tbuckley/cabot-search huggingface dataset:
Safety and efficacy of retreatment with immune checkpoint inhibitors (ICIs) in patients with metastatic RCC (mRCC) who have previously received an ICI.
Authors: Praful Ravi, Ziad Bakouny, Ronan Flippot, David A. Braun, Sarah Abou Alaiwi, Xiao X. Wei, Bradley Alexander McGregor, Kerry L. Kilbridge, Atish Dipankar Choudhury, Lauren Christine Harshman, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2020)

698 Background: Several ICIs are approved for use in first and subsequent lines of therapy in mRCC, either alone or in combination with another ICI or targeted therapy. There is limited data on whether patients who receive an ICI derive benefit from a subsequent line of ICI-based therapy. Methods: We reviewed mRCC patients at our institution who were treated with an ICI between 2009 and 2018 having previously received ICI-based therapy. The primary outcomes of interest were radiologic response and time to treatment failure (TTF) on ICI retreatment. Immune-related adverse events (irAEs) were graded using CTCAE v5.0. Results: A total of 31 patients were retreated with an ICI, either alone (n=15) or in combination with another ICI (n=8), tyrosine kinase inhibitor (n=2) or investigational agent (n=6); reasons for discontinuation of prior ICI were disease progression (n=23), toxicity (n=7) and study completion (n=1). Median age at the start of first-line therapy was 62 years and the majority of patients (n=30, 90%) had International Metastatic RCC Database Consortium intermediate- or poor-risk disease; median follow-up was 3.4 years (95% CI 2.5-4.6). The median number of lines of therapy received prior to ICI retreatment was 3 (range 1-7). Of 27 evaluable patients, 3 (11%) had a partial response (PR) to ICI retreatment (2 with ICI-ICI combination therapy and 1 with single-agent ICI), 13 (48%) had stable disease, and 11 (41%) had progressive disease (PD) as their best response; of the 3 with a PR, 2 had a PR and 1 had SD to prior ICI therapy. In comparison, 13 of 31 patients (42%) had a PR or better to first ICI-based therapy, with 4 (13%) having PD. Median TTF on ICI retreatment was 3.2 months (95% CI 1.8-5.2), compared to 8.2 months (3.3-10.0) on prior ICI. 19 patients experienced an irAE with ICI retreatment, with 8 (26%) suffering a grade 3 or higher irAE. Conclusions: Retreatment with ICIs after prior therapy with an ICI was relatively safe but demonstrated limited efficacy. Additional data, ideally from prospective studies, assessing outcomes of retreating patients with ICIs are needed to determine whether using different ICIs in sequence has a role in treatment of mRCC.
Clinical outcomes and patient (pt) profiles in REASSURE: An observational study of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Celestia S. Higano, Fred Saad, A. Oliver Sartor, Kurt Miller, Peter Conti, Daniel J. George, Cora N. Sternberg, Neal D. Shore, Juan Pablo Sade, Joaquim Bellmunt, Matthew Raymond Smith, Christopher Logothetis, Frank Verholen, Jan Kalinovsky, Inga Bayh, Bertrand F. TOMBAL
Journal: Journal of Clinical Oncology (2020)

32 Background: Ra-223 is a targeted alpha therapy that showed a survival advantage and favorable safety profile in the phase 3 ALSYMPCA trial in pts with mCRPC. REASSURE (NCT02141438) is evaluating the long-term safety of Ra-223 in routine clinical practice in pts with mCRPC over a 7-year follow-up period. Methods: In this global, prospective, single-arm, observational study, the second prespecified interim analysis (data cut-off March 2019) evaluated safety and clinical outcomes of Ra-223 in pts with mCRPC. Primary outcome measures were incidence of second primary malignancies (SPM), bone marrow suppression and short- and long-term safety in pts who had ≥1 Ra-223 dose. Secondary outcomes included overall survival (OS). Results: For 1465 pts in the safety analysis, median follow up was 11.5 months. Median PSA (n=1053), ALP (n=1048), and LDH (n=555) levels at baseline were 59 ng/mL, 135 U/L, and 269 U/L, respectively. 81% of pts had bone metastases only at baseline; 19% of pts had other metastatic sites, mostly in the lymph nodes. 19% of pts had &lt;6 metastatic sites, 47% had 6–20 sites, 20% had &gt;20 lesions but not a superscan, and 6% had a superscan. 45%, 38%, 37%, 9%, and 8% of pts received prior abiraterone, docetaxel, enzalutamide, cabazitaxel, or sipuleucel-T as prior therapies, respectively. Median number of Ra-223 doses received was 6; 67% of pts had ≥5 doses. SPM occurred in 1% of pts. The most common treatment-emergent drug-related adverse event (AE) of any grade was diarrhea (11%). 10% of pts had a bone-associated event, 5% had fractures, and 15% had a hematological AE. Median OS was 15.6 months (95% CI 14.6–16.5). Conclusions: In REASSURE, there was a low incidence of SPM, bone fractures, and bone marrow suppression after Ra-223 treatment, with no new AEs identified. This study confirms that in routine clinical practice, Ra-223 AE rates were low, and pts generally received ≥5 doses. Clinical trial information: NCT02141438. [Table: see text]
Association of cytoreductive nephrectomy and survival in the immune checkpoint inhibitor era.
Authors: Joseph Miccio, Sung Jun Ma, Oluwadamilola Temilade Oladeru, Daniel X. Yang, Gabrielle W. Peters, Krishan Jethwa, Henry S. Park, Michael E. Hurwitz, Michael Leapman, Preston Sprenkle, Paul Nguyen, James Yu, Kimberly Johung
Journal: Journal of Clinical Oncology (2020)

748 Background: Cytoreductive nephrectomy (CN) for patients (pts) with metastatic renal cell carcinoma (mRCC) improved overall survival (OS) in the interferon (IFN) era, but the benefit of CN in the immune checkpoint inhibitor (ICI) era is unknown. Methods: We identified pts with mRCC receiving immunotherapy (IT) from 2004-2015 in the National Cancer Database (NCDB). Pts with partial nephrectomy or ablation were excluded. The ICI era was defined as 2013-2015 based on a high-profile publication in 2012 demonstrating efficacy of ICI in mRCC and the IFN era was defined as 2004-2005 due to FDA approval of sorafenib in 12/2005. Pts receiving CN with TKI were excluded, as prior NCDB study showed an OS benefit to CN in contrast to the results of the CARMENA trial. Univariable (UVA) and multivariable (MVA) associates with OS during each era were identified using Cox regression analysis including age, sex, race, income, insurance, treatment facility type, treatment location, clinical T stage (cT), clinical N stage (cN), histology, Fuhrman grade (FG), other metastectomy, and CN. Results: There was a 65% decline in mRCC pts receiving IT from 2005 to 2006 (end of the IFN era), which remained low (11% rise from 2006-2012) until a 93% rise from 2012 to 2013 (start of the ICI era). 128 of 422 (30.3%) pts in the IFN era received CN compared to 218 of 526 (41.4%) patients in the ICI era, p&lt;0.001. Pts in each era were balanced with respect to median age, race, income, location, cT, and histology, but the ICI era had higher proportions of pts with private insurance, treatment at an academic center, N0 disease, FG 3-4, and other metastatectomy (p&lt;0.05). Most pts with CN in the ICI era had IT after CN (89.9%); this was not coded in the IFN era. In the IFN era, CN compared to IT alone was associated with improved OS on UVA (HR 0.59, 95% CI 0.47-0.73, p&lt;0.001) and MVA (HR 0.62, 95% CI 0.47-0.83, p=0.001). In the ICI era, CN compared to IT alone was associated with improved OS on UVA (HR 0.63, 95% CI 0.49-0.81, p&lt;0.001) but not on MVA (0.82, 95% CI 0.58-1.14, p=0.234). Conclusions: Despite increased utilization of CN for US pts with mRCC treated with IT during the ICI era, the lack of OS benefit in recent years suggests a need for prospective reevaluation of the value CN and its timing with ICI.
Phase 0 study to assess [111In]-DOTA-h11B6 to target human kallikrein-2 (hk2) in men with metastatic castration-resistant prostate cancer.
Authors: Michael J. Morris, Joseph A. O' Donoghue, Dushen Chetty, Mike Russell, Emma Zulch, Anjali Narayan Avadhani, Chaitanya R. Divgi, Neeta Pandit-Taskar
Journal: Journal of Clinical Oncology (2020)

TPS249 Background: Human kallikrein-2 (hk2) is a member of the kallikrein family, is produced by prostatic epithelium, has 80% DNA sequence homology with PSA, is both circulating and bound to prostatic tissue, and is highly expressed even in high grade tumors. hK2 holds the promise of serving as a new therapeutic target for radiopharmaceuticals in prostate cancer. h11B6 is a humanized antibody directed to an epitope found on the catalytically active form of hK2, which is permanently internalized after binding. This is a first-in-human trial of [111In]-DOTA-h11B6 to determine the radio-immunotherapeutic potential of targeting hK2 with nanomolar affinity. The trial will determine the most favorable antibody mass as well as assess tumor targeting. Methods: To determine the optimal antibody mass, two cohorts of patients will be studied. All patients will receive 2 mg of [111In]-labeled h11B6. The first cohort consists of escalating amounts of antibody mass in 2-6 patients: 2, 10 and 20 mg total antibody respectively. Patients will undergo serial whole-body images for up to a week, along with assessments of serum clearance kinetics and normal organ residence time. The lowest mass amount of antibody that demonstrates favorable biodistribution and evidence of radioactivity accumulation in tumor will be used for the second cohort. Up to 6 patients will be studied in the second cohort, which will focus on assessment of antibody tumor targeting. Following this optimization and targeting imaging trial, a phase 1 dose-escalation radioimmunotherapy trial may be performed. Clinical trial information: NCT04116164.
Neoadjuvant cisplatin-based chemotherapy in patients with ureteral obstruction secondary to muscle invasive bladder cancer.
Authors: Marshall Strother, Alexander Kutikov, Bianca Lewis, Mengying Deng, Elizabeth A. Handorf, Matthew Epstein, Pooja Ghatalia, Richard E. Greenberg, David Chen, Rosalia Viterbo, Fern Anari, Marc C. Smaldone, Matthew R. Zibelman, Robert Guy Uzzo, Elizabeth R. Plimack, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2020)

523 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for muscle-invasive urothelial bladder cancer (MIBC). 15-35% of MIBC patients present with ureteral obstruction. Poor renal function increases cisplatin toxicity. It is unknown whether patients with ureteral obstruction which has been relieved (whether by nephrostomy tube or nephroureteral stent) have the same risk of toxicity as patients without ureteral obstruction. Methods: We retrospectively reviewed an institutional database of all patients undergoing NAC for MIBC with either dose dense MVAC (ddMVAC) or gemcitabine and cisplatin (GC) from January 2004 through May 2017. Patients without ureteral obstruction prior to initiation of NAC (Group A) were compared to those who had ureteral obstruction which was relieved prior to undergoing NAC (Group B). Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using Fisher’s exact test. The primary outcome was premature discontinuation of NAC, which was defined as failure to complete all planned cycles. Logistic regression was used to test for differences between the groups in this outcome adjusting for age, ECOG performance status, and baseline glomerular filtration rate (GFR). Results: 160 patients in Group A and 59 patients in Group B were identified. Baseline age, Charlson Comorbidity Index, race, smoking status, and ECOG performance status were similar. Patients in Group B had lower GFR (99.2% vs 78.8% p &lt;0.001) and were more likely to be female (21.9% vs 27.3% p &lt;0.025) and to receive ddMVAC (65.0% vs. 83.1% p =0.012). There was no significant difference between groups in rates of premature NAC discontinuation (15.8% vs 22.0% p = 0.284) or grade ≥3 adverse events (23.4% vs 30.5% p = 0.285). Adjusted analysis showed no significant difference between the groups in frequency of premature NAC discontinuation (OR 1.96, 95% CI 0.84-4.57 p=0.12). Conclusions: We detected no difference in frequency of premature discontinuation of NAC in patients with relieved malignant ureteral obstruction relative to patients without obstruction. NAC for MIBC is likely safe in this population.
CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency
Authors: Feng Li, Yuqiao Sheng, Weizhou Hou, Padma Sampath, Daniel Byrd, Stephen Thorne, Yi Zhang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Natural killer (NK) cells have potent antitumor activities. Nevertheless, adoptive transfer therapy of NK cells has gained very limited success in patients with solid tumors as most infused NK cells remain circulating in the peripheral blood instead of entering tumor sites. Chemokines and their receptors play important roles in NK cell distribution. Enhancing chemokine receptors on immune cells to match and be driven to tumor-specific chemokines may improve the therapeutic efficacy of NK cells. Methods The CCR5-CCL5 axis is critical in NK cell homing to tumor sites. Thus, we analyzed CCR5 expression on NK cells from patients with cancer and healthy donors. We then upregulated CCR5 and CCL5 with lentiviruses and oncolytic viruses in NK and tumor cells, respectively. Animal experiments were also carried out to test the efficacy of the combination of oncolytic virus with NK cells. Results In NK cells from patients with various solid tumors or healthy subjects, CCR5 was expressed at low levels before and after expansion in vitro. CCR5-engineered NK cells showed enhanced tumor infiltration and antitumor effects, but no complete regressions were noted in the in vivo tumor models. To further improve therapeutic efficacy, we constructed CCL5-expressing oncolytic vaccinia virus. In vitro data demonstrated that vaccinia virus can produce CCL5 in tumor cells while infectivity remained unaffected. Supernatants from tumor cells infected by CCL5-modified vaccinia virus enhanced the directional movement of CCR5-overexpressed NK cells but not green fluorescent protein (GFP)-expressing cells. More importantly, NK cells were resistant to the vaccinia virus and their functions were not affected after being in contact. In vivo assays demonstrated that CCL5-expressing vaccinia virus induced a greater accumulation of NK cells within tumor lesions compared with that of the prototype virus. Conclusion Enhancement of matched chemokines and chemokine receptors is a promising method of increasing NK cell homing and therapeutic effects. Oncolytic vaccinia viruses that express specific chemokines can synergistically augment the efficacies of NK cell-based therapy.
Luminal B subtype as a predictive biomarker of docetaxel benefit for newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC): A correlative study of E3805 CHAARTED.
Authors: Anis Hamid, Xin Victoria Wang, Yu-Hui Chen, Felix Y Feng, Robert Benjamin Den, Gerhardt Attard, Eliezer Mendel Van Allen, Huei-Chung Huang, Amy Karns, Ryan Dittamore, Elai Davicioni, Glenn Liu, Robert S. DiPaola, Michael Anthony Carducci, Christopher Sweeney
Journal: Journal of Clinical Oncology (2020)

162 Background: Through gene expression profiling (GEP), the PAM50 classifier demonstrates prognostic value in localized prostate cancer (PCa). Pre-clinical drug response models predict increased taxane sensitivity in luminal subtypes compared to basal subtype. Men with mHSPC and high-risk features have greatest benefit from androgen deprivation therapy (ADT) plus docetaxel (D) vs ADT alone. We therefore sought to test the prognostic and predictive value of PAM50 in pre-ADT specimens from E3805 CHAARTED. Methods: Whole transcriptomic profiling of formalin-fixed, paraffin-embedded primary PCa biopsies from pts enrolled in the E3805 CHAARTED trial of ADT vs ADT+D was performed using the Human Exon 1.0 ST microarray platform (Decipher Biosciences). Normalized gene expression was used to classify subjects as luminal A, luminal B or basal subtype. Multivariable analyses (MVA) adjusted for ECOG status, de novo metastasis vs prior local therapy and volume of disease. The primary endpoint was overall survival (OS). Secondary endpoint was time to castration resistant PCa (TTCRPC). Results: Successful GEP was completed in 160 of 198 pts with available specimens. Eighty (50%), 77 (48%) and 3 (2%) pts were classified as luminal B, basal and luminal A, respectively. High volume disease was similarly present in luminal B (79%) and basal (78%) subtypes. In the ADT arm, luminal B subtype was associated with shorter OS vs basal (HR 1.75, p=0.05); consistent in MVA. Pts with luminal B subtype treated with ADT+D showed significant improvement in TTCRPC and OS (Table). By contrast, basal subtype showed no OS benefit from ADT+D even in pts with high volume disease. Conclusions: We demonstrate that GEP identifies tumor subtypes associated with differential benefit from chemohormonal therapy for mHSPC. Luminal B subtype is associated with poorer OS with ADT alone and benefits from addition of D. Basal subtype shows a lack of OS benefit from upfront ADT+D. We plan to validate these findings in independent trial cohorts.[Table: see text]
A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer.
Authors: Akash Patnaik, Priyanka Duttagupta, Kiranj Chaudagar, Raanan Alter, Hanna Hieromnimon, Russell Zelig Szmulewitz, Gini F. Fleming, Walter Michael Stadler
Journal: Journal of Clinical Oncology (2020)

TPS270 Background: Immune checkpoint blockade (ICB) therapies have had a major impact across a wide range of cancers. However, only subsets of patients across all malignancies benefit from ICB. In particular, metastatic castrate-resistant prostate cancers (mCRPC) have shown very limited responses to ICB. While there is ongoing work to identify predictive biomarkers to ICB responsiveness, early preclinical data from our group suggests that targeting fundamental DNA repair pathways could markedly increase the fraction of patients responsive to immunotherapeutic interventions. Based on these preclinical studies, we are conducting an investigator-initiated Phase Ib/IIa co-clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC patients. Methods: Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in T cell infiltration by RNA-seq analysis using established T-cell non-inflamed and inflamed gene signatures. Secondary objectives are to assess changes in immune cell infiltration via flow cytometry, multiplex IHC, transparent tissue tomography (3D mapping) and single-cell RNA-seq. We will correlate changes in the metastatic tumor microenvironment (TME) at baseline and following 4 weeks of treatment, with genomic alterations and clinical responses. We have currently enrolled 12 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study utilizes novel emerging technologies for in-depth TME analysis that will unravel the impact of PARP inhibition, singly and in combination with PD-1 blockade, on specific immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immuno-oncology combinations for specific genomic subsets of mCRPC. Clinical trial information: NCT03572478.
Evaluation of bone metastasis and prognosis of prostate cancer with bone metastasis during standard hormonal therapy and chemotherapy: A report of PROSTAT-BSI multicenter registry in Japan.
Authors: Atsushi Mizokami, Satoru Takahashi, Hideyasu Matsuyama, Gou Kaneko, Hiroaki Shiina, Tomohiko Ichikawa, Hiroyuki Horikoshi, Katsuyoshi Hashine, Yutaka Sugiyama, Takeshi Miyao, Manabu Kamiyama, Kenichi Harada, Akito Ito, Kenichi Nakajima
Journal: Journal of Clinical Oncology (2020)

215 Background: Quantitative evaluation of the change of bone metastasis (bMet) has not been clearly defined during treatments in prostate cancer (PCa). As therapeutic effects of bMet have become quantified with scintigraphic bone scan index (BSI), we performed a nation-wide observational prospective study in patients who were treated by hormonal therapy (HTx) or chemotherapy (CTx). Methods: A total of 237 patients were recruited at 30 hospitals in Japan, and this report summarized baseline demographics and prognosis of 203 patients. All had bMet and underwent either standard HTx (group H) or docetaxel CTx (group C). Bone scans were performed with 99mTc-MDP. Patients were followed up for 3 years, and changes in biochemical and tumor markers during HTx and CTx were recorded in addition to skeletal-related events, recurrence, and death. Results: The basic characteristics of the patients (n=203) at the time of registration during December 2016 were as follows: mean age 71 ± 8 years; median BSI calculated on-site 3.0 ± 3.2% and median PSA was 265 ng/mL (22-2923 ng/mL) and 33 (3-537 ng/mL), for Group H and C (p=0.0014), respectively. BSI was comparable (H: 3.0 ± 3.4 vs C: 3.0 ± 2.8%, p=n.s.) between the two groups. A total of 54 patients (24%) died from PCa. BSI flare defined as increase at 3 months and decrease at 6 months was 13% and 31% (p&lt;0.0069) for Groups H and C, respectively. When patients were classified into three groups with BSI &lt;0.9 (low), 0.9-3.3 (intermediate), and &gt;3.3% (high). Kaplan-Meier Survival analysis showed that mortality at 1100 days was 8%, 16%, and 35% for Group H (p=0.0097), and 50%, 55%, and 65% for Group C (p=ns) for the low, intermediate and high BSI group, respectively. In addition, patients who showed BSI decline &gt;20% until 6 months showed better prognosis than those who did not (p&lt;0.0001 and p= 0.038 and for Group H and C, respectively). Conclusions: The data of PROSTAT-BSI showed that BSI could be a good biomarker for prognosis in both Groups H and C, in particular for prognostic stratification of patients indicated for HTx. Six-month response of BSI by &gt;20% indicated better prognosis in both groups. Clinical trial information: UMIN000007858.
Once-daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI in inadequately controlled asthma: the CAPTAIN study
Authors: Ian Pavord, Guy Peachey, Huib Kerstjens, Edward Kerwin, Robert Nathan, Nicola Hanania, Steven Pascoe, Andrew Fowler, Zelie Bailes, Dawn Edwards, Neal Sule, Neil Barnes, Louis-Philippe Boulet, Maggie Tabberer, Laurie Lee
Journal: Journal of Allergy and Clinical Immunology (2020)
Quality Of Life in Patients with Food Allergy: A Systematic Review and Meta-Analysis of interventions Food Allergy Diagnosis and Immunotherapy Studies
Authors: Shu Cao, Matteo Borro, Sayantani Sindher, Dana Tupa, Andrew Long, Sharon Chinthrajah, Kari Nadeau, Sarah Alonzi
Journal: Journal of Allergy and Clinical Immunology (2020)