tbuckley/cabot-search huggingface dataset:
Differences in patterns of care in older vs. younger head and neck cancer patients.
Authors: Melissa Crawley, Janice Nhan Mullins, Jeff Caughran, Moon Jung Fenton, Noam Avraham VanderWalde
Journal: Journal of Clinical Oncology (2018)

e18079 Background: Treatment of head and neck squamous cell carcinoma (HNSCC) with multimodality therapy has improved locoregional control and overall survival. No benefit has been shown in patients over age 70. We evaluated patterns of care in older (≥65) vs. younger patients receiving curative-intent therapy. Methods: An institutional database was queried for patients diagnosed with HNSCC between January 2012 and May 2017, for whom curative-intent therapy was planned. Patients were stratified into a younger cohort (age 18-64 years) and an older cohort (≥ 65 years). Radiation treatment intent, use of chemotherapy, and completion of planned treatments were evaluated. Descriptive statistics were incorporated with Chi-squared or Fisher’s exact test. Logistic regression was used to estimate associations between age, stage, and chemotherapy received. Results: A total of 409 patients were identified, with 130 older patients. There was no difference in adjuvant vs. definitive treatment intent by age group (P = 0.54). Younger age was associated with higher likelihood of completing planned radiation dose (63.6% vs.28%, P = 0.04). There was no difference in variability of number of radiation days between the older and younger cohorts (49.6 ± 36.1 days, vs. 51.3 ± 13 days). Patients in the older subset were more likely to be treated with radiation alone (48.5% vs. 24.7%, P < 0.001), and less likely to be treated with a platinum-based regimen (47% vs. 69%, P < 0.001). Adjusted for T- and N-stage, there was a statistical trend between age and chemotherapy agent (P = 0.093); compared to receiving no chemotherapy, younger patients were 1.9 times more likely to receive a cisplatin-containing regimen compared to older patients (95% CI, 1.06-3.44). Conclusions: Older patients with HNSCC treated with curative therapy are less likely to receive chemotherapy, and less likely to receive platinum agents, compared to younger patients. Further study is needed to define populations of older adults who may better tolerate combined modality therapy.
Dendritic cell vaccine (DCVAC) with chemotherapy (ct) in patients (pts) with epithelial ovarian carcinoma (EOC) after primary debulking surgery (PDS): Interim analysis of a phase 2, open-label, randomized, multicenter trial.
Authors: Lukas Rob, Peter Mallmann, Pawel Knapp, Bohuslav Melichar, Jaroslav Klat, Lubos Minar, Zdenek Novotny, Jirina Bartunkova, Radek Spisek, Ladislav Pecen, Hariz Iskandar Bin Hassan, David Cibula
Journal: Journal of Clinical Oncology (2018)

5509 Background: Most pts with EOC relapse after PDS and ct. Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to ct could improve outcomes, including progression-free survival (PFS). Methods: Key eligibility criteria were FIGO stage III EOC (serous, endometrioid, or mucinous), PS 0 - 2, post-PDS with < 1cm maximal residuum and no prior systemic therapy. We randomized pts up to 6 weeks after PDS, 1:1:1, into arm A (A; DCVAC concomitantly with ct), arm B (B; DCVAC sequentially after ct) and arm C (C; ct alone). Pts were stratified by tumor residuum (0 or < 1cm). Ct consisted of 6 cycles of carboplatin (AUC 5 - 7) and paclitaxel (175mg/m2). Pts in A and B were to receive 10 doses of DCVAC (1 × 107 DCs/dose). The primary endpoint was investigator-assessed PFS. Key secondary endpoint was overall survival (OS). Results: Between November 2013 and March 2016, 99 pts were randomized in 3 countries (A/B/C, 34/34/31). Median age was comparable in all arms (range, 61.5 - 62.0 years). The % of pts with complete cytoreduction was 85% in A and B, and 84% in C. At the planned interim analysis, the ITT population included 31 pts in A, 30 pts in B, and 31 pts in C; pts who failed leukapheresis (LP) or manufacturing were excluded. A mean of 9.6 and 9.5 doses of DCVAC were administered in A and B, respectively. Median follow-up time was 26.8 months (range, 3.24 - 43.0; 1 pt withdrew informed consent early in the trial). Median PFS was 18.3 months in A, 24.3 months in B, and 18.6 months in C. Compared to C, PFS hazard ratios (95% CI) were 1.08 (0.53 - 2.21) in A and 0.43 (0.18 - 1.03) in B. The gain in PFS in the sequential arm was statistically significant (p = 0.05), and this was supported by the same trend in OS. Median OS was not reached in any arm (14% events). There were no grade ≥ 3 adverse events (AEs) related solely to DCVAC and it did not worsen the side effects of ct. Most common LP-related AEs were mild pyrexia and moderate hypocalcemia. Conclusions: DCVAC improved PFS when administered sequentially after ct. This provides a promising maintenance treatment option delaying progression of the disease. Clinical trial information: NCT02107937.
Priming PD-L1 expression by chemotherapeutic agents in non-small cell lung cancers.
Authors: Emily Pei-Ying Lin, Ching-Yao Yang, Ching-Wen Lin, Bo-Tsang Huang, Wei-Yun Lai, Yi-Ting Tseng, Pan-Chyr Yang
Journal: Journal of Clinical Oncology (2017)

e20087 Background: Immunotherapy targeting PD-1/PD-L1 axis has yielded fruitful results in non-small cell lung cancers (NSCLCs). Evidences showed that treatment responses are likely correlated with tumor PD-L1 expression levels, which is especially true in the first line setting. Results from Keynote-021 suggested that pembrolizumab plus platinum-pemetrexed doublet came out with better overall response rate and progression free survival as compared to chemotherapy alone even in the PD-L1 low-expression group. Nevertheless, grade III and IV toxicities were much frequently observed in the combinational arm. The aim of the current study is to investigate the effect of chemotherapeutics on PD-L1 priming in NSCLCs so as to provide a better option in the chemo-immunotherapy combinational setting. Methods: NSCLC cell lines CL1-5, CL141, and H1299 were treated with a platinum-based drug (cisplatin), microtubule-targeted agents (paclitaxel or vinorelbine), or antimetabolites (pemetrexed or gemcitabine) for 24 to 72 hrs. The concentration of each drug selected for experiments was stepping-down titrated from the IC50s, with the maximum concentration allowed being 10 μM. The priming effects of chemotherapeutics on PD-L1 expression were evaluated with RT-qPCR, Immunoblotting and FACSCalibur flow cytometer. The functionality of the induced PD-L1 was examined by the T cell cytotoxic assay and the IL-2 production ability, done with co-cultured systems containing chemo-primed tumor cells and activated T cells. Results: The results showed that pemetrexed or gemcitabine, but not cisplatin, paclitaxel or vinorelbine, effectively induced PD-L1 expression at concentrations below the IC50s. Membranous distribution of the induced PD-L1 was observed. Addition of anti-PD-L1 blocking antibody in the co-cultured system increased T cell cytotoxic ability and promoted IL-2 production, implicating the biological functionality of the induced PD-L1. Conclusions: The data suggested that pemetrexed or gemcitabine effectively primed the expression of biologically functional PD-L1 in NSCLC cells. The results implicate that pemetrexed or gemcitabine alone may be a good combinational candidate for PD-L1-targeted therapy in NSCLCs.
Survival associated with chronic obstructive pulmonary disease among elderly patients with non-small cell lung cancer.
Authors: Shweta Shah, Christopher Michael Blanchette, Marc Kowalkowski, Susan T Arthur, Joseph P Coyle, Reuben Howden
Journal: Journal of Clinical Oncology (2017)

e18107 Background: Lung cancer and chronic obstructive pulmonary disease (COPD) are among leading causes of morbidity and mortality worldwide. The association between pre-existing COPD and overall survival (OS) among patients with non-small cell lung cancer (NSCLC) remains unclear. We investigated the impact of pre-existing COPD and its subtypes: chronic bronchitis and emphysema on OS in elderly patients diagnosed with NSCLC at different stages. Methods: Using SEER-Medicare data, we identified patients diagnosed with NSCLC between January 1, 2006 and December 31, 2010, &gt; 66 years of age, and continuously enrolled in Medicare Parts A and B in the 12 months prior to diagnosis. Pre-existing COPD in patients with NSCLC were identified using ICD-9 codes. Kaplan Meier method and log-rank tests were used to examine OS by COPD status and COPD subtype. Cox proportional hazards models were fit to assess the risk of death after cancer diagnosis while adjusting for baseline factors. Results: We identified 66,963 patients with NSCLC. Of these, 22,497 (33.60%) had documented COPD before NSCLC diagnosis. For each stage of NSCLC, median OS was shorter in the COPD compared to the non-COPD group (stage I: 692 vs 1130 days, P &lt; 0.0001; stage II: 473 vs 627 days, P &lt; 0.0001; stage III: 224 vs 229 days; P &lt; 0.0001; stage IV: 106 vs 112 days, P &lt; 0.0001). For COPD subtype, median OS for patients with pre-existing chronic bronchitis was shorter compared to emphysema across all stages of NSCLC (stage I: 672 vs 811 days, P &lt; 0.0001; stage II 582 vs 445 days, P &lt; 0.0001; stage III: 255 vs 229 days, P &lt; 0.0001; stage IV: 105 vs 112 days, P &lt; 0.0001). After multivariable adjustment, COPD patients exhibited an 11% shorter time to death compared to non-COPD patients (Hazard Ratio: 1.11, 95% Confidence Interval: 1.09—1.13). Conclusions: There were marked differences in early stage NSCLC, with a decrease in OS from stage I to stage IV in the COPD group. Patients with chronic bronchitis had shorter OS at every stage of NSCLC compared to emphysema. The results may help inform early detection strategies for NSCLC and treatment selection in early and advanced cancer.
Validation of time to treatment change (TTC) as a surrogate end-point of progression free survival (PFS) for observational trials in metastatic breast cancer patients (MBC): The GIM-13 AMBRA study.
Authors: Marina Elena Cazzaniga, Paolo Pronzato, Icro Meattini, Laura Biganzoli, Cristiana Taverniti, Clara Natoli, Sabino De Placido, Caterina Aversa, Elio Bordin, Monica Giordano, Alessandra Bologna, Lucrezia Diodati, Livio Blasi, Ornella Garrone, Emanuela Romagnoli, Carmela Mocerino, Alessia D'Alonzo, Michela Piezzo, Giorgio Mustacchi
Journal: Journal of Clinical Oncology (2018)

e13081 Background: Real-world studies (RWS) are crucial in clinical outcome evaluation of cancer patients (pts), however results are difficult to compare to randomized trials, mainly regarding time parameters, such as PSF, which is not the case in RWS. AMBRA is an observational study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve MBC pts receiving chemotherapy (CHT). One of the aims is the validation of TTC as a surrogate parameter of PFS. The present analysis is focused on the comparison between TTC and PFS of 1-line Paclitaxel + Bevacizumab (P+B) as an example of TTC in RWS. Methods: PFS was calculated using the progression dates declared by researchers. TTC was defined as the time between 1st line CHT start and the beginning of the subsequent therapy, if any, or the last observation or death. Since some pts could have changed therapy due to side effects, we considered a difference of ± 8 weeks acceptable. Results: Pts treated with P+B were 173/607 CHT (28.5%). Median age was 52 years with median DFS of 49 months. Median TTC was 9.36 mos (40,67 wks) and median PFS 10.8 (46.92 wks).The difference of 6.2 weeks is not significant (Wilcoxon rank-sum Test, a 0.050, p = 0.089) and within the preplanned boundary limit. Median OS was 5.9 years. Median Survival from declared first progression was 18.1 months and from start of 1-line P+B of 16.1 mos (8 wks). A tentative comparison with P+B arm of E2100 trial (Miller, 2007) and our results is shown in Table 1. PFS in our study is 1 month shorter vs E2100, reliable if considering the different population (adjuvant taxanes and Luminal tumors). The 6 wks difference in 1st line and 8 wks in metastatic survival of TTC vs PFS confirm the reliability of TTC because of the increase of treatment delays as compared to the declared 2nd or further progression Conclusions: TTC is a valid surrogate end point of PFS in RWS and could be considered the most reliable choice for new observational trials. E2100 AMBRA-GIM13 Median PFS (months) 11.8 10.7 Median age 56 (29-84) 52 (32-83) Luminal subtype 65.4% 76.8% Visceral Disease 79.5% 72.8% DFS > 24 months 58.5% 78.6% Taxane Adjuvant 17.3% 37%
Clinical significance of 22C3-PD-L1 IHC expression in surgically resected non-small cell lung cancer.
Authors: Gen Lin, Chao Li, Cheng Huang, Rong Xi Fang, Peng Hai Xu, Dong xian Lin, Biao Wu, Xiaohui Chen, Chunwei Xu, Tony Mok
Journal: Journal of Clinical Oncology (2017)

e20507 Background: Multiple studies correlated PD-L1 expression with clinicopathologic and survival have reported conflicting results.Methods: We retrospectively collected 185 patients with NSCLC who underwent surgical resection to detect PD-L1 IHC using the clone 22C3 pharmDx kit and evaluated PD-L1 expression along with clinicalpathological characteristics and prognosis.Results: Most of tumors had TNM stage lower than stage III. Adenocarcinoma and squamous carcinoma was accounting for 56.8% and 43.2%, respectively. Heterogeneous distribution of PD-L1 staining was observed, PD-L1 strong-positive and weak-positive staining were detected in 11.4% and 24.3% of patients. In univariate analysis, smokers, squamous carcinoma, central type cancer, larger primary tumor size, metastatic lymphonode, neoadjuvant chemotherapy and TILs present was found associations with higher proportion of PD-L1 positive expression. In multivariate analysis, only primary tumor size, smoking status, TILs status and neoadjuvant chemotherapy were confirmed associations with PD-L1 positive expression. Especially, PD-L1 positive expression rate climbed gradually with the increase of tumor size, T≤3cm 21.0%, 3cm &lt; T≤5cm 32.8%, 5cm &lt; T 50.7%, respectively, p = 0.003. PD-L1 positive expression highly improved with patients with neoadjuvant chemotherapy versus without neoadjuvant chemotherapy, 88.9% vs 33.0%, respectively, p = 0.009. In survival analysis, neither PD-L1 expession/TILs status nor the interaction term between were confirmed as independent prognosis biomarkers . PD-L1 negative group had a tendency of longer OS than PD-L1 positive group, mOS 66.4 months (95%CI, 59.4-73.4) vs. 39.2 months (95%CI, 16.0-62.4), respectively, p = 0.096. Conclusions: PD-L1 expression showed heterogeneous distribution and was highly influenced by tumor size, smoking status, TILs and neoadjuvant chemotherapy.It indicated a strong spatial and temporal variability in the PD-L1 expression, which could be in part to explain the conflicting results in PD-L1 expression and correlation with clinicopathologic in multiple studies. The dynamics of PD-L1 expression may also limit its use as a prognosis biomarker.
Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible
Authors: Anubhuti Goel, Daniel A. Cantu, Janna Guilfoyle, Gunvant R. Chaudhari, Aditi Newadkar, Barbara Todisco, Diego de Alba, Nazim Kourdougli, Lauren M. Schmitt, Ernest Pedapati, Craig A. Erickson, Carlos Portera-Cailliau
Journal: Nature Neuroscience (2018)
Effect of FAK inhibitor defactinib on tumor immune changes and tumor reductions in a phase II window of opportunity study in malignant pleural mesothelioma (MPM).
Authors: Raphael Bueno, Ritu R. Gill, Patrick H. Lizotte, Kam Sprott, David Michael Jackman, Julianne Barlow, Sristi Sharma, Beow Y. Yeap, Lucian R. Chirieac, Abraham Lebenthal, Megan Cavanaugh, Amanda J Rode, Paul Kirschmeier, David J. Kwiatkowski, Kwok-Kin Wong, William G. Richards, David T. Weaver
Journal: Journal of Clinical Oncology (2017)

8555 Background: Defactinib is an oral Focal Adhesion Kinase (FAK) inhibitor with preclinical activity in MPM. We assessed responses to defactinib treatment prior to planned surgical resection in naive patients with MPM. Methods: Three cohorts of 10 participants each received defactinib 400mg BID for 12, 35 and 21 days. Pre- and post-treatment blood, tumor biopsies and imaging were obtained for biomarker, immune cell and tumor response (modified RECIST, Tumor volume and SUV max) assessment. Toxicity was monitored for 30 days post treatment. Results: Between 12/2013 and 12/2017, 31 participants were registered at our center; 1 withdrew prior to intervention. Among 30 treated, 24 (80%) were male; median age 70 (47-83) years; surgery was EPP 7%, complete pleurectomy decortication (PD) 10%, extended PD 60%, partial PD 10%, unresectable 13%; MPM subtype was epithelioid 67%, biphasic 17%, sarcomatoid 17%. Expected complications of FAK inhibition, diagnostic/staging/operative procedures occurred in 83% (grade 1, 30%; grade 2, 43%; grade 3, 10%). Unexpected adverse events occurred in 77% (grade 1, 63%; grade 2, 20%; grade 3, 17% [wound-infection, prolonged QT interval, and hyperglycemia in 3% each; increased INR in 7%]; grade 5, 7% [due to progressive disease in 3%, intraoperative anaphylactoid reaction unrelated to the drug in 3%]). Objective partial response was observed in 13%, stable disease in 67%, progression in 17%. Tumor volume decreased 3-72% in 47% patients and increased 1-82% in 53%. SUV max decreased 3-69% in 50% and increased 1-61% in 50%. Biological correlates of treatment included target inhibition (75% pFAK reduction); tumor immune microenvironment changes: increased naïve (CD45RA+PD-1+CD69+) CD4 and CD8 T cells, reduced myeloid and Treg immuno-suppressive cells, reduced exhausted T cells (PD-1+CD69+), reduced peripheral MDSCs; and histological subtype change (pleomorphic or biphasic to epithelioid) in 13% of cases. Conclusions: Brief preoperative defactinib exposure was well tolerated, did not alter resectability or mortality compared to prior series, and showed evidence of therapeutic and immunomodulatory effects. Clinical trial information: NCT02004028.
A novel approach to capture patient-reported toxicities of immunotherapy for non-small cell lung cancer using a foundation-sponsored patient registry.
Authors: Heather S.L. Jim, Sandra S. Shaw, Guneet Walia, David LeDuc, Adam P. Dicker
Journal: Journal of Clinical Oncology (2018)

e20506 Background: Immune checkpoint inhibitors have generated excitement for their ability to significantly prolong survival in cancers with poor prognoses. Success in slowing disease progression comes with the cost of significant toxicity. Little is known about patient-reported toxicities outside the context of a clinical trial. Clinical trial participants tend to be younger, healthier, less racially and ethnically diverse, and have lower rates of hospitalization than most cancer patients. The goal of the current study is to better understand patient-reported toxicity among patients treated with immunotherapies as part of standard care. Methods: The Addario Lung Cancer Foundation (ALCF) with the assistance of the American Lung Association and The International Association for the Study of Lung Cancer (IASLC) developed and implemented a community-based Internet survey of patient-reported toxicities in lung cancer patients treated with an immune checkpoint inhibitor. Survey questions were generated from 29 interviews with patients treated with immune checkpoint inhibitors, their caregivers, and providers. To be eligible, patients must be 18 years of age or older, English-speaking, and treated with a checkpoint inhibitor for lung cancer. Results: The study went live in January 2018; 49 participants have completed the survey to date. Respondents were patients (90%) and spouses/other relatives (10%). The mean age was 60 (range 29-79). Most participants were female (63%), white (86%), non-Hispanic (88%), married (85%), and had completed college (63%). Agents received were nivolumab (51%), pembrolizumab (39%), atezolizumab (8%), ipilimumab (4%), and durvalumab (2%). Updated sample and outcomes data will be presented. Conclusions: Results suggest use of an Internet-based survey is feasible for collecting patient-reported toxicity data. The study will provide important pilot data regarding patient-reported toxicities that can be used to help educate lung cancer patients and their families about what patient-reported side effects are likely to occur, when they will occur, and how they will impact quality of life.
A randomized, double-blind phase III trial of niraparib maintenance treatment in patients with HRD+ advanced ovarian cancer after response to front-line platinum-based chemotherapy.
Authors: Antonio Gonzalez-Martin, Floor Jennishens Backes, Klaus H. Baumann, Dana Meredith Chase, Mathias Konrad Fehr, Robert L. Coleman, Gilles Freyer, Paul DiSilvestro, Ofer Lavie, Thomas J. Herzog, Domenica Lorusso, Kathleen N. Moore, Mansoor Raza Mirza, Roisin Eilish O'Cearbhaill, Ignace Vergote, Bhavana Pothuri, John Balser, Shefali Agarwal, Bradley J. Monk
Journal: Journal of Clinical Oncology (2016)

TPS5606 Background: Niraparib is a highly selective PARP1/2 inhibitor that induces synthetic lethality in tumor cells with homologous recombination DNA repair deficiencies (HRD). Niraparib is administered orally once daily (QD) and may be taken without regard to meals, because food does not significantly affect the absorption or metabolism of niraparib. In a phase 1 study, niraparib was clinically active and well tolerated in patients with ovarian cancer. To address the need for novel therapies for recurrence, a randomized, double-blind phase 3 study is evaluating niraparib as maintenance treatment in patients with stage III/IV HRD+ ovarian, fallopian tube, or primary peritoneal cancer who responded to front-line platinum-based chemotherapy but are at high risk for progressive disease, based on cancer stage, use of neoadjuvant therapy, and residual disease after primary surgery. Methods: This multicenter trial is enrolling ≈305 patients with ovarian, fallopian tube, or peritoneal cancer.Eligible females are required to have histologically diagnosed stage III/IV cancer, an HRD+ tumor (myChoice HRD test), normal or > 90% decrease in CA-125 levels during front-line therapy, and no prior PARP inhibitor use. Patients who have undergone debulking surgery must have residual disease after primary surgery unless they received neoadjuvant therapy. Patients with a known history of myelodysplastic syndrome (MDS) or a baseline cytogenetic test result with a risk for a diagnosis of MDS or acute myeloid leukemia are excluded. Patients must have completed ≥ 4 cycles of platinum-based therapy and had a complete or partial RECIST response. Patients are randomized (2:1) to receive niraparib 300 mg QD or matched placebo in 28-day cycles. Tumors are assessed every 12 weeks per RECIST v1.1. The primary endpoint is progression-free survival (PFS) by blinded central review. After 258 PFS events, the study will have 90% power (one-sided a = 0.025) to detect an improvement in median PFS with hazard ratio = 0.65. Secondary endpoints are evaluation of overall survival, patient-reported outcomes, safety and tolerability, and time to progression on next therapy. Clinical trial information: NCT02655016.