tbuckley/cabot-search huggingface dataset:
Efficacy of olaparib therapy in metastatic pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency (HRD).
Authors: Elaine Tan, James Kevin Hicks, Kirsten Blue, Richard D. Kim, Estrella M. Carballido, Dae Won Kim
Journal: Journal of Clinical Oncology (2021)

e16266 Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T &gt; C, gCHEK2 c.1461+1 G &gt; A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease &gt; 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.
A study evaluating targeted therapies in participants who have advanced solid tumors with genomic alterations or protein expression patterns predictive of response (MyTACTIC).
Authors: Axel Grothey, Michael Howland, Lloryn Hubbard, Tania Szado, Anne McDonald, Walter C. Darbonne, Jonathan Levy, Eucharia Borden, David R. Spigel, Ari M. Vanderwalde, Lee S. Schwartzberg
Journal: Journal of Clinical Oncology (2021)

TPS1588 Background: Cancer treatment is evolving toward a more personalized approach in which the intersection of genomics, pathology and imaging methods leads to individualized care. Furthermore, identification of novel genomic alterations and other biomarkers has the potential to lead to customized, targeted treatments. Matching specific therapies to tumor biomarkers has the potential to yield valuable clinical information. Here we present a multiarm basket trial that matches patients with a broad array of metastatic solid cancers to investigational therapies alone or in combination based on specific, targetable genomic alterations or protein expression patterns that are potentially predictive of response (MyTACTIC). Historically, such trials have been conducted at large academic medical centers rather than community centers, where most US patients with cancer receive treatment. Prioritizing community centers for this study presents an exciting opportunity to generate data from a more representative patient population. Methods: This phase II, multicenter, nonrandomized, open-label study is enrolling approximately 200 participants with advanced solid tumors that harbor alterations including mutations, fusions, amplifications and protein loss in specific biomarkers that include human epidermal growth factor receptor 2 (HER2), phosphoinositide 3-kinase (PI3K), anaplastic lymphoma kinase (ALK), proto-oncogene tyrosine-protein kinase (ROS1), protein kinase B (AKT), phosphatase and tensin homolog (PTEN), high tumor mutational burden (TMB), high microsatellite instability (MSI) and deficient mismatch repair (dMMR). Patients aged ≥18 years with positive local biomarker results from tissue or blood samples will be enrolled from community oncology centers and practices. Eligibility criteria have been broadened to allow enrollment of a diverse population of patients, including those with nonmeasurable disease, HIV or viral hepatitis infections, and to allow for previous treatment with anticancer agents in the same class. Once general and arm-specific criteria are met, patients will be assigned to 1 of 10 treatment arms to receive mono- or combination therapy with targeted agents, immunotherapy and/or chemotherapy (≤25 patients per arm). The primary objective is to evaluate confirmed objective response rate, as assessed by the investigator according to RECIST version 1.1 or RANO criteria for primary central nervous system tumors. Progression-free survival, duration of response, overall survival and safety will also be assessed. Special attention has been paid to the study design and implementation to ensure equitable access, along with flexibility to add additional baskets. Enrollment is ongoing. Clinical trial information: NCT04632992.
Metastatic osteosarcoma at diagnosis: Analysis of 92 cases from a single institution.
Authors: Alessandra Longhi, Valquiria Broll, Alberto Righi, Antonio Carella, Michela Pierini, Cristina Ferrari, Marilena Cesari, Rossella Hakim, Anna Paioli, Emanuela Palmerini
Journal: Journal of Clinical Oncology (2021)

e23506 Background: Metastatic osteosarcoma (MOS) with synchronous metastases accounts for 20-25% of all new cases of osteosarcoma. Lungs are the most common site of metastases at presentation (80%) followed by Bone (10%). 5- years Overall Survival (OS) of MOS ranges from 11 to 40%. In a previous study from our institution (Bacci G 2006) on 57 pts &lt; 40 years old (1995-2000) the 2- and 5-year OS were 55% and 18%. Methods: Data of patients with pathologic and radiologic confirmed MOS with adequate follow up were reviewed (EC Approval N 916/2020/Oss/IOR). Time-to-event outcomes were estimate with Kaplan-Meier method and compared between groups with log-rank test and Cox model. Results: From August 2000 to October 2018, 92 patients had a diagnosis of MOS: median age 16.5 yrs (6-73, twelve pts &gt; 40 ), gender rate was M 51/F 41, axial primary tumor in 15 cases, extremity in 77. Lung only metastases were described in 66 (71.7%). In 75/90 cases primary tumor was surgically removed, 43 (46%) cases had at least one surgical metastasectomy. All patients received chemotherapy: preoperative only in 6 cases, postoperative in 6, and pre and postoperative in 66 patients. The 1 st line chemotherapy was a combination of drugs: Adriamycin in 91/92 pts, Cisplatin in 89/92, Ifosfamide in 88/92, Methotrexate in 83/92; 59 patients received a 2 nd line chemotherapy, 34 pts received a 3 rd line; most employed regimen were Gemcitabine-Docetaxel, Ifosfamide 15 gr/m 2 , Cyclophosphamyde-Etoposide, TKI (Pazopanib, Sorafenib), and a few received experimental drugs. Complete remission (CR) was obtained in 26/92 (28%), in 19 cases after surgical metastasectomy.In 30 pts the information of PGP (P- glycoprotein) was available; patients with positive PGP (19/30) had a worst overall survival as compared to those PGP negative (P = 0.038). Of those in Complete Remission 14/26 relapsed. At December 2020 with a median follow-up of 95 ms (IQR 34-159): 65/92 (70%) died , 12 are alive and free from disease , 6 are alive with disease, 9 were lost . The 2-yrs OS for all 92 pts from diagnosis was 66% (95%CI 55-75) and 5-yrs OS was 26% (95% CI 16-37). From the end of treatment, for those who reached a CR the 5-year OS was 57% vs 9% for those who did not (P &lt; 0.001). At univariate analysis, primary tumor site (2-y OS 48% axial vs 72% extremity, P &lt; 0.001), site of metastases (2-y OS 74% only lung vs 48% other, P = 0.004) and number of lung nodules (P = 0.007), were significantly associated to OS. At multivariate analysis, only site of metastases (other vs. only lung HR = 2.26, 95%CI: 1.21-4.22) and number of lung nodules (≥10 nodules vs ≤3 HR = 2.44, 95%CI: 1.24-4.81) were confirmed as significant for OS. Conclusions: Compared to our previous report from 20 yrs ago, 2-years and 5 yrs OS of MOS has improved but it remain unsatisfactory (66% vs 55% and 26% vs 18%).
Impact of the geriatric assessment on clinical treatment decision in older Indian persons with cancer.
Authors: Vanita Noronha, Anant Ramaswamy, Vijay Maruti Patil, Shreya Gattani, Nandini Menon, Sarika Mahajan, Renita Castelino, Ratan Dhekle, Anuradha Daptardar, Vikram Gota, Shripad Dinanath Banavali, Kumar Prabhash, Rajendra A. Badwe
Journal: Journal of Clinical Oncology (2021)

e24015 Background: The geriatric assessment (GA) is a multidimensional evaluation of an older person. Identification of the non-oncologic vulnerabilities, estimation of life expectancy and chemotherapy risk prediction aid the clinicians in the therapeutic risk-benefit ratio analysis. Globally, GA leads to changes in oncologic decisions in 28% of patients. Methods: An observational study with a retrospective and prospective cohort of patients who underwent a GA in the geriatric oncology clinic at the Tata Memorial Hospital in Mumbai, India. The study was approved by the institutional ethics committee (IEC) and registered with Clinical Trials Registry of India-CTRI/2020/04/024675. Written informed consent was obtained from the patients enrolled in the prospective part of the study; the IEC granted a consent waiver for the retrospective portion of the study. Patients aged 60 years and older with a diagnosis of malignancy were evaluated in the geriatric oncology clinic. The results of the GA were entered in the electronic medical records (EMR). The systemic therapy plan prior to the GA and the actual therapy plan made were retrospectively captured from the EMR. The primary objective was to determine the proportion of patients in whom the systemic therapy plan was changed following the GA. Results: Between June 2018 and Feb 2021, 340 patients were evaluated in the geriatric oncology clinic for whom the pre-GA and post-GA systemic therapy plans were available. The median age was 70 years (range, 60-100); 264 (78%) were men. The common malignancies were lung cancer in 134 (39.4%) and gastrointestinal in 119 (35%). The intent of therapy was palliative in 190 (56%) patients. Following the GA, the systemic therapy plan was changed in 125 (36.8%) patients. The most common change was deintensification of therapy in 106 patients (31.2%), including dose reduction in 41 (12%), decrease in the number of chemotherapy medicines in 8 (2.4%), substitution of chemotherapy by targeted therapy (4, 1.2%)/oral hormonal therapy (4, 1.2%)/oral TKI (11, 3.2%)/immunotherapy (2, 0.6%) and withholding systemic therapy in 36 (10.6%) patients. Withholding systemic therapy consisted of a change from chemoradiotherapy to radical radiation alone in 17 (5%), withholding neoadjuvant or adjuvant chemotherapy in 5 (1.5%) and a change to best supportive care in 14 (4.1%). Conclusions: The results of the GA led to a change in the management plan in over one-third of older Indian patients with cancer. GA is an important tool in the oncologic decision-making process for older persons with cancer. Clinical trial information: CTRI/2020/04/024675.
Improving cancer pain management in the emergency department: An EMR-based solution.
Authors: Christopher John Coyne, Ellen Kettler, Kelly Dong, James Killeen
Journal: Journal of Clinical Oncology (2021)

12110 Background: Pain is common reason for patients with cancer to seek care in the emergency department (ED). Unfortunately, these patients frequently receive inadequate doses of pain medication, partially due to opioid reduction efforts in the ED, as well as opioid tolerance among those with chronic cancer pain. The purpose of this study was to investigate the effectiveness of an electronic medical record (EMR) based best practice advisory (BPA) at improving analgesic dosing for cancer patients in the ED. Methods: We performed a retrospective cohort study on cancer pain at two academic medical centers from 05/18/20 to 10/27/20. The BPA algorithm identified ED patients with cancer that were taking prescription opioids with a morphine equivalent daily dose (MEDD) of at least 100, as calculated by the EMR. If the ED provider ordered opioids for these patients, a BPA alert appeared with a recommended opioid dose based on the patient’s individual MEDD. This alert also included pre-set safety orders for O 2 and end tidal CO 2 monitoring as well as naloxone. We compared outcomes based on whether an ED provider accepted or cancelled the BPA recommendation. These outcomes included the change in opioid dose and ED disposition. Continuous variables were compared using the students t-test, while categorical variables were compared with the chi-squared test with an alpha of 0.05. Results: Our BPA identified 92 patients that met our criteria, representing 143 BPA alerts. The mean age was 52, 43.5% were female, 54.3% had metastatic disease, and 56.5% presented with a painful chief complaint. Of the ED providers that accepted the BPA, 57.5% increased their dose of opioid medication. BPA usage led to a 33.3% mean increase in medication dosage (p &lt;.001). Patients that presented with a painful chief complaint, whose providers utilized the BPA were admitted at a rate of 60.5%, verses a 77.8% admission rate among those whose providers did not utilize the BPA (p &lt;.01). No patients required an opioid reversal agent. Conclusions: Among cancer patients on chronic opioids presenting to the ED, use of an EMR-based BPA led to more appropriate opioid dosing without the need for opioid reversal agents, and was associated with an overall decrease in hospital admissions.
Treatment with pembrolizumab in combination with the oncolytic virus pelareorep promotes anti-tumor immunity in patients with advanced pancreatic adenocarcinoma.
Authors: Devalingam Mahalingam, Siqi Chen, Ping Xie, Aparna Kalyan, Sheetal Mehta Kircher, Masha Kocherginsky, Jiahui Xu, Victoria Maurer, Pedro Antonio Hermida de Viveiros, Elena Vagia, Grey A Wilkinson, Matthew C. Coffey, Mary Frances Mulcahy, Al Bowen Benson, Bin Zhang
Journal: Journal of Clinical Oncology (2021)

4144 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). In prior studies, tumor tissue analysis from patients treated with pelareorep shows pelareorep replication, increased T cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab in patients with PDAC would lead to improved responses and anti-tumor immunological changes within peripheral blood and tumor biopsies in responding patients. Methods: PDAC patients who progressed after first-line treatment received pelareorep at a dose of 4.5x10 10 TCID 50 IV on Days 1, 2, 3 &amp; 8 of Cycle (C) 1, and Days 1 &amp; 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. The primary objective was overall response rate by RECIST v 1.1 criteria. Secondary objectives included evaluating immunological changes within tumor tissue and peripheral blood, performed by multi-plex immunohistochemistry and spectral flow cytometry (Cytek), respectively. Results: Thirteen patients were enrolled. Disease control was achieved in 33% of the 12 efficacy-evaluable patients. One patient achieved a partial response (PR). Three additional patients achieved stable disease (SD). On-treatment tumor biopsies, collected during C1, showed pelareorep replication, increased infiltration of CD8+ T cells and PD-L1+ cells, and decreased expression of VDAC1, a mitochondrial gatekeeper for tumor promotion, relative to archival tissue. Reduced infiltration of Foxp3+ regulatory T cells (Treg) was observed in patients showing tumor response. Peripheral blood was collected at day 1 of each cycle and on C1 day 8. Relative to pretreatment samples, the number of CD8+ effector memory T cells and B cells tend to increase while the number of Treg cells declined in C2 onwards in patients with tumor response. Furthermore, these patients had increased expression of the mitochondrial protein TOMM20 in CD8+ T cells and decreased expression of PD-1 and the H3K27me3 epigenetic mark in Treg. Treatment was well tolerated with most treatment-related adverse events, including flu-like symptoms, being grade 1 or 2. Conclusions: The combination of pelareorep and pembrolizumab showed a manageable safety profile and modest efficacy in an unselected PDAC population. Additional correlation analyses between treatment efficacy and immunological changes will be presented. The anti-tumor activity of pelareorep and checkpoint blockade therapy is being evaluated further in additional ongoing studies. Clinical trial information: NCT03723915.
Safety of trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive locally advanced or metastatic breast cancer (mBC): Final results from KAMILLA Cohorts 1 (global) and 2 (Asia).
Authors: Rachel Wuerstlein, Paul Ellis, Filippo Montemurro, Antonio Antón Torres, Suzette Delaloge, Qingyuan Zhang, Xiaojia Wang, Shusen Wang, Shao Zhimin, Huiping Li, Andhika Rachman, Mawin Vongsaisuwon, Haiying Liu, Simon Fear, Claudia Pena-Murillo, Carlos H. Barrios
Journal: Journal of Clinical Oncology (2021)

1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 [China, n=154; Thailand, n=15; Indonesia, n=12]). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enrolled 2185 pts (Cohort 1, n=2003; Cohort 2, n=182), of which 2002 and 181 in each cohort, respectively, received ≥1 study dose and were included in the safety population. Baseline characteristics were generally similar between cohorts. Median (range) T-DM1 exposure was 5.6 mo (0–46) for Cohort 1 and 5.0 mo (0–31) for Cohort 2. The overall G≥3 AEPI rate was higher in Cohort 2 vs Cohort 1 (Table), mostly driven by a higher G≥3 TCP rate in Cohort 2. In Cohort 2, G≥3 TCP (the most frequently reported G≥3 AEPI) did not appear to be associated with G≥3 hemorrhagic events — the majority of G≥3 TCP events (128/138) fully resolved, with a duration of ≤15 days for 98/138 of these events. G≥3 TRAE rates were 18.4% in Cohort 1 and 48.6% in Cohort 2, the latter mainly due to TCP and platelet count decreased; any-grade pneumonitis rates were 1.0% and 2.2%, respectively. No other safety signals were identified. Median progression-free survival and overall survival were similar for both cohorts (Table). Conclusions: These data confirm prior observations in an Asian subgroup of the phase 3 EMILIA trial of T-DM1 in pts with previously treated mBC. Although the G≥3 TCP rate was higher in the Asia cohort, the majority of these events resolved fully. OS and PFS were similar in both cohorts. These data reinforce the favorable T-DM1 benefit-risk profile in mBC. Clinical trial information: NCT01702571 .[Table: see text]
FDA Oncology Center of Excellence landscape analysis of real-world data submissions for oncology drugs.
Authors: Donna Rivera, Jennifer J. Lee, Melanie E Royce, Paul Gustav Kluetz
Journal: Journal of Clinical Oncology (2021)

e18787 Background: Aligning with 21st Century Cures legislation, the FDA is exploring trial design modernization and methodology to advance appropriate uses of Real World Data (RWD) to generate Real World Evidence (RWE). The Oncology Center of Excellence RWE Program was established in 2020 to advance RWE efforts specific to oncology drug development. Inclusion of RWD to support regulatory decision making has increased in oncology, and a landscape analysis was conducted to characterize the RWD included in submissions. Methods: A systematic search was conducted using internal FDA databases to identify RWD submissions from 2010 to 2020. Search terms included: real world evidence, real world data, electronic health record, cancer registry, administrative claims, external control arm, observational cohort, historical control arm, rwOS, rwRR, rwCR, and rwORR. Relevant regulatory submissions were reviewed, and pre-defined common data elements were extracted. A team of FDA reviewers assessed agreement through subset validation (20%). Descriptive statistics were calculated. Results: A total of 142 regulatory submissions included RWD from 2011 to 2020. A subset of 94 submissions met the criteria for evaluation, consisting of 78 unique studies evaluating 56 molecular entities. RWD submissions increased substantially over time, with 28 submissions in 2020. Nearly half of the RWD submissions were for solid tumor indications (68%), with lung cancer being the most predominant site. More than one third of the RWD submissions (37%) were for rare indications. The most common primary RWD study objective was effectiveness (62%) and the most commonly referenced RWD source was EHR/clinical data (54%). The most frequently used primary RWD endpoints were survival (rwOS, 35%) and response (rwORR/PR/BTR, 31%) outcomes (Table). Conclusions: Our review demonstrates a dramatic increase in RWD submissions to support FDA oncology drug development programs. Submissions included a variety of study objectives, data sources, and endpoints. While this landscape analysis provides a picture of potential regulatory objectives, the adequacy of each proposal to support regulatory decision making was not evaluated. Establishing a set of clear regulatory objectives can help advance the development of metrics for robust data characterization and outcome validation to ensure that RWD can be appropriately evaluated and provide the rigor necessary to be considered adequate RWE.[Table: see text]