tbuckley/cabot-search huggingface dataset:
Indirect mechanisms of action of a novel IgG1 monoclonal antibody, NEO-201, to enhance immune killing of tumor.
Authors: Philip M. Arlen, Christina M. Annunziata, Massimo Fantini, M. Pia Morelli, Kwong Y. Tsang
Journal: Journal of Clinical Oncology (2020)

17 Background: NEO-201 is an IgG1 mAb targeting variants of CEACAM5/6 that demonstrates tumor sensitivity and specificity. Functional analysis revealed that NEO-201 is capable of engaging innate immune effector mechanism including ADCC and CDC to directly kill tumor cells expressing its target. Previous studies demonstrated safety/tolerability in non-human primates, and an on going clinical trial at the NCI is currently exploring its dosing and safety. We have explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 has the ability to enhance NK activity by blocking the binding of CEACAM5 on tumor cells to CEACAM1 on NK cells. In addition NEO-201 can target and eliminate regulatory T cells (Tregs). Methods: In vitro functional assays, using various human tumor cell lines as target cells and NK-92 cells (CEACAM1 + /CD16 − ) as effectors, were conducted to assess the ability of NEO-201to enhance antitumor cytotoxicity of NK-92 cells by blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells. In addition, flow cytometry analsyis and CDC assays were performed to evaluate the ability of NEO-201 to target and eliminate human Tregs in vitro. Results: Addition of NEO-201 significantly enhanced NK-92 cell cytotoxicity against highly CEACAM5 + /NEO-201 + cells, suggesting that its activity is correlated with the level of CEACAM5 + /NEO-201 + tumor cells. Furthermore, NEO-201 targets human Tregs and mediates killing of opsonized T-reg cells via CDC. Conclusions: Previously we have demonstrated the ability of NEO-201 as an IgG1 mab to destroy tumor cells expressing its target directly through both ADCC and CDC. This study suggests that in addition, NEO-201may also mediate immune killing through additional mechanisms including blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to reverse CEACAM1-dependent inhibition of NK cytotoxicity. In addition, we have shown that NEO-201 is also able to recognize and eliminate human Tregs. Ongoing studies are looking at leveraging this phenomenon by combining NEO-201 with checkpoint inhibitors.
Differences Between Randomized Clinical Trial Participants and Real-World Empagliflozin Users and the Changes in Their Glycated Hemoglobin Levels
Authors: Nicolai E. Munk, Jakob S. Knudsen, Anton Pottegård, Daniel R. Witte, Reimar W. Thomsen
Journal: JAMA Network Open (2020)

Use of the sodium-glucose cotransporter 2 inhibitor empagliflozin has increased substantially since 2015. Little is known about characteristics of real-world patients who use empagliflozin or about empagliflozin's effectiveness in reducing glycated hemoglobin (HbA1c) levels in routine clinical care.To characterize real-world initiators of empagliflozin, to examine the proportion of initiators who would have been eligible for participation in phase 3 randomized clinical trials (RCTs) of empagliflozin, and to assess changes in HbA1c levels after empagliflozin initiation.This cross-sectional study used linked population-based medical databases containing complete information on redeemed prescriptions, laboratory tests, and diagnoses for all residents in Northern Denmark. A total of 7034 residents of Denmark who filled a first-time empagliflozin prescription from January 2014 to December 2018 were included. Data analysis was performed in August 2019.Empagliflozin initiation.Proportion of real-world users ineligible for RCT inclusion and absolute reduction in HbA1c level 6 months after empagliflozin initiation.Of 7034 first-time empagliflozin initiators (median [interquartile range] age, 61.50 [53.30-69.38] years; 4475 [63.6%] men), 3878 (55.1%) would have been ineligible for phase 3 RCT participation; frequent reasons were concurrent use of specific glucose-lowering drugs (1955 initiators [27.8%]), baseline HbA1c level outside the eligibility range (1772 [25.2%]), or presence of comorbidities (1067 initiators [15.3%]). Initiation of empagliflozin was associated with a mean HbA1c reduction of -0.91% (95% CI, -0.94% to -0.87%) after 6 months, similar to phase 3 RCT results. Real-world empagliflozin initiators who would have been eligible for RCT participation experienced slightly lower mean HbA1c reductions (-0.78%; 95% CI, -0.82% to -0.74%) compared with patients who would have been ineligible (-1.01%; 95% CI, -1.07% to -0.95%). Ineligible initiators had higher median (interquartile range) baseline HbA1c values than eligible initiators (8.5% [7.4% to 10.1%] vs 8.2% [7.6% to 9.8%]).In this cross-sectional study, more than half of empagliflozin initiators exhibited clinical characteristics that would have led to ineligibility for the RCTs leading to the drug's approval. While the findings suggest that the efficacy of empagliflozin in reducing HbA1c levels translates into real-world effectiveness, further studies should examine clinical outcome effectiveness and drug safety in routine clinical care.
Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, <i>RAS</i> wild-type colorectal cancer: OGSG 1602.
Authors: Katsuya Ohta, Takeshi Kato, Masahiro Goto, Tetsuji Terazawa, Shingo Noura, Hironaga Satake, Yoshinori Kagawa, Hisato Kawakami, Hiroko Hasegawa, Kazuhiro Yanagihara, Tatsushi Shingai, Ken Nakata, Masahito Kotaka, Masayuki Hiraki, Ken Konishi, Shiro Nakae, Daisuke Sakai, Yukinori Kurokawa, Toshio Shimokawa, Taroh Satoh
Journal: Journal of Clinical Oncology (2020)

106 Background: Single agent of panitumumab (Pmab) is expected to be well tolerated and to improve survival in first-line setting in patients (pts) who are not eligible for intensive chemotherapy, although the efficacy and safety of Pmab for chemotherapy-naïve frail or elderly Japanese pts with wild-type (wt) RAS unresectable colorectal cancer (CRC) have not been yet studied. Methods: We conducted a multi-center phase II study. Pts aged over 76 years, or over 65 who were considered unsuitable for intensive chemotherapy. Pmab 6 mg/kg was administered intravenously every 2 weeks. The primary endpoint was disease control rate (DCR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and the incidence of grade 3 or 4 toxicities. Sample size was set to 36 with exact p-value of 0.05, a power of 0.90, the null of hypothesis of 45% and alternative hypothesis of 70% based on the Clopper-Pearson method. Results: A total 36 pts were enrolled in February 2017 to August 2018. Two pts were excluded; one was a lack of image examination at baseline, and the other was a lack of measurable lesion. The median age was 81 (67-88), with 29 pts (85%) being aged over 76 years. There were 33 (92%) pts with performance status (PS) 0/1, while two (6%) and one (3%) pts were PS 2/3, respectively. Twenty-eight pts (78%) had left-sided CRC, while eight pts had right-sided CRC. The RR was 50.0% (95%CI, 32.4-67.6) including three cases (8.8%) of complete response, and SD was 26.5%, yielding 76.5% of DCR (p &lt; 0.001, 90% confidence interval [CI], 61.5-87.7). The RR with left sided tumor was 65% (95%CI, 44.3-82.8), while that pts with right-sided tumor was 0% (95%CI, 0.0-36.9)(p = 0.003). The major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 17%), hypomagnesemia (n = 4, 11%), fatigue (n = 3, 8%), paronychia (n = 3, 6%), and hyponatremia (n = 3, 6%). The grade 3 hematologic toxicities was neutropenia (n = 1, 3%). Conclusions: Pmab monotherapy showed the favolable efficacy and feasibility in the frail or elderly pts with RAS wt, unresectable CRC. The survival analysis including OS, PFS and TTF is awaiting. Clinical trial information: UMIN000024528.
Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor
Authors: Alastair J.J. Wood, Graham J. Lieschke, Antony W. Burgess
Journal: New England Journal of Medicine (1992)

Therapeutic ApplicationsAcute Neutropenia after Myelotoxic Anticancer TherapyThe administration of a colony-stimulating factor after standard-dose chemotherapy may be either prophylactic (i.e., given to prevent infectious complications) or therapeutic (i.e., given to patients in whom fever develops while they have neutropenia). Except in experimental treatment approaches for myeloid neoplasms, the administration of a colony-stimulating factor should not immediately precede or overlap with cytotoxic therapy, because the cycling of hematopoietic progenitor cells stimulated by the factor may increase their sensitivity to cytotoxic drugs, thus increasing rather than reducing the myelotoxicity of the cytotoxic agent.85 , 86 A theoretical precaution relates to the observation . . .
ARID1A mutation to define an immunologically active subgroup in patients with microsatellite-stable colorectal cancer.
Authors: Amir Mehrvarz Sarshekeh, Jason Roszik, Ganiraju C. Manyam, Shailesh M. Advani, Jason Willis, John Paul Y.C. Shen, Jeffrey Morris, Jennifer S. Davis, Jaffer A. Ajani, Dipen M. Maru, Michael J. Overman, Scott Kopetz
Journal: Journal of Clinical Oncology (2020)

215 Background: AT-rich interactive domain 1A (ARID1A) is a chromatin regulator mutated in human cancers, frequently resulting in truncation and loss of expression of this protein. ARID1A recruits MSH2 during DNA replication to perform mismatch-repair. ARID1A deficiency has been shown to increase mutational load and immune activation in preclinical models (Shen J, Nat Med 2018) but its role in colorectal cancer (CRC) patients (pts) is being explored. Methods: The DNA sequencing and gene expression profiling of microsatellite-stable (MSS) CRC pts were extracted from TCGA and MD Anderson Cancer Center databases. The expression levels were normalized according to the mean values of each dataset. The mutational burden and expression signatures for IFN-γ and various immune markers were compared according to the ARID1A mutational status. Results: Among 417 pts with MSS CRC, 28 pts (6.7%) had a non-silent mutation in ARID1A. Out of the 58 genes most commonly mutated in CRC, non-silent mutation in ARID1A had the strongest association with the frame-shift mutation rate in MSS cases (8-fold increase, p&lt; .001). ARID1A mutation had also a strong correlation with the IFN-γ expression signature in MSS CRC (Δz score +1.91, p&lt; .001) . Compared with ARID1A wild-type pts, higher expression signatures for cytotoxic T cell function, NK cells, and immune checkpoints were observed in MSS ARID1A mutated cases. ARID1A mutant cases showed higher expressions of various immune checkpoint genes (CD274, CTLA4, HAVCR2, IDO1, LAG3, PDCD1, and PDCD1LG2) compared to wild-type cases (all p &lt; .05). All findings were observed independently in both datasets. Conclusions: In MSS CRC, ARID1A mutation is associated with a high expression of IFN-γ pathway and immune signatures (such as cytotoxic T cell function and immune checkpoint markers). The immunogenicity of ARID1A mutant cases is likely due to the increased level of neoantigens resulting from the increased rate of frame-shift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should likely be recognized as a unique molecular subgroup in future immune therapy trials.
Treatment outcomes of patients with G3 neuroendocrine neoplasms.
Authors: Henning Jann, Antonin Kayser, Bertram Wiedenmann, Frank Tacke, Christoph Roderburg
Journal: Journal of Clinical Oncology (2020)

622 Background: Extra-pulmonary neuroendocrine carcinomas (NEC) and neuroendocrine tumors (NET) G3 are aggressive neoplasia that are associated with a limited prognosis. Data on this entity is scarce and optimal treatments are only poorly defined. Methods: 105 patients (♀ = 46; 43.8% and ♂ = 59; 56.2%) with histologically confirmed neuroendocrine carcinoma (NEC; n = 83) or neuroendocrine tumor G3 (NET G3; n = 12) or mixed neuroendocrine non-neuroendocrine neoplasms G3 (MiNEN G3; n = 10) were included into this study. Clinical and pathological characteristics at diagnosis, therapies, outcomes and survival data were recorded. Results: Primary tumor localizations included esophagus/stomach (n = 9; 8.7%), pancreas/duodenum (n = 29; 27.9%), appendix/colon/rectum (n = 25; 24.0%), the genitourinary tract (n = 9; 8.7%) and CUP (n = 32; 30.8%). Median Ki-67 across all patients was 70% (range 25-95) with a statistically significant difference in NEC G3 vs. NET G3 (74%, range 25-95 vs. 33.5%, range 25-69; p &lt; .001). Median overall survival (mOS) was 19.2 (±1.6)months and was significantly higher in NET G3 (38 vs. 16.8 months in NEC; p = .012). First-line therapy in most patients was cisplatin or carboplatin in combination with etoposide (n = 64; 61.0%), followed by FOLFOX (n = 29; 27.6%). Twelve Patients (11.4%) received other chemotherapies. Best overall response to first-line chemotherapy was CR (5.7%), PR (52.4%) SD (17.1%) and PD (21%). In patients with Ki-67 &lt; 55% (n = 40) no significant difference between the different regimens was found. In analyzing median PFS (mPFS) in patients with Ki-67 &gt; 55% (n = 65) the combination of cis- or carboplatin with etoposide (mPFS 6.1±0.5 months) was superior to FOLFOX (mPFS 2.8±1.4 months; p = 0.038). Strikingly, in patients with small-cell NEC (n = 28) the combination of cisplatin/etoposide (mPFS 12.3±3months) showed a superior outcome compared to carboplatin/etoposide (mPFS: 6±1.4months; p = .022). Conclusions: Patients with non resectable NEN G3 should be treated with chemotherapy. In cases with proliferative index &gt; 55% the 1 st -line regimen of choice should be platinum in combination with etoposide. The difference in efficacy between carboplatin and cisplatin in our data should be evaluated in a prospective setting.
The impact of additional treatment after endoscopic submucosal dissection for esophageal squamous cell carcinoma in real-world clinical practice.
Authors: Nanako Sakaguchi, Toshifumi Yamaguchi, Yasunobu Ishizuka, Hiroyuki Kodama, Takahiro Miyamoto, Tetsuji Terazawa, Yuichi Kojima, Takayuki Kii, Makoto Sanomura, Masahiro Goto, Kazuhide Higuchi
Journal: Journal of Clinical Oncology (2020)

305 Background: Endoscopic submucosal dissection (ESD) is the standard therapy for the T1a- EP/LPM esophageal squamous cell carcinoma (ESCC), although it is difficult to diagnose the invasion depth accurately before ESD. The incidence of lymph node metastases in ESCC involving the muscularis mucosae (pT1a-MM) and the submucosa (pT1b-SM) is reported to range from approximately 10% to 30%. For the patients with MM, SM or involving LVI or positive vertical margin after ESD, additional treatment (AT) is recommended to prevent local recurrence. However, the AT is not always performed to the frail or elderly patients. The aim of this study is to investigate the outcome of AT and non-AT (NAT) after ESD for ESCC in the real-world clinical practice. Methods: We retrospectively reviewed the ESCC patients who were pathologically confirmed T1a-MM or T1b-SM (UICC-TNM7th) after ESD at Osaka medical college hospital between 2004 and 2016. Results: Among 224 patients who received ESD, 52 patients were pT1a-MM (n = 36; 69.2%) or pT1b-SM (n = 16; 30.8%).Twelve of 52 patients (23%) received AT and forty patients (77%) received NAT. Six patients (AT group: 2 patients, NAT group: 4 patients) had local lymph node recurrence. Five of them underwent salvage therapy. Median follow up time were 54.3 months (range: 48.4-62.4). The 3-, 5-year RFS rate and the 3-, 5-year OS rate were 83.8%[95%CI: 68.2- 92.6], 73.4% [95%CI: 56.0- 85.7] and 94.7% [95%CI: 81.3- 98.6], 91.7% [95%CI: 77.1- 97.3] in all patients, respectively. The 5-year RFS and OS rate were 77.8%, 90.0% in the AT group and 71.6, 92.2% in the NAT group. Conclusions: Although the AT tended to prevent local recurrence, the OS was comparable with NAT because of salvage therapy. The active surveillance is recommended for T1a-MM or T1b-SM ESCC.
Evaluation of ICD codes and phecodes for the identification of pancreatic cancer in a large genomic database.
Authors: Chelsea Anne Isom, Eric R. Gamazon, Marcus Chuan Beng Tan
Journal: Journal of Clinical Oncology (2020)

642 Background: Large genomic databases linked to electronic health records promise to shed light on molecular mechanisms underlying rare diseases, such as pancreatic cancer. However, accurately identifying patients with the desired phenotype can be challenging. This is particularly the case for pancreatic tumors, since ICD codes do not distinguish between pancreatic adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET). Previous studies have shown that ICD codes aggregated by phenotype, known as “phecodes”, have a higher accuracy in identifying specific phenotypes than ICD codes themselves; however, their performance in identifying cancers of the pancreas has not been studied. Methods: From a large deidentified genomic database, two queries were performed to identify all adults with pancreatic cancer for a GWAS study, one using ICD-9/10 codes and the other using phecodes. The medical records for all patients identified from both queries were then reviewed to confirm the presence and histologic type of pancreatic cancer. Results: Of the 91,985 genotyped adults in the database, ICD-9/10 codes identified 1,247 patients with pancreatic cancer, compared with only 422 patients identified by the phecode query. All patients in the phecode cohort were also found in the ICD cohort. Of the 1,247 patients in the ICD cohort, 760 were confirmed to have pancreatic cancer on review of the health records (594 with PDAC, 166 with pNET) whereas in the phecode cohort, only 251 were confirmed to have pancreatic cancer (159 with PDAC, 92 pNET). The positive predictive value (PPV) for PDAC in the ICD query was 47%, compared with 38% for the phecode cohort. The ICD and phecode cohorts had similarly low numbers of pre-malignant cystic tumors (5% in each cohort) and other periampullary cancers (3%). Conclusions: In this large genomic database, the use of ICD-9/10 codes for pancreatic cancer was able to identify nearly three times as many patients with pancreatic cancer and had a higher PPV compared to using phecodes. Therefore, ICD codes, rather than phecodes, should be used to identify patients with pancreatic cancer for subsequent genotyping analysis, though caution is required because the PPV is still low.
New response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor.
Authors: Tomo Ishida, Tsuyoshi Takahashi, Takuro Saito, Yukinori Kurokawa, Kotaro Yamashita, Koji Tanaka, Tomoki Makino, Makoto Yamasaki, Kiyokazu Nakajima, Masaki Mori, Yuichiro Doki
Journal: Journal of Clinical Oncology (2020)

838 Background: While the introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal tumor (GIST), the response evaluation criteria have not been optimized. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib. Methods: We retrospectively reviewed 55 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups; active MR (morphologic response) (+) group and active MR (-) group, judging from the morphological features including the sharpness of the outline and the attenuation of target lesion. We investigated the association between the presence of active MR and clinical outcomes. Similarly, clinical outcomes classified by response evaluated by RECIST and Choi criteria were analyzed respectively. Results: Thirty-two patients had active MR (+). The median Progression-free survival(PFS) was 7 months vs 31 months (active MR(-) vs active MR(+), P = 0.013) and the median overall survival (OS) was 58 months vs 91 months ( P = 0.086), respectively. Although PFS of RECIST PD (progression disease) or Choi PD patients was shorter than that for PR (partial response) or SD(stable disease) patients ( P = 0.0037 for RECIST, P = 0.0058 for Choi), the number of PD patients was very small (N = 3, both in RECIST and Choi). Conclusions: The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with inoperative GIST.
Efficacy of SBP-101, in combination with gemcitabine and nab-paclitaxel, in first-line treatment of metastatic pancreatic ductal adenocarcinoma.
Authors: Dusan Kotasek, Adnan Nagrial, Sumit Lumba, Niall C. Tebbutt, Thomas J. George, Sheri Lynn Smith, Suzanne Gagnon, Michael T. Cullen, Michael J. Walker
Journal: Journal of Clinical Oncology (2020)

710 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (&gt; 2 prior regimens, N=4) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the safety, tolerability, PK, and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m 2 ) and A (125 mg/m 2 ) were administered intravenously on Days 1, 8, and 15 of each cycle. Safety and tolerability were evaluated by clinical and laboratory assessments. PK was evaluated on day 1 of cycle 1. Efficacy was assessed by CA19-9 levels, objective response as assessed by RECIST criteria, progression-free survival (PFS) and overall survival (OS). Results: Fifteen patients have been enrolled in 3 cohorts (1: N=4, 2: N=7, 3: N=4) and received up to 6 cycles of treatment (7 subjects are ongoing in cohorts 2 and 3). The most common adverse events related to SBP-101 are fatigue (N=4), nausea (N=2) and injection site pain (N=2). There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. One patient in cohort 2 developed grade 3-4 reversible liver enzyme elevation. PK parameters in cohort 1 were below the limits of detection at most time points, but plasma C max and AUC 0-t were measurable in cohorts 2 and 3. In those cohorts, CA19-9 levels decreased 76-95% in 7 of 8 evaluable subjects (1 additional subject TBD), with 5 patients achieving partial responses (4 ongoing) and 1 achieving stable disease. Median PFS and OS have not yet been reached. Conclusions: Preliminary results suggest SBP-101 is well tolerated when administered with G and A. Signals of efficacy support continued development of SBP-101 in combination first-line treatment for PDA. Clinical trial information: NCT03412799.