tbuckley/cabot-search huggingface dataset:
A randomized phase II study comparing nivolumab (NIVO) with carboplatin-pemetrexed (CbPEM) for patients (pts) with EGFR mutation-positive non-small cell lung cancer (NSCLC) who acquire resistance to tyrosine kinase inhibitors (TKIs) not due to a secondary T790M mutation (WJOG8515L).
Authors: Hidetoshi Hayashi, Shunichi Sugawara, Yasushi Fukuda, Yuki Sato, Satoru Miura, Keiichi Ota, Yuichi Ozawa, Satoshi Hara, Junko Tanizaki, Koichi Azuma, Shota Omori, Motoko Tachihara, Kazumi Nishino, Shinobu Hosokawa, Yasutaka Chiba, Koji Haratani, Kazuko Sakai, Kazuto Nishio, Nobuyuki Yamamoto, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2021)

9037 Background: Although the efficacy of antibodies to programmed cell death–1 (PD-1) appears to be less pronounced in patients with NSCLC harboring epidermal growth factor receptor gene ( EGFR) mutations, patients who develop disease progression (PD) to TKIs due to mechanisms other than secondary T790M mutation of EGFR might be more likely to benefit from NIVO. Here, we report the results of first randomized phase II trial to compare NIVO with the CbPEM in those population. Methods: Pts with advanced EGFR mt NSCLC who experienced PD after EGFR-TKIs were randomized 1:1 to NIVO or CbPEM. Eligibility criteria included the treatment history with TKIs as follow; no evidence of T790M after PD on 1st/2nd generation (gen) TKIs (A) after PD on 3rd gen TKIs as a 2nd line for T790M positive tumor (B) or 3rd gen TKIs as a front-line (C). The primary end point is progression-free survival (PFS) and biomarker analysis were included for exploratory analysis. Results: A total of 102 patients was randomized. Median PFS and overall survival (OS) were 1.7 and 20.7 months (mo), respectively, for NIVO arm (n = 52) versus 5.6 and 19.9 months for CbPEM (n = 50) (Hazard ratio [HR] = 1.92 and 0.88, respectively). Overall response rate and duration of response were 9.6% and 5.3 months for NIVO and 36.0% and 5.5 months for CbPEM. PD-L1 expression on tumor cells and tumor mutation burden (TMB) were evaluated in 77 (TPS 0%. 1-49%, &gt; 50%, n = 46, 20, and 11) and 50 (Median TMB 6.2mt/mb). Immune-related gene expression profiling was under evaluation and the results will be demonstrated in the meeting. The efficacy of NIVO in PD-L1 strong positive (&gt;50%, n = 8) and no evidence of T790M after PD on 1st/2nd gen TKIs (n = 29) was tended to be better than their counterparts. There was no significant correlation between TMB and the efficacy of NIVO. Pneumonitis was observed in one patient (1.0%) for NIVO arm and no new safety signals were noted. Conclusions: NIVO was not associated with longer PFS than CbPEM in selected pts with advanced EGFR mt NSCLC. OS was similar between groups. Baseline PD-L1 status and genetic alteration features may be relevant predictive markers to select pts who would benefit from NIVO. Clinical trial information: jRCTs051180133. [Table: see text]
CMP-001-007: Open-label, phase 2 study of intratumoral CMP-001 + pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma.
Authors: Deborah J.L. Wong, Aru Panwar, Ari Rosenberg, Vidhya Karivedu, Douglas Earl Laux, Dan Paul Zandberg, Dmitri Bobilev, Luping Zhao, James Wooldridge, Art M. Krieg, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2021)

TPS6089 Background: PD-1 blockade ± chemotherapy has recently become a primary systemic therapy recommended by NCCN guidelines for patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, most pts still do not respond to treatment, indicating a large unmet need for pts with unresectable disease. CMP-001 is a toll-like receptor 9 (TLR9) agonist comprising a CpG-A oligodeoxynucleotide packaged in a virus-like particle that can induce type I interferon secretion from tumor-associated plasmacytoid dendritic cells, promoting a Th1-like chemokine milieu in the tumor microenvironment and inducing an antitumor CD8+ T-cell response. In a phase (ph) 1b study in pts with metastatic melanoma, intratumoral (IT) injection of CMP-001 + intravenous (IV) pembrolizumab (pembro) reversed PD-1 blockade resistance, induced responses in injected and noninjected lesions, and had an acceptable safety profile (Milhem et al, SITC 2020). This combination is therefore being tested in pts with HNSCC. Methods: CMP-001-007 (NCT04633278) is an open-label, multicenter, ph 2 study designed to investigate the efficacy and safety of CMP-001 + IV pembro in adult pts with histologically or cytologically confirmed R/M HNSCC considered incurable by local therapies. Eligible pts have undergone a pretreatment tumor biopsy, received no prior systemic therapy in the R/M setting, and have primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. In addition, pts must have PD-L1-positive tumors (combined positive score ≥1), known tumor human papillomavirus (HPV) status (for oropharyngeal cancer), and measurable disease per RECIST v1.1 with ≥1 lesion amenable to IT injection. Pts with primary tumors in the nasopharynx are excluded. Enrolled pts will receive CMP-001 10 mg once weekly for 7 doses and every 3 weeks (Q3W) thereafter. The first dose may be administered subcutaneously or via IT injection, with all subsequent doses administered IT. All pts will also receive pembro 200 mg IV Q3W after the CMP-001 injection. Treatment continues until unacceptable toxicity or disease progression. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include safety, duration of response (DOR), progression-free survival (PFS), overall survival, and effects of HPV infection and PD-L1 expression on ORR, DOR, and PFS. Exploratory endpoints include analyses of baseline and changes from baseline in tumor or serum biomarkers related to TLR9, immune checkpoints, and potential predictors of response, as well as serum concentrations of CXCL10 and CMP-001. Refer to clinicaltrials.gov/ct2/show/NCT04633278 for the most current information on enrolling sites. Clinical trial information: NCT04633278.
Update of a phase II, multicenter study of high-dose chemotherapy with autologous stem cell transplant followed by maintenance romidepsin for T-cell lymphoma.
Authors: Niloufer Khan, Farhad Khimani, Andrei R. Shustov, Mazyar Shadman, Jia Ruan, Alison J. Moskowitz, David J. Straus, Anita Kumar, Craig Steven Sauter, Andrew David Zelenetz, Ariela Noy, Gunjan L. Shah, Matthew J. Matasar, Pamela Drullinsky, Audrey M. Hamilton, Esther N. Drill, Koen Van Besien, Sergio Giralt, Steven M. Horwitz, Parastoo Dahi
Journal: Journal of Clinical Oncology (2021)

7533 Background: Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes with conventional chemotherapy. Autologous hematopoietic stem cell transplant (AHCT) is a therapeutic strategy for patients in first complete or partial remission (CR1 or PR1), with median progression-free survival (PFS) after AHCT of 36-48% by intent to treat (d’Amore et al JCO 2012, Reimer et al JCO 2009). Romidepsin (romi) is a histone deacetylase inhibitor approved for treatment of relapsed/refractory T-cell lymphoma. We present updated data of the first multicenter study to evaluate PFS of patients (pts) receiving maintenance therapy with romi after AHCT. Methods: This was a phase 2, open-label, investigator-initiated study (expected PFS 45%, desired PFS 70%; success achieved if 15 or more pts out of 25 were progression-free at 2 years post-AHCT). 26 pts transplanted in CR1 or PR1 were evaluable for the primary endpoint of 2-year PFS (Cohort 1, Table). An exploratory cohort (Cohort 2, n=7) enrolled pts either transplanted ≥ CR/PR2 (n=5) or with high risk histologies (n=2). Pts underwent AHCT with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. Maintenance romi 14 mg/m2 started days 42-80 post AHCT; every other week through 6 mon, every 3 weeks through 1 year and every 4 weeks through 2 years post AHCT. PFS was estimated by Kaplan-Meier. Results: 47 pts consented; 13 did not receive romi (no AHCT, n=2; relapse before romi, n=3; cardiac comorbidity, n=3, patient declined, n=5). 1 consented pt did not have PTCL. 15 out of the first 25 pts in Cohort 1 were progression free after 2 years; median follow up of 31 mon (21 - 36 mon). Estimated 2-year PFS was 62% (45-83%, 95% CI); median PFS 30 mon (12.0- NA, 95% CI). In Cohort 2, estimated 2-year PFS was 43% (18 – 100, 95% CI); median follow up of 30 mon (range, 24 – 37 mon); median PFS 14 mon (5 – NA, 95% CI). Across cohorts, 5 pts required dose reduction. The most common toxicities (≥10% of pts, all grades) were fatigue (n=24, 73%), decreased platelets (n=16, 48%) and anemia (n=16, 48%). Conclusions: While the study did not meet its desired primary efficacy endpoint, maintenance romi was well-tolerated with an estimated 2-year PFS of 62%, greater than historical data. A larger, randomized study would be needed to determine the superiority of this approach. Clinical trial information: NCT01908777. [Table: see text]
Parameters of cellular immunity in patients with lymphomas after COVID-19.
Authors: Inna A. Kamaeva, Irina B. Lysenko, Aleksandr B. Sagakyants, Elena S. Bondarenko, Oksana G. Shulgina, Nadezhda V. Nikolaeva, Elena A. Kapuza, Tatiana F. Pushkareva, Yakha S. Gaysultanova, Oleg I. Kit, Viktoria V. Dmitrieva, A. V. Velichko
Journal: Journal of Clinical Oncology (2021)

e19572 Background: The development of lymphomas is accompanied by disorders in the structural and functional organization of the immune system leading to immune deficiency. Such patients are at greater risk of severe SARS-CoV infection. Our purpose was to assess the parameters of cellular immunity in patients with lymphomas with a history of multi-course chemotherapy, therapy with anti-CD20+ antibodies and PCR-confirmed COVID19. Methods: The study included 12 adult patients with lymphoproliferative diseases (non-Hodgkin's large B-cell lymphomas (NHL) - 7, Hodgkin's lymphomas (HL) - 5) with a history of PCR-confirmed COVID-19. All patients underwent 4 to 6 chemotherapy cycles. The relative numbers of the main populations of leukocytes, T- and B-lymphocytes, as well as subpopulations of T-lymphocytes, were assessed in the whole blood collected in K2EDTA anticoagulant using the BD FACSCanto II flow cytometer with a panel of antibodies according to the manufacturer's instructions (Becton Dickinson, USA). Results: Patients with HL showed a number of changes in the parameters of cellular immunity. The content of total lymphocytes and monocytes was reduced in comparison with patients with NHL by 34% and 56%, respectively: 14.3 (11; 17) vs. 21.7 (15.2; 32), and 6.0 (4.8; 7.1) vs. 13.5 (12.9; 13.7), respectively. An increase in granulocytes by 30% was revealed in patients with HL. No differences were found in the content of both general and main populations (CD3+, CD3+CD4+, CD3+CD8+, central and effector memory cells). However, the content of naive CD3+CD4+ and CD3+CD8+ lymphocytes in patients with HL increased by 43% and 62%, respectively. While the number of CD3+CD4-CD8- lymphocytes was 47% lower, the number of CD3+CD4+CD8+, on the contrary, exceeded the values in patients with NHL by 4.6 times. Patients with HL also showed a tendency towards a decrease in the number of NK and NKT-lymphocytes. Conclusions: The increased levels of naive lymphocytes and both populations of memory cells and a sharp increase in double-negative T-lymphocytes and B-lymphocytes in patients with HL could indicate certain characteristics of the disease course affected by COVID-19. The data require additional research and can be used to assess the condition of patients and to predict the therapy efficacy.
Early clinical experience with trifluridine/tipiracil for refractory metastatic colorectal cancer: The ROS study.
Authors: Pilar Garcia-Alfonso, Andres J. Muñoz Martín, Jeronimo Jimenez-Castro, Paula Jiménez-Fonseca, Carles Pericay, Federico Longo, Carmen Reyna, Guillem Argiles, Beatriz Gonzalez Astorga, Maria Jose Gomez-Reina, Ana Ruíz Casado, Nuria Rodriguez-Salas, Rafael Lopez-Lopez, Alberto Carmona Bayonas, Veronica Conde-Herrero, Enrique Aranda
Journal: Journal of Clinical Oncology (2021)

e15556 Background: Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. Methods: This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience program in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. Results: A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently favoured OS: ≤2 metastases, no liver metastasis, alkaline phosphatase &lt; 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio &lt; 5. Grade ≥3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropenia (23.2%), anaemia (12.1%), and thrombocytopenia (5.3%). Conclusions: This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.
Favorable prognostic factors of oligometastatic breast cancer: A subset analysis of OLIGO-BC1.
Authors: Kun Wang, XiWen Bi, Guangyu Liu, Takayuki Ueno, Shintaro Takao, Sung Hoon Sim, Young-Hyuck Im, Seock-Ah Im, Sung Gwe Ahn, Jeong Eon Lee, Yeon Hee Park, Manabu Futamura, Masakazu Toi, Yasuhiro Fujiwara, Mari Saito-Oba, Yuko Kitagawa, Masahiko Nishiyama, Shigeru Imoto
Journal: Journal of Clinical Oncology (2021)

1026 Background: The Federation of Asian Clinical Oncology (FACO) conducted an international retrospective cohort study of oligometastatic breast cancer (BC) (OLIGO-BC1) (UMIN No.000030047). At ASCO2020, we demonstrated that locoregional and systemic therapy prolonged overall survival (OS) for patients with oligometastatic BC, especially for cases with some type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval from a multivariate analysis (#1025). Although BC is heterogeneous and a retrospective dataset has many kinds of bias, we attempted a subset analysis based on intrinsic subtype and several prognostic factors. Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered from CSCO, KSMO and JSCO. OS period was measured from the diagnosis of oligometastases to the latest follow-up. ER, PgR and HER2 status were determined by immunohistochemistry and/or in situ hybridization. A hazard ratio (HR) of OS was calculated by using a univariate analysis. Results: In 1200 eligible cases, one oligometastatic site was found in 578 cases, two in 289, three in 154, four in 102 and five in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Luminal subtype was recorded in 526 cases (44%), luminal-HER2 in 189 (16%), HER2 in 154 (13%), triple-negative in 166 (14%) and others in 165 (13%). In any subtype, locoregional and systemic therapy and ECOG performance status 0 were beneficial for OS. Stage I BC, one oligometastatic site and longer disease-free interval were also related to favorable prognosis in luminal and HER2 subtype. However, triple-negative subtype had no survival advantage with these 3 factors. On the other hand, pathological negative or micrometastatic lymph nodes at primary BC and one oligometastatic site of lymph node, lung, liver and bone were favorable prognostic factors. In addition, cases treated locally with surgical resection and conventional radiation therapy were expected to prolong OS. Discussions: Locoregional therapy for oligometastatic BC may be considered in luminal and HER2 subtype with some conditions. As reported in ASCO2020, triple-negative BC should be managed with systemic therapy. Conclusions: Oligometastatic BC is diagnosed by chance, but some cases seem to survive with multidisciplinary treatment. It is worthwhile to consider locoregional therapy in oligometastatic BC after evaluating favorable prognostic factors.
Dynamics of oxidative blood status and activity of antioxidant system of erythrocytes in patients with cervical cancer receiving combination therapy with dendritic cell vaccine.
Authors: Irina A. Goroshinskaya, Anna P. Menshenina, Elena M. Frantsiyants, Tatiana I. Moiseenko, Ekaterina V. Verenikina, Ludmila A. Nemashkalova, Anastasia V. Chudilova, Anna A. Cherkasova, Tatiana G. Chalabova
Journal: Journal of Clinical Oncology (2021)

e17516 Background: The combination treatment with plasmapheresis and non-specific immunotherapy for locally advanced cervical cancer (CC) is shown to be effective. We studied the effect of immunotherapy with dendritic cell vaccine (DCV) as a part of combination therapy on the intensity of the lipid peroxidation (LPO) and activity of antioxidant enzymes. Methods: Plasma and erythrocyte content of malondialdehyde (MDA), the activity of superoxide dismutase (SOD), catalase, glutathione dependent enzymes and the content of reduced glutathione (GSH) in erythrocytes were determined in 24 patients with CC of T2a-2bN0-1M0 stages and in 25 women without cancer. The patients underwent neoadjuvant chemotherapy (CT) with cisplatin and bleomycin, followed by 2 cycles of DCV, for a total of 6 courses of CT and 12 cycles of DCV. Results: Initially, patients demonstrated intensification of free radical processes enhancing after PCT and the first two DCV: MDA in erythrocytes elevated by 52.2-111.7%, in the blood plasma by 2.2-3.5 times. Subsequent DCV cycles normalized the LPO. MDA levels after 4 DCV cycles were lower than the initial values in erythrocytes by 30.4% (p = 0.04), in plasma by 55.6% (p = 0.007), i.e. were similar to the levels in healthy women. The SOD activity was decreased by 16.7-27.3% (p &lt; 0.005) after 4-6 DCV cycles and normalized after the 7th cycle. The catalase activity in erythrocytes was decreased before treatment and after PCT by 42.4% (p = 0.000000), during vaccine therapy by 20.5-37.7% (p &lt; 0.0005). In reduced catalase activity, inactivation of hydrogen peroxide was realized, apparently, by glutathione peroxidase (GPO), and its increased activity (by 37-102.3%, p≤0.00005) was supported by a high GSH content - by 11.6-52.4% (p &lt; 0.02) above the norm at all stages after the 2nd DCV cycle. And only with the complete normalization of the erythrocyte MDA content, the GPO activity after the 7th DCV cycle decreased by 46.7% (p = 0.000000) relative to the levels before the treatment and did not differ significantly from the values in donors. Conclusions: Vaccine therapy helped to enhance the activity of the glutathione system becoming the most important component of antioxidant protection in the blood of CC patients. Already 3-4 DCV cycles normalized the LPO sharply increased in CC patients during CT. Multi-course vaccine therapy allowed maintaining the optimal oxidative status of the blood.
Addition of selpercatinib to overcome osimertinib resistance in non-small cell lung cancer (NSCLC) with acquired RET fusion detected in ctDNA at very low allele frequency.
Authors: Leeseul Kim, Young Kwang Chae, Chan Mi Jung, Alice Daeun Lee, Emma Yu
Journal: Journal of Clinical Oncology (2021)

3046 Background: Osimertinib, a highly selective third generation EGFR tyrosine kinase inhibitor (TKI) became the standard front-line therapy for EGFR-mutant NSCLC. However, therapeutic options are limited for TKI resistance which commonly occurs. Therefore, overcoming acquired resistance to osimertinib remains an important high unmet need in the field of precision oncology. Herein, we present the first case of advanced adenocarcinoma of the lung that showed notable response with the addition of selpercatinib after acquired resistance to osimertinib monotherapy. Methods: Case presentation. Results: A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab. Based on the EGFR exon19 deletion detected from ctDNA NGS assay (Guardant 360) [variant allele frequency (VAF) 62.7%], the treatment regimen was changed to osimertinib monotherapy (80mg PO daily). Bevacizumab was empirically added given CNS involvement. She maintained overall stable disease for 10 months before subsequent CT showed disease progression. The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy. She tolerated 6 cycles of the regimen in 4 month before a subsequent brain MRI revealed progression of the metastatic brain disease with new leptomeningeal disease. Whole brain radiotherapy was performed and decision was made to start combination TKI treatment of selpercatinib (120mg BID) added to the osimertinib (80mg daily) monotherapy based on her repeat ctDNA NGS assay result showing concurrent acquired CCDC6RET fusion (VAF 0.05%) and EGFR exon 19 deletion (VAF 10.0%). The 6 week follow-up CT demonstrated significant decrease in the largest lung mass (33.95*24.22mm-&gt;32.50*16.07mm). Repeat ctDNA NGS assay at one week after selpercatinib use showed disappearance of RET fusion and significant decrease in EGFR clone (VAF 10.0% to 0.05%). Conclusions: It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors. Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors. To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency. We for the first time report the case of overcoming acquired resistance to osimertinib by adding selpercatinib, a selective RET inhibitor in NSCLC patients with acquired RET fusion detected in ctDNA at VAF of 0.05%.
Neuropsychiatric disorders and COVID-19
Authors: Josef Finsterer
Journal: The Lancet Psychiatry (2021)

In the appendix of the Article, the authors state that "for chronic illnesses, only first diagnoses were counted". 1 In the case of dementia, were patients with a history of mild cognitive impairment (eg, F06•7) or delirium (F05) excluded?This clarification would help to establish whether COVID-19related encephalopathy is associated with the rapid onset of dementia, or whether these patients were already a group at risk of developing dementia, considering that delirium and mild cognitive impairment can act as markers of vulnerability to dementia and can themselves lead to dementia. 3,4 We wondered if there were any data reporting on the psychiatric outcomes in patients with asymptomatic COVID-19 (given that it is suspected that these patients account for at least one-third of all COVID-19 cases 5 ), or in patients with only mild symptoms?This information would be useful for future planning of mental health services.Finally, given that the estimated incidence of a neurological or psychiatric diagnosis in the 6 months after a COVID-19 diagnosis was 33•62%, we would propose a number of measures.First, we would suggest that questions about past COVID-19 infection become a standard part of clinical history taking.Second, we would propose that psychiatrists become an integral part of long COVID clinics nationwide.Finally, we would like to introduce the notion of reverse redeployment, in which health-care workers from general medicine might support mental health services, given the expected increased demand after this pandemic.