tbuckley/cabot-search huggingface dataset:
Biomarkers for early prognostication of outcome in patients with bone-metastatic castration-resistant prostate cancer treated with enzalutamide.
Authors: Katrin Schlack, Martin Boegemann, Laura-Maria Krabbe, Karoline Kannen, Axel Semjonow, Yvonne Klaile
Journal: Journal of Clinical Oncology (2017)

e16507 Background: Enzalutamide (Enza) prolongs survival in men with mCRPC in pre- and post chemotherapy setting. Commonly used prostate-specific antigen (PSA) may lead to non-straightforward prognosis. This is especially true for bone mCRPC (bmCRPC) in which initial bone-flare may add to difficult decision making. During other therapies, bouncing of alkaline phosphatase (ALP-Bounce) was shown as a promising surrogate for survival outcome. The purpose of this study was to evaluate the prognostic ability of ALP-Bounce compared to standard PSA and lactate dehydrogenase (LDH) after initiation of Enza. Methods: Patients with bmCRPC were included and analyzed. PSA, LDH and ALP were monitored at 2, 4, 8 and 12 weeks under very early Enza treatment. ALP-Bounce vs. no Bounce was analyzed using Kaplan-Meier estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bounce was defined as an increase of ALP after initiation of Enza with a subsequent, significant decline below baseline during the first 8 weeks of therapy. Results: Eighty-nine men were evaluable for analysis. The median overall survival (OS) of men with ALP-Bounce was 19 months (95% confidence interval: 7.9-30.1) compared to 12 months (7.7-16.3) for no Bounce. Analysis of progression-free survival (PFS) showed similar results with 8 (0-16.3) vs. 3 months (1.9-4.1). In UV no ALP-Bounce (Hazard Ratio (HR): 1.9 (1.1-3.3); p = 0.02), no PSA-decline ≥50% (HR: 2.3 (1.5-3.7); p &lt; 0.01) and no LDH-Normalization (HR: 2.5 (1.6-4.1); p &lt; 0.01) were significantly associated with worse PFS. In MV only no ALP-Bounce showed a trend towards worse PFS (HR: 2.1 (0.9-4.5); p = 0.09). In UV no LDH-normalization was a significant prognosticator of poor OS (HR: 2.6 (1.6-4.2); p &lt; 0.01) while ALP-Bounce and PSA decline ≥50% were non-prognostic. In MV no LDH-normalization remained an independent prognosticator of poor OS (HR: 2.0 (1.1.-3.5); p = 0.02). Conclusions: ALP-Bounce and LDH-Normalization may add to identification of bmCRPC-patients with favorable prognosis during early therapy with Enza. The early occurence of ALP-Bounce might be beneficial. These results have to be validated in a prospective trial.
Peri-operative modified FOLFIRINOX in resectable pancreatic cancer: A pilot study.
Authors: Robert de Wilton Marsh, Shuang Qin Zhang, Marshall Baker, Daniel V.T. Catenacci, Mark Kozloff, Blase N. Polite, Mitchell C. Posner, Kevin K. Roggin, Mark S. Talamonti, Kristen Wroblewski, Hedy L. Kindler
Journal: Journal of Clinical Oncology (2016)

4103 Background: Surgical resection followed by adjuvant gemcitabine or 5-FU is standard for resectable pancreatic cancer (PC). FOLFIRINOX has substantial activity in metastatic PC. The efficacy and tolerability of peri-operative modified FOLFIRINOX (mFFx) in resectable PC is unknown. Methods: Patients (pts) with ECOG PS 0/1 and resectable PC confirmed by multidisciplinary review received 4 cycles of mFFX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 day 1, 5-FU 2400 mg/m2 x 48 hours, peg-filgrastim 6 mg SQ day 4) both pre- and post-surgery. Results: 21 enrolled pts started therapy (median age: 63 (range 47-78), 81% ECOG 0). 20/21 pts completed 4 cycles of preoperative (pre-op) mFFX (1 withdrew for toxicity). 17/21 pts underwent resection (3 had metastatic disease intra-operatively). 14/21 completed 4 cycles of postoperative (post-op) mFFX (2 pts expired within 90 days of surgery: 1 had an MI and 1 had GI bleed). Radiographic response by RECIST after pre-op mFFx: 1 CR, 3 PR, 16 SD, 0 PD, (ORR 4/20, 20%). Of the 17 (81%) patients who had curative-intent surgery, 16/17 (94%) had R0 resections. Treatment effect was seen in 10/17 (59%) specimens with 1 pathologic CR. Dose modifications were required in 30% pre-op (neuropathy 1; thrombocytopenia 2; neutropenia 3; diarrhea 2) and in 26% post-op (neuropathy 3; diarrhea 3; allergic reaction 1). Grade 3/4 adverse events occurred in 23% and 14% pts pre-op and in 26% and 0.06% pts post-op, respectively. In the 20 pts who completed pre-op mFFX, median OS was 33.4 months (mo) (95% CI: 13-not estimable); PFS was 11.4 mo (95% CI: 3.2 - 17.8). In the 17 pts who underwent surgical resection, median DFS was 9.7 mo (95% CI: 7.1-16.0). Conclusions: Eight cycles of mFFX is a feasible and tolerable peri-operative regimen in good PS pts with resectable PC. No pts progressed on pre-op mFFX. A high (94%) R0 resection rate in those pts undergoing surgery was observed. The OS of 33.4 mo compares favorably with historical data. Further study of mFFX may be warranted in the peri-op setting. Clinical trial information: NCT01660711.
A systematic review and meta-analysis of randomized controlled trials to evaluate the risk of hypophosphatemia, hypertension, and hematological toxicities in patients with cancer treated with regorafenib.
Authors: Henry Palangdao Igid, Kyaw Zin Thein, Anita Sultan, Sriman Swarup, Sanjay Awasthi, Catherine Jones, Fred L. Hardwicke
Journal: Journal of Clinical Oncology (2018)

e22218 Background: The vascular endothelial growth factor (VEGF) signaling pathways and the proto-oncogenes KIT, RET and RAF1 are implicated in cancer development and progression. Regorafenib has shown antitumor activity by blocking the activity of several protein kinases involved in VEGF signaling pathways, the tumor microenvironment, and the proto-oncogenes. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of hypophosphatemia, hypertension, and hematological toxicities in patients treated with regorafenib. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception through August 2017 were searched. Phase 3 RCTs that mention hypophosphatemia, hypertension, and any hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: Four phase 3 RCTs with a total of 1723 patients with hepatocellular, colorectal cancer, and gastrointestinal stromal tumors were eligible for analysis. Studies compared regorafenib versus placebo. The RR of all-grade side effects were as follows: hypophosphatemia, 8.155 (95% CI: 2.779–23.930, p < 0.0001); hypertension, 4.119 (95% CI: 3.001–5.654, p < 0.0001); anemia, 3.499 (95% CI: 1.716–7.136; p = 0.01); and thrombocytopenia, 5.995 (95% CI: 2.938–12.237; p < 0.0001). The RR of high-grade adverse effects were as follows: hypophosphatemia, 9.474 (95% CI: 2.666–33.662, p = 0.001); hypertension, 5.232 (95% CI: 2.920–9.375, p < 0.0001); anemia, 4.518 (95% CI: 1.035–19.729; p = 0.045); and thrombocytopenia, 6.713 (95% CI: 1.599–28.177; p = 0.009). Conclusions: Our study showed that patients on regorafenib experienced a significant increase in all-grades of hypophosphatemia with a relative risk of 9.47 for grade 3 and 4 hypophosphatemia. They also contributed to significant toxicity of all-grade and high-grade hypertension as well as hematological toxicities.
Coping with long-lasting incurable cancer: An ethnographic study in a comprehensive cancer centre.
Authors: Hilde Buiting, Marleen van Ark, Otto Dethmers, Jogien Stoker, Gabe S. Sonke
Journal: Journal of Clinical Oncology (2018)

e22214 Background: Advances in oncology increasingly result in protracted disease trajectories for patients with incurable cancer. In this protracted disease phase, patients are aware of the incurable nature of their disease but do not approach the last phase of life yet. We explored patient’s coping strategies. Methods: Qualitative ethnographic study at the day-care unit of a comprehensive cancer hospital (2015-2017). In total, 19 patients with incurable breast cancer (at least one year after diagnosis) and 11 patients with incurable lung cancer (at least 6 months after diagnosis) with cancer remission were included. Observations and conversations (n = 33) were openly framed; coping strategies were defined as efforts to reduce associated distress. Results: Most patients with long-lasting incurable cancer talked about their disease in a positive or neutral way and expressed delight in life. They were grateful that extra lifetime was given. They also expressed fear, which was communicated explicitly and implicitly, often related to the possibility that scan- or blood results would indicate disease progression. Moreover, patients mentioned that they grew accustomed in having incurable cancer. Associated fear than slowly faded away. Besides fear, patients reported to be hopeful and often tried to look at the bright side of life, frequently enforced by optimistic doctors, nurses and close relatives. Patient’s optimistic stance could also be downplayed, however, by close relatives who sometimes indicated that the patient’s positive mood was unrealistic. Patients seldom asked for professional psycho-social help. Conclusions: Just as cancer patients in other disease phases, patients with protracted disease trajectories experience uncertainty, fear of cancer recurrence and hope. Hope dominated while tumours were in remission and patients had grown accustomed to having long-lasting incurable cancer. More research is warranted to explore whether the optimistic attitude of nurses can be considered as appropriate. Moreover, the added value of either a palliative care- or a survivorship approach, e.g. interventions for cancer recurrence or treatment, for this expanding group of patients need to be further explored.
Immune profiling of head and neck squamous cell carcinoma (HNSCC) by a multiplex immunofluorescence (mIF) panel using multispectral microscopy.
Authors: Janis De La Iglesia, Laura Martin, Tessa Van Veen, Feifei Song, Nicholas Gimbrone, Ruchira S. Ranaweera, Jude Masannat, Janaki Parameswaran, J Wadsworth, Bruce Wenig, Juan Hernandez-Prera, Louis B Harrison, Jimmy J. Caudell, Anna Giuliano, Robbert Slebos, Christine H. Chung
Journal: Journal of Clinical Oncology (2018)

6061 Background: Treatments based on immune checkpoint inhibition have shown great promise in HNSCC. Comprehensive evaluation of lymphoid-inflamed tumor-immune microenvironment may contribute to the identification of a subgroup of patients that may have a favorable outcome using immunotherapy. Methods: HNSCCs were analyzed by a mIF panel (CD3, CD8, FOXP3, PD-1, PD-L1, pancytokeratin AE1/AE3, and DAPI) using multispectral microscopy and image analysis. Three regions of tumor core, tumor margin and adjacent stroma were chosen for measurement. The mIF results were correlated with clinical parameters. Results: Sixty-eight HNSCC were stained and numbers of positive cells from all 7 markers could be obtained. In the subset of 9 tumors with known p16 status (4 positive, 5 negative), numbers of PD-L1+ cells were marginally significantly higher in p16- tumor cores (p < 0.1) compared to p16+ tumor cores while numbers of CD3+ and CD8+ cells were higher in stroma of p16- tumors compared to p16+ tumors (p < 0.01 and p = 0.02, respectively). Regardless of p16 status, numbers of CD3+ and CD8+ cells in the tumor cores were marginally significantly higher in never smokers (N = 12) (both p < 0.1) and numbers of CD8+ cells within 25 micron from the tumor cells were again higher in never smokers (p = 0.048) compared to former (N = 14) and current smokers (N = 42). Patients with tumors harboring high numbers of CD8+ cells within 25 micron of the tumor cells showed a trend towards longer survival times (p = 0.16). Conclusions: This is the first study to examine the distribution of immune cells in tumor core, the invasive margin, and adjacent stroma and the proximity between immune and tumor cells. Our data suggest that p16- tumors may be more immunosuppressed by increased expression of PD-L1 while CD8+ cells are unable to infiltrate the tumor mostly residing in the stroma. In addition, never smokers may have more active immune response by having closer proximity of CD8+ cells to tumor cells compared to never and former smokers. Complete data from a total of 176 patients will be presented at the meeting.
Development of an online drug-drug interaction resource to support safe prescription of oncolytics.
Authors: Nielka P. Van Erp, Kaylee R.M. Ferrier, Sarah E. Gibbons, David Burger, Katie McAllister, Jasmine L.M. Martin, Saye H. Khoo, Frank Jansman, Nienke A.G. Lankheet
Journal: Journal of Clinical Oncology (2018)

e18574 Background: Patients treated for cancer are at high risk of drug-drug interactions (DDI), which affects nearly 60% of patients on therapy. We developed a freely available DDI resource (www.cancer-druginteractions.org) to support anti-cancer drug prescribing, based on successful implementation for HIV (www.hiv-druginteractions.org) and hepatitis (www.hep-druginteractions.org) treatments. Methods: A review of literature and registration documents was performed to evaluate the available evidence for potential DDI of several oncolytics. Decision trees based on the FDA guideline on DDI studies were used to assess clinical relevance of DDI. Comedications that are frequently used by cancer patients were selected. Interaction potential of drug combinations was classified using a straightforward ‘traffic light’ classification and quality of evidence was classified according to a derivative GRADE system. Advice on management of the interaction was included where appropriate. All records were reviewed by an expert panel of clinical pharmacologists. Results: Thus far, 23 targeted oncolytics for among others renal cell carcinoma, sarcoma, prostate cancer and chronic myeloid leukemia have been reviewed. These represent 18 targeted small molecules and 5 monoclonal antibodies (MoAB). Potential DDI between the oncolytics and > 400 comedications have been classified. From website launch on June 1st till December 31st 2017 6,627 queries were performed; 5109 queries for targeted oncolytics and 1518 queries for targeted MoABs. 19% of the queries show a potential interaction which requires action of prescribers. Conclusions: The DDI checker currently includes comprehensive and ready-to-use advices for DDI with targeted oncolytics for nine indications (these are due to be expanded in the coming months). The freely available, independently developed website with ‘traffic light’ classification will facilitate health care professionals’ and patients’ awareness of potential DDI between oncolytics and frequently used comedications.
Clinical features and outcome of patients with poor-prognosis myelofibrosis based on platelet count &lt;50 x 10<sup>9</sup>/L: A single-center experience in 1100 myelofibrosis patients.
Authors: Ahmad Alhuraiji, Lucia Masarova, Prithviraj Bose, Naval Guastad Daver, Jorge E. Cortes, Sherry Pierce, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2016)

7068 Background: Thrombocytopenia (platelets < 100x109/L) is an independent negative prognostic factor for overall survival (OS) in patients with myelofibrosis (MF) according to the dynamic international prognostic scoring system-plus. Furthermore, for patients with platelets < 50x109/L therapeutic options are limited. Clinical features of patients with MF and low platelet counts are not well described. Methods: In this retrospective cohort analysis we evaluated the clinical characteristics and outcome of patients with MF (primary MF or post-polycythemia vera/essential thrombocythemia MF) who presented to MD Anderson Cancer Center between 1984 and 2013 with platelets below 50x109/L. Results: Of 1109 available patients, 123 (11%) had platelets < 50x109/L at presentation; 161 (15%) had platelets between 50-100x109/L. Patients with platelets < 50x109/L had significantly shorter OS than those with platelets between 50-100x109/L, and those with platelets > 100x109/L (median 14.7, 33.8, and 88.8 months, respectively; p < 0.001; HR 2.2). Patients with platelets < 50x109/L (vs. other) were statistically significantly older, with lower hemoglobin and white blood cell counts, but higher percentage of peripheral blasts, transfusion dependence, abnormal/unfavorable cytogenetic, and IPSS risk score. These patients had mostly primary MF and advanced bone marrow fibrosis grade. There was no significant difference in splenomegaly, leukemia free survival or percent of driver mutations (JAK2, MPL and CALR). Fewer patients with low platelets received cytoreductive therapy, most likely due to their lower blood counts. In multivariate analysis, thrombocytopenia was a significant negative predictor for OS (p = 0.002). Conclusions: Low platelet count is an important surrogate marker of survival in MF patients, with associated poor clinical features. These patients require novel therapy.
Clinical activity, safety and tolerability of ASN002, a dual JAK/SYK inhibitor, in patients with non-Hodgkin lymphoma (NHL), myeolfibrosis (MF), chronic lymphocytic leukemia (CLL) and solid tumors.
Authors: Stefan K. Barta, Drew W. Rasco, Andy I. Chen, Stephanie Elkins, Michael Wang, Louis J. Denis, Sarper Toker, Helen Usansky, Sanjeeva Reddy, Niranjan Sathyanarayana Rao
Journal: Journal of Clinical Oncology (2018)

TPS7084 Background: ASN002 is a novel, potent inhibitor of Janus Kinases (JAK) and Spleen Tyrosine Kinase (SYK). Pre-clinical studies indicate that ASN002 has low nM IC50s against SYK and JAK, decreases proliferation in ibrutinib-resistant cell lines, and suppresses tumor growth in rodent xenograft models of NHL and other hematologic malignancies. Methods: This Phase 1/2 clinical trial in patients with solid tumors and hematologic malignancies evaluated escalating ASN002 oral doses of 10, 20, 30, 40, 50 and 75 mg BID and 80 and 120 mg QD. Phase 1 allowed patients with solid tumors or hematologic malignancies; Phase 2 allows only patients with mantle cell lymphoma (MCL), myelofibrosis (MF), Peripheral T-cell Lymphoma (PTCL) and Chronic Lymphocytic Leukemia (CLL). Endpoints include safety, tolerability, pharmacokinetics, serum markers of inflammation, and response using Lugano criteria (NHL), IWG-MRT (MF), or IWG-CLL. Results: Forty-six patients have enrolled in the study at doses of 10 –75 mg BID and 80-120 mg QD. All patients had multiple prior lines of treatment (range: 2 – 8). ASN002 was well tolerated at doses up to 75 mg BID. The DLT at 100 mg BID was Grade 3 infection. 75 mg BID was the recommended Phase 2 dose. Most drug-related adverse events were Gr 1/2 (e.g. headache, fatigue). Steady-state systemic exposure was high (Cmax, AUC (0-12h)) and increased in a dose related manner up to 100 mg BID. Robust reduction of inflammatory markers CRP, IL-18, MIP1β, VCAM-1, TNFR2 was observed at all dose levels. Stable disease (9+ months) in a patient with primary peritoneal cancer, about 50% reduction in target lesions at 3 months in a FL patient, stable disease and reduction of pruritus in a PTCL patient after 2 months, and significant disappearance of skin lesions in another PTCL patient after one month were observed. Early improvement in symptoms within 2 weeks of treatment in MF has also been reported in an ongoing patient. Accrual of patients continues. Conclusions: ASN002 was safe and well tolerated. Encouraging preliminary evidence of efficacy in NHL and MF patients was observed. Updated and detailed results will be presented. Clinical trial information: NCT02440685.
A bayesian network comparison of different agents or regimens as first-line treatment for advanced EGFR-mutated NSCLC.
Authors: Wenhua Liang, Qihua He, Jianrong Zhang, Long Jiang, Caicun Zhou, Jianxing He
Journal: Journal of Clinical Oncology (2016)

e20528 Background: Several EGFR-TKI associating regimens have been studied and available as firstline treatment for advanced EGFR-mutated NSCLC. We sought to perform a network meta-analysis to comprehensively compare and rank these regimens. Methods: Randomized control trials (RCTs) that enrolled EGFR-mutated patients were eligible. The primary endpoint was progression free survival (PFS) estimated by hazard ratio (HR). Bayesian networks were built based on overall population or different sensitive mutations (19DEL/L858R) respectively. Chemotherapy (chemo) was used as a common comparator. Rank probabilities were calculated. Results: Nineteen phase II/III RCTs involving 2,641 participants with EGFR mutations were incorporated to generate the networks. The relative HRs of erlotinib, gefinitib, afatinib, erlotinib plus bevacizumab, chemo plus bevacizumab, erlotinib plus chemo, gefitinib plus chemo and gefitinib plus maintenance chemo compared with chemo was 0.31 (0.25-0.40), 0.41 (0.34-0.48), 0.37 (0.30-0.46), 0.50 (0.34 -0.72), 0.39 (0.22-0.71), 0.40 (0.29-0.55), 0.39 (0.22-0.69) and 0.28 (0.19-0.40) respectively in all mutated patients; 0.26 (0.20-0.35), 0.38 (0.31-0.47), 0.24 (0.17-0.32), 0.41 (0.24-0.71), N.A., N.A., N.A. and 0.16 (0.26-0.40) respectively in patients with 19 exon deletions; 0.37 (0.27-0.51), 0.44 (0.35-0.55), 0.46 (0.33-0.64), 0.67 (0.38-1.18), N.A., N.A., N.A. and 0.25 (0.14-0.46) respectively in patients with L858R mutations. There was no significant difference between any pair of positive comparators. Gefitinib plus chemotherapy showed the greatest probability to rank the first in efficacy (57.6%), regardless of mutation types (19DEL patients, 30.6%; L858R patients, 86.4%) and sensitivity adjustments for different study selection criteria. Among single agents, erlotinib had the highest first-place ranking (16.3%). Conclusions: Although not any of the EGFR-TKIs or combinations presented significantly superior efficacy compared with any other regimen, gefitinib plus maintenance chemo (pemetrexed) showed the greatest probability to rank first in both sensitive mutations, and erlotinib ranked best among single-agent EGFR-TKIs.