Targeted Oncology最新文献

{"title":"Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors.","authors":"Taizo Uchimoto, Shuya Tsuchida, Kazumasa Komura, Wataru Fukuokaya, Takahiro Adachi, Yosuke Hirasawa, Takeshi Hashimoto, Atsuhiko Yoshizawa, Masanobu Saruta, Mamoru Hashimoto, Takuya Higashio, Takuya Matsuda, Kazuki Nishimura, Takuya Tsujino, Ko Nakamura, Tatsuo Fukushima, Kyosuke Nishio, Shutaro Yamamoto, Kosuke Iwatani, Fumihiko Urabe, Keiichiro Mori, Takafumi Yanagisawa, Shunsuke Tsuduki, Kiyoshi Takahara, Teruo Inamoto, Jun Miki, Kazutoshi Fujita, Takahiro Kimura, Yoshio Ohno, Ryoichi Shiroki, Hirotsugu Uemura, Haruhito Azuma","doi":"10.1007/s11523-024-01047-y","DOIUrl":"10.1007/s11523-024-01047-y","url":null,"abstract":"<p><strong>Background: </strong>Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice.</p><p><strong>Objective: </strong>The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients.</p><p><strong>Patients and methods: </strong>A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms.</p><p><strong>Results: </strong>One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4 months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29 months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS (p = 0.124), PFS (p = 0.936), nor ORR (p = 0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5 months, p = 0.049). For OS, the difference was not statistically significant (27 and 11 months in EV and re-challenging chemotherapy, respectively: p = 0.05).</p><p><strong>Conclusions: </strong>A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy.</p>","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":"401-410"},"PeriodicalIF":4.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319217","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}

{"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":"11 1","pages":""},"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}

{"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 &lt; 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13–0.90; <i>p</i> &lt; 0.01] and immunotoxicity G &lt; 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 &lt; 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> &lt; 0.01), arterial hypertension G &lt; 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52–0.87; <i>p</i> &lt; 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":"41 1","pages":""},"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}

{"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_inf 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":"18 1","pages":""},"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}

{"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":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Background&lt;/h3&gt;&lt;p&gt;The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different &lt;i&gt;MYD88&lt;/i&gt; and &lt;i&gt;CD79B&lt;/i&gt; mutation status merit further investigation.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Objective&lt;/h3&gt;&lt;p&gt;This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt;, &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt;, and &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt; DLBCL patients.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Patients and Methods&lt;/h3&gt;&lt;p&gt;Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt;, &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt;, and &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt; treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences &amp; Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;In the MCD subtype, patients with &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; showed comparable progression-free survival (PFS) and overall survival (OS) compared to &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; or &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;. However, in the non-MCD subtype, patients with &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; exhibited significantly inferior OS than &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; or &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;, while there was no significant OS difference between &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; and &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt; (median OS: 68.8 [95% CI 22–NA] vs NA [95% CI 112–NA] vs 177.7 [95% CI 159–NA] months; &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; vs &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt;: &lt;i&gt;p &lt;/i&gt;= 0.02; &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; vs &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;: &lt;i&gt;p &lt;/i&gt;= 0.03; &lt;i&gt;MYD88&lt;/i&gt;/&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;single-mut&lt;/sup&gt; vs &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-wt&lt;/sup&gt;: &lt;i&gt;p &lt;/i&gt;= 0.33). Regarding patients with &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt;, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the &lt;i&gt;MYD88&lt;/i&gt;-&lt;i&gt;CD79B&lt;/i&gt;&lt;sup&gt;co-mut&lt;/sup&gt; group, patients with &lt;i&gt;PIM1&lt;/i&gt;&lt;sup&gt;mut&lt;/sup&gt; had better PFS than &lt;i&gt;PIM1&lt;/i&gt;&lt;sup&gt;wt&lt;/sup&gt; (median PFS: 8.34 [95% CI 5.56–NA] vs 43.8 [95% CI 26.4–NA] months; &lt;i&gt;p &lt;/i&gt;= 0.02). Possible mechanisms contributing to the superior PFS of &lt;i&gt;PIM1&lt;/i&gt;&lt;sup&gt;mut&lt;/sup&gt; 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":"71 1","pages":""},"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}

{"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":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Background&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Objective&lt;/h3&gt;&lt;p&gt;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).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;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).&lt;/p&gt;&lt;h3 data-test","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"3 1","pages":""},"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}

{"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/&lt; 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low &lt; 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 &lt; 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":"15 1","pages":""},"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}

{"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":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Background&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Objective&lt;/h3&gt;&lt;p&gt;We aimed to assess the prognostic and predictive effects of specific &lt;i&gt;RAS&lt;/i&gt; mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Patients and methods&lt;/h3&gt;&lt;p&gt;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 &lt;i&gt;RAS&lt;/i&gt; analysis, involving &lt;i&gt;KRAS&lt;/i&gt; exon 2–4 and &lt;i&gt;NRAS&lt;/i&gt; exon 2–4, and &lt;i&gt;BRAF&lt;/i&gt; were the main criteria for inclusion in this retrospective evaluation. Patients with &lt;i&gt;BRAF&lt;/i&gt; mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and &lt;i&gt;RAS&lt;/i&gt; mutational status (wild-type [WT], &lt;i&gt;KRAS&lt;/i&gt; codon 12 mutations, &lt;i&gt;KRAS&lt;/i&gt; codon 13 mutations, &lt;i&gt;KRAS&lt;/i&gt; rare mutations and &lt;i&gt;NRAS&lt;/i&gt; mutations, &lt;i&gt;KRAS&lt;/i&gt; G12C mutation and &lt;i&gt;KRAS&lt;/i&gt; G12D mutation).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to &lt;i&gt;RAS&lt;/i&gt; 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 &lt;i&gt;RAS&lt;/i&gt; 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 (&lt;i&gt;p&lt;/i&gt; = 0.005) as well as the population receiving TFD/TPI alone (&lt;i&gt;p&lt;/i&gt; &lt; 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 (&lt;i&gt;p&lt;/i&gt; = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (&lt;i&gt;p&lt;/i&gt; = 0.0004), G12D group (&lt;i&gt;p&lt;/i&gt; = 0.003), and the rare mutations group (&lt;i&gt;p&lt;/i&gt; = 0.02), in addition to all-RAS WT patients (&lt;i&gt;p&lt;/i&gt; = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the &lt;i&gt;KRAS&lt;/i&gt; codon 12 group (&lt;i&gt;p&lt;/i&gt; = 0.003).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions&lt;/h3&gt;&lt;p&gt;","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":"54 1","pages":""},"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}

{"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":"72 1","pages":""},"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}

{"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":"14 1","pages":""},"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}