tbuckley/cabot-search huggingface dataset:
Prognostic value of serum soluble programmed death-ligand 1 (sPDL1) and dynamics during chemotherapy in advanced gastric cancer patients.
Authors: Woochan Park, Ju-Hee Bang, Ah-Rong Nam, Ji Eun Park, Mei Hua Kim, Kyoung Seok Oh, Yung-Jue Bang, Do-Youn Oh
Journal: Journal of Clinical Oncology (2019)

4034 Background: The soluble form Programmed Death-Ligand 1(sPDL1) is suggested to have immunosuppressive activity and under investigation as candidate biomarker for immuno-oncology drug development. In this study, we measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC). Methods: We prospectively enrolled 68 GC patients who were candidates for palliative standard 1 st -line chemotherapy, and blood was serially collected at pre-and post-one cycle of chemotherapy, at best response and disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progression-free survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off values of sPDL1 levels and changes for survivals were found using C-statistics. Results: The median baseline sPDL1 was 0.8ng/mL(range, 0.06 - 6.06ng/mL). The median OS and PFS were 14.9 months (95% CI: 7.33-22.47) and 8.0 months (95% CI: 5.96-10.0), respectively. sPDL1 and NLR showed a positive correlation. Patients with low levels of sPD-L1 at diagnosis ( &lt; 1.92 ng/mL) showed a better OS and PFS than the patients with a high sPDL1 (OS: 18.3 vs. 95 months, P = 0.057, PFS: 8.9 vs. 6.0 months, P = 0.04). The baseline sPDL1 before treatment were higher in the PD group than in the SD and PR groups (mean:2.91, 1.17, 1.19, P = 0.019). Patients whose sPDL1 increased after 1 st cycle of chemotherapy showed the tendency of worse PFS and OS. When disease progressed, sPDL1 increased compared with baseline (mean:1.31, 1.45, P = 0.029). Conclusions: sPDL1 at pre-chemotherapy confers the prognostic value for PFS and OS in GC patients under palliative 1 st -line chemotherapy. The dynamics of sPDL1 during chemotherapy correlates with disease courses.
Safety and preliminary clinical activity of repotrectinib in patients with advanced <i>ROS1</i> fusion-positive non-small cell lung cancer (TRIDENT-1 study).
Authors: Byoung Chul Cho, Alexander E. Drilon, Robert Charles Doebele, Dong-Wan Kim, Jessica Jiyeong Lin, Jeeyun Lee, Myung-Ju Ahn, Viola Weijia Zhu, Samuel Ejadi, D. Ross Camidge, Yuwei Juliet Liu, Shanna Stopatschinskaja, Jingrong Jean Cui, David Michael Hyman, Sai-Hong Ignatius Ou, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2019)

9011 Background: Repotrectinib is a next-generation ROS1/TRK/ALK TKI inhibiting ROS1 with &gt; 90-fold greater potency than crizotinib. Preclinical studies showed robust kinase inhibitory activity of repotrectinib against all known ROS1 fusion positive resistance mutations, including the most common ROS1 solvent-front mutation (SFM) G2032R. Methods: In this ongoing phase 1 study (NCT03093116), TKI-naïve and TKI-refractory (≥1 TKI) patients (pts) with advanced ROS1/TRK/ALK+ solid tumors received repotrectinib treatment. Endpoints include safety, PK, and confirmed overall response (cORR). Safety analysis for all pts (n = 75) and efficacy analysis for ROS1+ NSCLC pts (n = 28) enrolled on the study was conducted. Results: As of 31-Oct-2018, 75 pts were treated with repotrectinib at dose levels from 40 mg QD to 200 mg BID. Most AEs were manageable and grade (Gr) 1-2. Common ( &gt; 20%) treatment-related AEs were dizziness (49%), dysgeusia (48%), paresthesia (28%), and constipation (20%). Four DLTs (Gr3 dyspnea/hypoxia (n = 1); Gr2 (n = 1) and Gr3 (n = 1) dizziness at 160 mg BID, and Gr3 dizziness (n = 1) at 240 mg QD) occurred and were managed with dose modifications. The MTD has not been reached. Median number of prior TKI treatment was 1 (0-3) with all of TKI naïve and 83% of TKI pre-treated pts received prior chemotherapy. Among 10 evaluable TKI-naïve ROS1+ NSCLC pts, confirmed ORR by Blinded Central Review (BCR) was 90% (95% CI 56 - 100) with median duration of response (DOR) not reached ((range 5.5+ – 14.9+ months (mos)). Among 18 TKI-pretreated pts, confirmed ORR by BCR was 28% (95% CI 10 – 54) with DOR of 10.2 mos. Subgroup analysis showed cORR 44% (95% CI 14 - 79) in 9 prior TKI pts and treated at dose levels of 160 mg QD or above. In 7 pts with measurable target CNS lesions at baseline, the intracranial ORR was 3/3 (100%) with DOR (5.5+; 7.2+; 14.85+ mo) in TKI-naïve pts and 2/4 (50%) with DOR (5.5+;14.8+, mo) in TKI-pretreated pts, respectively. Conclusions: Repotrectinib was well tolerated and demonstrated encouraging overall and intracranial clinical activity in pts with ROS1 fusion-positive NSCLC. Enrollment in phase 1 continues until the RP2D is determined. A global phase 2 study is planned. Clinical trial information: NCT03093116.
Quality of life (QoL) and symptom burden in patients (pts) with advanced melanoma during the treatment-free interval (TFI) after discontinuation of nivolumab (NIVO) or NIVO plus ipilimumab (IPI).
Authors: Fiona Taylor, Meredith M. Regan, Dirk Schadendorf, Michael B. Atkins, Rachael Lawrance, Alejandro Moreno-Koehler, Andriy Moshyk, Sumati Rao, Corey Ritchings, SRIVIDYA KOTAPATI, Jennifer Lord-Bessen, Jasmine I. Rizzo, David F. McDermott, Mark R. Middleton
Journal: Journal of Clinical Oncology (2019)

9568 Background: The TFI after discontinuation of study therapy has been reported to be longer with NIVO+IPI compared to NIVO or IPI alone, but QoL during the TFI has not been reported in advanced melanoma (MEL) studies. 1-y data from CheckMate (CM) 067 showed maintenance of QoL after treatment (tx) discontinuation with NIVO or NIVO+IPI. Here, we present long-term QoL results from CM 067 during the TFI (period off study tx and free of subsequent therapy), based on an updated 4-y dataset. Methods: In CM 067, 945 pts were randomized 1:1:1 to receive NIVO 3 mg/kg + placebo; NIVO 1 mg/kg + IPI 3 mg/kg × 4, then NIVO 3 mg/kg; or IPI 3 mg/kg × 4 + placebo. Patient-reported outcomes (PRO) were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, visual analog scale) at baseline, on-tx visits, and follow-up (FU) visits 1 (FU1; 30 d after last dose) and 2 (FU2; 84 d after FU1). EQ-5D-3L was also collected at survival FU visits every 3 mo after FU2 in the first year and every 6 mo thereafter. Within the PRO analysis population, 480 of 764 pts who discontinued protocol tx (for any reason, including drug toxicity; n = 155) had PRO scores, collected prior to initiation of subsequent anticancer therapy, evaluated. Mean changes in PRO scores from last on-tx visit were reported for each FU visit. Results: Across tx arms, PRO scores were maintained from last on-tx visit to FU1 or FU2 for pts who discontinued for any reason. EORTC QLQ-C30 functional and symptom scales remained stable during the TFI. Among pts who discontinued tx due to toxicity, clinically meaningful deterioration in QoL was observed in a few subscales at FU1, but QoL was restored to the same level as the last on-tx visit in all except one subscale by FU2. PRO scores remained stable beyond FU2 for the EQ-5D-3L, regardless of reason for discontinuation. Data interpretation at later FU visits was limited due to smaller sample sizes. Sensitivity analyses for mean change in PRO scores from randomization to FU visits will be presented. Conclusions: QoL was maintained during the TFI, compared to last on-tx visit, in pts with MEL treated with NIVO or NIVO+IPI.
Economic benefits of adaptive abiraterone therapy for advanced prostate cancer.
Authors: Neil Thomas Mason, Jason M Burkett, Ryan Nelson, Julio M. Pow-Sang, Robert A Gatenby, Timothy Edward Kubal, John Williamson Peabody, Douglas D. Letson, Howard L. McLeod, Jingsong Zhang
Journal: Journal of Clinical Oncology (2019)

e18343 Background: We recently completed a study showing that adaptive abiraterone therapy (AT) led to more than a doubling of the time to radiographic progression (TTP) compared to continuous therapy (CT) in patients with metastatic castration resistant prostate cancer (mCRPC), [Nat Commun. 2017; 1816]. This study compared the cost of care in the AT cohort versus the standard of care CT cohort. Methods: We conducted a retrospective economic analysis of mCRPC patients receiving intermittent AT compared to patients receiving CT abiraterone. The study followed the adaptive therapy trial protocol (NCT02415621). The primary endpoints were costs of care per patient per year and cost per treatment month. We used itemized billing data and standardized to Medicare reimbursement rates to determine the pharmacy, lab, and imaging costs. Results: Patients receiving adaptive abiraterone therapy (N = 15) had a mean annual cost of care of $80,668 compared to a mean annual cost of care of $132,631 for CT patients. The cost of treatment per month was $6,713 for the AT versus $11,088 for the CT. The economic benefits persisted even after taking into account the cost of abiraterone (Table). Conclusions: The reduction in cost of care in patients with mCRPC with nearly an additional year of TTP from adaptive abiraterone therapy demonstrates the potential value of novel precision medicine approaches. If confirmed by other, larger scale studies, AT may provide significant economic value from far more effective therapy. [Table: see text]
Galician lung cancer group: Afatinib´s data as first-line treatment for elderly patients.
Authors: Sara Agraso Busto, Vanesa Varela, Natalia Fernández Núñez, Jose-luis Firvida, Lucía Santomé, Francisco Javier Afonso, Cristina Azpitarte, Noemi De Dios Alvarez, Jorge Garcia, Begoña Campos Balea, Maria Carmen Areses Manrique, Diego Pereiro Corbacho, Gerardo Huidobro, Martin Lazaro Quintela, Joaquín Casal Rubio
Journal: Journal of Clinical Oncology (2019)

e20662 Background: There are scarcy data or studies on safety and efficacy of afatinib in elderly patients. Methods: Retrospective study on patients from differents hospitals in Galicia (Spain) diagnosed of metastasic lung adenocarcinoma with EGFR positive mutation who have received first line treatment with afatinib between July 2015 and September 2018 were included. Main objectives were to asses safety, dose reductions and as well as its effects on effectiveness of the treatment in patients 70 years old or older (elderly patients) comparing with data from patients under 70 years of age. Results: 45 patients were included in our analysis (33 women, 12 men). Median age was 71.2 years (39-91) with 24 patients (53.3%) being 70 years old or older. Common adverse events grade 3/4 were mucositis and skin toxicity (28.6% in patients under 70 years and 20.8% in elderly patients) and diarrhea (9.5% and 16.7% respectively). The dose was reduced in 47.6% patients under 70 vs 75% in elderly patients. Treatment was discontinued in 14.3% patients vs 20.8% patients respectively owing to adverse events. Overall response was 76% and 62.5% respectively. Disease control rates were 90.3% (95% CI: 96.7-83.8) and 83.3% (95% CI: 98.2-68.4) respectively. Median progression free survival (PFS) was 27 months (95% CI 14.8-39.1) and overall survival was not reached. By ages, median PFS was 20 months (95% CI: 7.4-32.5) vs not reached in elderly patients although being unable to demonstrate differences in progression-free survival between both groups. Conclusions: PFS was 20 months in people under 70 years vs not reached in elderly patients. Elderly patients need more treatment interruption or dose adjustments compared with younger patients, but this does not seem to impair safety and does not compromise effectiveness either.
Characterizing PD-L1/PD-1 expression in hepatocellular carcinoma and implications on postresection treatment response.
Authors: Mark Farha, Michael Green, Issam El Naqa
Journal: Journal of Clinical Oncology (2019)

e15626 Background: Despite recent progress in the treatment of liver cancer, its outcomes remain poor and recurrence rates are as high as 70% in 5 years. Here we seek to use PD-1 and PD-L1 expression to characterize the tumor immune microenvironment and determine whether the expression profile can be associated with response to specific treatments and be applied to personalize treatment regimens in the post-resection setting. Methods: Patients in the study had a mean age of 59, and the majority were caucasian (73%). Most were classified as Child-Pugh A (60%) and TNM stage 1-2 disease (63%). RNA Seq by Expectation Maximization (RSEM) values from the TCGA hepatocellular carcinoma (HCC) dataset for the PD-1 and PD-L1 genes were collected and normalized. RSEM values above the median were labeled “high”, while values below the median were labeled “low”. Corresponding clinical and demographic data were recorded. Survival analysis and multivariate Cox regression analyses were performed, and the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) scores were included to further characterize the tumor purity and the immune cell infiltration. Results: The median post-treatment survival of all patients was 32.4 months. Significant covariates impacting survival were age (HR = 1.05), AJCC TNM stage (HR = 1.61), and high PD-L1 expression (HR = 0.37). When stratified by ESTIMATE, the PD-1 high/PD-L1 high patient cohort had a mean immune score of 450, which was significantly higher than the other cohorts and the only positive score. Furthermore, when patients in this cohort were treated with chemotherapy, radiation, or sorafenib, their time-to-death was 20 months longer than patients from the same cohort treated with local embolization or ablation. Conclusions: We have provided data suggesting a survival advantage for patients with a positive ESTIMATE immune score and high PD-L1 and PD-1 expressions when treated with chemo, radiation, or sorafenib. Existing data suggests that immunotherapy can further synergize with these treatments in HCC and offer another promising approach to improve survival after resection for about 30% of HCC patients with this immune profile.
Value appraisal of FDA approved cancer drugs over the past decade.
Authors: Ryan Huey, Seerat Anand, Jane Rogers, Arvind Dasari, Gauri Rajani Varadhachary, Anirudh Gothwal, Jonathan M. Loree, Lee M. Ellis, Michael J. Overman, Kanwal Pratap Singh Raghav
Journal: Journal of Clinical Oncology (2019)

e18385 Background: Value based drug pricing is emerging as an imperative health care precept in recognition of the ever-increasing drug costs, especially in oncology. Though novel therapies are regularly approved based on benefit, they are often associated with physical and financial toxicities to patients. We aimed to assess the value of FDA approved oncology drugs defined as their expected clinical benefit compared to their toxicities and costs. Methods: We reviewed all new cancer drug approvals by the FDA from 7/2008-6/2018. Current analysis was restricted to approvals based on overall survival (OS) and progression-free survival (PFS). Data regarding approval indication, effect size, and toxicity were collected from FDA website and publications. Toxicity was estimated as adverse events ≥ grade 3 (or serious adverse events) as reported. Micromedex RED BOOK was used to estimate the total drug price using 2018 average wholesale prices. Price was estimated over 3 months to account for difference in drug regimens. Results: Among the 231 trials used by FDA for approvals in oncology, 115 had OS or PFS as their primary endpoint. Median patients per trial was 539. Of 79 trials with a PFS endpoint, the median HR was 0.50 (range: 0.15 - 0.91); median 3-month drug price was $45,903.72. Compared to the control arm, median toxicity for new drugs was 7% higher (range: -34.4 - 55%). Correlation of HR benefit to 3-month price was 0.06 (95% CI: -0.17 - 0.28, P = 0.61). Correlation of net toxicities to 3-month price was 0.01 (95% CI: -0.25 - 0.26, P = 0.94). Of 43 trials with an OS endpoint, the median HR was 0.72 (range: 0.37 - 0.94); median 3-month price was $43,523.46. Relative to control arm, median toxicity for new drugs was 4% higher (range: -34.4 - 45.8%). Correlation of HR benefit to 3-month price was 0.38 (95% CI: 0.08 - 0.62, P = 0.012). Correlation of net toxicities to 3-month price was -0.12 (95% CI: -0.45 - 0.24, P = 0.50). Conclusions: Drug approvals in oncology come with a high cost and drug prices have very little correlation with estimated benefit in outcomes and toxicities. As policies evolve to promote higher value in health care, attention should be paid to benefits of drugs in relation to pricing and using biomarker-based patient selection to maximize benefits and minimize toxicities.
Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C).
Authors: Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Anuradha Chougule, Abhishek Mahajan, Amit Janu, Nilendu Purandare, Rajiv Kumar, Sucheta More, Supriya Goud, Nandkumar Kadam, Nilesh Daware, Srushti Shah, Akanksha Yadav, Amit Dutt, Vaishakhi Trivedi, Vichitra Behel, Shripad Dinanath Banavali, Kumar Prabhash
Journal: Journal of Clinical Oncology (2019)

9001 Background: Standard first-line therapy for EGFR mutant advanced non-small cell lung cancer (NSCLC) is an EGFR-directed oral TKI. We evaluated whether adding pemetrexed-carboplatin to oral TKI would improve outcomes. Methods: Phase III randomized trial in advanced chemotherapy-naïve NSCLC harboring EGFR sensitizing mutation (exon 19, 21 or 18) with performance status (PS) 0 to 2 planned for palliative therapy. Patients were stratified for PS and EGFR mutation and randomly assigned (computer-generated randomization by independent biostatistician) 1:1 to gefitinib 250 mg orally daily (gef) or gefitinib 250 mg orally daily with pemetrexed 500 mg/m 2 IV and carboplatin AUC 5 IV every 3 weeks for 4 cycles, followed by maintenance pemetrexed 500 mg/m 2 IV every 3 weeks (gef+C). Restaging was every 2 to 3 mths; therapy continued until progression or intolerable toxicity. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), toxicity and response rate. Survival endpoints were assessed in the intention-to-treat population. Results: Between Aug 2016 and Aug 2018, 350 patients were randomly assigned to gef (n = 177) and gef+C (n = 173). Median age was 54 yrs, 48% were females, 84% never-smokers, 21% were PS 2 and 18% had brain metastases. Median follow-up in surviving patients was 17 months (range, 7 to 30). Radiologic response rates were 81% and 69% in gef+C and gef respectively, P = 0.012. 234 patients (67%) have had events for PFS, 98 in gef+C and 136 in gef. Estimated median PFS was significantly longer with gef+C than gef (16 months, [95% CI, 13.7 to 18.3] vs. 8 months [95% CI, 7.1 to 8.9]; hazard ratio for disease progression or death, 0.5; 95% CI, 0.39 to 0.65; P &lt; 0.001). 120 patients (34%) have died, 42 in gef+C and 78 in gef. Estimated median OS was significantly longer with gef+C than gef (not reached vs. 18 months [95% CI, 14.28 to 21.72]; hazard ratio for death, 0.45; 95% CI, 0.31 to 0.66; P &lt; 0.001). Clinically relevant ≥ grade 3 toxicities occurred in 51% and 25% of patients in gef+C and gef arms respectively, P &lt; 0.001. Conclusion: Adding pemetrexed-carboplatin chemotherapy to gefitinib significantly prolonged progression free and overall survival but also increased toxicity. Pemetrexed-carboplatin-gefitinib represents a new standard first-line therapy for EGFR mutant NSCLC. Clinical trial information: CTRI/2016/08/007149.
AMG 458, a potent small molecule c-Met inhibitor, has significant anti-tumor activity in vivo
Authors: Paula Kaplan-Lefko, Karen Rex, Jodi Moriguchi, Yajing Yang, Yihong Zhang, April Chen, Jasmine Lin, Steve Kaufman, Tae-Seong Kim, Longbin Liu, Aaron Siegmund, Jean-Christophe Harmange, Roman Shimanovich, Teresa Burgess, Richard Kendall, Robert Radinsky, Angela Coxon, Isabelle Dussault
Journal: Cancer Research (2008)

4976  c-Met is a receptor tyrosine kinase that signals through its ligand, hepatocyte growth factor (HGF), to mediate multiple biological activities including proliferation, survival, motility and migration. In cancer, HGF/c-Met signaling is often deregulated. Overexpression of c-Met occurs frequently in numerous types of tumors. Gene amplification and activating mutations leading to constitutive receptor activation have also been described in patient tumors. In addition, altered expression of this axis in several mouse models has implicated c-Met in tumorigenesis. Therefore, targeting c-Met has promise as an approach to treating patients with tumors harboring activated c-Met. AMG 458 was identified as a selective, orally bioavailable, ATP-competitive small molecule c-Met inhibitor. AMG 458 potently inhibited c-Met enzymatic activity with an IC50 of 2 nM and blocked c-Met phosphorylation in PC3 cells with an IC50 of 60 nM. AMG 458 inhibited signaling in a dose-dependent manner in vitro in NIH-3T3 cells stably expressing TPR-Met, a constitutively active form of c-Met. Consistent with its activity in vitro, AMG 458 significantly inhibited HGF-mediated c-Met phosphorylation in the mouse liver at 30 mg/kg PO (p
Genomic landscape of de novo stage IV breast cancer.
Authors: Ana Christina Garrido-Castro, Liam Spurr, Melissa E Hughes, Yvonne Y. Li, Andrew D. Cherniack, Brittany L. Bychkovsky, Romualdo Barroso-Sousa, Simona Di Lascio, Janet Files, Priti Kumari, Ethan Cerami, Ian E. Krop, Laura E MacConaill, Neal Ian Lindeman, Barrett J Rollins, Bruce E. Johnson, Nikhil Wagle, Eric P. Winer, Deborah Dillon, Nancy U. Lin
Journal: Journal of Clinical Oncology (2019)

1022 Background: Genomic profiling of primary and recurrent metastatic breast cancer (rMBC) has revealed potential resistance mechanisms to therapy. In contrast, de novo stage IV breast cancer (DNIV) represents an opportunity to elucidate metastatic drivers in the absence of treatment selection. Methods: Targeted NGS (Oncopanel, OP) using multiplexed copy number variation (CNV) and mutation (mut) detection across the full coding regions of 300 genes and selected intronic regions of 35 genes was performed on either primary or metastatic samples collected in patients (pts) with DNIV or rMBC. Mut/CNV in primary and metastatic tumors were compared per subtype between DNIV and rMBC using Fisher´s exact test (significant p&lt;0.05). FDR were computed ( q&lt;0.25). Results: Between 8/2013-9/2016, of 929 pts who underwent OP testing 212 presented with DNIV; 136 HR+/HER2- (64%); 35 HR+/HER2+ (17%); 25 TNBC (12%); 16 HR-/HER2+ (8%). In 168 (79%) pts, the primary was tested; 44 had a metastatic site tested. Comparison of primary HR+/HER2- tumors showed that DNIV pts were more likely to harbor mut in CDKN1B, SETD2 and PMS2 and less likely to have TP53 mut than rMBC (Table). Metastases in HR+/HER2- DNIV (n=29) had higher mut in CDH1, PTCH1 and CTNNB1 and fewer CCND1 amplification (amp) than rMBC (n=121), albeit these findings lost significance after FDR correction. DNIV primary TNBC (n=19) was significantly enriched for CIITA mut (26% vs. 0%; q=0.046) and MYB amp (21% vs. 0%, q=0.098) compared to rMBC (n=101). TP53 mut, amp in RAD21, MYC, MYB, PTK2 and EGFR, and deletions in CDKN2A/2B and MAP2K4 significantly predicted poorer overall survival in DNIV. Conclusions: DNIV primary and metastatic tumors have distinct genomic profiles compared to rMBC. Alterations in genes involved in epigenetic modulation ( KMT2D, SETD2) and epithelial-mesenchymal transition ( CDH1, PTCH1, CTNNB1) are more prevalent in HR+/HER2- DNIV. DNIV TNBC is enriched for CIITA mut, described to promote immune escape via reduced MHC class II expression. If validated, these findings may provide insight into mechanisms underlying metastatic potential. [Table: see text]