated using unsupervised k-means clustering of molecularly-tailored therapy recommendations formulated by the MTB. Progression-free survival was documented across all lines of therapy. Results: Personas based on multi-omic profiles and expert-driven recommendations were representative of molecular phenotypes reported in previous studies (e.g. DNA damage response deficiencies, BRAF mutations, other non-KRAS-drivers, SWI/SNF alterations, squamous-associated genes, cell cycle regulators, etc.). To streamline the exploration of real-world outcomes, we developed an interactive dashboard that enables users to compare PFS survival curves across Personas for various therapies such as gemcitabine/nab-paclitaxel, FOLFIRINOX, other standard regimens, immunotherapy, PARP inhibitors, RAF/MEK/ERK inhibitors, and more. Persona types associated with increased/decreased sensitivity to several classes of agents were identified (e.g. PD-1/L1 inhibitors in a persona enriched for cell cycle dysregulation, PARP inhibitors in a persona enriched for BRCA mutations). Conclusions: Empowering oncologists with personalized insights into real-world outcomes may promote investigator-initiated trials and augment clinical decision support, particularly when choosing between standard of care regimens or when exploring potential clinical trial options.
Characteristics of medical oncologists participating in the Oncology Care Model.
Authors: Ravi Bharat Parikh, Justin E. Bekelman, Qian Huang, Joseph Martinez, Ezekiel J. Emanuel, Amol S. Navathe
Journal: Journal of Clinical Oncology (2019)

e18017 Background: The Oncology Care Model (OCM) is Medicare’s first bundled payment program for patients with cancer. Because practices voluntarily enrolled in the OCM in 2016, there may be differences between OCM-participating and non-participating oncologists that impact the OCM’s generalizability. We examine baseline characteristics of OCM participants and markets with high OCM physician participation. Methods: In this cross-sectional study, we identified characteristics of US medical oncologists practicing in 2016 using a national telephone-verified physician database. We linked this data with Dartmouth Atlas and Medicare claims data to identify market characteristics of areas with high OCM participation. We used logistic regression to examine relationships between market characteristics and OCM participation. Results: Of 10428 US medical oncologists, 2605 (24.9%) were listed on an OCM-participating practice’s website. There were no differences in sex or medical training between OCM participants and non-participants, although OCM participants were younger. OCM participants were more likely to be affiliated with large, group, and urban practices that were not part of a health system (Table). Southwest, Southeast, and mid-Atlantic markets had higher OCM participation. Markets with high OCM physician participation had higher specialist density, Hospital Care Intensity Index, and acute care utilization at the end of life (all p &lt; 0.001). Market penetration of Accountable Care Organizations (adjusted odds ratio [aOR] 4.65, 95% CI 3.31-6.56, p &lt; 0.001) and Medicare Advantage (aOR 2.82, 95% CI 1.97-4.06, p &lt; 0.001) were associated with higher OCM participation. Conclusions: We found differences in provider and practice demographics, care intensity, and prior exposure to alternative payment models between OCM-participants and non-participants. Differences in practice and market characteristics influence oncologists’ participation in alternative payment models and should be accounted for in Medicare’s OCM evaluation. [Table: see text]
Dendritic cell vaccination in metastatic uveal melanoma as compassionate treatment: Immunological and clinical responses.
Authors: Alvaro Moreira, Stefanie Gross, Ugur Uslu, Jan Doerrie, Mirko Kummer, Stefan Schliep, Felix Sponagl, Christopher Lischer, Michael Erdmann, Lucie Heinzerling, Gerold Schuler, Beatrice Schuler-Thurner
Journal: Journal of Clinical Oncology (2019)

e21024 Background: Other than cutaneous melanoma, metastatic uveal melanoma (UM) is minimally responsive to checkpoint inhibitors. The prognosis remains very poor with mortality rates nearly unchanged over the last decades. The recently growing insight that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of vaccines including dendritic cell (DC) vaccines. Methods: We vaccinated an UM patient in a compassionate use setting and assessed the immunological and clinical responses. Based on this experience we performed individual compassionate treatments in other UM patients using DC loaded by peptide pulsing and/or mRNA transfection (autologous tumor RNA or RNA coding for tumor antigens). Results: The first patient was vaccinated in 2013 after a liver metastasis was resected and checkpoint blockade with ipilimumab was started. In 2014 the patient showed progression in the liver. We continued DC vaccination in shorter intervals and adapted antigen loading (with mRNA coding for an individual GNAQ driver mutation) accompanied by a further cycle of ipilimumab. Therapy resulted in complete remission of liver metastases, but the patient developed new skin metastases. Again the loading of DC was adapted (peptides of passenger mutations predicted after Next-Generation Sequencing) and infusions with pembrolizumab were started. Pathology from some regressing lesions showed a massive T cell infiltration and in parallel GNAQ mutation-specific T cells could be found in the patient’s blood. Skin metastases regressed and the patient is now free of detectable tumor after 65 months. Immune monitoring in the patient’s blood showed a vaccine-induced functional T cell response against the QNAQ-driver mutation. Three of other four patients are also still alive, one in complete remission under DC vaccination in combination with pembrolizumab, two of them showing measurable disease, and one deceased disease related after 28 months, resulting in a median OS of the five patients of 36.4 months. Immune monitoring in one of those patients showed a CD4+ and CD8+ INF-gamma T cell response against the autologous tumor RNA vaccine. No grade 3 or 4 toxicity occurred. Conclusions: The observed prolonged median OS and the fact that 2/5 patients remain disease-free is definitely encouraging. Vaccination immunotherapy with antigen-laden DC is a potential therapeutic option for patients with metastatic uveal melanoma. Combinations with checkpoint inhibitors proved promising, and should be further evaluated in clinical trials.
First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): Updated results for KEYNOTE-427 cohort A.
Authors: Scott S. Tykodi, Frede Donskov, Jae-Lyun Lee, Cezary Szczylik, Jahangeer Malik, Boris Yakovlevich Alekseev, James M.G. Larkin, Vsevolod Borisovich Matveev, Rustem Gafanov, Piotr Tomczak, Poul F. Geertsen, Pawel J. Wiechno, Sang Joon Shin, Frederic Pouliot, Teresa Alonso-Gordoa, Rachel Kloss Silverman, Rodolfo F. Perini, Charles Schloss, David F. McDermott, Michael B. Atkins
Journal: Journal of Clinical Oncology (2019)

4570 Background: KEYNOTE-427 (NCT02853344) is an open-label, single-arm, phase 2 study to evaluate efficacy and safety of first-line single-agent pembro, a programmed death 1 (PD-1) inhibitor, in patients (pts) with ccRCC (cohort A) and non–clear cell RCC (cohort B). Updated follow up from cohort A are presented. Methods: Pts with histologically confirmed ccRCC, measurable per RECIST v1.1, and no prior systemic therapy were eligible. Pts received pembro 200 mg IV Q3W for 2 y or until confirmed progressive disease, unacceptable toxicity, or pt decision to withdraw. Primary end point was objective response rate (ORR; per RECIST v1.1 blinded independent central review). Additional end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: 110 pts enrolled; median (range) follow-up was 18.0 (2.5-22.7) mo. Median age (range) was 64 (29-87); 38.2%, 47.3%, and 14.5% had favorable, intermediate, and poor IMDC risk, respectively; 47.3% were PD-L1 positive. Confirmed ORR was 36.4% with 3 (2.7%) CRs and 37 (33.6%) PRs. Median DOR was not reached. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached. Results by IMDC category are outlined in the table. By PD-L1 status, confirmed ORR was 44.2% and 29.3% for positive and negative, respectively. By sarcomatoid differentiation (n=11), confirmed ORR was 63.6%. Treatment-related AEs occurred in 80.9%, with pruritus (28.2%) and fatigue (28.2%) most commonly reported. One pt died of treatment-related pneumonitis. Conclusions: With a median 18-months’ follow up, first-line pembro monotherapy continued to show antitumor activity in pts with ccRCC. Meaningful responses were observed in pts with intermediate/poor IMDC risk, PD-L1 positive and sarcomatoid differentiated tumors. Safety profile was comparable to previously reported. Clinical trial information: NCT02853344. [Table: see text]