tbuckley/cabot-search huggingface dataset:
Phase II study of nivolumab and ipilimumab for advanced bladder cancer of variant histologies (BCVH).
Authors: Bradley Alexander McGregor, Matthew T Campbell, Wanling Xie, Arlene O. Siefker-Radtke, Amishi Yogesh Shah, Aradhana M. Venkatesan, Kerry L. Kilbridge, Guru Sonpavde, Glenn Bubley, Rana R. McKay, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2019)

4518 Background: Patients with BCVH have poor outcomes and data regarding the management of this heterogeneous group of patients is limited. Nivolumab and ipilimumab has demonstrated safety and efficacy in urothelial carcinoma and other malignancies. In this multicenter, single arm, multi-cohort phase II trial we evaluate the efficacy of nivolumab and ipilimumab in patients with BCVH and other advanced rare genitourinary cancers (NCT 03333616). Herein, we report the preliminary results of the fully accrued BCVH cohort. Methods: Eligible patients had metastatic BCVH, ECOG performance status of 0-2 and were either untreated or had received any number of lines of prior therapy excluding prior immunotherapy. Patients underwent a baseline biopsy and blood collection for correlative studies and received treatment with nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 cycles with continued maintenance of nivolumab 480 mg IV every 4 weeks. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Results: 19 BCVH patients were enrolled at 4 institutions between 4/2018 and 1/2019: squamous cell (n = 6), small cell (n = 3), adenocarcinoma (n = 3), urachal (n = 5), plasmacytoid (n = 1), and spindle cell (n = 1). 13 (68%) patients had received prior systemic therapy including platinum-based chemotherapy in 92% patients. Median number of cycles of ipilimumab plus nivolumab received was 3 (range 1-8) and median follow-up was 3.6 (0.3-8.8) months. 13 patients had undergone at least one scan; ORR was 31% (4/13, 80%CI: 14-52%), with partial responses seen in small cell carcinoma (n = 2), urachal (n = 1) and a complete response in 1 patient with plasmacytoid carcinoma. 3 patients (16%) developed treatment-related grade 3 toxicities with 1 (5%) grade 4 toxicity. Conclusions: Nivolumab and ipilmumab resulted in objective responses in a subset of patients with BCVH with manageable toxicities. Updated clinical and correlative data will be presented. This combination may warrant further investigation in patients with BCVH, which has substantial unmet needs. Clinical trial information: NCT 03333616.
Effect of a novel long-acting interleukin-7 agonist, NT-I7, on survival in mouse models of glioma.
Authors: Jian Li Campian, Vaishali Kapoor, Kaylan Griffith, Anita Mahadevan, Andrea Collins, Sukrutha Thotala, Arijita Jash, Tong Hu, Byung Ha Lee, Donghoon Choi, Se Hwan Yang, Dennis Hallahan, Milan G Chheda, Dinesh Thotala
Journal: Journal of Clinical Oncology (2019)

e13516 Background: Glioblastoma is one of the most devastating cancers, with a 5-year overall survival &lt; 10%. Patients are routinely treated with radiation therapy (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia which is associated with shorter survival. Interleukin-7 (IL-7) is a cytokine that preferentially supports growth and survival of CD4+ and CD8+ lymphocytes. IL-7 levels were inappropriately low in glioblastoma patients treated with chemoradiation who developed severe treatment-related lymphopenia (TRL). NT-I7 (rhIL-7-hyFc, from NeoImmuneTech, Inc.) is a long-acting cytokine consisting of recombinant human IL-7 fused to a hybrid Fc (hyFc) region of IgD and IgG4. Similarly to murine IL-7, human IL-7 also induces proliferation of murine cell lines. Consequently, NT-I7 can be studied using comparable dosing in both mice and humans. We hypothesized that administration of NT-I7 could mitigate TRL and improve survival. Methods: We developed a murine glioma model with chemoradiation induced lymphopenia. The C57BL/6 mice were injected intracranially with mouse glioma cells (GL261) expressing luciferase. Tumor-bearing mice were treated with clinically-relevant RT (2 Gy for 5 consecutive days) and concomitant TMZ (33mg/kg daily during RT) to induce lymphopenia. NT-I7 was given subcutaneously at 10 mg/kg one day after completion of RT/TMZ. Peripheral blood samples were collected on days 1, 3, 7, 14- and 28-days post-RT/TMZ. Lymphocyte counts including CD3, CD4, CD8, and CD19 were analyzed by flow cytometry. Tumor growth was monitored by bioluminescence imaging and mouse survival was monitored daily. Results: We found that 1) NT-I7 significantly improved lymphocyte count recovery post RT/TMZ; 2) mice receiving NT-I7 lived significantly longer than controls. Presently, we are elucidating the mechanisms of survival benefit found by NT-I7 administration. Conclusions: Overall, our data suggest that NT-I7 may be a feasible solution for immune reconstitution and may synergize anti-tumor effect with standard chemoradiation in glioma. Further studies are ongoing to confirm these findings in a different glioma model and to evaluate whether NT-I7 can alter tumor micro-environment.
Clinical characteristics and outcome of metaplastic breast cancer: A retrospective tertiary care center experience.
Authors: Bicky Thapa, Salome Arobelidze, Xuefei Jia, Hassan Awada, Tariq Zuheir Kewan, Fahrettin Covut, Mita Patel, Hamed Daw, Timothy Peter Spiro, Abdo S. Haddad
Journal: Journal of Clinical Oncology (2019)

1095 Background: Metaplastic breast cancer (MBC) is a rare neoplasm which accounts for less than 1% of all breast cancers. MBC is associated with worse prognosis and there is a paucity of literature on management. We evaluated the clinical characteristic and outcomes of MBC patients at our institution. Methods: After IRB approval, 136 patients diagnosed with MBC were reviewed from the Cleveland Clinic tumor registry from 2000-2017. Patients were evaluated for overall survival (OS) and progression free survival (PFS) using univariable analysis. Time to event variables were estimated by Kaplan-Meier method. Results: A total of 136 pathologically proven MBC patients were included in the study. Median age at diagnosis was 60 years (27-92). Eighty two percent (n = 112) had nuclear grade III, 7% (n = 10) had high grade dysplasia, 2% (n = 3) had nuclear grade I, and 4% (n = 5) had nuclear grade II; 60% (n = 82) patients were diagnosed at stage II, 21% (n = 28) at stage I, 14% (n = 19) at stage III, and 5% (n = 7) at stage IV. Estrogen receptor, progesterone receptor and Her2 expression were positive in 16% (n = 22), 9% (n = 12), and 10% (n = 14) respectively. Only 37% (n = 50) patient had lumpectomy, 18% (n = 25) received hormonal therapy, 56% (n = 76) received radiation, 51% (n = 70) received anthracycline chemotherapy and 26% (n = 36) received non-anthracycline chemotherapy; 37% (n = 50) had chemotherapy after 4 weeks of surgery and 35% (n = 48) patients had chemotherapy within 4 weeks of surgery. On univariable analysis, the 5-year OS for stage III was 30% (14% - 64%), hazard ration (HR) of 4.53 (95% CI, 1.71 - 12.01) (p = 0.002), for stage IV HR of 43.26 (95% CI, 12.34 - 151.64) (p = 0.001); chemotherapy within 4 weeks of surgery was associated with a higher risk of death, HR of 0.30 (95% CI, 0.12 - 0.74) (p = 0.009). Hormonal therapy, radiation therapy, surgery and type of chemotherapy was not associated with significant change in OS and PFS. In our cohort, 2-year OS was 79 % (73 % - 87 %) and 5-year OS was 69 % (61 % - 77 %); 2-year PFS was 61 % (52 % - 70 %) and 5-year PFS was 72 % (65 % - 81 %). Conclusions: Stage of MBC and chemotherapy within 4 weeks of surgery was associated with statistically significant OS and PFS on univariable analysis. Randomized clinical trials are warranted to improve outcomes in MBC patients.
Analysis of trends in mortality in patients with lymphoepithelial carcinoma of the head and neck.
Authors: Marcus Kyle Weldon, Takefumi Komiya, Achuta Kumar Guddati
Journal: Journal of Clinical Oncology (2019)

e17583 Background: Squamous cell carcinoma is the most common subtype of malignancy found in patients with Head and Neck malignancy. There are other rare subtypes which are not adequately reported in medical literature. Lymphoepithelial carcinoma consists of lymphocytic infiltration in a background of undifferentiated carcinoma cells and has a high malignant potential. They are most often seen in salivary glands but can also be found in other structures of the head and neck region. This analysis reports the nation-wide mortality of patients diagnosed with lymphoepithelial carcinoma of the Head and Neck. Methods: Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) Database from the years 2000 to 2014. Incidence-based mortality for all stages was queried and results were grouped by gender and race (Caucasian/White, African American/Black, American Indian/Alaskan native and Asian/Pacific Islander). Paired T-test was used to determine statistically significance difference between various subgroups. Results: Incidence-based mortality has been improving for African American/Black patients and has been worsening for Caucasian/White, American Indian/Alaskan native and Asian/Pacific Islander for the period of 2000 to 2014. The differences in mortality trends were statistically different (P &lt; 0.05). The highest mortality rate per 1000 patients was seen in Asian/Pacific Islander population, followed by African American/Black, American Indian/Alaskan native and the least mortality was noted in Caucasian/White patients. When a similar analysis with linearized trend lines on gender was conducted, only African American/Black males and Asian/Pacific Islander females showed an improving trend in mortality. The sample size was a major limitation of this study (Caucasian/White - 134, African American/Black - 30, American Indian/Alaskan native - 5 and Asian/Pacific Islander – 87). Conclusions: Lymphoepithelial carcinoma is a rare subtype of Head and Neck malignancies whose incidence-based mortality showed a worsening trend. This study showed significant race and gender disparity amongst patients with lymphoepithelial carcinoma. Due to its rarity, this subtype warrants further study; especially with regards to its etiology, clinical course and cure rates.
Prognostic value of serum tumor marker (STM) rate of decline during high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) for relapsed germ-cell tumors (rGCT).
Authors: Nabil Adra, Sandra K. Althouse, Hao Liu, Rafat Abonour, Mohammad Issam Abu Zaid, Clint Cary, Timothy A. Masterson, Richard Foster, Costantine Albany, Nasser H. Hanna, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2019)

e16044 Background: Rate of STM decline is prognostic in patients (pts) with metastatic GCT receiving first-line chemotherapy. We investigated the prognostic value of STM decline in pts with rGCT treated with HDCT and PBSCT. Methods: 444 consecutive pts with rGCT were treated with HDCT and PBSCT at Indiana University between 2004-2018. All pts were planned for 2 consecutive HDCT courses. Pts with elevated STM (AFP &gt; 25 and/or hCG &gt; 4.9) were included in this analysis. Slope and half-life (T 1/2 ) were calculated for weekly AFP and hCG values during HDCT starting with peak value during days 1-7 to avoid interference from lysis. T 1/2 AFP≤7 days and hCG≤3 days were categorized as satisfactory (SAT); normalization within 7 days was also considered SAT regardless of T 1/2 . Pts with elevated AFP and hCG must have adequate decline in both to be SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier methods. Results: 2-yr PFS for pts with elevated STM at initiation of HDCT (N = 335) was inferior to pts with normal STM (N = 109) [49% vs. 89%; p &lt; 0.001]. Among the 335 pts with elevated STM, 300 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (285), mediastinum (25), and retroperitoneum/other (25). Metastatic sites included retroperitoneum (267), lung (226), liver (81), brain (76), and bone (21). At initiation of HDCT, 73 pts had elevated AFP only, 215 had elevated hCG only, and 47 had elevated both AFP and hCG. Median AFP 9 (1-21,347) and hCG 115 (1-178,140). 307 pts (92%) completed 2 planned cycles of HDCT. Overall, 45/335 pts had SAT decline (13 for AFP; 29 for hCG; 3 for both). Pts with SAT STM decline had superior outcomes compared to UNSAT: 2-yr PFS 71% vs 46% (p = 0.004) and 2-yr OS 77% vs 52% (p = 0.004). When evaluating each STM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 76% vs 47% (p = 0.002). There was statistically non-significant difference in outcomes for AFP: 2-yr PFS 50% vs 43% (p = 0.55). Conclusions: SAT rate of STM decline predicts superior outcomes in pts with rGCT undergoing HDCT and PBSCT. Although UNSAT STM decline does not preclude long-term remissions, these pts are at higher risk of relapse and death.
Songbird Ventral Pallidum Sends Diverse Performance Error Signals to Dopaminergic Midbrain
Authors: Ruidong Chen, Pavel A. Puzerey, Andrea C. Roeser, Tori E. Riccelli, Archana Podury, Kamal Maher, Alexander R. Farhang, Jesse H. Goldberg
Journal: Neuron (2019)
Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: A phase I clinical trial.
Authors: Fei Ma, Qiao Li, Xiuwen Guan, Shanshan Chen, Zongbi Yi, Bo Lan, Puyuan Xing, Ying Fan, Jiayu Wang, Yang Luo, Peng Yuan, Ruigang Cai, Pin Zhang, Qing Li, Binghe Xu
Journal: Journal of Clinical Oncology (2019)

1035 Background: Cross-signaling in the ErbB family is an important mechanism in Trastuzumab resistance. Pyrotinib is an irreversible pan-ErbB inhibitor targeting EGFR/HER1, HER2 and HER4, which may offer the potential for improved efficacy to block HER2 signaling in trastuzumab-resistant breast cancer. This phase I study assessed the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics, antitumor activity and predictive biomarkers of pyrotinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1000mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected predose on day 1 and day 14 of treatment. Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) to probe for predictive biomarkers of this combination. Results: A total of 28 patients were enrolled. All 28 (100%) patients experienced at least one treatment-related Adverse Events (AE), which were predominantly grade 1 or 2. Grade 3 treatment-related AE occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. Three (10.7%) patients discontinued capecitabine administration due to AEs. The overall response rate (ORR) was 78.6% (95% CI: 59.0% to 91.7%), and the disease control rate (complete response+ partial response+ stable disease) was 96.4% (95% CI: 81.7% to 99.9%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0 to 26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naive patients. NGS analysis of all genetic alterations of HER2 bypass signaling pathway, PI3K/Akt/mTOR pathway and TP53 in baseline blood samples suggested that concomitant (two or more) genetic alterations were significantly associated with poorer PFS compared to none or one genetic alteration (median, 15.8 vs. 26.2 months, p = 0.006). Conclusions: Pyrotinib in combination with capecitabine are well-tolerated and demonstrate promising antitumor activity in HER2-positive MBC patients. Clinical trial information: NCT02361112.
First-in-human study of REGN3767 (R3767), a human LAG-3 monoclonal antibody (mAb), ± cemiplimab in patients (pts) with advanced malignancies.
Authors: Kyriakos P. Papadopoulos, Nehal J. Lakhani, Melissa Lynne Johnson, Haeseong Park, Ding Wang, Timothy A Yap, Afshin Dowlati, Robert G. Maki, Filipa Lynce, Susanna Varkey Ulahannan, Karen Kelly, Tasha Nicholle Sims, Amy-Lee Bredlau, Derrick Bramble, Ana Gonzalez Ortiz, Min Zhu, Huanyu Chen, Maria Karasarides, Glenn Kroog
Journal: Journal of Clinical Oncology (2019)

2508 Background: We present initial safety, pharmacokinetics (PK), and efficacy from the dose escalation study of R3767, alone (mono) or in combination with cemiplimab (REGN2810), a PD-1 mAb (combo), in pts with advanced malignancies (NCT03005782). Methods: Pts who had progressed on prior therapy(ies) and/or for whom no therapy with clinical benefit was available were enrolled; most pts had received no prior anti-PD-1/PD-L1. Pts received R3767 1, 3, 10, or 20 mg/kg every 3 weeks (Q3W) ± cemiplimab 3 mg/kg or 350 mg Q3W IV for ≤51 weeks. Crossover from mono to combo was allowed at progression. R3767 PK were evaluated. Tumor measurements were performed Q6W for the first 24 weeks and subsequently Q9W. Data cut-off date was Aug 25, 2018. Results: Mono: 27 pts (median age: 66 yr; ECOG PS: 0 [n=4], 1 [n=23]) were treated. There were no dose-limiting toxicities (DLTs). The most common treatment-emergent adverse event (TEAE) was nausea (22.2%). Grade ≥3 immune-related adverse events (irAEs) of increased alanine and aspartate aminotransferases (each 3.7%) were reported. By investigator-assessment (per RECIST 1.1; INV), best response was stable disease in 11 pts. Combo: 42 pts (median age: 60 yr; ECOG PS: 0 [n=15], 1 [n=27]) were treated. One pt treated with R3767 3 mg/kg Q3W + cemiplimab 3 mg/kg Q3W experienced DLT of grade 4 elevated blood creatine phosphokinase, associated with grade 3 myasthenia syndrome and grade 1 elevated troponin. The most common TEAEs were fatigue (33.3%) and nausea (21.4%). Grade 3 irAE of hypothyroidism (2.4%) was also reported. By INV, 2 (both small cell lung cancer) combo pts and 2 (endometrial cancer and cutaneous squamous cell carcinoma) of 12 additional pts who crossed over from mono to combo had partial responses. PK: R3767 concentrations in serum increased in a dose-dependent manner and were unaffected by combo. Conclusions: The safety profile of R3767 ± cemiplimab was generally tolerable; PK was linear. Early efficacy signals were detected despite the difficult-to-treat pt population. Biomarker studies are ongoing. R3767 20 mg/kg or 1600 mg fixed dose equivalent Q3W as mono and combo were selected for further evaluation. Clinical trial information: NCT03005782.
Integrative molecular analysis of metastatic Merkel cell carcinoma to identify predictive biomarkers of response to avelumab.
Authors: Sara Georges, Parantu K. Shah, Irina Shapiro, Christine Hicking, Lei Lu, Meliessa Hennessy, Sandra P. D'Angelo, Ti Cai
Journal: Journal of Clinical Oncology (2019)

9569 Background: Avelumab, an FDA-approved human anti–PD-L1 IgG1 monoclonal antibody for patients (pts) with metastatic Merkel cell carcinoma, showed an objective response rate (ORR; by RECIST v1.1) of 31.8% in a second-line phase 2 trial (NCT02155647). We assessed the association of tumor mutational burden (TMB; nonsynonymous somatic variants/megabase), PD-L1 expression, Merkel cell polyomavirus (MCPyV) status, and CD8+ tumor-infiltrating T-cell density with ORR and survival. Molecular profiles (RNAseq and WEX) also were analyzed. Methods: Baseline tumors (n = 36) were profiled using RNAseq and WEX sequencing. PD-L1 expression (≥1% cutoff), MCPyV status, and CD8+ T-cell density at the tumor invasive margin were evaluated by IHC. MHC locus expression was measured with OptiType and loss of heterozygosity (LOH) with LOHHLA. Results: Of 36 pts profiled, 12 had a response, 27 were PD-L1+, and 23 were MCPyV+. The TMB upper tertile and quartile values were 1.34 and 3.16, respectively. Consistent with literature, MCPyV− pts had a higher median TMB (2.72) than MCPyV+ pts (0.49). PD-L1+ tumors trended toward a higher TMB. An empirical cohort-specific TMB cutoff of ≥2 was chosen to include sufficient pts per subgroup. Pts with TMB ≥2 vs TMB &lt; 2 had higher ORR (5 of 11 [45.5%] vs 7 of 25 [28.0%]) and 6-mo PFS rates (60% vs 38%). Among pts with TMB ≥2, the highest ORRs were reported in MCPyV− (4 of 7 pts), PD-L1+ (5 of 9 pts), and CD8+ T-cell density higher than median (5 of 6 pts) subgroups. MHC expression trended with ORR and survival. Higher mean MHC expression was found in pts with CD8+ T-cell density higher than median (p &lt; 0.05). Mutations in antigen presentation genes were detected: LOH at the HLA locus in 9 of 30 pts (28%), including 4 with a response; an NK cell activation signature was also associated with response. These data may suggest that ADCC contributes to response. Factorial analysis of gene signature scores identified signatures (eg, IFNγ, TP53 pathway) associated with MCPyV status and response. Conclusions: Responses in this data set were not attributed to any specific biomarker alone. Future analysis is focused on validating these results and identifying rational drug combinations with avelumab. Clinical trial information: NCT02155647.
The clinical characteristic and prognostic factors of leptomeningeal metastasis in patients with non-small-cell lung cancer: A retrospective study from one single cancer institute.
Authors: Weiwei Yan, Jinming Yu
Journal: Journal of Clinical Oncology (2019)

e13502 Background: Leptomeningeal metastasis (LM) is a detrimental complication of advanced NSCLC, and the optimal therapeutic approach for LM patients is in shortage. The retrospective study was to investigate clinical features and prognostic factors of NSCLC patients with LM. Methods: We retrospectively reviewed the records of NSCLC patients with LM at the Shandong Cancer Hospital and Institute between July 2014 and March 2018. Identified cases had pathology-proven NSCLC with either positive CSF cytology or LM enhancement by MRI. Results: One hundred and thirty-six NSCLC patients (58 men, 78 women) with LM were enrolled in the retrospective study, median age was 55 years (range, 29–89 years). Fifty-one patients harbored EGFR mutations and ALK rearrangement was detected in six patients. Treatment for LM consisted of EGFR-TKIs alone in 11 patients, WBRT alone in 19 patients, Chemotherapy (ChT) alone in 12 patients, EGFR-TKIs plus WBRT in 30 patients, WBRT plus ChT in 25 patients, and EGFR-TKIs plus ChT in 24 patients. The median progression free survival (PFS LM ) was 3.9 months (95% CI, 3.178-4.622) and the median overall survival (OS LM ) was 9.8 months (95% CI,7.5-12.1). A multivariate analysis indicated that KPS ≥ 80 (HR = 0.592, 95% CI:0.369-0.95; p = 0.03) and EGFR-TKIs (HR = 0.507, 95% CI:0.283-0.908; p = 0.022) after LM diagnosis were independent favourable predictors of survival, whereas smoking (HR = 1.181, 95 % CI:1.009-3.246; p = 0.047) was an independent predictor of poor survival. Conclusions: Patients with good performance status, non-smokers and the administration of EGFR-TKIs might improve clinical outcomes in NSCLC patients with LM.