المؤلفون: Lakhani, Nehal J., Chow, Laura Q. M., Gainor, Justin F., LoRusso, Patricia, Lee, Keun-Wook, Chung, Hyun Cheol, Lee, Jeeyun, Bang, Yung-Jue, Hodi, Frank Stephen, Kim, Won Seog, Santana-Davila, Rafael, Fanning, Philip, Squifflet, Pierre, Jin, Feng, Kuo, Tracy C., Wan, Hong, I, Pons, Jaume, Randolph, Sophia S., Messersmith, Wells A.

المساهمون: Bang, Yung-Jue

مصطلحات موضوعية: THERAPEUTIC TARGET, CD47 BLOCKADE, CELL, PHAGOCYTOSIS, RITUXIMAB

الوصف: Background Both innate and adaptive immune responses are important components of anticancer immunity. The CD47-SIRP alpha interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours. Methods We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0middot3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of ...

العلاقة: The Lancet Oncology, Vol.22 No.12, pp.1740-1751; https://hdl.handle.net/10371/189502Test; 000729806300031; 2-s2.0-85120342219; 153819

الإتاحة: https://hdl.handle.net/10371/189502Test

المؤلفون: Kim, Tae Won, Burris, Howard H.A., de Miguel Luken, María José, Pishvaian, Michael M.J., Bang, Yung Jue, Gordon, Michael, Awada, Ahmad, Camidge, David Ross, Hodi, Frank Stephen, McArthur, Grant A, Miller, Wilson W.H., Cervantes, Andrés, Chow, Laura Q M LQ, Lesokhin, Alexander A.M., Rutten, Annemie, Sznol, Mario, Rishipathak, Deepali, Chen, Shang Chiung, Stefanich, Eric, Pourmohamad, Tony, Anderson, Maria, Kim, Jeong, Huseni, Mahrukh, Rhee, Ina, Siu, Lillian Lai Yun L.L.

المصدر: Clinical cancer research, 28 (16

مصطلحات موضوعية: Cancérologie

الوصف: Purpose: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-inhuman study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. Patients and Methods: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3þ3 dose-escalation stage (0.2–1,200 mg; n ¼ 34) was followed by expansion cohorts at 300 mg (n ¼ 138) for patients with melanoma, renal cell carcinoma, non–small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. Results: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1–2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. Conclusions: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists. ; SCOPUS: ar.j ; info:eu-repo/semantics/published

وصف الملف: 1 full-text file(s): application/pdf

العلاقة: uri/info:doi/10.1158/1078-0432.CCR-21-4020; uri/info:scp/85136956244; https://dipot.ulb.ac.be/dspace/bitstream/2013/372584/1/doi_356228.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/372584Test

الإتاحة: http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/372584Test

المؤلفون: Chow, Laura Q. M., Barlesi, Fabrice, Bertino, Erin M., van den Bent, Martin J., Wakelee, Heather A., Wen, Patrick Y., Chiu, Chao-Hua, Orlov, Sergey, Chiari, Rita, Majem, Margarita, McKeage, Mark, Yu, Chong-Jen, Garrido, Pilar, Hurtado, Felipe K., Arratia, Pilar Cazorla, Song, Yuanbo, Branle, Fabrice, Shi, Michael, Kim, Dong-Wan

المساهمون: Kim, Dong-Wan

مصطلحات موضوعية: TYROSINE KINASE INHIBITORS, OPEN-LABEL, CRIZOTINIB, CHEMOTHERAPY, SURVIVAL, MANAGEMENT, DIAGNOSIS, CARCINOMATOSIS, ALECTINIB, OUTCOMES

الوصف: Purpose: Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK(+)) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK(+) NSCLC metastatic to the brain and/or leptomeninges. Patients and Methods: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naive; arm 4: no radiotherapy/ALKi-naive). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses. Results: Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2-92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs 95%) CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier. Conclusions: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease. ; N ; 1

العلاقة: Clinical Cancer Research, Vol.28 No.12, pp.2506-2516; https://hdl.handle.net/10371/184627Test; 000813269600001; 2-s2.0-85131604877; 165769

الإتاحة: https://doi.org/10.1158/1078-0432.CCR-21-1838Test
https://hdl.handle.net/10371/184627Test

المؤلفون: Pfister, David G., Haddad, Robert I., Worden, Francis P., Weiss, Jared, Mehra, Ranee, Chow, Laura Q. M., Liu, Stephen V., Kang, Hyunseok, Saba, Nabil F., Wirth, Lori J., Sukari, Ammar, Massarelli, Erminia, Ayers, Mark, Albright, Andrew, Webber, Andrea L., Mogg, Robin, Lunceford, Jared, Huang, Lingkang, Cristescu, Razvan, Cheng, Jonathan, Seiwert, Tanguy Y., Bauml, Joshua M.

المصدر: Cancer Medicine ; volume 12, issue 6, page 6603-6614 ; ISSN 2045-7634 2045-7634

الوصف: Background We performed an integrated biomarker evaluation in pembrolizumab‐treated patients with R/M HNSCC enrolled in KEYNOTE‐012 or KEYNOTE‐055. The relationship between biomarkers and HPV status was explored. Methods We evaluated PD‐L1 (combined positive score [CPS]), TMB, T‐cell‐inflamed gene expression profile (Tcell inf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). Results Two hundred and fifty‐seven patients (KEYNOTE‐012, n = 106; KEYNOTE‐055, n = 151) had TMB data available; of these, 254 had PD‐L1 and 236 had Tcell inf GEP. TMB, PD‐L1, and Tcell inf GEP were each significantly associated with ORR ( p < 0.01). Kaplan–Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD‐L1 or Tcell inf GEP (Spearman ρ = −0.03 and ρ = −0.13, respectively); PD‐L1 and Tcell inf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD‐L1, and Tcell inf GEP were each independently predictive for ORR ( p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD‐L1 or TMB and Tcell inf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD‐L1, TMB, and Tcell inf GEP) were associated with response. HPV detection by p16‐immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method. Conclusions TMB and the inflammatory biomarkers PD‐L1 and Tcell inf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.

الإتاحة: https://doi.org/10.1002/cam4.5434Test

المؤلفون: Haddad, Robert I, Seiwert, Tanguy Y, Chow, Laura Q M, Gupta, Shilpa, Weiss, Jared, Gluck, Iris, Eder, Joseph P, Burtness, Barbara, Tahara, Makoto, Keam, Bhumsuk, Kang, Hyunseok, Muro, Kei, Albright, Andrew, Mogg, Robin, Ayers, Mark, Huang, Lingkang, Lunceford, Jared, Cristescu, Razvan, Cheng, Jonathan, Mehra, Ranee

المساهمون: Merck & Co., Inc.

المصدر: Journal for ImmunoTherapy of Cancer ; volume 10, issue 2, page e003026 ; ISSN 2051-1426

الوصف: Background To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study. Methods Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV + , mapping >20 HPV reads) in pretreatment tumor samples (n=106). Results TMB, clonality-weighted TMB, and Tcell inf GEP were significantly associated with objective response (p = 0.0276, p = 0.0201, and p = 0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p = 0.0550 and p = 0.0682, respectively). No correlation was observed between TMB and Tcell inf GEP (Spearman ρ=–0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between Tcell inf GEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods. Conclusions TMB and inflammatory biomarkers (Tcell inf GEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed. Trial registration number NCT01848834 .

الإتاحة: https://doi.org/10.1136/jitc-2021-003026Test

المؤلفون: Creelan, Benjamin C., Yeh, Tammie C., Kim, Sang-We, Nogami, Naoyuki, Kim, Dong-Wan, Chow, Laura Q. M., Kanda, Shintaro, Taylor, Rosemary, Tang, Weifeng, Tang, Mei, Angell, Helen K., Roudier, Martine P., Marotti, Marcelo, Gibbons, Don L.

المساهمون: 김동완, Kim, Dong-Wan

مصطلحات موضوعية: OPEN-LABEL, CHEMOTHERAPY, EXPRESSION, OSIMERTINIB, ASSOCIATION, INHIBITORS, DOCETAXEL, NIVOLUMAB, AFATINIB, THERAPY

الوصف: Background EGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advancedEGFRm NSCLC was evaluated. Methods This Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19delEGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy. Results From dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9-80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5-15.2) and median response duration was 9.2 months (95% CI: 3.7-14.0). Conclusions Durvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients withEGFRm NSCLC. ; Y ; 1

العلاقة: British Journal of Cancer, Vol.124 No.2, pp.383-390; 122024; https://hdl.handle.net/10371/179091Test; 000575032800002; 2-s2.0-85092048603

الإتاحة: https://doi.org/10.1038/s41416-020-01099-7Test
https://hdl.handle.net/10371/179091Test

المؤلفون: Hellmann, Matthew D., Gettinger, Scott, Chow, Laura Q. M., Gordon, Michael, Awad, Mark M., Cha, Edward, Gong, Xiaohua, Zhou, Gongfu, Walker, Chris, Leopold, Lance, Heist, Rebecca S.

المصدر: International Journal of Cancer ; volume 147, issue 7, page 1963-1969 ; ISSN 0020-7136 1097-0215

الوصف: Epacadostat is a potent and highly selective inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO1). Here we report results from the open‐label, dose‐escalation, Phase 1b ECHO‐110 study evaluating epacadostat plus atezolizumab in patients with previously treated Stage IIIB/IV nonsmall cell lung cancer (NSCLC). Eligible patients had received ≥1 prior line of platinum‐based chemotherapy (≥2 cycles) and no prior checkpoint/IDO inhibitors treatment. Oral epacadostat (25, 50, 75, 100, 200 or 300 mg) was administered twice daily (BID) with intravenous atezolizumab 1,200 mg every 3 weeks (Q3W). Primary endpoints were safety, tolerability and dose‐limiting toxicities (DLTs). Twenty‐nine patients received ≥1 dose of treatment. The maximum tolerated dose of epacadostat was not reached. Two patients had DLTs: one patient with Grade 3 dehydration and hypotension (epacadostat 200 mg BID); one patient with Grade 3 hyponatremia and Grade 4 autoimmune encephalitis (epacadostat 300 mg BID). Twenty‐three patients (79%) had treatment‐related adverse events (AEs); seven patients (24%) experienced Grade 3/4 events; five patients (17%) discontinued treatment due to treatment‐related AEs. No fatal treatment‐related AEs occurred. One patient achieved a partial response (objective response rate, 3%), which was maintained for 8.3 months; eight patients had stable disease. Baseline tumoral programmed cell death ligand 1 (PD‐L1) and IDO expression were low among patients with evaluable samples (1 of 23 expressed PD‐L1; 5 of 17 expressed IDO). Epacadostat pharmacokinetics was comparable to historical controls. Epacadostat, at doses up to 300 mg BID, combined with atezolizumab 1,200 mg Q3W was well tolerated in patients with previously treated NSCLC, although clinical activity was limited.

الإتاحة: https://doi.org/10.1002/ijc.32951Test

المؤلفون: Creelan, Benjamin C., Yeh, Tammie C., Kim, Sang-We, Nogami, Naoyuki, Kim, Dong-Wan, Chow, Laura Q. M., Kanda, Shintaro, Taylor, Rosemary, Tang, Weifeng, Tang, Mei, Angell, Helen K., Roudier, Martine P., Marotti, Marcelo, Gibbons, Don L.

المساهمون: AstraZeneca PLC

المصدر: British Journal of Cancer ; volume 124, issue 2, page 383-390 ; ISSN 0007-0920 1532-1827

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Background EGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advanced EGFR m NSCLC was evaluated. Methods This Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19del EGFR m. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy. Results From dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9–80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5–15.2) and median response duration was 9.2 months (95% CI: 3.7–14.0). Conclusions Durvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients with EGFR m NSCLC.

الإتاحة: https://doi.org/10.1038/s41416-020-01099-7Test
https://www.nature.com/articles/s41416-020-01099-7.pdfTest
https://www.nature.com/articles/s41416-020-01099-7Test

المؤلفون: Al Achkar, Morhaf, Marchand, Lucille, Thompson, Matthew, Chow, Laura Q M, Revere, Debra, Baldwin, Laura-Mae

المصدر: BMJ Open ; volume 10, issue 3, page e032639 ; ISSN 2044-6055 2044-6055

الوصف: Objective Lung cancer is increasingly recognised as a heterogeneous disease. Recent advances with targeted therapies for lung cancer with oncogenic mutations have greatly improved the prognosis for this subset of patients, yet little is known about their experiences. This study aimed to identify the needs and explore the healthcare experiences of these advanced patients with oncogenic mutation driven lung cancer. Design Qualitative interviews with patients with advanced or metastatic non-small cell lung cancer with oncogenic alterations in anaplastic lymphoma kinase, epidermal growth factor receptor or c-ros oncogene 1. Settings Patients were recruited from online lung cancer support groups within the USA. Interviews were conducted remotely or in person, transcribed verbatim and analysed using an iterative inductive and deductive process. Participants We included 39 patients (11 males and 28 females) with a median age of 48. Results Two primary theme categories emerged: patients' unmet needs and improving healthcare experiences. Unmet needs are related to patients’ desire to view their disease as a chronic illness, aspire to live a meaningful existence without financial devastation, desire for understanding along with emotional support and needing help with practical matters. Improving healthcare experiences involved patients’ desire to trust the expertise of clinical providers, receive reliable care and be treated holistically and as informed partners. Conclusions Patients with lung cancer with oncogenic mutations live uncharted experiences. Targeted therapy brings hope, but uncertainty is daunting. Patients grapple with the meaning and purpose of their lives while day-to-day obligations remain challenging. Healthcare teams are instrumental in their care experiences, and patients desire providers who are up-to-date on advances in the field and treat them as whole persons.

الإتاحة: https://doi.org/10.1136/bmjopen-2019-032639Test

المؤلفون: Mehra, Ranee, Seiwert, Tanguy Y., Gupta, Shilpa, Weiss, Jared, Gluck, Iris, Eder, Joseph P., Burtness, Barbara, Tahara, Makoto, Keam, Bhumsuk, Kang, Hyunseok, Muro, Kei, Geva, Ravit, Chung, Hyun Cheol, Lin, Chia-Chi, Aurora-Garg, Deepti, Ray, Archana, Pathiraja, Kumudu, Cheng, Jonathan, Chow, Laura Q. M., Haddad, Robert

المصدر: British Journal of Cancer ; volume 119, issue 2, page 153-159 ; ISSN 0007-0920 1532-1827

مصطلحات موضوعية: Cancer Research, Oncology

الإتاحة: https://doi.org/10.1038/s41416-018-0131-9Test
http://www.nature.com/articles/s41416-018-0131-9Test
http://www.nature.com/articles/s41416-018-0131-9.pdfTest