tbuckley/cabot-search huggingface dataset:
Peripheral natural killer cells are a prognostic factor in advanced oesogastric adenocarcinoma and are associated with intestinal types in the randomized trial PRODIGE17-ACCORD20 (UNICANCER GI).
Authors: Magali Terme, Simon Pernot, Elie Marcheteau, Florence Castan, Olivier Bouche, Jaafar Bennouna, Eric Francois, Francois Ghiringhelli, Valerie Boige, Christelle De La Fouchardiere, Emmanuelle Samalin, Jean Baptiste Bachet, Christophe Borg, Trevor Stanbury, Sophie Gourgou, David Malka, Julien Taieb
Journal: Journal of Clinical Oncology (2016)

4061 Background: Natural Killer cells (NK) are associated with a better prognosis in many types of tumors. Their value is not well known in oesogastric adenocarcinoma (OGA), but tumor infiltrating NK seem to be associated with a good prognosis. The quantification of NK in peripheral blood of patients (pts) could be a simple and reproducible prognostic factor. Objective: To evaluate the prognostic impact of circulating NK among pts with advanced OGA. Methods: 134 pts included in the randomized trial PRODIGE 17-ACCORD 20 (MEGA) (FOLFOX alone or with either panitumumab or rilotumumab in 1st-line treatment of advanced OGA) and having consented to the biological study were collected. Rate of NK in total circulating leukocytes was measured by flow cytometry after immunophenotyping (CD56+ CD3-) at diagnosis. Prognostic effect of NK was analysed through the Cox model by testing several thresholds determined by the distribution of this parameter. Results: NK were measured in 85 pts (63%) included in the study. The median rate was 8.5% with a range of [0.6-34.8]. Patients with NK > 17% (top quintile) had significantly higher PFS (9.2 months vs. 5.8 months; HR = 0.56 [0.31-1.00], p = 0.04), and OS (25.8 months vs. 11.5 months; HR 0.47, [0.23-0.96], p = 0.03). This effect was maintained by adjusting for age, ECOG, location of primitive tumor, histological type (intestinal vs diffuse) and number of metastases (PFS: HR 0.44; [0.23-0.83]; p = 0.01, OS: HR 0.44; [0.21-0.92], p = 0.03). There was no interaction between NK and treatment received. In gastric adenocarcinomas, the rate of NK was significantly lower in diffuse forms than in intestinal forms (p = 0.02). The prognostic value of NK was maintained in the intestinal sub-group, but not in the diffuse subgroup. Conclusions: Measurement of circulating NK in advanced AOG is a simple and reproducible prognostic tool. Pts with NK > 17% have a significantly better OS and PFS. Finally, the low rate of NK in diffuse forms suggests low immunogenicity of this type of tumor, which could be related to a lower antigenic load and potentially with poorer efficacy of immunotherapy. Clinical trial information: NCT01443065.
Visualzing toxicity: A single score to summarize toxicity in randomized clinical trials.
Authors: Mariana Carbini, Mayte Suarez-Farinas, Robert G. Maki
Journal: Journal of Clinical Oncology (2016)

6605 Background: Both efficacy and toxicity impact a person’s experience with chemotherapy, as recognized in a recently published ASCO framework. A number of approved chemotherapy agents require early dose reductions from approved doses/schedules. We sought to simplify the evaluation of toxicity to a single number (scalar), to more easily compare the cost vs. benefit of a given systemic treatment. Methods: We developed matrices employing (1) linear, (2) weak exponential, and (3) strong exponential scores for all 790 grade 1-4 National Cancer Institute Common Toxicity Criteria. We generated summary toxicity scores from the matrix products of clinical trial toxicity data and the three toxicity matrices. The trace of the matrix products yields an index for a given treatment on a given trial. We term this index the Weighted Toxicity Score(WTS). Results: As a group of studies to examine systematically, we identified 51 randomized clinical trials of kinase-directed inhibitors approved for treatment of cancer between 11/2004 and 7/2015. We correlated the frequency of dose reductions in each trial with each difference and ratio of WTS (experimental vs. control arms). Differences in dose reduction rates in the 18 placebo-controlled studies with complete data correlated most strongly with differences in WTS using a weak exponential scoring matrix. Conversely, there was not a statistically significant relationship between WTS and the hazard ratio for progression free survival (PFS) between trial arms, indicating that greater toxicity was not associated with greater PFS benefit. Conclusions: The WTS distills the toxicity of a given treatment into a single value. As a result, the WTS allows toxicity and benefit to be compared simultaneously. Iterations on WTS matrices may allow more accurate dose finding and comparison of chemotherapy agents across phase I-III clinical trials, or as a way to calculate a toxicity area-under-the-curve, with a goal of greater patient safety before and after regulatory approval.
Baseline lactate dehydrogenase (LDH) and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with everolimus (EVE) versus sunitinib (SUN): Predictive biomarker analysis from the RECORD-3 trial.
Authors: Martin Henner Voss, David Chen, Mahtab Marker, Jennifer Knox, James Hsieh, Maurizio Voi, Robert J. Motzer
Journal: Journal of Clinical Oncology (2016)

e16118 Background: Data from a randomized mRCC trial of temsirolimus vs interferon reported elevated baseline LDH to be a favorable predictive marker for OS with mTOR inhibitors (Armstrong, JCO 2012). As a product of anaerobic glycolysis, LDH was hypothesized to reflect mTOR activation in tumor cells. We explored this association in the RECORD-3 trial, which randomly assigned untreated pts to the mTOR inhibitor EVE vs the VEGFR TKI SUN without difference in OS (Knox, ASCO 2015). Methods: Pts were grouped by baseline LDH (low, ≤1×ULN; high, > 1×ULN). Treatment arms were stratified by MSKCC risk group. Cox proportional hazards and log-rank tests were used to test the association of LDH category with OS and progression-free survival (PFS). Correlation between LDH category and genomically defined subgroups (somatic mutations in BAP1 or PBRM1, both commonly altered in RCC with reported effects on OS for EVE-treated pts) was tested using Fisher exact test. Results: Among 468 randomly assigned pts, 13% were LDH high and 87% LDH low, with a median of 0.73×ULN (range, 0.15-10.54×ULN). High baseline LDH adversely affected OS for pts receiving EVE (HR 2.96; P< .0001) but showed no association for those receiving SUN (HR 1.18; P= .09). When comparing outcomes with first-line EVE vs SUN, OS was shorter for EVE in LDH-high pts but was not different in LDH-low pts. Associations between LDH and PFS were seen for EVE (HR 2.3; P< .0001) but not for SUN (HR 1.04; P.33). No statistically significant association was seen between LDH category and mutation status of BAP1 (P= .54) or PBRM1 (P= .47). Conclusions: Elevated baseline LDH correlated adversely with PFS and OS for first-line EVE but not SUN. Notably, this predictive effect for EVE is opposite that previously reported in the randomized trial for the mTOR inhibitor temsirolimus vs interferon. Clinical trial information: NCT00903175.Comparison Within HR for OS 95% CI for HR Log-Rank P LDH high vs low EVE arm 2.96 1.83 4.77 < .0001 LDH high vs low SUN arm 1.18 0.71 1.95 .0932 EVE vs SUN LDH low 0.96 0.75 1.24 .4036 EVE vs SUN LDH high 2.42 1.32 4.43 .0024
Expanding indications of existing drugs and associated costs under risk reimbursement models.
Authors: Ray D. Page, Peter G. Ellis, Kathleen Lokay, Amanda Barry
Journal: Journal of Clinical Oncology (2017)

e18306 Background: New payment models in oncology will likely include taking risk on drug costs. While new drugs could be excluded, existing drugs with expanded indications are problematic as the payer has limited data needed to exclude these costs. Recent label expansion for pembrolizumab (PB) in 1 st line NSCLC for &gt; 50% PD-L1 expression is an example of this risk. A broader indication in the future will likely result in use of PB for almost all 1 st line patients. Methods: We reviewed treatment starts documented by providers in the Via Portal (VP) for 1 st , maintenance (MT) and 2 nd lines of therapy in non-squamous mutation-negative NSCLC for the 12 months ended 11/30/16. We assumed 6 month treatment lengths and calculated cost to Medicare (MC). We calculated a hypothetical alternative where PB received full 1 st line and maintenance indication given with pemetrexed (PM) and carboplatin (per recent FDA filing and results of KEYNOTE-021 trial 1 ). We assumed 2 nd line patients received either docetaxel or ramucirumab/docetaxel (using 3 rd line treatments in VP). Results: Total MC cost in the actual arm (n = 208) was $13,943,412, $12,190,264 and $11,614,488 for 1 st , MT and 2 nd line, respectively. The total MC cost in the hypothetical arm (n = 208) was $25,477,452, $25,687,168 and $6,415,575 for 1 st , MT and 2 nd line, respectively. This represents a total increase of $19,832,031 (52.5%) or $95,346 per patient. Conclusions: Bundled rates and shared savings that include oncology drugs are subject to significant financial risk for providers when existing drugs receive expanded indications to a new, larger population of patients. Langer CJ, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508.
Lactate dehydrogenase (LDH) levels to predict benefit from the continuation of bevacizumab (bev) beyond progression in metastatic colorectal cancer (mCRC): Subgroup analysis of the randomized BEBYP study.
Authors: Federica Marmorino, Chiara Cremolini, Fotios Loupakis, Cecilia Barbara, Francesco Dargenio, Emanuela Miraglio, Gianluca Masi, Lisa Salvatore, Lorenzo Marcucci, Lorenzo Antonuzzo, Silvana Chiara, Chiara Banzi, Marta Schirripa, Domenico Amoroso, Andrea Bonetti, Angelo Martignetti, Myriam Paris, Luca Boni, Daniela Tomcikova, Alfredo Falcone
Journal: Journal of Clinical Oncology (2016)

e15127 Background: Different antiangiogenic agents are available as 2nd line options for mCRC patients (pts). Up today, no clinical or molecular predictors of benefit have been identified. In preclinical and clinical studies LDH levels are a marker of angiogenesis activity. High LDH levels are associated with worse prognosis in never pretreated mCRC pts and a potential positive predictive impact with regard to the efficacy of 1st line bev has been hypothesized in retrospective analyses. The aim of this analysis was to assess the prognostic and predictive impact of LDH levels measured before the beginning of the 2nd line treatment in pts randomized to continue or not bev after progression to 1st line CT plus bev in the BEBYP study. Methods: Baseline LDH levels were reported for 134 out of 170 pts enrolled in the BEBYP study and were defined as high or low according to a cut-off value of 300 U/L. Results: Out of 134 pts with available data, 51 (39%) and 83 (61%) had low and high LDH levels, respectively. A significant interaction between LDH levels and treatment effect was reported: pts with low LDH levels achieved higher PFS benefit from the continuation of bev (HR:0.39 [95%CI:0.23-0.65]), as compared to pts with high LDH levels (HR:1.10 [95%CI:0.74-1.64] (p for interaction = 0.002). Similarly, pts with low LDH levels achieved greater benefit from bev in terms of OS (HR:0.55 [95%CI:0.33-0.92]) than pts with high LDH levels (HR:1.01 [95%CI:0.67-1.53] (p for interaction = 0.075). In the overall population, no significant correlation between LDH and clinical outcome was evident in PFS (high vs low LDH: HR:1.22 [95%CI:0.88-1.68], p = 0.232) or OS (HR:1.35 [95%CI:0.96-1.88], p = 0.081). Conclusions: Low LDH levels at the time of disease progression to 1st line CT plus bev predict benefit from the continuation of bev beyond progression. By a biological perspective, low LDH levels may indicate that angiogenesis inhibition by bev is still efficacious. Given their potential clinical value these data deserve prospective and retrospective confirmation in subgroup analyses of other randomized trials of 2nd line CT with or without an antiangiogenic. Clinical trial information: NCT00720512.
Association of eosinophila with efficacy in non-melanoma patients treated with programmed death 1 inhibitors.
Authors: Matthew R. Zibelman, Julia Judd, Elizabeth Handorf, John O'Neill, Sasini Bentota, Jamie Doyle, Robert G. Uzzo, Jessica Ruth Bauman, Hossein Borghaei, Elizabeth R. Plimack, Ranee Mehra, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2016)

e14510 Background: Programmed death-1 inhibitors (PD-1Is) have demonstrated durable responses in patients (pts) with a variety of tumor types. We explored the association between eosinophilia and response to PD-1Is in non-melanoma pts. Methods: Non-melanoma pts treated at our center with single agent nivolumab (N) or pembrolizumab (P) either on or off-trial from Nov 2011-Dec 2015 were included in this retrospective study. Complete blood counts were reviewed at baseline and prior to each dose. Outcomes and response were assessed via RECIST at the first restaging scan. Clinical endpoints were response rate (RR), overall survival (OS), and time to next therapy or death (TTNTD), defined as time from start of PD-1I to subsequent therapy or death. We evaluated whether any increase in absolute eosinophil count (AEC) during the first 12 weeks of treatment was associated with clinical endpoints. Fisher’s exact test was used for the association between AEC and RR, and Kaplan-Meier curves with log-rank tests were used for determination of OS and TTNTD. Results: 122 pts received ≥ 2 doses and had adequate follow-up for analysis. The average age was 64, 66% were male, and 74% received N. Twenty-one pts (17%) received 2 doses, 19 (16%) 3 doses, 59 (48%) 4-10 doses, and 23 (19%) > 10 doses. Cancer subtypes included: non-small cell lung cancer (53, 43%), renal cell carcinoma (27, 22%), head and neck cancer (23, 19%), urothelial carcinoma (16, 13%), and other (3, 2%). At first scan 21 pts (19%) achieved a partial response and 27 pts (25%) had stable disease with no complete responses. Increases in AEC, defined by any increase > 100/mm3 from baseline to the time of administration of doses 2-4 or > 400/mm3 at weeks 8 or 12, occurred in 24 pts (20%). RR was higher in those with an AEC increase (35% vs. 15%, p = 0.04). TTNTD was improved in pts with an increase in AEC (median TTNTD = 3.9 vs 9.9 mo, p = 0.04), although significance was not maintained after stratification by number of doses received (2, 3, or 4+, p = 0.32). There was no impact on OS. Conclusions: In a cohort of non-melanoma pts treated with single agent PD-1Is, an increase in AEC was associated with improved RR and TTNTD on unadjusted analysis. Larger studies are warranted to confirm this finding.
PSA density to predict the risk of biochemical relapse in high-risk prostate cancer patients who underwent radical prostatectomy.
Authors: Arash Samiei, Ralph Miller, Jeffery Cohen, John Lyne, Shifeng Mao
Journal: Journal of Clinical Oncology (2018)

e17045 Background: PSA density (PSA-D) has an established role in prostate cancer (PCa) screening by improving the diagnostic value of PSA, but its correlation with biochemical relapse after radical prostatectomy (RP) has not been identified. A comparative study using PSA-D in high-risk PCa patients with long-term follow-ups is still lacking. Objective: To investigate the association between PSA-D and biochemical recurrence (BCR) in high-risk PCa patients who underwent RP. Methods: We conducted a retrospective study of high-risk PCa patients who underwent RP. All RPs were performed by two trained surgeons in a single center from 2003 to 2013. Parameters, including pre-operation PSA, Gleason score, pathologic stage, time to biochemical recurrence, surgical margin status and prostate volume were analyzed. High-risk patients were defined according to the National Comprehensive Cancer Network (NCCN) guideline. PSA-D was calculated by dividing preoperative PSA (ng/ml) with the volume of the surgically resected prostate (ml). BCR was defined as two consecutive PSA rise above 0.2 ng/ml postoperatively. Results: A total of 280 high-risk PCa patients were included in this study. Among them, 81.4% had pathologic stage ≥ T3a; 41.8% had GS ≥ 8 and 13.2% of patients had Pre-operation PSA ≥ 20. The median follow-up time was 44 [6 -140] months. BCR was observed in 55% of patients. 41.07% of patients had PSA-D ≥ 0.15 ng/ml2. Positive surgical margin rate was more in patients with PSA-D ≥ 0.15 than PSA-D < 0.15 (55.2% vs 40.2%, p = 0.011). A multiple logistic regression model demonstrated patients with PSA-D ≥ 0.15 had a 3-fold higher risk of BCR compared to patients with PSA-D < 0.15 (OR: 3.23, p = 0.01). Conclusions: PSA-D ≥ 0.15 ng/ml2 correlates with a higher chance of BCR among high-risk prostate cancer patients following radical prostatectomy. PSA-D could be a valuable tool in assessing the risk of BCR and strategized adjuvant treatment decision.
Correlation between baseline characteristics and clinical outcome of patients with pretreated advanced melanoma who received pembrolizumab (PEMBRO) in an expanded access program (EAP).
Authors: Elisa A. Rozeman, Yanina Jansen, MarnixMarnix Heimen Geukes Foppen, Max Schreuer, Sofie Wilgenhof, Johannes V. Van Thienen, John B. A. G. Haanen, Christian U. Blank, Bart Neyns
Journal: Journal of Clinical Oncology (2016)

e21058 Background: the PD-1 blocking mAb PEMBRO is approved for the treatment of patients (pts) with advanced melanoma. The correlation between baseline clinical characteristics and outcome of pts treated outside of a prospective clinical trial has not been established. Methods: using Kaplan-Meier survival probability analysis, log-rank testing and multivariate Cox-regression analysis, correlations were investigated between baseline clinical variables and survival (PFS and OS) in pts with pretreated advanced melanoma who received PEMBRO in an EAP. An independent pt-cohort served to confirm the correlations found in an exploratory cohort. Results: all pts in the exploratory (EC; N = 98) and confirmatory (CC; N = 91) cohort had advanced pretreated melanoma and received at least one administration of PEMBRO (2 mg/kg, every 3 wks). Baseline characteristics of the EC + CC population (N = 189) were: median age 60y (range 26-93); 56% F; primary site: 81% skin, 15% UKN, 4% mucosal; 49% BRAF V600mut; 82% AJCC stage IV-M1c; 33% brain metastases; 52% CRP > ULN; 36% LDH > ULN; 18% absolute lymphocyte count (ALC) < 1000/mm³. For the total population median PFS was 13 wks (95% 9-17), median OS was not reached. PFS and OS did not differ between EC and CC populations. Age, gender and primary site were not correlated with survival in either cohort. In both cohorts a significant correlation (univariate analysis) was found between PFS/OS and PS, ALC < 500/mm³ and LDH > ULN. EC-pts with baseline stage IV-M1c, brain metastases, and CRP > 5xULN had a significantly worse PFS/OS but these correlations did not reach significance in the CC-pts. All pts with a baseline ALC of < 500/mm³ (N = 7 [4%] in the EC + CC) were found to have a PFS/OS of < 9 wks. In the subgroup of pts with baseline ALC > 500/mm³ (N: 179), mutivariate analysis identified PS, LDH > 1.5xULN and CRP > 5xULN as independent baseline co-variables for PFS/OS. Conclusions: PFS and OS of pts with pretreated advanced melanoma who received PEMBRO in an EAP was comparable to that of similar populations treated in prospective clinical trials. Significant correlations were found between baseline PS, ALC, LDH, CRP and survival.
Phase II study of cabozantinib (cabo) in patients (pts) with recurrent/metastatic endometrial cancer (EC): A study of the Princess Margaret, Chicago, and California phase II consortia.
Authors: Neesha C. Dhani, Hal W. Hirte, Julia V. Burnier, Angela Jain, Marcus O. Butler, Stephanie Lheureux, Jean Hurteau, Stephen Welch, Koji Matsuo, Michael Method, Waldo Jimenez, Carolyn Johnston, Erica Stringer, Mihaela C. Cristea, Anjali Mehta, Judy Quintos, Susie Tan, Lisa Wang, John Joseph Wright, Amit M. Oza
Journal: Journal of Clinical Oncology (2017)

5524 Background: Recurrent/metastatic EC has a poor prognosis with no standard 2 nd line therapy. Cabo is a multi-targeted kinase inhibitor of MET, VEGFR, TIE2, AXL &amp; KIT, relevant in epithelial-stromal cross-talk. The role of MET/HGF in aggressive EC biology, where transient benefit of VEGF-targeting is due to MET/HGF, TIE2 &amp; AXL, provides rationale for MET targeting in EC. Methods: PHL86 (NCI#9322/NCT01935934) is a multi-centre, phase II trial of cabo (60mg oral daily dose) in pts with EC recurring within a year of adjuvant chemotherapy (ctx), or with progression after 1 line of ctx for metastatic disease. Experimental (E) cohort was stratified by histology (serous (SER) vs endometroid (END)) in a Simon two-stage design for co-primary endpoints of response rate ( &gt; 30%) &amp; 12-week progression-free-survival (PFS) ( &gt; 55%). Activity was defined as &gt; 7 partial responses (PRs) or &gt; 15 instances of 12 wk-PFS in 36 pts. Pts with rare histology EC were treated in a parallel exploratory (Ex) cohort. Results: From May 2013 to Nov 2016, 102 pts (E: 71; Ex: 31) have been treated with cabo after prior radiation (59) and/or ctx (no. lines: 1(77); 2(22)). Cabo was well tolerated with common toxicities of fatigue, nausea, diarrhea &amp; hand-foot syndrome. Most frequent Grade 3/4 toxicity was hypertension (32/101 pts). Fistula/perforation occurred in 4 of 71 SER/END pts &amp; 4 of 31 Ex pts; no risk factors were identified. In 33 END pts, 6 PRs &amp; 24 instances of &gt; 12-wk PFS were observed; median PFS is 4.8 mths (95% CI: 4.4 – 6.4) with estimated 6-mth PFS of 43% (95% CI: 27 to 59%). In 34 SER pts, 4 PRs &amp; 20 instances of &gt; 12-wk PFS were observed; median PFS is 4.0 mths (95% CI: 2.7 – 4.7) with estimated 6-mth PFS of 30% (95% CI: 15 to 46%). 4 pts have had PFS &gt; 12 mths, 1 SER pt remains on study after 25mths. Mutational analysis demonstrated presence of KRAS with PTEN or PIK3CA mutations in 9 (SER/END) pts, of whom 8/9 pts met 12-wk PFS endpoint, with a median PFS 5.9 mth (4.1 to 15.4). Conclusions: Cabo has single agent activity in END and SER EC with durable disease control. Concurrent mutation in KRAS/PTEN/PIK3CA may enrich for response. The current data support further evaluation of cabo in EC. Clinical trial information: NCT01935934.