Pub Date : 2024-04-30DOI: 10.1007/s11523-024-01064-x
Yuan Li, Weili Zhang, Jie Du, Jinlong Hu, Ruixi Hu, Ziyang Zeng, E-er-man-bie-ke Jin-si-han, Shaopu Lian, Hao Wang, Yunfeng Li, Zhizhong Pan, Cheng Feng, Xuan Zhang, Zhenhai Lu
Background
Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently.
Objective
This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer.
Methods
Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate.
Results
Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a “watch and wait” strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up.
Conclusions
Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.
{"title":"Efficacy and Safety of Neoadjuvant Subcutaneous Envafolimab in dMMR/MSI-H Locally Advanced Colon Cancer","authors":"Yuan Li, Weili Zhang, Jie Du, Jinlong Hu, Ruixi Hu, Ziyang Zeng, E-er-man-bie-ke Jin-si-han, Shaopu Lian, Hao Wang, Yunfeng Li, Zhizhong Pan, Cheng Feng, Xuan Zhang, Zhenhai Lu","doi":"10.1007/s11523-024-01064-x","DOIUrl":"https://doi.org/10.1007/s11523-024-01064-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a “watch and wait” strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-30DOI: 10.1007/s11523-024-01061-0
Mara Persano, Margherita Rimini, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Federico Rossari, Changhoon Yoo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Gianluca Masi, Francesca Bergamo, Elisabeth Amadeo, Francesco Vitiello, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Massimo Alberto Iavarone, Giuseppe Cabibbo, Margarida Montes, Francesco Giuseppe Foschi, Caterina Vivaldi, Caterina Soldà, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Mariangela Bruccoleri, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Atsushi Hiraoka, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio..
Background
In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors.
Objective
This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting.
Patients and methods
The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea).
Results
Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13–0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24–0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43–0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38–0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65–0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52–0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64–0.98; p = 0.03) as independent prognostic factors for progression-free survival.
Conclusions
As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.
背景在接受全身治疗的肝细胞癌(HCC)患者中,不良事件(AEs)的出现与所报告的疗效结果之间的相关性是众所周知的,并且得到了广泛的研究。这项回顾性多中心真实世界研究旨在探讨阿特珠单抗联合贝伐单抗一线治疗 HCC 患者的 AEs 的潜在预后价值。结果73.3%的患者在研究期间至少出现过一次AE。最常见的不良反应是蛋白尿(29.6%)、动脉高血压(27.2%)和疲劳(26.0%)。总共有 17.3% 的 AE 为 3 级(G)。多变量分析证实出现了食欲下降 G < 2 [与 G ≥ 2 相比;危险比 (HR) 0.60; 95% 置信区间 (CI) 0.13-0.90; p < 0.01]和免疫毒性 G < 2 (与 G ≥ 2 相比;HR:0.70; 95% CI 0.24-0.99; p = 0.04)为总生存期的独立预后因素,出现食欲下降 G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01)、腹泻 (有与无; HR: 0.57, 95% CI 0.38-0.85; p = 0.01)、乏力(是与否;HR:0.82,95% CI 0.65-0.95;p <;0.01)、动脉高血压 G <;2(与 G ≥ 2;HR:0.68,95% CI 0.52-0.87;p <;0.01)和蛋白尿(是与否;HR:0.79,95% CI 0.64-0.98;p = 0.结论 正如其他疗法一样,阿特珠单抗联合贝伐珠单抗治疗HCC患者的AEs发生率与预后之间也存在相关性。
{"title":"Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab","authors":"Mara Persano, Margherita Rimini, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Federico Rossari, Changhoon Yoo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Gianluca Masi, Francesca Bergamo, Elisabeth Amadeo, Francesco Vitiello, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Massimo Alberto Iavarone, Giuseppe Cabibbo, Margarida Montes, Francesco Giuseppe Foschi, Caterina Vivaldi, Caterina Soldà, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Mariangela Bruccoleri, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Atsushi Hiraoka, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio..","doi":"10.1007/s11523-024-01061-0","DOIUrl":"https://doi.org/10.1007/s11523-024-01061-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting.</p><h3 data-test=\"abstract-sub-heading\">Patients and methods</h3><p>The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13–0.90; <i>p</i> < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24–0.99; <i>p</i> = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43–0.95; <i>p</i> = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38–0.85; <i>p</i> = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65–0.95; <i>p</i> < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52–0.87; <i>p</i> < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64–0.98; <i>p</i> = 0.03) as independent prognostic factors for progression-free survival.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-29DOI: 10.1007/s11523-024-01054-z
Michael Maris, Gilles Salles, Won Seog Kim, Tae Min Kim, Roger M. Lyons, Martha Arellano, Reem Karmali, Gary Schiller, Elizabeth Cull, Camille N. Abboud, Connie Batlevi, Ioannis Kagiampakis, Marlon C. Rebelatto, Young Lee, Lyndon C. Kirby, Fujun Wang, John Bothos, Danielle M. Townsley, Amir T. Fathi, Vincent Ribrag
Background
MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer.
Objective
This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies.
Patients and methods
Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity.
Results
As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%.
Conclusions
Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD.
The study was registered with ClinicalTrials.gov (NCT03106428).
{"title":"ASCT2-Targeting Antibody-Drug Conjugate MEDI7247 in Adult Patients with Relapsed/Refractory Hematological Malignancies: A First-in-Human, Phase 1 Study","authors":"Michael Maris, Gilles Salles, Won Seog Kim, Tae Min Kim, Roger M. Lyons, Martha Arellano, Reem Karmali, Gary Schiller, Elizabeth Cull, Camille N. Abboud, Connie Batlevi, Ioannis Kagiampakis, Marlon C. Rebelatto, Young Lee, Lyndon C. Kirby, Fujun Wang, John Bothos, Danielle M. Townsley, Amir T. Fathi, Vincent Ribrag","doi":"10.1007/s11523-024-01054-z","DOIUrl":"https://doi.org/10.1007/s11523-024-01054-z","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies.</p><h3 data-test=\"abstract-sub-heading\">Patients and methods</h3><p>Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>As of 26 March 2020, 67 patients were treated (AML: <i>n</i> = 27; MM: <i>n</i> = 18; DLBCL: <i>n</i> = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUC<sub>inf</sub> geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD.</p><p>The study was registered with ClinicalTrials.gov (NCT03106428).</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-21DOI: 10.1007/s11523-024-01057-w
Zucheng Xie, Yan Qin, Xinrui Chen, Sheng Yang, Jianliang Yang, Lin Gui, Peng Liu, Xiaohui He, Shengyu Zhou, Changgong Zhang, Le Tang, Yuankai Shi
Background
The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different MYD88 and CD79B mutation status merit further investigation.
Objective
This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt DLBCL patients.
Patients and Methods
Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology.
Results
In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable progression-free survival (PFS) and overall survival (OS) compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt. However, in the non-MCD subtype, patients with MYD88-CD79Bco-mut exhibited significantly inferior OS than MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while there was no significant OS difference between MYD88/CD79Bsingle-mut and MYD88-CD79Bco-wt (median OS: 68.8 [95% CI 22–NA] vs NA [95% CI 112–NA] vs 177.7 [95% CI 159–NA] months; MYD88-CD79Bco-mut vs MYD88/CD79Bsingle-mut: p = 0.02; MYD88-CD79Bco-mut vs MYD88-CD79Bco-wt: p = 0.03; MYD88/CD79Bsingle-mut vs MYD88-CD79Bco-wt: p = 0.33). Regarding patients with MYD88-CD79Bco-mut, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the MYD88-CD79Bco-mut group, patients with PIM1mut had better PFS than PIM1wt (median PFS: 8.34 [95% CI 5.56–NA] vs 43.8 [95% CI 26.4–NA] months; p = 0.02). Possible mechanisms contributing to the superior PFS of PIM1mut patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal t
背景不同MYD88和CD79B突变状态的弥漫大B细胞淋巴瘤(DLBCL)患者的临床和遗传特征以及治疗结果值得进一步研究。目的本研究旨在探讨MYD88-CD79Bco-突变、MYD88/CD79Bsingle-突变和MYD88-CD79Bco-wt DLBCL患者的临床表现、遗传特征和治疗结果的差异。患者和方法分析了中国医学科学院肿瘤医院、中国协和医科大学和六个外部队列中2696名接受R-CHOP/R-CHOP类方案治疗的MYD88-CD79Bco-mut、MYD88/CD79Bsingle-mut和MYD88-CD79Bco-wt DLBCL患者的临床和遗传特征以及治疗结果。结果在MCD亚型中,与MYD88/CD79Bsingle-mut或MYD88-CD79Bco-wt相比,MYD88-CD79Bco-mut患者的无进展生存期(PFS)和总生存期(OS)相当。然而,在非 MCD 亚型中,MYD88-CD79Bco-mut 患者的 OS 明显低于 MYD88/CD79Bsingle-mut 或 MYD88-CD79Bco-wt 患者,而 MYD88/CD79Bsingle-mut 和 MYD88-CD79Bco-wt 患者的 OS 没有显著差异(中位 OS:68.8 [95% CI] [95%CI]):68.8 [95% CI 22-NA] vs NA [95% CI 112-NA] vs 177.7 [95% CI 159-NA] 个月;MYD88-CD79Bco-mut vs MYD88/CD79Bsingle-mut:p = 0.02;MYD88-CD79Bco-mut vs MYD88-CD79Bco-wt:p = 0.03;MYD88/CD79Bsingle-mut vs MYD88-CD79Bco-wt:p = 0.33)。对于MYD88-CD79Bco-mut患者,MCD亚型和非MCD亚型患者的PFS和OS没有显著差异。在MYD88-CD79Bco-mut组中,PIM1mut患者的PFS优于PIM1wt患者(中位PFS:8.34 [95% CI 5.56-NA] vs 43.8 [95% CI 26.4-NA] 个月;P = 0.02)。导致 PIM1mut 患者 PFS 更优的可能机制包括活化的淋巴细胞介导的免疫和干扰素反应、更高比例的自然杀伤 T 细胞和类浆细胞树突状细胞,以及血管生成和上皮-间质转化受到抑制,成纤维细胞和基质评分降低。结论 在MCD亚型中,与MYD88/CD79Bsingle-mut或MYD88-CD79Bco-wt相比,MYD88-CD79Bco-mut患者的PFS和OS相当,而在非MCD亚型中,他们的OS明显较差。在MCD和非MCD亚型中,MYD88-CD79Bco-mut的PFS和OS没有明显差异。MYD88-CD79Bco-突变组中PIM1mut的存在与较好的PFS相关,这可能是免疫过程和肿瘤微环境改变错综复杂的相互作用的结果。
{"title":"Deciphering the Prognostic Significance of MYD88 and CD79B Mutations in Diffuse Large B-Cell Lymphoma: Insights into Treatment Outcomes","authors":"Zucheng Xie, Yan Qin, Xinrui Chen, Sheng Yang, Jianliang Yang, Lin Gui, Peng Liu, Xiaohui He, Shengyu Zhou, Changgong Zhang, Le Tang, Yuankai Shi","doi":"10.1007/s11523-024-01057-w","DOIUrl":"https://doi.org/10.1007/s11523-024-01057-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different <i>MYD88</i> and <i>CD79B</i> mutation status merit further investigation.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup>, <i>MYD88</i>/<i>CD79B</i><sup>single-mut</sup>, and <i>MYD88</i>-<i>CD79B</i><sup>co-wt</sup> DLBCL patients.</p><h3 data-test=\"abstract-sub-heading\">Patients and Methods</h3><p>Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup>, <i>MYD88</i>/<i>CD79B</i><sup>single-mut</sup>, and <i>MYD88</i>-<i>CD79B</i><sup>co-wt</sup> treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In the MCD subtype, patients with <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup> showed comparable progression-free survival (PFS) and overall survival (OS) compared to <i>MYD88</i>/<i>CD79B</i><sup>single-mut</sup> or <i>MYD88</i>-<i>CD79B</i><sup>co-wt</sup>. However, in the non-MCD subtype, patients with <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup> exhibited significantly inferior OS than <i>MYD88</i>/<i>CD79B</i><sup>single-mut</sup> or <i>MYD88</i>-<i>CD79B</i><sup>co-wt</sup>, while there was no significant OS difference between <i>MYD88</i>/<i>CD79B</i><sup>single-mut</sup> and <i>MYD88</i>-<i>CD79B</i><sup>co-wt</sup> (median OS: 68.8 [95% CI 22–NA] vs NA [95% CI 112–NA] vs 177.7 [95% CI 159–NA] months; <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup> vs <i>MYD88</i>/<i>CD79B</i><sup>single-mut</sup>: <i>p </i>= 0.02; <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup> vs <i>MYD88</i>-<i>CD79B</i><sup>co-wt</sup>: <i>p </i>= 0.03; <i>MYD88</i>/<i>CD79B</i><sup>single-mut</sup> vs <i>MYD88</i>-<i>CD79B</i><sup>co-wt</sup>: <i>p </i>= 0.33). Regarding patients with <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup>, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the <i>MYD88</i>-<i>CD79B</i><sup>co-mut</sup> group, patients with <i>PIM1</i><sup>mut</sup> had better PFS than <i>PIM1</i><sup>wt</sup> (median PFS: 8.34 [95% CI 5.56–NA] vs 43.8 [95% CI 26.4–NA] months; <i>p </i>= 0.02). Possible mechanisms contributing to the superior PFS of <i>PIM1</i><sup>mut</sup> patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal t","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140625367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-20DOI: 10.1007/s11523-024-01049-w
James R. Berenson, Andrea Limon, Stephanie Rice, Tahmineh Safaie, Ralph Boccia, Honghao Yang, Mehdi Moezi, Stephen Lim, Gary Schwartz, Shahrooz Eshaghian, Matthew Brobeck, Regina Swift, Benjamin M. Eades, Sean Bujarski, Yohana Sebhat, Rudra Ray, Susanna Kim, Ashley Del Dosso, Robert Vescio
Background
Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically.
Objective
This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP).
Methods
In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1–21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed.
Results
Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3–12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5–36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8–36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7–15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3–25.9 months).
{"title":"A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone","authors":"James R. Berenson, Andrea Limon, Stephanie Rice, Tahmineh Safaie, Ralph Boccia, Honghao Yang, Mehdi Moezi, Stephen Lim, Gary Schwartz, Shahrooz Eshaghian, Matthew Brobeck, Regina Swift, Benjamin M. Eades, Sean Bujarski, Yohana Sebhat, Rudra Ray, Susanna Kim, Ashley Del Dosso, Robert Vescio","doi":"10.1007/s11523-024-01049-w","DOIUrl":"https://doi.org/10.1007/s11523-024-01049-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1–21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3–12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5–36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8–36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7–15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3–25.9 months).</p><h3 data-test","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-13DOI: 10.1007/s11523-024-01052-1
Hiroyuki Yamamoto, Hiroyuki Arai, Ritsuko Oikawa, Kumiko Umemoto, Hiroyuki Takeda, Takuro Mizukami, Yohei Kubota, Ayako Doi, Yoshiki Horie, Takashi Ogura, Naoki Izawa, Jay A. Moore, Ethan S. Sokol, Yu Sunakawa
Background
Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known.
Objective
We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups.
Methods
This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/< 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low < 10 Muts/Mb), Epstein–Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate’s correction.
Results
Genes with frequent alterations included TP53 (60.1%), ARID1A (19.6%), CDKN2A (18.2%), KRAS (16.6%), and CDH1 (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; ATM (4.4%), BRAF V600E (0.4%), BRCA1 (1.5%), BRCA2 (2.9%), ERBB2 amplification (9.2%), IDH1 (0.2%), KRAS G12C (0.7%), microsatellite instability-high (4.8%), NTRK1/2/3 fusion (0.13%), PIK3CA mutation (11.4%), and tumor mutational burden-high (9.4%). CDH1 alterations and MET amplification were significantly more frequent in patients aged < 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%).
Conclusions
Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.
{"title":"The Molecular Landscape of Gastric Cancers for Novel Targeted Therapies from Real-World Genomic Profiling","authors":"Hiroyuki Yamamoto, Hiroyuki Arai, Ritsuko Oikawa, Kumiko Umemoto, Hiroyuki Takeda, Takuro Mizukami, Yohei Kubota, Ayako Doi, Yoshiki Horie, Takashi Ogura, Naoki Izawa, Jay A. Moore, Ethan S. Sokol, Yu Sunakawa","doi":"10.1007/s11523-024-01052-1","DOIUrl":"https://doi.org/10.1007/s11523-024-01052-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/< 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low < 10 Muts/Mb), Epstein–Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate’s correction.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Genes with frequent alterations included <i>TP53</i> (60.1%), <i>ARID1A</i> (19.6%), <i>CDKN2A</i> (18.2%), <i>KRAS</i> (16.6%), and <i>CDH1</i> (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; <i>ATM</i> (4.4%), <i>BRAF</i> V600E (0.4%), <i>BRCA1</i> (1.5%), <i>BRCA2</i> (2.9%), <i>ERBB2</i> amplification (9.2%), <i>IDH1</i> (0.2%), <i>KRAS</i> G12C (0.7%), microsatellite instability-high (4.8%), <i>NTRK1/2/3</i> fusion (0.13%), <i>PIK3CA</i> mutation (11.4%), and tumor mutational burden-high (9.4%). <i>CDH1</i> alterations and <i>MET</i> amplification were significantly more frequent in patients aged < 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-13DOI: 10.1007/s11523-024-01050-3
Michele Basso, Carlo Signorelli, Maria Alessandra Calegari, Jessica Lucchetti, Ina Valeria Zurlo, Emanuela Dell’Aquila, Giulia Arrivi, Federica Zoratto, Fiorenza Santamaria, Rosa Saltarelli, Giovanni Trovato, Giulia Caira, Lorenzo Angotti, Marta Schirripa, Annunziato Anghelone, Francesco Schietroma, Mario Giovanni Chilelli, Lisa Salvatore, Carmelo Pozzo, Giampaolo Tortora
Background
There are few molecular markers driving treatment selection in later lines of treatment for advanced colorectal cancer patients. The vast majority of patients who progress after first- and second-line therapy undergo chemotherapy regardless of molecular data.
Objective
We aimed to assess the prognostic and predictive effects of specific RAS mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both.
Patients and methods
This was a retrospective observational study based on data from a previous study of our research network, involving nine Italian institutions over a 10-year timeframe (2012–2022). Extended RAS analysis, involving KRAS exon 2–4 and NRAS exon 2–4, and BRAF were the main criteria for inclusion in this retrospective evaluation. Patients with BRAF mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and RAS mutational status (wild-type [WT], KRAS codon 12 mutations, KRAS codon 13 mutations, KRAS rare mutations and NRAS mutations, KRAS G12C mutation and KRAS G12D mutation).
Results
Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to RAS extended analysis, although a trend toward a better median survival in patients carrying G12D mutation (12.0 months), Codon 13 mutation (8.0 months), and Codon 12 mutation (7.0 months) has been observed, when compared with WT patients (6.0 months). Overall survival did not significantly differ in TFD/TPI-treated patients according to RAS extended analysis, although a trend toward a better median survival in WT patients had been observed (9.0 months) in comparison with the entire population (7.0 months). Patients receiving both drugs displayed a longer survival when compared with the population of patients receiving rego alone (p = 0.005) as well as the population receiving TFD/TPI alone (p < 0.001), suggesting a group enriched for favorable prognostic factors. However, when each group was analyzed separately, the addition of TFD/TPI therapy to the rego-treated group improved survival only in all-RAS WT patients (p = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (p = 0.0004), G12D group (p = 0.003), and the rare mutations group (p = 0.02), in addition to all-RAS WT patients (p = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the KRAS codon 12 group (p = 0.003).
{"title":"Efficacy of Regorafenib and Trifluridine/Tipiracil According to Extended RAS Evaluation in Advanced Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Analysis","authors":"Michele Basso, Carlo Signorelli, Maria Alessandra Calegari, Jessica Lucchetti, Ina Valeria Zurlo, Emanuela Dell’Aquila, Giulia Arrivi, Federica Zoratto, Fiorenza Santamaria, Rosa Saltarelli, Giovanni Trovato, Giulia Caira, Lorenzo Angotti, Marta Schirripa, Annunziato Anghelone, Francesco Schietroma, Mario Giovanni Chilelli, Lisa Salvatore, Carmelo Pozzo, Giampaolo Tortora","doi":"10.1007/s11523-024-01050-3","DOIUrl":"https://doi.org/10.1007/s11523-024-01050-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>There are few molecular markers driving treatment selection in later lines of treatment for advanced colorectal cancer patients. The vast majority of patients who progress after first- and second-line therapy undergo chemotherapy regardless of molecular data.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>We aimed to assess the prognostic and predictive effects of specific <i>RAS</i> mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both.</p><h3 data-test=\"abstract-sub-heading\">Patients and methods</h3><p>This was a retrospective observational study based on data from a previous study of our research network, involving nine Italian institutions over a 10-year timeframe (2012–2022). Extended <i>RAS</i> analysis, involving <i>KRAS</i> exon 2–4 and <i>NRAS</i> exon 2–4, and <i>BRAF</i> were the main criteria for inclusion in this retrospective evaluation. Patients with <i>BRAF</i> mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and <i>RAS</i> mutational status (wild-type [WT], <i>KRAS</i> codon 12 mutations, <i>KRAS</i> codon 13 mutations, <i>KRAS</i> rare mutations and <i>NRAS</i> mutations, <i>KRAS</i> G12C mutation and <i>KRAS</i> G12D mutation).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to <i>RAS</i> extended analysis, although a trend toward a better median survival in patients carrying G12D mutation (12.0 months), Codon 13 mutation (8.0 months), and Codon 12 mutation (7.0 months) has been observed, when compared with WT patients (6.0 months). Overall survival did not significantly differ in TFD/TPI-treated patients according to <i>RAS</i> extended analysis, although a trend toward a better median survival in WT patients had been observed (9.0 months) in comparison with the entire population (7.0 months). Patients receiving both drugs displayed a longer survival when compared with the population of patients receiving rego alone (<i>p</i> = 0.005) as well as the population receiving TFD/TPI alone (<i>p</i> < 0.001), suggesting a group enriched for favorable prognostic factors. However, when each group was analyzed separately, the addition of TFD/TPI therapy to the rego-treated group improved survival only in all-RAS WT patients (<i>p</i> = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (<i>p</i> = 0.0004), G12D group (<i>p</i> = 0.003), and the rare mutations group (<i>p</i> = 0.02), in addition to all-RAS WT patients (<i>p</i> = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the <i>KRAS</i> codon 12 group (<i>p</i> = 0.003).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear.
Objective
This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis.
Patients and Methods
We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020.
Results
Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17–39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3–7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12–9.68; p = 0.03).
Conclusions
Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.
背景虽然奥希替尼是一种治疗晚期表皮生长因子受体(EGFR)突变阳性肺癌的有效药物,但在接受该药物治疗的日本患者中,肺炎的发病率特别高。此外,包括表皮生长因子受体-酪氨酸激酶抑制剂(TKI)再挑战在内的后续抗癌治疗的安全性和有效性仍不清楚,这些治疗将在肺炎康复后进行。本研究调查了一线奥希替尼诱发肺炎患者再挑战表皮生长因子受体-TKI的安全性,主要关注复发性肺炎。患者和方法我们回顾性回顾了2018年8月至2020年9月期间日本34家机构中EGFR突变阳性肺癌患者的数据,这些患者在接受一线奥希替尼治疗后出现了初次肺炎。EGFR-TKI再挑战后12个月的肺炎复发率为27%(95%置信区间[CI] 17-39)。奥希替尼组的复发性肺炎累积发生率明显高于第一代和第二代EGFR-TKI(传统EGFR-TKI)组(危险比[HR]3.1;95% CI 1.3-7.5;P = 0.013)。多变量分析显示,无论初始肺炎的严重程度或状态如何,EGFR-TKI类型(奥西美替尼或传统EGFR-TKI)与肺炎复发之间存在显著关联(HR 3.29;95% CI 1.12-9.68;p = 0.03)。
{"title":"Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101)","authors":"Naoya Nishioka, Hisao Imai, Masahiro Endo, Akifumi Notsu, Kosei Doshita, Satoshi Igawa, Hiroshi Yokouchi, Takashi Ninomiya, Takaaki Tokito, Sayo Soda, Takasato Fujiwara, Tetsuhiko Asao, Shinji Nakamichi, Takahisa Kawamura, Minehiko Inomata, Kazuhisa Nakashima, Kentaro Ito, Yasuhiro Goto, Yukihiro Umeda, Soichi Hirai, Ryota Ushio, Keiki Yokoo, Takayuki Takeda, Tomoya Fukui, Masashi Ishihara, Takashi Osaki, Sousuke Kubo, Takumi Fujiwara, Chie Yamamoto, Takeshi Tsuda, Nobumasa Tamura, Shinobu Hosokawa, Yusuke Chihara, Satoshi Ikeda, Naoki Furuya, Yoshiro Nakahara, Satoru Miura, Hiroaki Okamoto","doi":"10.1007/s11523-024-01048-x","DOIUrl":"https://doi.org/10.1007/s11523-024-01048-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (<i>EGFR</i>) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis.</p><h3 data-test=\"abstract-sub-heading\">Patients and Methods</h3><p>We retrospectively reviewed the data of patients with <i>EGFR</i> mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17–39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3–7.5; <i>p</i> = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12–9.68;<i> p</i> = 0.03).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1007/s11523-024-01056-x
Abstract
Background
Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification.
Objective
To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC.
Patients and Methods
Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher’s exact tests.
Results
A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+.
Conclusions
We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.
{"title":"Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer","authors":"","doi":"10.1007/s11523-024-01056-x","DOIUrl":"https://doi.org/10.1007/s11523-024-01056-x","url":null,"abstract":"<h3>Abstract</h3> <span> <h3>Background</h3> <p>Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the <em>ERBB2</em> gene have been shown to play an oncogenic role similar to <em>ERBB2</em> amplification.</p> </span> <span> <h3>Objective</h3> <p>To describe and compare the frequency and nature of genomic alterations (GA) of <em>ERBB2</em>-altered (mutations, amplification) and <em>ERBB2</em> wild-type UBC.</p> </span> <span> <h3>Patients and Methods</h3> <p>Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by <em>ERBB2</em> alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher’s exact tests.</p> </span> <span> <h3>Results</h3> <p>A total of 602 (6.3%) UBC cases featured <em>ERBB2</em> extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured <em>ERBB2</em> kinase domain SV GA (KDmut+), 866 (9.1%) cases had <em>ERBB2</em> amplification (amp+), and 7797 (81.9%) cases were <em>ERBB2</em> wild-type (wt). European genetic ancestry of ECDmut+ was higher than <em>ERBB2</em>wt. Numerous significant associations were observed when comparing GA by group. Notably among these, <em>CDKN2A/MTAP</em> loss were more frequent in <em>ERBB2</em>wt versus ECDmut+ and amp+. <em>ERBB3</em> GA were more frequent in ECDmut+ and KDmut+ than <em>ERBB2</em>wt. <em>TERT</em> GA were more frequent in ECDmut+, KDmut+, and amp+ versus <em>ERBB2</em>wt. <em>TOP2A</em> amplification was significantly more common in ECDmut+ and amp+ versus <em>ERBB2</em>wt, and <em>TP53</em> SV GA were significantly higher in <em>ERBB2</em> amp+ versus <em>ERBB2</em>wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in <em>ERBB2</em>wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus <em>ERBB2</em>wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus <em>ERBB2</em>wt. MSI-high status was more frequent in KDmut+ versus <em>ERBB2</em>wt, and in <em>ERBB2</em>wt than in amp+.</p> </span> <span> <h3>Conclusions</h3> <p>We noted important differences in co-occurring GA in <em>ERBB2</em>-altered (ECDmut+, KDmut+, amp+) versus <em>ERBB2</em>wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the <em>ERBB2</em>-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for <em>ERBB2</em>-altered UBC.</p> </span>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-11DOI: 10.1007/s11523-024-01039-y
Dian Jin, Haoguang Chen, Jingsong He, Yi Li, Gaofeng Zheng, Yang Yang, Yi Zhao, Jing Le, Wenxiu Shu, Donghua He, Zhen Cai
Background
AML1/ETO fusion confers favorable prognosis in acute myeloid leukemia (AML) treated with intensive chemotherapy (IC). However, the impact of AML1/ETO fusion on the efficacy of venetoclax in the treatment of AML is unclear.
Objective
The aim of this study was to evaluate the efficacy of venetoclax plus hypomethylating agents (VEN/HMAs) in patients with AML1/ETO-positive AML.
Patients and Methods
Patients with newly diagnosed AML in two centers were reviewed and divided into three cohorts: AML1/ETO-positive AML treated with frontline VEN/HMA (Cohort A), AML1/ETO-negative AML treated with frontline VEN/HMA (Cohort B), or AML1/ETO-positive AML treated with frontline IC (Cohort C). The response and survival were compared between the cohorts.
Results
A total of 260 patients were included in the study. Patients in Cohort A had a significantly lower overall response rate (ORR) than patients in Cohort B (40.9% vs 71.2%, p = 0.005). The median event-free survival (EFS) in Cohort A and Cohort B was 2.7 months and 7.7 months, respectively, with no significant difference. The ORR and median EFS in Cohort C were 80.8% and 14.9 months, respectively, which were significantly superior to those in Cohort A, and the advantages remained significant after propensity score matching. ORR and EFS in KIT-mutated patients with AML1/ETO-positive AML receiving VEN/HMA were much inferior to those in KIT wild-type patients (ORR 0.0% vs 81.8%, p = 0.001; EFS 1.2 months vs not reached, p < 0.001).
Conclusions
Newly diagnosed AML patients with AML1/ETO fusion had a poor response to frontline VEN/HMA treatment. When determining induction therapy for patients with AML1/ETO-positive AML, IC should be preferred over VEN/HM.
背景AML1/ETO融合使接受强化化疗(IC)的急性髓性白血病(AML)患者预后良好。然而,AML1/ETO融合对venetoclax治疗急性髓细胞白血病疗效的影响尚不清楚。本研究旨在评估venetoclax加低甲基化药物(VEN/HMAs)在AML1/ETO阳性急性髓细胞白血病患者中的疗效:AML1/ETO阳性AML患者接受一线VEN/HMA治疗(队列A),AML1/ETO阴性AML患者接受一线VEN/HMA治疗(队列B),或AML1/ETO阳性AML患者接受一线IC治疗(队列C)。研究共纳入了 260 例患者。A组患者的总反应率(ORR)明显低于B组患者(40.9% vs 71.2%,P = 0.005)。A 组和 B 组患者的中位无事件生存期(EFS)分别为 2.7 个月和 7.7 个月,无明显差异。队列C的ORR和中位无事件生存期分别为80.8%和14.9个月,明显优于队列A,倾向得分匹配后优势依然显著。KIT突变的AML1/ETO阳性AML患者接受VEN/HMA治疗的ORR和EFS远逊于KIT野生型患者(ORR为0.0% vs 81.8%,p = 0.001;EFS为1.2个月 vs 未达到,p <0.001)。在决定对AML1/ETO阳性的急性髓细胞性白血病患者进行诱导治疗时,IC应优于VEN/HM。
{"title":"Impact of AML1/ETO Fusion on the Efficacy of Venetoclax Plus Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia","authors":"Dian Jin, Haoguang Chen, Jingsong He, Yi Li, Gaofeng Zheng, Yang Yang, Yi Zhao, Jing Le, Wenxiu Shu, Donghua He, Zhen Cai","doi":"10.1007/s11523-024-01039-y","DOIUrl":"https://doi.org/10.1007/s11523-024-01039-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p><i>AML1/ETO</i> fusion confers favorable prognosis in acute myeloid leukemia (AML) treated with intensive chemotherapy (IC). However, the impact of <i>AML1/ETO</i> fusion on the efficacy of venetoclax in the treatment of AML is unclear.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>The aim of this study was to evaluate the efficacy of venetoclax plus hypomethylating agents (VEN/HMAs) in patients with <i>AML1/ETO</i>-positive AML.</p><h3 data-test=\"abstract-sub-heading\">Patients and Methods</h3><p>Patients with newly diagnosed AML in two centers were reviewed and divided into three cohorts: <i>AML1/ETO</i>-positive AML treated with frontline VEN/HMA (Cohort A), <i>AML1/ETO</i>-negative AML treated with frontline VEN/HMA (Cohort B), or <i>AML1/ETO</i>-positive AML treated with frontline IC (Cohort C). The response and survival were compared between the cohorts.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 260 patients were included in the study. Patients in Cohort A had a significantly lower overall response rate (ORR) than patients in Cohort B (40.9% vs 71.2%, <i>p</i> = 0.005). The median event-free survival (EFS) in Cohort A and Cohort B was 2.7 months and 7.7 months, respectively, with no significant difference. The ORR and median EFS in Cohort C were 80.8% and 14.9 months, respectively, which were significantly superior to those in Cohort A, and the advantages remained significant after propensity score matching. ORR and EFS in <i>KIT</i>-mutated patients with <i>AML1/ETO</i>-positive AML receiving VEN/HMA were much inferior to those in <i>KIT</i> wild-type patients (ORR 0.0% vs 81.8%, <i>p</i> = 0.001; EFS 1.2 months vs not reached, <i>p</i> < 0.001).</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Newly diagnosed AML patients with <i>AML1/ETO</i> fusion had a poor response to frontline VEN/HMA treatment. When determining induction therapy for patients with <i>AML1/ETO</i>-positive AML, IC should be preferred over VEN/HM.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}