TY - JOUR
T1 - Phase II Trial of Imatinib Plus Binimetinib in Patients With Treatment-Naive Advanced Gastrointestinal Stromal Tumor
AU - Chi, Ping
AU - Qin, Li Xuan
AU - Nguyen, Bastien
AU - Kelly, Ciara M.
AU - D'Angelo, Sandra P.
AU - Dickson, Mark A.
AU - Gounder, Mrinal M.
AU - Keohan, Mary L.
AU - Movva, Sujana
AU - Nacev, Benjamin A.
AU - Rosenbaum, Evan
AU - Thornton, Katherine A.
AU - Crago, Aimee M.
AU - Yoon, Sam
AU - Ulaner, Gary
AU - Yeh, Randy
AU - Martindale, Moriah
AU - Phelan, Haley T.
AU - Biniakewitz, Matthew D.
AU - Warda, Sarah
AU - Lee, Cindy J.
AU - Berger, Michael F.
AU - Schultz, Nikolaus D.
AU - Singer, Samuel
AU - Hwang, Sinchun
AU - Chen, Yu
AU - Antonescu, Cristina R.
AU - Tap, William D.
N1 - Publisher Copyright:
© 2022 American Society of Clinical Oncology. All rights reserved.
PY - 2022/3/20
Y1 - 2022/3/20
N2 - PURPOSE Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST. METHODS In this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in . 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity. RESULTS Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response ($90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%). CONCLUSION The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.
AB - PURPOSE Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST. METHODS In this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in . 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity. RESULTS Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response ($90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%). CONCLUSION The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.
UR - https://www.scopus.com/pages/publications/85125199130
U2 - 10.1200/JCO.21.02029
DO - 10.1200/JCO.21.02029
M3 - Article
C2 - 35041493
AN - SCOPUS:85125199130
SN - 0732-183X
VL - 40
SP - 997
EP - 1008
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 9
ER -