tbuckley/cabot-search huggingface dataset:
A phase I/II study of albumin-bound rapamycin nanoparticles in the treatment of bacillus calmette-guerin refractory non-muscle invasive transitional cell bladder cancer.
Authors: James M. McKiernan, Ifeanyi Onyeji, Danny Lascano, Jennifer Ahn, Neil Desai, Cory Abate-Shen, Dara Denise Holder, Arindam RoyChoudhury, Sam Chang, Guarionex Joel DeCastro
Journal: Journal of Clinical Oncology (2016)

e16008 Background: Up to 40% of patients treated with intravesical agents for non-muscle invasive bladder cancer (NMIBC) will recur. Our lab has previously demonstrated the feasibility of mTOR inhibition in mouse models of bladder cancer, so we sought to use rapamycin encapsulated in albumin-bound nanoparticles (ABI-009) as a potential targeted therapy for NMIBC. Methods: Inclusion criteria of this phase I trial were high-grade (HG) Ta, T1 or Tis urothelial cell carcinoma of the bladder and refractoriness to 6 weeks of Bacillus Calmette-Guerin (BCG) induction plus 3 weeks of maintenance. ABI-009 was administered weekly over 6 weeks at an initial dose of 100mg with a 3+3 dose escalation rule until the maximum tolerable dose was attained. Drug serum levels were monitored at each instillation. Primary endpoints were maximum deliverable dose and dose-limiting toxicity. Efficacy was assessed by cystoscopy with biopsy and cytology at 3 months. Those without evidence of disease at 3 months received monthly maintenance. Results: 13 patients have completed treatment. Characteristics of the cohort include: mean age (73.6 years), sex (12 male, 1 female), number of prior BCG cycles (mean 2.3), stage [cis (6), HG Ta (3), HG T1 (2), mixed LG Ta and cis (1), mixed HG T1 and cis (1)], and number of prior salvage therapies [BCG+interferon (7), valrubicin (6), nab-paclitaxel (3), mitomycin (4), taxotere (1)]. All toxicities are shown in Table 1. Mean serum drug level after instillation over the study period was 19.7ng/ml. Two patients had no evidence of disease at post-treatment cystoscopy with biopsy, and no patient exhibited disease progression. Conclusions: Intravesical ABI-009 exhibited minimal local toxicity and no systemic toxicity in this first in man clinical trial. Serum levels of rapamycin were achieved at all dose levels, indicating tissue penetration of the drug. A combined phase II trial is currently being planned to further investigate its efficacy. Clinical trial information: NCT02009332.Toxicities. Doses 1x100mg 1x200mg 2x100mg 1x300mg 1x400mg Dysuria G1 x 1 0 G1 x 1 0 0 Urinary retention 0 0 0 0 0 Urinary frequency G1 x 2 G1 x 1 G2 x 1 0 G1 x 1 Hematuria 0 G2 x 1 0 0 G1 x 1 Bladder spasms G1 x 2 G1 x 1 G1 x 1 0 G1 x1
A randomized phase 2 study of abemaciclib versus docetaxel in patients with stage IV squamous non-small cell lung cancer (sqNSCLC) previously treated with platinum-based chemotherapy.
Authors: Giorgio V. Scagliotti, Igor Bondarenko, Tudor-Eliade Ciuleanu, Maciej Bryl, Andrea Fülöp, David Vicente, Helge Bischoff, Karla Hurt, Yi Lu, Shawn Estrem, Sameera R. Wijayawardana, Alan Chiang, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2018)

9059 Background: Abemaciclib is a potent and selective inhibitor of CDK4 & 6 approved for treatment of HR+, HER2- metastatic breast cancer. In a Phase 1 study, abemaciclib showed activity in pts with advanced and/or metastatic NSCLC. This Phase 2 study evaluated the safety and efficacy of abemaciclib vs docetaxel in pts with Stage IV sqNSCLC previously treated with platinum-based chemotherapy. Methods: This multicenter, randomized, open-label trial, evaluated abemaciclib (200 mg PO every 12 hours daily) vs docetaxel (75 mg/m2 IV on Day 1); both on 21 day cycle until disease progression. Adults with confirmed Stage IV NSCLC with measurable disease, ECOG PS ≤1, and who progressed during/after platinum-based chemotherapy were eligible. Pts were randomized 2:1 to receive abemaciclib or docetaxel. Primary endpoint was investigator-assessed PFS. Key secondary endpoints were ORR, DCR, OS, and safety. Results: 159 pts were randomized to abemaciclib (N = 106) and docetaxel (N = 53). Median age was 64 years. 84.3% pts were men. In ITT pts 125 PFS events were observed with median PFS of 2.5 m (95% CI: 1.7, 2.9) for abemaciclib and 4.2 m for docetaxel (95% CI: 2.8, 5.7; stratified HR: 1.77 [95% CI: 1.17, 2.67]; P = .0068). ORR was 2.8% (95% CI: 0.0, 6.0) for abemaciclib and 20.8% (95% CI: 9.8, 31.7) for docetaxel. The DCR (CR + PR + SD) was 50.9% (95% CI: 41.4, 60.5) for the abemaciclib treatment arm and 64.2% (95% CI: 51.2, 77.1) for the docetaxel treatment arm. Median OS was 7.0 m (95% CI: 5.0, 8.8) for abemaciclib and 12.4 m for docetaxel (95% CI: 7.1, 16.0; stratified HR: 1.33 [95% CI: 0.88, 2.02]; P = .1746). Exploratory biomarker data will be available at the meeting. The most common TEAEs with abemaciclib were anemia and diarrhea. Conclusions: In this Phase 2 study, single agent abemaciclib 200 mg did not improve the progression-free survival time over docetaxel; the instantaneous rate of disease progression/death at any given time point was higher with abemaciclib vs docetaxcel. No specific safety concerns were observed. Clinical trial information: NCT02450539.
Association of Akt inhibition with change in immunophenotype of tumor microenvironment (TME) in breast cancer (BC).
Authors: Douglas Kanter Marks, Robyn Denise Gartrell, Margueritta El Asmar, Shuobo Boboila, Thomas D Hart, Camden L Esancy, Yan Lu, Hanina Hibshoosh, Eileen Connolly, Kevin Kalinsky, Yvonne M. Saenger
Journal: Journal of Clinical Oncology (2018)

12057 Background: The PI3K/Akt/mTOR pathway is a known regulator of oncogenic growth in BC. In addition, this pathway also modulates host immune function and may indirectly affect tumorigenesis. Clinicopathologic studies have demonstrated that tumor infiltrating lymphocyte density is predictive of chemosensitivity and improved prognosis in BC, while myeloid infiltration has been hypothesized to play a deleterious role. To define the impact of Akt inhibition on the TME, we analyzed tumor tissue from patients (pts) with early-stage BC treated with MK-2206, an Akt inhibitor, as part of a presurgical trial (NCT01319539). Methods: Transcriptomic analysis was performed on surgical specimens to assess if differences exist in mRNA expression of tumor-associated and immune genes between pts treated with MK-2206 (n = 6) and untreated matched controls (n = 5) (nanoString). Quantitative immunofluorescence (qmIF) was performed for CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin on 4uM sections from biopsy and surgical specimens of both groups. Images acquired using Vectra (PerkinElmer), allowing for multiparameter phenotyping. Statistical analysis performed using t-Test and Z- test. Results: mRNA expression supports in vivo activity of MK-2206 with decreased expression of cell cycle, proliferation and antiapoptotic genes (CTNNB1, CCND2, BAX, p < 0.05) and a numerical decrease in FasL (p = 0.12) in MK-2206 treated pts. Additionally, MK-2206 was associated with marked decrease of expression of myeloid markers (CSF1R, CD163, TGFBR2, CLEC7A) in post-treatment tissue (p < 0.05). On qmIF analysis, MK-2206 treated pts exhibited a significant increase in median CD3+CD8+ cell (CTL) density between pretreatment biopsy and surgical excision specimens, as compared to the control pts (87% vs.0.2%, p < 0.05). Conclusions: Combined mRNA and qmIF analysis suggest that Akt inhibition, may decrease myeloid infiltration and increase recruitment of CTLs. Thus, Akt inhibition may promote a favorable TME. At present, there are both FDA approved and investigational agents that target the PI3K pathway. Further investigation is warranted to understand the impact of Akt inhibition on the TME and its potential therapeutic implication.
Comparative effectiveness of primary radiotherapy versus surgery in oropharyngeal squamous cell carcinoma in elderly patients: A SEER-Medicare analysis.
Authors: David Jonathan Sher, Jingsheng Yan, Tobin Joel Strom, Saad A. Khan, Hong Zhu
Journal: Journal of Clinical Oncology (2017)

e18124 Background: Primary radiotherapy (RT) and primary surgery (PS) are considered equally viable local therapy modalities for oropharyngeal squamous cell carcinoma (OPSCC). The relative efficacy and toxicity of these competing therapies are often debated, and treatment choice is based on a paucity of comparative data. Methods: Eligible individuals were elderly patients in the SEER-Medicare registry diagnosed with OPSCC between 2000 and 2011. Patients were categorized as receiving either primary RT +/- chemotherapy, or PS +/- adjuvant RT or chemoradiotherapy (CRT). Overall survival (OS) was analyzed using Cox multivariable analysis (MVA). Risks of gastrostomy dependence (GD), esophageal stricture (ES), and osteoradionecrosis (ORN) at 1 year were determined through claims and analyzed using logistic regression. Results: A total of 3,804 patients (70% RT, 30% PS) were included in this cohort. At a median follow-up of 24.2 months, median and 2-year OS were 37.9 months and 61.1%, respectively. Patients treated with RT and PS experienced 2-year OS and median survival outcomes of 58.5%/34.9 months and 66.4%/48.0 months, respectively (p &lt; 0.001). In early-stage OPSCC, MVA found older age, unmarried status, increasing comorbidity, SEER region, tumor site, and no prior PET associated with inferior OS; treatment was not associated with OS. For locally advanced OPSCC, increasing age, unmarried status, increasing comorbidity, lower income, tumor site, higher stage, no prior PET, and RT alone (HR = 1.24 for RT alone vs. PS, p = 0.0020, whereas HR 1.08 for CRT vs. PS, p = 0.1955) were associated with inferior OS. Multivariable predictors of ES (9.5% of cohort) were SEER region, grade, and PS treatment (OR = 1.03 and 0.70 for RT and CRT vs. PS, p = 0.015). Independent predictors of GD at 6 months (21.5%) included married status, smoking, tongue site, advanced stage, and CRT treatment (OR = 1.13 and 2.30 for RT and CRT vs PS, p &lt; 0.001). The 1 year risk of ORN was 3.8% and not associated with treatment. Conclusions: Without a clearly dominant modality in elderly patients, local therapy decisions for OPSCC must be individualized to each patient’s disease and functional status.
Adverse events associated with checkpoint and signal transduction inhibitors in unselected survivors with metastatic melanoma.
Authors: Taryn A Gitter, Leo Chen, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2016)

e21624 Background: New targeted therapies and immuno-oncology agents in advanced melanoma have resulted in an unprecedented number of survivors. Because side effects can impact their long-term quality of life (QOL), we aimed to characterize the incidence of toxicities among real-world patients (pts) receiving either class of drugs, describe clinical factors associated with side effects, and examine how drug-related toxicities are managed in a population-based cohort of metastatic melanoma pts in order to better inform their survivorship care. Methods: Pts diagnosed with stage III/IV melanoma from 2012 to 2014, evaluated at any 1 of 6 cancer centers in British Columbia, and treated with a CTLA4 or PD1 inhibitor were reviewed. Descriptive statistics were used to summarize patterns of drug-related toxicities and management. Multivariate analyses were conducted to determine the associations between clinical factors and toxicities. Results: We included 113 pts: median age was 59 (range 15-82) years, 66% were male, and 89% reported ECOG 0 or 1. Of the 74 pts receiving ipilimumab, mean number of cycles was 3.1. Among them, 314 adverse events were observed with most pts experiencing multiple toxicities. Intervention was required in 55 of these cases while 14 pts proceeded to a dose reduction or cessation of therapy. Advanced stage was associated with worse nausea (p = 0.068) and increased fatigue (p = 0.061). Likewise, a smoking history also correlated with worse diarrhea (p = 0.021) and increased fatigue (p = 0.089). Conversely, 57 pts received a mean number of 6.6 cycles of vemurafenib. In this group, 425 adverse events occurred of which 66 necessitated intervention and 29 pts needed to either stop therapy or reduce dose. ECOG 2+ predicted for fatigue (p = 0.001), dry skin (p < 0.001), and diarrhea (p = 0.067) while smoking history predicted for arthralgia (p = 0.073). Conclusions: Checkpoint and signal transduction inhibitors in metastatic melanoma pose significant toxicities. In pts receiving ipilimumab and/or vemurafenib, we observed a relationship between specific clinical factors and adverse events, which may facilitate clinicians and pts in treatment decision making that optimizes QOL.
Oxaliplatin, 5FU and nab-paclitaxel as neoadjuvant regimen in patients with resectable oesogastric adenocarcinoma: A GERCOR phase 2 study (FOXAGAST).
Authors: Sarah Sophie Watson, Christelle De La Fouchardiere, Stefano Chong Hun Kim, Romain Cohen, Jean-Baptiste Bachet, Christophe Tournigand, Jean-Marc Ferraz, Marine Lefevre, Delphine Colin, Magali Svrcek, Aurelia Meurisse, Christophe Louvet
Journal: Journal of Clinical Oncology (2018)

4035 Background: Peri-operative chemotherapy is the standard of care in Resectable OesoGastric Adenocarcinoma (ROGA), with several validated regimens such as Cisplatin-5FU, FOLFOX, ECF/X, or FLOT. Nanoparticle-bound (Nab) paclitaxel is active in OGA. Tumor regression grade (TRG) is an objective parameter for assessing efficacy of neoadjuvant chemotherapy (NACT). The study objective was to evaluate TRG with Nab-paclitaxel combined with FOLFOX in ROGA patients (pts). Methods: HER2-negative ROGA pts over 18 yrs received Nab-paclitaxel (150mg/m2) and FOLFOX (oxaliplatin 85 mg/m2; 5FU 2400mg/m2 over 48h, and leucovorin 400mg/m2) on D1 q2w for 6 cycles in preoperative setting. 6 postoperative cycles were kept at investigator’s discretion. Primary endpoint was pathological complete response rate (TRG1) after NACT. According to Fleming design 49 pts had to be included to test H0 (10% TRG1) and H1 (25% TRG1) with unilateral α of 5% and ß of 10%. To reject H0, TRG1 had to be achieved in at least 8 pts. Results: 49 pts (36 male, median age 63.7 yrs, 53% N+) were included between 6/2015 and 3/2017. Median number of NACT cycles was 6 (range 3-6). Median dose-intensity was 96% (38-103), 97% (47-103) and 99% (50-112) for Nab-paclitaxel, oxaliplatin, and 5FU, respectively. Surgery could not be performed in 5 (10.2%) pts due to tumor progression or poor performance status. Tumor resection was R0 for 42/44 (95.5%) pts. Centrally blinded review classified tumors as TRG1 to TRG5 for 8 (16.3%), 11 (22.5%), 4 (8.2%), 18 (36.7%) and 3 (6.1%) pts, respectively. With a median follow-up of 14.2 m, 12 m-PFS was 88.4 % (95% CI: 74.2-95.0). Grade 3 or worse toxicities in NACT phase were non febrile neutropenia in 10 pts (20.4%), nausea in 4 (8.2%), diarrhea in 4 (8.2%) and neuropathy in 3 (6.1%). 14/44 (31.8%) pts experienced per or post-operative complications, including fistulas (5 pts), ischemic complications (4), infections (3), and anesthesia-related complications (2). 3/44 (6.8%) pts died from surgical complications. Conclusions: This regimen shows promising activity in ROGA with a high rate of TRG1/TRG2 responses. Toxicity is manageable but a high rate of surgical complications was observed. Clinical trial information: NCT02486601.
The association between ATG4B and HER2 status in breast cancer.
Authors: Svetlana Bortnik, Courtney Choutka, Hugo Horlings, Samuel Leung, Wieslawa Dragowska, Marcel Bally, Karen A. Gelmon, Torsten O. Nielsen, Sharon Gorski
Journal: Journal of Clinical Oncology (2016)

e23275 Background: During the past decade, a tremendous amount of effort has been devoted to better understanding the dynamic role of autophagy, a lysosome-mediated degradation and recycling process, in different cancers. However, little progress has been made in applying this knowledge clinically for diagnostic and therapeutic purposes. In this study, we addressed one of the outstanding challenges in the autophagy field: determining whether certain cancer subtypes are sensitive to specific autophagy-related inhibition strategies, with the longer term aim of better patient selection for relevant treatments. Methods: We examined a tissue microarray from 330 breast cancer patients to determine the prognostic value of two autophagy-related markers, LC3B and ATG4B, in all major breast cancer subtypes. Results: We found that punctate LC3B positivity significantly correlated with the triple-negative subtype and was prognostic of poor outcome (disease-specific survival) across all breast cancer subtypes, and especially in triple-negative breast cancer. We also found that ATG4B expression was significantly associated with the HER2-positive subtype. We validated this novel correlation in vitro and established a functional link between ATG4B and HER2. HER2-positive breast cancer cells demonstrated high sensitivity to ATG4B inhibition under stress, and combination of trastuzumab with ATG4B inhibition resulted in a greater reduction in cell viability than trastuzumab treatment alone. Conclusions: Together these results demonstrate an association of ATG4B with HER2-positive breast cancers and indicate that this subtype might be a good candidate for ATG4B inhibition.
Survival outcomes for various treatment modalities in early-stage grade 3 follicular lymphoma (FL3): a National Cancer Database (NCDB) study.
Authors: Upama Giri, Eric Vick, Sophia SeoHyeon Lee, Alaa Altahan, Noam Avraham VanderWalde, Paxton Vandiver Dickson, Jeremiah Lee Deneve, Michael Gary Martin
Journal: Journal of Clinical Oncology (2017)

7551 Background: The prognosis, response to therapy and curability of FL3 is controversial. 5-year Overall Survival (OS) in the literature ranges from 35-72% (Ganti 2006). The aim of this study was to compare the OS for patients with early-stage FL3 managed with single- and multi-agent chemotherapy (CT) with and without radiotherapy (RT). Methods: We identified patients (pts) diagnosed with stage I &amp; II FL3 between 2004 – 2012 from the NCDB and categorized into 3 groups based on therapy – pts given single agent CT with or without RT were combined due to small sample sizes (SA±RT), multi-agent CT without RT (MA-RT), and multi-agent CT with RT (MA+RT). We calculated OS for each group using Kaplan-Meier method and compared the results using Log Rank test. Cox regression model was used to identify factors which had significant impact on OS. Results: 1,563 pts were identified – 827 (53%) with stage I and 736 (47%) with stage II FL3. Median age was 61 yrs (range 18-90yrs); 750 (48%) males, 813 (52%) females; 1423 (91%) whites, 76 (5%) blacks. 112 (7%) received SA±RT, 886 (57%) MA-RT and 565 (37%) MA+RT. 5-year OS for MA+RT (95%) was significantly more than MA-RT (87%; HR 0.33, P&lt;0.001) or SA±RT (88%; HR 0.38, P=0.007). Cox regression indicated that age (HR 1.05, P&lt;0.001), sex (HR 0.66 for females, P=0.02), comorbidities (HR 1.60 for Charlson Deyo Score 1, P=0.04; HR 3.07 for Score 2, P=0.001), stage (HR 1.79, P=0.001), insurance status (HR 0.22 for insured, P&lt;0.001) and increasing year of diagnosis (HR 0.92, P=0.03) also had significant impact on OS. Median radiation dose for the MA+RT was 36Gy (interquartile range 30.6 – 36Gy), and the proportion of patients who received greater than 36Gy decreased from 55% in 2004 to 38% in 2012 and at the same time, the proportion of patients who received intensity modulated RT increased from 5% in 2004 to 15% in 2012. Use of MA CT declined (2004 95% v 2012 89%, P=0.02) but there was no significant trend in use of RT (2004 39% v 2012 34%) during the periods studied. Conclusions: For pts with early-stage FL3, there was an association of improved survival with the use of MA+RT over other treatment strategies and appear to have outcomes superior to what has been previously reported.
Phase Ib study of tepotinib in EGFR-mutant/c-Met-positive NSCLC: Final data and long-term responders.
Authors: Yi-Long Wu, Ross A. Soo, Dong-Wan Kim, James Chih-Hsin Yang, Jürgen Scheele, Wenfeng Chen, Andreas Becker, Keunchil Park
Journal: Journal of Clinical Oncology (2017)

8547 Background: Patients (pts) with NSCLC that is initially responsive to EGFR tyrosine kinase inhibitors (EGFR TKI) typically develop resistance, often associated with aberrant c-Met activity. Dual inhibition of EGFR and c-Met is therefore a rational option to treat c-Met+ EGFR TKI-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising activity against solid tumors. We report final data from a phase Ib trial of tepotinib + gefitinib in pts with c-Met+/EGFR-mutant NSCLC conducted in Asia. Methods: Eligible pts were adults with locally advanced/metastatic NSCLC and ECOG PS 0–1. Tumors had to express EGFR with an activating mutation be resistant to EGFR TKI therapy and be c-Met+ by IHC. Pts received tepotinib 300 or 500 mg QD combined with gefitinib 250 mg QD (T300G250 or T500G250). The primary objective was to determine the recommended phase II dose (RP2D) of tepotinib in combination with gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity. Results: 18 pts were enrolled (median age 65 [41–78]; 8 male); 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg QD was confirmed as the RP2D. 17 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), mostly grade ≤2 and most commonly diarrhea (12), rash (8), and amylase increase (6). Grade ≥3 TRTEAEs were increased amylase (n = 4), increased lipase (3), neutropenia (1), and hyperglycemia (1). The best overall response was partial response in 6 pts; 4/7 pts with IHC 3+ tumors responded (all treated with T500G250) vs 2/11 with IHC 2+ tumors. Response durations of pts with PR were 4.2–12.5 months. 4/18 pts (IHC 2+, n = 3) had stable disease. 8 pts experienced progression free survival &gt; 5 months, 3 pts &gt; 10 months. PK were as expected from previous studies. Conclusions: Tepotinib in combination with gefitinib was well tolerated. The RP2D of tepotinib for use in combination with gefitinib in NSCLC is 500 mg QD. T500G250 showed signs of activity against c-Met+ tumors. A phase II trial is randomizing ≈156 pts with c-Met+/T790M– tumors who have failed first-line EFGR TKI 2:1 to tepotinib + gefitinib or pemetrexed + cisplatin/carboplatin. Clinical trial information: NCT02864992.