tbuckley/cabot-search huggingface dataset:
Impact of varying approaches used to compare costs between drug regimens.
Authors: Peter G. Ellis, Kathleen Lokay, Stephanie McCutcheon, John M. Kirkwood
Journal: Journal of Clinical Oncology (2016)

e18262 Background: Via Pathways’ Disease Committees request cost comparison data from the staff at Via Oncology (VIA) only when two drug regimens are considered comparable in efficacy and toxicity. For Medicare Part B drugs, VIA calculates cost to the payer/patient by assessing estimated units to be billed and using current Medicare allowables per billable unit. Historically, VIA used an assumed fixed weight of 80 kg to represent the typical American. These calculations also accounted for whether or not compensated waste is billed, anticipated number of cycles, and rounding of the calculated dose to the nearest billable increment. Two immuno-oncology drugs, nivolumab (NIV) and pembrolizumab (PEM), are FDA approved. Both of these are dosed based on weight only. During 2016, at the request of one of VIA’s Disease Committees, VIA calculated the cost of each drug regimen using two approaches: a single fixed weight and a range of reasonable weights reflective of actual variability among patients. Methods: VIA calculated the relative cost of NIV and PEM assuming 3 mg/kg and 2 mg/kg, respectively. A total of 24 weeks of therapy were compared for each, resulting in 12 cycles of NIV (Q14 days) and 8 cycles of PEM (Q21 days). Two approaches were taken: first, a fixed weight of 80 kg was used to calculate the total dose per cycle; second, a range of 26 sequential weights from 70 kg to 95 kg (average of 82 mg to match CDC data) was used to calculate the total dose per cycle. Results: With the fixed weight assumption of 80 kg, there was zero difference between the relative costs of the two regimens. However, with the variable weights assumption, PEM was less expensive than NIV in 21 out of 26 scenarios and equal to NIV in five scenarios, for an average difference across 26 weights of 9%. This difference when using a sequential range of weights is due to the billable unit differences between the drugs. Conclusions: Assumptions used in comparing the costs of IV drug regimens billed under Medicare Part B need to reflect real-world variables such as whether waste can be billed, the billable increments, and a range of expected patient heights and weights.
Cetuximab administered once every second week to patients with advanced head and neck cancer: Safety and feasibility of maintenance schedule after first-line chemotherapy.
Authors: Raffaele Addeo, Liliana Montella, Salvatore Del Prete, Bruno Vincenzi, Amerigo Mastella, Salvatore Mazzone
Journal: Journal of Clinical Oncology (2018)

e18006 Background: Cetuximab is typically adm inistered on a weekly schedule for patients with recurrent or metastatic head and neck squamous cell cancer (HNSC C). This study explores cetuximab administered every 2 weeks (q2w) (Group A) and compares the results with those obtained in a historical control group (Group B) of patients receiving weekly cetuximab . Methods: In Group A biweekly cetuximab was administered at 500 mg/m2, instead Group B, a control group of patients treated at our institution previously, received weekly infusion of cetuximab at 250 mg/m2. Seventy-two patients were enrolled: 36 in Group A and 26 in Group B. Results: Confirmed partial response rates were 19% for Group A (7/36) and 17% for Group B (6/36)according to intention to treat analysis. No verified partial responses were observed among 11 patients with pharynx primaries. Median progression-free survival (PFS) were similar for both groups (PFS, 4.9 and 4.0 months, respectively). In the biweekly group, patients performed 95% of the expected infusions compared to 88% of the control group. The most common cetuximab-related adverse events (all grades) among treated subjects included fatigue, rash, and hypomagnesemia. In the weekly Cetuximab group we observed a greater number of dose reduction, 9 than 5 in the biweekly group. Conclusions: Every-other-week maintenance cetuximab schedule was well tolerated and did not worsen toxicity that occurred during chemotherapy. Our data suggest that patients compliance and adherence improve using the biweekly schedule.
Comparative gene expression analysis for identifying clinically relevant overexpressed genes in childhood brain tumors.
Authors: Lauren Sanders, Brittany Rose-Dey, Holly Beale, Ellen Kephart, Jacob Pfeil, Olena Morozova, Sameer Agnihotri, Sofie R. Salama, David Haussler
Journal: Journal of Clinical Oncology (2018)

e14033 Background: Diffuse intrinsic pontine glioma (DIPG) is a rare and invasive pediatric brain tumor with limited treatment options and poor prognosis. Methods: The Treehouse Childhood Cancer Initiative at UC Santa Cruz has developed a comparative gene expression analysis method which identifies outlier genes in gene expression data from tumor samples. This method may be useful for identifying consistently activated pathways in difficult-to-treat tumors such as DIPG. Results: We show here that this method identifies HARS and HMGCR as over-expressed genes in a cohort of DIPG patient tumor derived cell lines. Differential expression analysis demonstrates that these genes are significantly over-expressed in DIPG tumors as compared to normal brain tissue, indicating that they may be therapeutically relevant. Targeting these genes in vitro with FDA-approved drugs significantly reduces cell line viability, and targeting both genes at once in combinatorial therapy is more effective than targeting each gene separately. These drugs do not reduce viability of normal human astrocytes or neural stem cells. The cholesterol biosynthesis pathway, which is driven by HMGCR expression and is a known driver pathway in gliomas, is enriched in DIPG cell lines and in DIPG patient samples. Conclusions: Our results indicate that the cholesterol biosynthesis pathway may be enriched in a subset of DIPG tumors and may be a viable therapeutic target. Future experiments will test our results on a larger cohort of DIPG cell lines.
Lowering the <i>P</i> Value Threshold
Authors: Val Gebski, Karen Byth
Journal: JAMA (2018)

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Implications of KRAS status in first line chemotherapy with bevacizumab in advanced colorectal cancer: A phase IV study of Hellenic Oncology Research Group (HORG).
Authors: Anna Koumarianou, Nikolaos Ziras, Stylianos Kakolyris, Michael Vaslamatzis, Aristidis Polyzos, Nikolaos K. Kentepozidis, Athina Christopoulou, Spyros Xynogalos, Athanasios Athanasiadis, Ilias Athanasiadis, Athanasios Anagnostopoulos, Athanasios Karampeazis, Christos E. Emmanouilides, Ioannis Boukovinas, Paris Makrantonakis, Charalambos Kouroussis, Efthimios Prinarakis, Dora Hatzidaki, Vassilis Georgoulias
Journal: Journal of Clinical Oncology (2018)

e15521 Background: Bevacizumab (BEV) is an active antiangiogenic agent for the treatment of all patients (pts) with advanced colorectal cancer (CRC). We investigated the toxicity, compliance and survival of pts with locally advanced/inoperable or metastatic CRC treated with BEV-based treatment according to KRAS status. Methods: This phase IV study recorded prospectively (July 2009-June 2016) the clinicopathologic characteristics, safety and survival of pts receiving BEV with 1st line chemotherapy according to oncologist’s preference. Results: Of 682 pts providing consent for BEV-based therapy, 382pts completed treatment; 144pts had disease progression and 156pts discontinued treatment (adverse events: 58pts; toxic deaths: 2pts; consent withdrawn: 34pts; lost to follow up: 5pts; other reasons: 33pts whereas 24pts underwent curative metastasectomy/surgery). On treatment initiation KRAS status was recorded as mutant (mtKRAS) in 229pts (33.65%), wild type (wtKRAS) in 177pts (26%) and unknown (uKRAS) in 276pts (40.5%). Chemotherapy regimens included FOLFOX (243pts; 37%), FOLFIRI (197pts; 30%), XELOX (147pts; 22.5%) and XELIRI (69pts; 10.5%). The median follow up was 34.9m (0.4–66.3), the mPFS of the entire cohort was 10.8m (0.4-66.3) [mtKRAS 11.0m (1.0-55.7), wtKRAS 9.7m (0.9-61.9), uKRAS 11.3m (0.4-66.3); p = 0.033 (all three), p = 0.051 (mt vs u), p = 0.020 (wt vs u)] and the mOS was 26.4m (0.4-66.3) [mtKRAS 25.6m (1.4-61.3), wtKRAS 25.2m (2.2-63.7) and uKRAS 28.1m (1.4-66.3); p = 0.796 (all three)]. The ORR (CR+PR) in evaluable pts was 46.6% (104pts) in mtKRAS, 56.1% (97pt) in wtKRAS and 40.9% (112pt) in uKRAS [p = 0.007 (all three); p = 0.063 (mt vs wt); p = 0.002 (wt vs u)]. The ORR for FOLFOX/BEV was 48.3% (115pts), FOLFIRI/BEV 47.7% (92pts) and XELOX/BEV 45% (65pts) regardless the KRAS status. Toxicity profile was similar to previous BEV-investigating studies. BEV-related SAEs were myocardial infarction (1pt; G5), ileus (2pts; G4) and thromboembolism (8pts; G4). Conclusions: This phase IV study adds on evidence that BEV-based front line therapy is highly efficacious in pts with advanced CRC independently of mutant, wild or unknown KRAS status. Clinical trial information: NCT01811108.
TCT-620 Influence of diabetes mellitus and chronic kidney disease on diagnostic accuracy of Quantitative Flow Ratio (QFR).
Authors: Martyna Zaleska, Lukasz Koltowski, Jakub Maksym, Mariusz Tomaniak, Aleksandra Chabior, Aleksandra Pohadajło, Mateusz Soliński, Adam Rdzanek, Arkadiusz Pietrasik, Zenon Huczek, Tomasz Mazurek, Grzegorz Opolski, Janusz Kochman
Journal: Journal of the American College of Cardiology (2018)
Allometric scaling of Trastuzumab-MCC-DM1, a HER2 antibody drug conjugate
Authors: Jay tibbitts, Nelson Jumbe, Doug Leipold, Paul Fielder
Journal: Cancer Research (2007)

1550  The extrapolation of nonclinical pharmacokinetics (PK) to prediction of human pharmacokinetics is a critical step in drug development. Several strategies have been employed for such extrapolations, often based on the pharmacokinetics of one or more nonclinical animal species. The success of these strategies has been limited, often by the lack of similarity between the physiology of the selected nonclinical species and that of humans. For biotherapeutics, whose pharmacokinetics often depend on target binding, this dissimilarity is often more apparent.  Trastuzumab-MCC-DM1 is an antibody drug conjugate (ADC) currently in development for the treatment of metastatic breast cancer. This conjugate is binds to HER2, an antigen expressed only in humans and primates.  In this work, we utilized multiple methods for predicting the pharmacokinetics of an antibody drug conjugate in humans. Using PK data from mice, rats, and cynomolgus monkeys, we used simple allometry, simple allometry with corrections (eg. brain weight, maximum lifespan), and species invariant time methods. Because the ADC exhibited dose dependent pharmacokinetics in monkeys, and was expected to behave similarly in humans, it was difficult to employ simple allometry methods. Species invariant time methods, however, were capable of incorporating this pharmacokinetic behavior and appropriately propagating it to predictions of human pharmacokinetics. For the species invariant scaling of the ADC to humans, it was assumed that ADC pharmacokinetics in monkeys scaled to humans as a function of metabolic rate. Concentration-time curves for the ADC were transformed using kallynochron times for a 70 kg human. This provided predicted concentration-time curves for humans, from which pharmacokinetic parameters could be determined. The resulting predicted mean ± SD population PK estimates of human total clearance (CLt, L/day) and terminal half-lives (t1/2β, days) at 0.3, 3, and 30 mg/kg were 1.51 ± 0.48, 0.772 ± 355, and 0.336 ± 0.0471 L/day; and 2.80, 5.28, and 9.89 days, respectively. The mean population estimate for volume of distribution was 2.92 L. Trastuzumab-MCC-DM1 is currently being studied in a Phase I trial for the treatment of metastatic breast cancer; a trial that will provide PK data for comparison to the allometric predictions shown above.
Association between metastatic free interval and recurrent metastatic breast cancer survival: Findings from the Surveillance, Epidemiology and End Results database.
Authors: Enoch Chang, Sarah Schellhorn Mougalian, Kerin B. Adelson, Melissa R. Young, James B. Yu
Journal: Journal of Clinical Oncology (2018)

e13069 Background: The prevalence of patients living with prolonged interval between initial breast cancer diagnosis and development of subsequent metastatic disease may be increasing with improved treatment. In order to counsel these patients as to their prognosis, our study of a population-level U.S. cohort investigates the association between metastatic-free interval (MFI) and subsequent survival from newly diagnosed metastatic breast cancer (MBC). Methods: The Surveillance, Epidemiology and End Results database was used to identify patients with both an initial stage 1-3 breast cancer diagnosis and subsequent MBC diagnosis recorded from 1988-2014. Patients were stratified by MFI ( < 5 years, 5-10 years, > 10 years). The association between MFI and metastatic breast cancer-specific mortality (MBCSM) was analyzed with Fine-Gray competing risks regression. Results: Patients with > 10 year MFI were less likely to die of breast cancer when compared with a referent group of patients with < 5 years MFI (standard hazard ratio (SHR) 0.77 [95% CI 0.65-0.90;] P < 0.001). There was no significant difference for patients with MFI of 5-10 years (SHR 0.92 [95% CI 0.81-1.04, P = 0.191]) compared to < 5 years. Other prognostic factors like White race, lower tumor grade, and ER/PR positive receptors were also associated with improved cancer-specific survival after diagnosis of MBC. Conclusions: Prolonged metastatic free interval greater than 10 years between initial breast cancer diagnosis and subsequent metastatic disease was found to be associated with improved recurrent MBC survival. This has potential implications for counseling patients as to prognosis, choice of treatment, as well as the stratification of patients considered for MBC clinical trials.
Immune checkpoint inhibitors and stereotactic radiosurgery (SRS) in melanoma brain metastases.
Authors: Charlotte Fenioux, Idriss Troussier, Jean-Jacques Mazeron, Charles Henry Canova, Philippe Saiag, Magali Fort, Jean-Philippe Spano, Antoine Kourilsky, Ioannis Lamproglou, Philippe Maingon, Charles Valery
Journal: Journal of Clinical Oncology (2018)

e21523 Background: Major advances have been made in management of metastatic melanoma with immune checkpoint therapy (ICT) such as anti-CTLA4 and anti-PD1 therapies. However, data on the use of ICT in combination with brain radiation therapy is limited. In this study, we reported toxicities and efficiency outcomes of patients undergoing concurrent administration of ICT and Gamma-knife radiosurgery. Methods: From an institutional database, we identified, all consecutive patients with melanoma brain metastasis, treated with Gamma Knife radiosurgery, who receiving concurrent ICT with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Results: From January 2014 to December 2016, 62 patients with 296 lesions were included, and 55 patients (88%) had ongoing ICT at the time of irradiation. Median follow-up time was 18 months (13-22). Minimal median dose at 50% reference isodose was 18 Gy, with a median tumor volume of 0.22 cm3. Median healthy tissue receiving 12 Gy per lesion was 1.04 cm3. 10 patients (16,1%) had adverse events of all grade following irradiation, with 5 grade > = 3, and one patient had radionecrosis. The 1 year control rate per lesion irradiated was 90%. Thirty patients (48%) developed distant brain metastases after a median time of 3.2 months following GK procedure. At the time of analysis, 35 patients had died. Median OS was 14 months from the date of radiation treatment. Median OS in subgroup treated with Ipilimumab (n = 35), Nivolumab (n = 15), multiples immunotherapy (n = 8) were respectively: 13 months, 14 months, 13.5 months; and was not reached for the Pembrolizumab subgroup (n = 12). In univariate analysis, predictive factors of OS were: DS-GPA score ≥3 (p = 0,022), number of lesions irradiated (p = 0,0011), localization in the brainstem (p = 0,013), total volume (p = 0.01), previous irradiation (p = 0.05). Conclusions: Association of Gamma-knife radiosurgery and immune checkpoint inhibitor in melanoma brain metastasis is safe and shows favorable outcomes in this population excluded from most trials.
Cumulative corticosteroid exposure in patients experiencing checkpoint inhibitor toxicity.
Authors: Romaana Mir, Heather May Shaw, Hariharan Kuhan, Veronique Bataille, Roy Vergis, Carie Corner, Paul D. Nathan
Journal: Journal of Clinical Oncology (2017)

e21010 Background: Despite significant gains from systemic immunotherapy, prompt recognition and management of immune related adverse events (irAEs) remains key to minimising acute and chronic morbidity, and can sometimes allow treatment to be re-initiated. Active management of irAEs is corticosteroid based, with additional immunosuppressants used for steroid-refractory toxicity. Although the majority of irAEs resolve promptly, prolonged steroid exposure is required to maintain irAE control. Patients are therefore frequently exposed to cumulative high doses of steroids that in turn can be associated with significant long-term morbidity. Methods: Melanoma patients treated at Mount Vernon Cancer Centre (UK) with ipilimumab, pembrolizumab or combination ipilimumab and nivolumab; who were managed for checkpoint inhibitor-induced colitis had their corticosteroid exposure calculated. Data was collected on patient characteristics, onset of colitis and the subsequent use of corticosteroids, immunosuppressant and anti-TNFα agents until complete resolution of symptoms. Results: Of 137 patients, 18 (13.1%) had grade 3-4 colitis. Median time to onset of colitic symptoms was 13 days (IQR 7-20) with 8 (44%) requiring intravenous corticosteroid. Median time from commencement of steroid treatment to grade 1 colitis was 11.5 days (IQR 6.75-25.25), with resolution of symptoms seen at a median of 43 days. Median total corticosteroid exposure was 3000mg oral prednisolone equivalent (range 540-7580mg) with median duration of corticosteroid exposure being 103.5 days (IQR 67-136). 8 patients experienced flare of colitis during corticosteroid dose reduction. In all cases of colitis flare, the anti-TNFα agent infliximab resulted in improvement to grade 1 toxicity within 48 hours. Conclusions: Patients requiring treatment with corticosteroids for checkpoint inhibitor induced colitis are exposed to high doses of corticosteroids for prolonged periods of time, with the potential for significant steroid-associated sequelae. Alternative steroid-sparing regimens to manage checkpoint inhibitor induced autoimmune toxicities are required.
Evolution and clinical impact of genomic alterations detectable in circulating tumor DNA of 1150 advanced EGFR-mutant (mt) lung cancer patients.
Authors: Collin M. Blakely, Wei Wu, Matthew A. Gubens, Julia Rotow, Victoria Wang, Kimberly Banks, Richard B. Lanman, Philip C. Mack, Hatim Husain, Caroline Elizabeth McCoach, Robert Charles Doebele, Jonathan Riess, Trever Grant Bivona
Journal: Journal of Clinical Oncology (2017)

9009 Background: Advanced EGFR-mt lung adenocarcinomas (LUAD) frequently harbor additional genetic alterations. The clinical significance of these concurrent alterations and how they evolve with treatment are unclear. Methods: We performed next-generation sequencing (NGS) of ~70 cancer related genes from the circulating tumor DNA (ctDNA) of 1150 consecutive advanced LUAD patients (pts) with detectable EGFR mts. The analysis included 113 samples from 81 pts for whom clinical outcome data were known. Clinical response to EGFR TKI treatment was correlated to mutational status in 12 cancer-related pathways. Results: EGFR-mt cases contained an average of 3.6 genetic alterations (range 1-18). There was enrichment for co-alterations in TP53, CDK6, CTNNB1 and SMAD4 in EGFR-mt cases compared to a control cohort of 1008 EGFR WT cases. Enrichment for the EGFR T790M mutation was found upon progression to first-line EGFR TKI treatment, as expected. Analysis of 450 T790M-mt cases showed enrichment for co-alterations in genes controlling the cell cycle (28% vs. 21%, p = 0.01), DNA repair (12% vs. 8%, p = 0.03), and WNT (16% vs. 11%, p = 0.03) signaling. The number of genetic alterations increased during progression on each line of therapy in a manner unlinked to age, gender, or tobacco exposure (mean 3.2 pre-TKI vs. 6.4 after 2 nd line, p = 0.001). Upon progression to second-line treatment, analysis revealed further selection for co-alterations in TP53, CCNE1, MYC and PIK3CA and the associated pathway-level classifications. We found an increased frequency of co-alteration in cell cycle genes in EGFR TKI non-responders versus responders (33% vs. 0%, p = 0.0005). Conclusions: Within the landscape of advanced EGFR-mt LUAD, we uncover features of evolutionary selection for multiple concurrent oncogenic pathway alterations including TP53, WNT, PI3K, MYC, and cell cycle genes. This large clinical and genetic dataset prompts a re-evaluation of the prevailing paradigm of monogenic-based molecular stratification to monotherapy, and highlights an alternative model of genetic collectives as a previously underappreciated determinant of lung cancer progression and therapy resistance.