tbuckley/cabot-search huggingface dataset:
Cost-effectiveness of new therapies in first-line treatment of advanced melanoma for patients with independent BRAF mutation status from a Brazilian private payer perspective.
Authors: Christina Matteucci, Joao PsDN Lima, Graziela Bernardino, Ana Paula Oliveira, Daniela Galdeano Maia
Journal: Journal of Clinical Oncology (2018)

e21546 Background: The objective of this study was to assess the cost-effectiveness of emerging therapies (nivolumab, ipilimumab+nivolumab, pembrolizumab) as first line treatment in advanced melanoma for patients with independent BRAF mutation status from the Brazilian private payer perspective. Methods: A CEA using a three-state partitioned survival structure was developed to estimate accrued life years, total drug acquisition, follow-up and toxicity costs over a lifetime horizon (30 years). The model utilized the intent-to-treat 24-month progression-free survival data and overall survival data from recently reported 36-month follow-up from CheckMate 067 trial and, a network meta-analysis which considers time-varying hazard ratios. The model takes the perspective of a Brazilian third party payer, hence indirect costs are not taken into account. Drug acquisition, administration, follow-up, and adverse event costs were estimated using a micro-costing approach and prices were obtained from official Brazilian price lists – CMED, Simpro, Planserv 2008 and CBHPM 2015. Adverse event frequencies were derived from the CM 067 trial and published literature. Results: In relation to ipilimumab incremental cost-effectiveness ratios (ICER) for nivolumab monotherapy, nivolumab + ipilimumab and pembrolizumab were R$74,387, R$52,986 and R$66,247 respectively. Among the considered therapies, nivolumab + ipilimumab resulted in the greatest accrued survival with 6.111 life-years over the 30-year time horizon, followed by nivolumab monotherapy (4.744 life-years) and pembrolizumab (3.864 life-years). Conclusions: All evaluated interventions (ipi+nivo, nivo, pembrolizumab) were considered cost-effectivewhen compared to ipilimumab as first line treatments in advanced melanoma for patients regardless BRAF mutation status.
TP53 mutations as predictor of response and longer survival under immune checkpoint inhibitors in advanced non-small cell lung cancer
Authors: S. Assoun, N. Theou-Anton, M. Nguenang, A. Cazes, C. Danel, B. Abbar, J. Pluvy, V. Gounant, A. Khalil, C. Namour, S. Brosseau, G. Zalcman
Journal: Annals of Oncology (2018)

Background: Tumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and predict ICI benefit. Methods: TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS). Results: In total, 72 patients (median [interquartile range] age: 61 [33-83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0-1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more. In 65 patients with available data, 36 (55%) expressed PD-L1 in ≥ 50% of tumor cells, 20 (31%) in 1-49% of cells, and nine (14%) were PD-L1-negative. Non-synonymous TP53 mutations were observed in 41 (57%) and 25 (35%) harbored KRAS-mutated tumors. After a median follow-up of 15.2 months (95% confidence interval [CI] 10.3-17.4m), the median OS in the TP53-mutated group was 18.1 months (95% CI 6.6-not reached), vs. 8.1 months (95% CI 2.2-14.5, hazard ratio [HR]=0.48; 95% CI 0.25-0.95, p = 0.04) in the TP53-wild-type group. Median progression-free survival was significantly longer in TP53-mutated patients (4.5 months, 95% CI 2.8-18.1 versus 1.4, 95% CI 1.1-3.5; p = 0.03). Objective response rate (ORR) was higher in TP53 mutation patients (51.2% vs. 20.7%; p = 0.01). In multivariate analysis, TP53 mutations independently associated with longer OS (HR = 0.35, 95% CI 0.16-0.77, p = 0.009). Conclusions: TP53-mutated status correlated with immunotherapy clinical benefit in aNSCLC. Legal entity responsible for the study: Pr Gérard Zalcman. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Clinical significance of detection of secreted paraprotein type in multiple myeloma.
Authors: Nailya Guskova, Oleg Ivanovich Kit, Irina B. Lysenko, Irina Aleksandrovna Goroshinskaya, Anastasia Nozdricheva, Yulia Grishakova, Kristina Avanesova, Irina Tselishcheva, Izabella Torpudzhyan
Journal: Journal of Clinical Oncology (2016)

e19500 Background: The purpose of the study was to assess clinical significance of the level and type of secreted paraprotein in the blood serum of patients with multiple myeloma. Methods: Concentration and type of paraprotein (PP) were studied by capillary electrophoresis (Helena Bioscience V8, UK) in blood serum of 25 patients aged 47-76 years with multiple myeloma (MM) before and during polychemotherapy (PCT). Results: Monoclonal PP was detected in blood serum of 22 patients (88%), while PP secretion was absent in 3 patients, along with noted decrease in gamma globulin levels and presence of plasma cells with aberrant immunophenotype in bone marrow (nonsecreting MM). 14 patients (63.6%) had IgG PP, 8 (36.4%) – IgA. Differences in IgG PP detection rate were found between men (75.0%) and women (50.0%). IgA PP was more frequently registered in women (50%) than in men (25%). Analysis of kappa (κ) and lambda (λ) isotypes of light chains demonstrated an increased detection rate for κ chains in both IgA (75.0%) and IgG (57.1%) PP secretion. 81.8% of patients showed migration of PP to γ-region of electrophoretogram and 18.2% - to β-region. PP in γ-M-spike was 66.22±5.24 g/l and in β-M-spike – 35.89±4.64 g/l (p < 0.001). Monoclonal component of the γ-M-spike was more often represented by IgG heavy chains – in women in 71.4%, men – 81.8%; IgА type was observed in 28.6% and 18.2% of the cases, respectively (p < 0.001). IgG κ and λ light chains were detected in women in 40% and 60%, respectively, and in men – 66.7% and 33.3%. Both men and women showed IgА κ chains only. β-M-spike in all patients involved IgA only: women - κ chains in 66.7%, λ chains in 33.3%, and men – λ light chains only. Complete remission was achieved in IgG MM patients only (14.2%); partial remission in IgG MM – 14.5%, in IgA MM – 12.5%; stabilization – 57.1% and 62.5%, progression - 7.1% and 12.5%, resistance to treatment – 7.1% and 12.5%, respectively. Conclusions: Detection of the level and type of monoclonal component in the blood is important for MM diagnostics and monitoring. Monoclonal component involves heavy IgG chains and κ light chains more often. Polychemotherapy showed its most effectiveness in patients with IgG MM.
A multicentre, open-label phase II study of irinotecan, capecitabine, and oxaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Arthur Gregory Ang Lui, Karen E. Mulder, Christine Brezden-Masley, Michael M. Vickers, Jose Gerard Monzon, Hagen F. Kennecke, Rakesh Goel, Sunita Ghosh, Horia Marginean, Larissa Joy Vos, SeeSee Juliana Raynard, Kristine Lee Young, Anthony L.A. Fields, Jean Alfred Maroun, Jennifer L. Spratlin
Journal: Journal of Clinical Oncology (2016)

4032 Background: Metastatic gastric and GEJ cancer is a leading cause of cancer-related mortality. Systemic chemotherapy remains the primary treatment but optimal agents and schedule remain controversial. This study determined the safety and efficacy of first-line IXO in metastatic gastric/GEJ adenocarcinoma. Methods: The Bryant&Day two-stage design was used with dual primary endpoints of response rate (RR) and toxicity. As specified by design, after accrual of 15 patients (pts), if < 7 pts responded or ≥ 6 pts experienced dose limiting toxicity (DLT), accrual would be terminated concluding IXO was not active or too toxic; otherwise, second stage accrual would occur to 50 pts and if > 19 pts responded and DLT occurred in ≤ 17 pts, IXO would be declared active and nontoxic. Eligible pts with HER2 unamplified/unknown metastatic gastric/GEJ adenocarcinoma were treated with IXO in a 21-day (D) cycle at either dose level 1 (DL1) (D1 O-100mg/m2 IV & I-160mg/m2 IV, D2-15 X-1900mg/m2/day PO) or dose level -1 (DL-1) (D1 O-85mg/m2 IV & I-120mg/m2 IV, D2-15 X-1425mg/m2/day PO). Secondary endpoints were overall survival (OS), progression free survival (PFS), and health-related quality of life (HRQL). Results: After accrual of 9 pts at DL1, RR was 78% with 56% DLTs thus doses were adjusted to DL-1 without modifying sample size. Stage I accrual at DL-1 yielded a RR of 66.7% while 6.3% of pts had DLT allowing for accrual to stage 2. In total, 50 pts (48 and 49 pts evaluable for efficacy and safety, respectively) were enrolled in an intention to treat analysis and received a median of 7 cycles (range 1-21). Overall RR was 54% (26/48) with a disease control rate of 85.4%. DLTs were experienced in 22% (11/49) (DL1 = 5/9 (56%); DL-1 = 6/40 (15%)). The most frequent grade 3/4 AEs were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 11.0 and 12.9 months, respectively. HRQL data is yet to be analyzed. Conclusions: IXO demonstrates impressive ORR, PFS, OS, and acceptable toxicity compared to standard triplet chemotherapy regimens. IXO should be evaluated in phase III trials in this patient population. Clinical trial information: NCT01129310.
Sustained impact of primary platinum-free interval and BRCA1/2 mutation status on survival in patients with ovarian cancer after multiple lines of therapy.
Authors: Michael A. Bookman, Jerzy E. Tyczynski, Janet L. Espirito, Thomas Wilson, Ancilla Fernandes
Journal: Journal of Clinical Oncology (2016)

5566 Background: The relationship between primary (1°) platinum-free interval (PFI), BRCA mutation status, and overall survival (OS) in patients (pts) with recurrent ovarian cancer (OC) receiving 2nd, 3rd, and 4th line (2L, 3L, 4L) therapy (tx) was evaluated in a retrospective observational cohort study of newly diagnosed, adult pts with stage III-IV high-grade OC. Methods: Data were obtained from The US Oncology Network/McKesson Specialty Health EHR, including pt characteristics, subsequent tx, and 1° PFI; BRCA was status stratified as BRCA 1/2 mutation (BRCAm), wild type (BRCAwt), and unknown. OS was analyzed by Kaplan-Meier method, stratified by 1° PFI and BRCA status. Results: Of 1037 pts identified, 750 pts were randomly selected for chart abstraction. Median age at start of 1° tx was 66 y; 70% of tumors were stage III at diagnosis with serous histology. BRCA status was known in 267 pts (16% BRCAm). Proportion of patients with known BRCA test results by year of 1° tx was 30%, 36%, 38%, and 37% from 2010-2013, respectively. Median OS (mOS) from the start of 1° tx for the entire population was 40.9 mo (95% CI, 36.8-48.8 mo). Conclusions: Median OS was significantly increased in pts with 1° PFI ≥6 mo at 2L and 3L. BRCA status was known in 36% of pts, and there was a trend for increased mOS in pts with BRCAm across multiple tx lines. This large, nonselected, community database provides benchmarks for OS over multiple tx lines. Support: This study was sponsored by AstraZeneca. mOS estimates. Unadjusted mOS (mo)a 95% CI Log-rank P value Pts on 2L Tx (n=422) 19.4 15.9-21.9 1° PFI ≥6 mo (n=242) 25.4 20.4-32.4 <0.001 1° PFI <6 mo (n=177) 12.0 10.6-15.2 BRCAm (n=20) NR 11.1-NR 0 .22 BRCAwt (n=141) 23.7 19.6-34.2 Pts on 3L Tx (n=236) 11.8 10.2-14.5 1° PFI ≥6 mo (n=128) 15.2 11.0-24.4 0.003 1° PFI <6 mo (n=104) 10.2 6.8-12.4 BRCAm (n=12) 21.4 5.6-NR 0.56 BRCAwt (n=88) 13.0 9.0-22.1 Pts on 4L Tx (n=136) 8.7 6.6-13.2 1° PFI ≥6 mo (n=77) 9.7 6.6-17.4 0.30 1° PFI <6 mo (n=56) 7.4 5.2-13.2 BRCAm (n=8) 18.0 0.1-18.0 0.37 BRCAwt (n=55) 10.4 7.1-18.0 N may not add up due to missing data; For BRCA status, only pts with known BRCA mutation status included; aUnadjusted mOS measured from start of indexed tx (2L, 3L, or 4L); NR=not reached
Application of molecular techniques to improve quality control (QC) of target detection using immunohistochemistry (IHC).
Authors: Inga Rose, Heather A. O'Neill, Annemarie Benton, Melissa N. Richards, Phil Ellis, Peggy Teresi, Zoran Gatalica
Journal: Journal of Clinical Oncology (2016)

e23212 Background: IHC performance variability can occur due to multiple factors. Laboratories performing predictive IHC tests need to consider implementing additional QC procedures beyond those mandated by the regulatory agencies (QC of standard detection techniques). A thorough examination of the antibody (Ab) sensitivity, dynamic range, and specificity to the protein target of interest, as well as consistency of Ab production, should be examined when considering which antibody to implement in predictive clinical assays. Methods: Ab performance was analyzed using IHC, western blot (WB) and mass spectrometry (MS). IHC was performed on formalin fixed paraffin embedded (FFPE) tissues utilizing polymer detection systems and automated staining platforms (Ventana or DAKO). Abs were chosen based on published clinical predictive utility (PD-L1: Garon et al. NEJM 2015; TLE3: Kulkarni et al. Breast Cancer Res 2009; RRM1: Gong et al. Lung Cancer 2012). Primary Abs against PD-L1, TLE3 and RRM1 were probed by western blotting against cell lysates and recombinant protein. LC-MS/MS was used to examine the protein profile of bands that correlated with the positively staining bands observed in the WB. Results: Four anti-PD-L1 Abs (SP142, SP263, 22c3, and 28-8) showed consistent and expected reactivity to PD-L1 protein by WB with bands at 33kDa and 48-55kDa. By IHC there was > 90% concordance between 4 Abs in respect to cancer PD-L1 expression but a variable reactivity in the inflammatory cells. Three anti-TLE3 antibodies showed reactivity to the TLE3 protein in WB (83kDa), with additional, inconsistent binding at 55, 115 and 225kDa bands. Inconsistent staining by IHC was observed in FFPE tumor samples, resulting in elimination of 2 of the Ab candidates. Investigation of Ab performance consistency across 2 different lots of anti-RRM1 showed one lot reacting with a 90kDa band (expected RRM1), whereas the second lot did not detect a band at the expected MW. MS confirmed the target was only present in the bands of expected MW. Conclusions: The results demonstrate how WB and MS can be utilized as a supplement to traditional (tissue based) QC, in order to provide accuracy and precision needed in predictive biomarker testing.
Comparison of PACE clinical trial versus real-world (RW) ponatinib (PON) prescribing and duration of therapy (DOT) in US chronic-phase chronic myeloid leukemia (CP-CML) patients (pts).
Authors: Michael J. Mauro, Lisa McGarry, Mo Yang, Stephanie Lustgarten, Hui Huang
Journal: Journal of Clinical Oncology (2016)

e18540 Background: PON demonstrated efficacy in pts with highly-resistant CP-CML in the pivotal PACE trial. Introduced to the US market in Dec’12, PON was reintroduced in Jan’14 after an 11-wk withdrawal to review data on vascular occlusive events and revise US prescribing information. In the US, PON is available exclusively through a specialty pharmacy that maintains RW prescribing data for all US pts treated with PON since Jan’14. Comparing RW data to PACE may reveal differences in DOT due to potential RW noncompliance or availability of alternative therapies. Methods: We compared PACE, which enrolled pts Sep’10–Oct’11, to RW data for CP-CML pts starting PON Jan’14–Dec’15. RW data came from referring physicians, pharmacy intake forms and dispensing records. Pt characteristics and dosing were compared overall and by line of therapy (LOT) using non-parametric tests; average dose was calculated, including therapy gaps as “zero” dose. DOT was assessed using Kaplan-Meier techniques and log-rank tests. Results: PACE enrolled 270 CP-CML pts; 333 US RW CP-CML pts started treatment over the 2-yr period. PACE pts were older (median 60 vs 55 yrs; p=0.004) but % male was the same (53% vs 53%; p=0.195). Comparing PACE to 258 RW pts with known LOT, 7% PACE vs 16% RW were in 2nd line (2L), 36% vs 28% 3rd line (3L) and 57% vs 56% ≥4th line (4L+) (p=0.084.) All PACE pts received 45 mg initial dose; in RW PON use, 48% initially received 45 mg, 30% 30 mg, and 22% 15 mg; however, average dose was similar in PACE vs RW (2L: 29.4 vs 29.0 mg/day; 3L: 26.0 vs 25.9; 4L+: 26.4 vs 26.9; all p>0.05.) DOT was similar in 2L and 4L+ pts in PACE vs RW, but longer in PACE vs RW for 3L pts (Table). Conclusions: RW CP-CML PON pts are younger but otherwise similar to PACE pts. As expected, the RW DOT is somewhat shorter than PACE; however, the majority of RW PON pts across all LOT were on therapy for >1.5 yrs. Clinical trial information: NCT01207440.Therapy duration PACE versus RW CP-CML Pts by LOT. LOT Population (n) 6mo % 12mo % 18mo % 24mo % p 2L PACE (19) 95 89 84 68 (0.077) RW (42) 63 63 63 -- 3L PACE (97) 79 69 68 64 (0.047) RW (72) 69 59 59 -- 4L+ PACE (154) 79 62 58 53 (0.311) RW (144) 67 57 56 -- Total PACE (270) 80 66 63 58 (<0.001) RW (333*) 66 54 52 -- *Includes 75 pts with missing LOT
A phase 1, multicenter, open-label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed WHO grade IV malignant glioma (glioblastoma, ndGBM): Dose-escalation results.
Authors: Daniela Annenelie Bota, Santosh Kesari, David Eric Piccioni, Dawit Gebremichael Aregawi, Patrick Roth, Roger Stupp, Annick Desjardins, Steven D. Reich, Ileana Elias, Mingyu Li, Nancy Levin, Benjamin Winograd, Warren P. Mason
Journal: Journal of Clinical Oncology (2018)

e14083 Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma preclinical activity was combined with standard-of-care (SOC) TMZ/RT in ndGBM (NCT02903069), to determine the recommended dose (RD). Methods: Patients enrolled in separate concomitant (TMZ/RT+MRZ) and adjuvant (TMZ+MRZ) cohorts in dose-escalation (3+3 design, MRZ at 0.55, 0.7, 0.8, and 1.0 mg/m2), followed by dose-expansion at RD in concomitant followed by adjuvant treatment. MRZ (10 min IV infusion): Concomitant D1, 8, 15, 29, 36; Adjuvant (28D-cycle) D1, 8, 15. Results: (as of 01Feb2018): Dose-escalation completed (N = 33; 15 concomitant and 18 adjuvant); mean age 56 yrs, 73% male. Dose-limiting toxicities (DLT): one (fatigue) at 0.7 mg/m2adjuvant cohort, 3 (ataxia/diarrhea; ataxia/confusion; myocardial infarction) in concomitant and 2 (delirium/ataxia; ataxia/fatigue) in adjuvant cohorts at 1.0 mg/m2. Grade ≥3 treatment-emergent AEs (TEAE) in 11 of 12 patients at 1.0 mg/m2including one Grade 4 and one Grade 5 TEAE; at ≤0.8 mg/m2 MRZ, Grade 3 TEAEs in 9 of 21 patients; severe TEAEs generally ameliorated with dose reductions, allowing patients to stay on therapy. Most common TEAE (≥20% patients, all grades): fatigue, nausea, vomiting, hallucination, ataxia, headache. Currently 15 active of 20 patients enrolled in dose-expansion; 9 patients from dose-escalation also remain active, with 5 longest patients on study 12-18 months. Conclusions: MRZ demonstrated a steep dose-response; TEAEs/DLTs predominately CNS adverse events (ataxia, hallucinations), dose-related, short-lasting, reversible and ameliorated by subsequent dose reductions. The RD is 0.8 mg/m2 MRZ in combination with SOC. MRZ at the RD with adjuvant TMZ+Optune is now enrolling to assess the safety of this combination. Based on the safety and tolerability of MRZ in this study and earlier results in recurrent GBM, an EORTC-sponsored phase 3 study will open in Spring 2018 to assess the overall survival benefit of MRZ added to SOC in ndGBM. Clinical trial information: NCT02903069.
Comparative effectiveness of photodynamic therapy for patients with non-small cell lung cancer.
Authors: Ravishankar Jayadevappa, Patrick Ross, Sumedha Chhatre
Journal: Journal of Clinical Oncology (2016)

e20063 Background: We assessed the effectiveness of integrating photodynamic therapy (PDT) in a treatment algorithm, compared to non-PDT ablation or ablation via radiation with or without chemotherapy in patients with non-small cell lung cancer (NSCLC). Methods: Retrospective cohort analysis using SEER-Medicare data. Patients with NSCLC diagnosed between 2000 and 2011 were identified and followed for one-year pre and up to five-year post diagnosis. We analyzed survival, cost and health service use in follow-up period for four groups: + PDT, + non-PDT ablation, radiation alone, and radiation with chemotherapy. We used Cox regression to assess all-cause and lung cancer-specific mortality, and GLM log-link models to study total costs, controlling for clinical and demographic covariates. Propensity score was used to minimize selection bias. Results: Of NSCLC cohort (n = 359,608), 77,536 had radiation therapy alone, 136 received + PDT, 1405 received + non-PDT ablation, and 53,878 received radiation with chemotherapy. Stages for + PDT group were: Stage I 19.1%, Stage II 6.6%, stage III 42.7% and Stage IV 16.2%. Un-adjusted five year survival days were highest for + PDT group (mean 801, SD 643), followed by + non-PDT ablation (mean 625, SD 592), and radiation with chemotherapy (mean 571, SD 533). Un-adjusted five year survival days were lowest for radiation alone group (mean 424, SD 534). Compared to radiation alone, + PDT group showed decreased hazard of overall five year mortality (HR = 0.64, CI = 0.53, 0.77). Hazard was also lower for those receiving +non-PDT ablation (HR = 0.72, CI = 0.68, 0.77), and radiation with chemotherapy (HR = 0.63, CI = 0.62, 0.64). Similar results were found for lung cancer- specific mortality. Five year medical care cost was higher for +PDT (β = 1.53, p < .0001), +non-PDT ablation therapy (β = 1.26, p < .0001), and radiation with chemotherapy (β = 1.44, p < .0001) groups, compared to radiation alone group. Conclusions: Adding endoluminal ablation to other treatment gives survival advantage to NSCLC patients.There is a trend to advantages with PDT compared to non-PDT ablation.Future research should address effective combination, timing and cost effectiveness to understand clinical value of PDT in NSCLC patients.