Daniel H Ahn, Maya Ridinger, Timothy L Cannon, Lawrence Mendelsohn, Jason S Starr, Joleen M Hubbard, Anup Kasi, Afsaneh Barzi, Errin Samuëlsz, Anju Karki, Ramanand A Subramanian, Divora Yemane, Roy Kim, Chu-Chiao Wu, Peter J P Croucher, Tod Smeal, Fairooz F Kabbinavar, Heinz-Josef Lenz
{"title":"Onvansertib 联合化疗和贝伐单抗二线治疗 KRAS 突变转移性结直肠癌：单臂 II 期试验。","authors":"Daniel H Ahn, Maya Ridinger, Timothy L Cannon, Lawrence Mendelsohn, Jason S Starr, Joleen M Hubbard, Anup Kasi, Afsaneh Barzi, Errin Samuëlsz, Anju Karki, Ramanand A Subramanian, Divora Yemane, Roy Kim, Chu-Chiao Wu, Peter J P Croucher, Tod Smeal, Fairooz F Kabbinavar, Heinz-Josef Lenz","doi":"10.1200/JCO-24-01266","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of <i>KRAS</i>-mutant metastatic colorectal cancer (mCRC).</p><p><strong>Patients and methods: </strong>This multicenter, open-label, single-arm study enrolled patients with <i>KRAS</i>-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m<sup>2</sup> once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in <i>KRAS</i>-mutant CRC.</p><p><strong>Results: </strong>Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, <i>P</i> < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, <i>P</i> < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.</p><p><strong>Conclusion: </strong>Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with <i>KRAS</i>-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2401266"},"PeriodicalIF":42.1000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of <i>KRAS</i>-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.\",\"authors\":\"Daniel H Ahn, Maya Ridinger, Timothy L Cannon, Lawrence Mendelsohn, Jason S Starr, Joleen M Hubbard, Anup Kasi, Afsaneh Barzi, Errin Samuëlsz, Anju Karki, Ramanand A Subramanian, Divora Yemane, Roy Kim, Chu-Chiao Wu, Peter J P Croucher, Tod Smeal, Fairooz F Kabbinavar, Heinz-Josef Lenz\",\"doi\":\"10.1200/JCO-24-01266\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of <i>KRAS</i>-mutant metastatic colorectal cancer (mCRC).</p><p><strong>Patients and methods: </strong>This multicenter, open-label, single-arm study enrolled patients with <i>KRAS</i>-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m<sup>2</sup> once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in <i>KRAS</i>-mutant CRC.</p><p><strong>Results: </strong>Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, <i>P</i> < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, <i>P</i> < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.</p><p><strong>Conclusion: </strong>Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with <i>KRAS</i>-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).</p>\",\"PeriodicalId\":15384,\"journal\":{\"name\":\"Journal of Clinical Oncology\",\"volume\":\" \",\"pages\":\"JCO2401266\"},\"PeriodicalIF\":42.1000,\"publicationDate\":\"2024-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/JCO-24-01266\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/JCO-24-01266","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.
Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC).
Patients and methods: This multicenter, open-label, single-arm study enrolled patients with KRAS-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m2 once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC.
Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.
Conclusion: Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).
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The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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