tbuckley/cabot-search huggingface dataset:
Preliminary results of single arm phase 2 trial of brigatinib in patients (pts) with progression disease (PD) after next-generation (NG) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in <i>ALK</i> + non-small cell lung cancer (NSCLC).
Authors: Tom Stinchcombe, Robert Charles Doebele, Xiaofei F. Wang, David E. Gerber, Leora Horn, D. Ross Camidge
Journal: Journal of Clinical Oncology (2019)

9027 Background: NG ALK TKIs are the standard first-line therapy for patients with advanced ALK + NSCLC. Brigatinib has activity against ALK resistance mutations and has CNS activity. The efficacy of brigatinib after NG ALK TKI is undetermined. Methods: Pts with stage IIIB/IV ALK + NSCLC, and PD after NG ALK TKI’s were eligible. Pts were required to have measurable disease, performance status 0-2, and adequate organ function. Pts were required to undergo tumor biopsy ≤ 60 days of enrollment; ctDNA was collected at baseline, at time of imaging, and PD. Brigatinib treatment was 90 mg daily for 7 days and then 180 mg daily (1 cycle = 28 days). Primary objective was objective response rate (ORR), and ORR of 20% was determined to be worthy of further investigation. Response was assessed every 2 cycles. A 2-stage design was used; if &gt; 2 responses in 20 pts in the 1 st stage, study proceeded to 2 nd stage; if ≥ 5 responses in 40 pts therapy considered active. Results: Between 3/2017 and 11/2018, 20 pts were enrolled in the 1 st stage. Pt characteristics were: median age 55 years (range 32 to 71), median number of prior therapies 3 (range 1 to 6), 12 had CNS disease at the baseline (8 pts had CNS PD). ALK resistance mutation detected in 3 of 8 pts on standard of care molecular testing. ORR results were confirmed partial response (n = 8), stable disease (n = 7), PD (n = 3), unconfirmed response (n = 1), and non-evaluable due adverse events (AE’s) (n = 1). The grade 3 or 4 AE’s were: pneumonitis (n = 2); 1 of each: acute renal failure, respiratory failure, sepsis, hypertension, CPK elevation, and headache. With median follow-up of 6.7 months (11 PFS events), the median PFS was 6.4 months (95% CI: 4.6 to NE). Overall survival data is immature. 3 of 3 pts with a known ALK mutation (F1174C in 2 pts, I1171T in 1 pt) responded, 2 of 5 pts without ALK mutation responded. Additional study related tumor analysis and ctDNA analyses are ongoing. Conclusions: Brigatinib has activity after progression on next generation ALK TKI. The study is enrolling additional patients in the second stage. Detailed molecular and site of disease (CNS versus extra-CNS) activity analyses are underway Clinical trial information: NCT02706626.
Impact of cholesterolemia and body mass index on outcome of metastatic non small cell lung cancer treated with immunotherapy.
Authors: Giulia Galli, Paola Corsetto, Roberto Ferrara, Arsela Prelaj, Claudia Proto, Diego Signorelli, Nicoletta Zilembo, Alessandro De Toma, Filippo Pagani, Giovanni Randon, Monica Ganzinelli, Antonio Sica, Filippo G. De Braud, Marina Chiara Garassino, Giuseppe Lo Russo
Journal: Journal of Clinical Oncology (2019)

e20691 Background: Immunotherapy (IO) is effective against metastatic Non Small Cell Lung Cancer (mNSCLC). Nonetheless, a minority of patients (pts) gains a benefit from IO and predictive variables of response are scarcely understood. Previous retrospective studies have showed a superior outcome for obese pts and preclinical data suggest a role of lipid profile. We aimed at investigating these topics in a cohort of pts with mNSCLC. Methods: We retrospectively collected data about all consecutive pts with mNSCLC treated with IO at our Institution between 12/2017 and 12/2018. Body Mass Index (BMI) was calculated as weight/height 2 ; pts were classified as overweight if having a BMI≥25 kg/m 2 . Basal Cholesterolemia (BC) was dosed between one month (mo) before and one mo after the beginning of IO, with a cut-off for normality of 200 mg/dL. Survival was estimated with Kaplan-Meier method. Cox model was used for multivariate analyses. Results: We identified 55 pts. Thirty-three had a normal baseline BMI, the remaining were overweighted. Median BC was 171.5 mg/dL (range 15-313); 14 pts had hypercholesterolemia. No correlation was evident between BMI and BC ( p .1772). Neither BMI nor BC were associated to first and best response to IO. Median Progression Free Survival (PFS) was 3.75 mos; median Overall Survival (OS) was 6.78 mos. Hypercholesterolemia was related to longer PFS (9.44 vs 3.71 mos, p .0484), confirmed at multivariate analysis ( p.0392). Both hypercholesterolemia and BMI≥25 kg/m 2 were associated to longer OS (15.56 vs 5.13 mos, p.0411, and 16.67 vs 4.97 mos, p.0222, respectively), but only BMI retained significance at multivariate analysis ( p .0279). Conclusions: Hypercholesterolemia shows a positive impact on outcome of mNSCLC treated with IO. The independence of this correlation from BMI suggests the existence of a true different metabolic pathways. Moreover, overweight patients have a longer OS than those with normal BMI. This result confirms previous data on obese patients, extending the range of BMI values that are linked to a better prognosis. In conclusion, the role of metabolism and body composition in defining the benefit from IO in mNSCLC is likely multifaceted, warranting further investigation.
CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: A network meta-analysis (NMA) of randomized controlled trials (RCTs).
Authors: Muhammad Husnain, Irbaz Bin Riaz, Farva R. Gondal, Saad Malik, Qurat Ul Ain Riaz Sipra, Ammad Raina, Mahnoor Islam, Gilberto Lopes
Journal: Journal of Clinical Oncology (2019)

e12545 Background: Palbociclib(P), Ribociclib(R) and Abemaciclib(A) in combination with Endocrine therapy (ET) have demonstrated progression free survival (PFS) in patients with metastatic hormone receptor positive, HER2-negative breast cancer as compared to ET alone. In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison for P, R and A using network Meta-Analysis (NMA). Methods: MEDLINE, EMBASE and the Cochrane Library were searched to identify RCTs comparing P+ET, R+ET, A+ ET vs ET alone. NMA for PFS and toxicity endpoints was conducted using a multivariate random-effects meta-regression, using a consistency model, as described by White and colleagues. We used a frequentist approach and provided a point estimate from the network and a 95% CI from the frequency distribution of the estimate. We also estimated the relative ranking of the different treatments for each outcome using the distribution of the ranking probabilities and the surface under the cumulative ranking curves (SUCRA). Risk of bias was assessed using Cochrane Collaboration tool. Results: 8 RCTs were identified including 4580 patients. Risk of bias was low. 5 RCTs tested CDK 4/6 inhibitors in endocrine naive and 2 in the refractory setting, while MONALESSA-3 included patients both with endocrine naive and endocrine resistant disease. In the endocrine naïve patients, PFS for P was similar when compared indirectly with R (HR, 0.95, 95% CI 0.67-1.35) or A (HR, 1.00, 95% CI 0.62-1.61). Similarly, indirect comparison between R vs A did not show any statistical significant (HR, 0.95, 95% CI 0.62-1.45). In endocrine refractory patients, P showed no difference when compared indirectly to A (HR 1.12, 95% CI 0.67-1.87) or R (HR 0.98, 95% CI 0.52-1.86). R vs A did not show any statistically significant PFS either (HR, 1.14, 95% CI 1.61-4.51). P was ranked first in terms of PFS in frontline setting (SUCRA of 70.5) while R ranked first in the refractory setting (SUCRA of 39.5). QT prolongation was reported for R only. P caused more neutropenia while A caused more fatigue, anemia and diarrhea, although the results were not statistically significant. Conclusions: The efficacy of using either palbociclib, ribociclib or abemaciclib in combination with ET was similar in terms of PFS in either endocrine naïve or resistant disease. Palbociclib causes more neutropenia, abemaciclib causes more fatigue, anemia and diarrhea while ribociclib causes QT prolongation.
Early PSA progression in abiraterone/enzalutamide-treated patients with metastatic castration-resistant prostate cancer.
Authors: Fernando López-Campos, Alfonso Gomez-Iturriaga, Casilda Llacer Perez, Ivan Henriquez, Paula Peleteiro, Rebeca Lozano, Ana Castaño, Nuria Romero-Laorden, Javier Molina-Cerrillo, Sara Alvarez-Rodríguez, Teresa Piquer, Joaquin Navarro-Castellón, Antonio José Conde-Moreno, Miguel Ramirez-Backhaus, Patricia Barrionuevo, Raquel García, María de los Llanos Pérez-Haro, Elena Castro, David Olmos, David Lorente
Journal: Journal of Clinical Oncology (2019)

e16530 Background: Changes in PSA are widely used as a biomarker for the monitoring of treatment outcome in Metastatic Castration-Resistant Prostate Cancer (mCRPC) in the clinical real-world setting. Early PSA changes (before 12 weeks) are not considered in the definition of PSA Progression (PSAProg) due to the potential for spurious “flare” reactions. We aimed to evaluate the significance of an early PSA increase in Abiraterone/Enzalutamide (Abi/Enz)-treated mCRPC patients (pts). Methods: We retrospectively evaluated Abi/Enz-treated mCRPC pts from 11 hospitals between 2011-2018. Early PSAProg was defined as a 25% increase in PSA from baseline at 4 (PSAProg4) or 8 (PSAProg8) weeks after treatment initiation. PSA progression at 12 weeks (PSAProg12) was confirmed by a second reading. Uni- and multivariable (MV) Cox regression models were conducted to explore the association of PSAProg and overall (OS) and radiographic progression-free (rPFS) survival. Sensitivity (Se), specificity (Sp) and predictive values (PPV, NPV) for the association of early PSAProg with PSAProg12 were calculated. Results: We analyzed 581 mCRPC pts; median follow-up: 19.1 months. 96 (17.1%); 105 (21.6%) and 85 (16.9%) pts had PSAprog at 4, 8 and 12 wks. PSAProg4 and PSAProg8 were significantly associated with confirmed PSAProg12. 55.3% of pts with PSAProg4 and 66.7% of pts with PSAProg8 had a confirmed PSAProg12. Only 9% of pts with no PSA prog at 4 wks and 4.1% of pts with no PSAProg8 had a confirmed PSAProg12. PSAProg4 had Se: 56.6%, Sp: 90.5%, PPV: 55.2%, NPV: 91% for the detection of PSAProg12. PSAProg8 had Se: 81.9%, Sp: 91.2%, PPV: 66.7%, NPV: 95.9% for the detection of PSAProg12. PSAprog at 4, 8 and 12 wks was significantly associated with OS and rPFS in uni- and MV Cox models (Table). Conclusions: Early PSAProg after Abi/Enz is significantly associated with both confirmed PSA Prog at 12 wks and outcome, and may help identify pts not benefitting from Abi/Enz before clinical or radiographic progression. Prospective validation studies are needed. [Table: see text]
Maintenance Olaparib for Germline <i>BRCA</i>-Mutated Metastatic Pancreatic Cancer
Authors: Talia Golan, Pascal Hammel, Michele Reni, Eric Van Cutsem, Teresa Macarulla, Michael J. Hall, Joon-Oh Park, Daniel Hochhauser, Dirk Arnold, Do-Youn Oh, Anke Reinacher-Schick, Giampaolo Tortora, Hana Algül, Eileen M. O’Reilly, David McGuinness, Karen Y. Cui, Katia Schlienger, Gershon Y. Locker, Hedy L. Kindler
Journal: New England Journal of Medicine (2019)

Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.
Final results from the randomized CABADOC trial: Patient preference between cabazitaxel and docetaxel for first-line chemotherapy in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Giulia Baciarello, Remy Delva, Gwenaelle Gravis, Youssef Tazi, Christine Theodore, Marine Gross-Goupil, Emmanuelle Bompas, Florence Joly, Tifenn Lharidon, Thierry Nguyen Tan Hon, Philippe Barthelemy, Stephane Culine, Jean Francois Berdah, Mathilde Deblock, Philippe Beuzeboc, Aude Flechon, Caroline Cheneau, Geraldine Martineau, Isabelle Borget, Karim Fizazi
Journal: Journal of Clinical Oncology (2019)

5017 Background: Docetaxel and cabazitaxel represent now the standard of care in men with mCRPC with similar efficacy reported in metastatic first-line setting in the FIRSTANA phase 3 trial. We assessed patients’ preference between the two taxanes. Methods: Patients with taxane-naïve mCRPC were randomized in a 1:1 ratio to receive either docetaxel 75mg/m2/q3w x 4 followed by cabazitaxel 25mg/m2/q3w x 4 (DO-CA), or the reverse sequence (CA-DO). Randomization was stratified based on prior next generation AR axis inhibitors use. The primary endpoint was patient preference between taxanes, as assessed by questionnaires in patients who had received at least one cycle of each taxane and who had not experienced a progression while on the first taxane. Results: From June 2014 to October 2016, 195 men were randomized in 17 centers. After adjusting for the treatment period effect, more patients preferred cabazitaxel (43%) vs docetaxel (27%) (p &lt; 0.004); 30% had no preference between taxanes. Fatigue, patient-defined quality of life, hair loss, and pain were the most common factors influencing patient preference. Febrile neutropenia was experienced by 5 (7.1%) men treated with cabazitaxel during the first period who received G-CSF and by 2 (7.1%) of those who did not. No febrile neutropenia was reported with docetaxel in both arms and with cabazitaxel during the 2nd period, irrespectively of the use of G-CSF. The incidence of diarrhea during the first 3-month period was slightly reduced with G-CSF use in men receiving cabazitaxel (32.1% vs 24.3%) but not in those receiving docetaxel (23.8% vs 25%). The median progression-free survival was 9.81 in the DO-CA arm and 9.33 months in the CA-DO arm. The median overall survival was also similar in the two groups (22.64 in the DO-CA arm and 20.73 months in the CA-DO arm. Conclusions: Although cabazitaxel and docetaxel have similar efficacy when used as first-line in mCRPC men, more patients prefer cabazitaxel. Clinical trial information: NCT02044354.
Remote patient monitoring using smart phone derived patient reported outcomes and Fitbit data to enable longitudinal predictive modeling in prostate cancer: Feasibility results and lessons on platform development.
Authors: Andrew L. Laccetti, Rebecca Slack Tidwell, Nipa P Sheth, Christopher Logothetis, Michael VanAlstine
Journal: Journal of Clinical Oncology (2019)

e18068 Background: Wearable activity trackers and frequent interrogation of remote patient reported outcomes (PROs) have the potential to revolutionize oncology clinical trial design, therapeutic sequencing and patient (pt) safety. Established feasibility and novel systems of data processing are necessary to substantiate value for these methods. Methods: Expanding upon our clinical research data platform, Prometheus, we have developed a HIPPA compliant, remote pt monitoring system capable of collecting minute-by-minute step count and heart rate (via Fitbit) in addition to smart phone derived symptom surveys. To pilot this program, a cohort of metastatic castration resistant prostate cancer (mCRPC) pts participated in continuous Fitbit monitoring and thrice weekly NCI-PRO-CTCAE survey for 26 weeks. Pre-specified interim feasibility results were examined with a focus on pt characteristics, treatment and compliance. Qualitative assessment of barriers to pt enrollment and device use was performed. Results: 15 mCRPC pts completed our pilot program: mean age 63.1 years (range 48-79), pre-treatment PSA 33.2 ng/mL (range 0.3 – 499.9), 80.0% stage M1b, ECOG 0 or 1. All pts were treated per protocol NCT02703623: abiraterone/prednisone/apalutamide for 8 weeks followed by continuation of therapy (5 pts), cabazitaxel/carboplatin (6 pts) or addition of ipilimumab (2 pts). 33.3% of pts reported grade 3 clinician interpreted adverse events. 14 pts had data available for compliance analysis. Mean Fitbit compliance was 62.6% (STD 35.5%) with rates trending down over the study duration (week 1 vs 26 = 86.7% vs 33.3%; p= 0.002; R 2 = 0.716). Mean smart phone derived NCI-PRO-CTCAE survey completion rate was 37.1%. Barriers to pt enrollment included slow Fitbit app download times, incompatible smart phones and the need for extensive device use education/counseling. Barriers to data collection were missed survey text prompts and inconsistent use of Bluetooth. Conclusions: MD Anderson’s novel, home-grown, remote pt monitoring platform, utilizing Fitbit and smart phone derived PROs, is feasible in function and pt use. Automated compliance checks, streamlined enrollment and pt education are critical to future application. This foundational work will facilitate longitudinal signal variation benchmarked against standard monitoring methods, ultimately aiming to improve outcomes and support of discovery through enriched access to pt experience.
Correlation between peripheral CD8+PD-1+ T cells diversity, tumor mutation burden (TMB) and T cell clones with anti-PD-1 antibody treatment of lung cancer patients: TCR repertoire as a novel predictive biomarker.
Authors: Seiji Matsumoto, Takaji Matsutani, Yoshiko Fujita, Kazutaka Kitaura, Yukio Nakamura, Toru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Masaki Hashimoto, Nobuyuki Kondo, Tadasu Shini, Ryuji Suzuki, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2019)

e14041 Background: Anti-PD-1 antibodies (nivolumab) are effective in the treatment of many cancers. There is a demand for less invasive biomarkers. Peripheral and tumor CD8+PD-1+ T cells share neoantigen-specific T-cell receptors (TCRs), and are presumed to act as effector T cells with an antitumor effect at the tumor site. We analyzed the diversity in terms of TCR α and β repertoires on peripheral CD8+PD-1+ T cells, tumor mutation burden and examined the relationship between this diversity and therapeutic effect of nivolumab. Methods: This study used patients administered nivolumab after exhibiting no response to chemotherapy for recurrence following surgery. Peripheral blood mononuclear cells were collected from patients before administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Six of 12 patients responded to treatment. Upon comparing these responders (CR, PR) with non-responders (SD, PD), there were no differences in the proportion of PD-1+ in CD8+ T cells and the proportion of CD8+PD-1+ T cells in gated lymphocytes. TCR α diversity was significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (P &lt; 0.05, P &lt; 0.05, P &lt; 0.01, respectively). TCR β diversity was also significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (all P &lt; 0.01). Progression-free survival (PFS) was 371 days for responders and 148 days for non-responders. Overall survival (OS) was 633 days for responders and 308 days for non-responders, showing a significant difference between the groups. TCR repertoire was proportional to TMB. Clones found in multiple patients were more frequent in indel than in SNP. Conclusions: TCR repertoire analysis was performed on CD8+PD-1+ T cells in easily-obtainable peripheral blood before nivolumab treatment in patients with NSCLC, and nivolumab was observed to be effective in patients with high TCR diversity. This result indicates the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to ICI therapy.
AB0115 SEMAPHORIN 4A PERPETUATE SYNOVIAL FIBROBLAST INTERACTIONS WITH CD4+ T CELLS AND OSTEOCLAST DIFFERENTIATION: IMPLICATION IN RHEUMATOID ARTHRITIS
Authors: Zhu Chen, Yuanyuan Zhang, Xu Zheng, LI Xiaomei
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rheumatoid arthritis synovial fibroblast (RASF) and T cells are important contributors in the pathogenesis of RA. Semaphorin 4A has been reported to be elevated in RA patients and play crucial role in promoting inflammation of RA. However, whether semaphorin 4A could facilitate RASF interactions with CD4<sup>+</sup> T cells and osteoclastogenesis is less known. <h3>Objectives</h3> The present study aims to investigate the role of semaphorin 4A-Plexin B1 axis in RASF interactions with CD4<sup>+</sup> T cells and osteoclastogenesis in vitro. <h3>Methods</h3> Mouse synovial fibroblasts (SF) were isolated from collagen-induced arthritic mice and cultured in vitro with TNF-α and IL-β for 24h. Small interfering RNA (siRNA) against Semaphorin 4A and Plexin B1 were constructed and transfected into SF via adenovirus. Splenic CD4<sup>+</sup> T cells isolated from arthritic mice were cocultured with SF under anti-CD3 and anti-CD28. The proportion of CD4<sup>+</sup>IL-17<sup>+</sup> Th17 cells was determined at day 5. PBMC isolated from blood of healthy donors were incubated with 1μg/ml Plexin D1 neutralizing antibody overnight. Cells were washed for monocyte enrichment and cultivated for 14 days in α-MEM supplemented with MCSF and RANKL. Osteoclast differentiation was evaluated by TRAP staining. Total RNA was extracted and expression of osteoclast markers were examined by quantitative real-time PCR. <h3>Results</h3> Adenovirus-Mediated siRNA efficiently inhibited expression of Semaphorin 4A and Plexin B1 in SF. The proportion of Th17 cells was significantly decreased in both Semaphorin 4A and Plexin B1 transfected SF cocultures. The number of Trap positive osteoclasts were significantly decreased in cultures that pretreated with Plexin D1. Consistently, blocking of Plexin D1 signaling dramatically downregulated mRNA expression level of Trap, Cathepsin K and NFATc1. <h3>Conclusion</h3> Semaphorin 4A perpetuate synovial fibroblasts interactions with CD4<sup>+</sup> T cells by promoting Th17 differentiation. Moreover, Semaphorin 4A-Plexin D1 axis promote osteoclastogenesis and therefore might serve as a potential therapeutic target in the treatment of RA. <h3>References</h3> [1] Iyer AS, et al. Neuroimmune Semaphorin 4A in Cancer Angiogenesis and Inflammation: A Promoter or a Suppressor?Int J Mol Sci. 2018Dec30;20(1). [2] Chapoval SP, et al. Semaphorins 4A and 4D in chronic inflammatory diseases. Inflamm Res. 2017Feb;66(2):111-117 [3] Wang L, et al. Expression of Semaphorin 4A and its potential role in rheumatoid arthritis. Arthritis Research &amp; Therapy (2015) 17:227. <h3>Disclosure of Interests</h3> None declared