Phase II Trial of Imatinib Plus Binimetinib in Patients With Treatment-Naive Advanced Gastrointestinal Stromal Tumor

Abstract

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.

Conflict of interest statement

Ping ChiStock and Other Ownership Interests: ORIC Pharmaceuticals (I)Consulting or Advisory Role: Deciphera, Exelixis, Merck (I)Research Funding: Deciphera (Inst), Pfizer (Inst)Patents, Royalties, Other Intellectual Property: Royalties from ORIC (I) Li-Xuan QinThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: Viela Bio (I), Sironax (I)Leadership: Viela Bio (I), Sironax (I)Stock and Other Ownership Interests: Viela Bio (I), Sironax (I) Bastien NguyenEmployment: Loxo/Lilly Ciara M. KellyEmployment: Daichii Sankyo (I)Stock and Other Ownership Interests: Daichii Sankyo (I)Consulting or Advisory Role: Exicure, ImmunicumResearch Funding: AGIOS (Inst), Amgen (Inst), Merck (Inst), Incyte (Inst), Kartos Therapeutics (Inst), Exicure (Inst), Xencor (Inst) Sandra P. D'AngeloConsulting or Advisory Role: EMD Serono, Amgen, Nektar, Immune design, GlaxoSmithKline, Incyte, Merck, Adaptimmune, ImmunocoreResearch Funding: EMD Serono (Inst), Amgen (Inst), Merck (Inst), Incyte (Inst), Nektar (Inst), Bristol Myers Squibb (Inst), Deciphera (Inst)Travel, Accommodations, Expenses: Adaptimmune, EMD Serono, Nektar Mark A. DicksonConsulting or Advisory Role: CelgeneResearch Funding: Lilly (Inst), AADi (Inst) Mrinal M. GounderHonoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health, PERConsulting or Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, TYME, Ayala PharmaceuticalsSpeakers' Bureau: Amgen, Karyopharm Therapeutics, Boehringer IngelheimPatents, Royalties, Other Intellectual Property: UpToDate, GODDESS PRO Desmoid Tumor (Inst)Travel, Accommodations, Expenses: EpizymeOther Relationship: Desmoid Tumor Research FoundationUncompensated Relationships: Foundation Medicine, Rain Therapeutics, AthenexOpen Payments Link: https://openpaymentsdata.cms.gov/physician/459583 Sujana MovvaConsulting or Advisory Role: GenmabResearch Funding: Hutchison MediPharma (Inst) Benjamin A. NacevUncompensated Relationships: Delfi Diagnostics, Rapafusyn Pharmaceuticals, QuadW Foundation Katherine A. ThorntonConsulting or Advisory Role: More Health, Adaptimmune, Macrogenics, Deloitte, GlaxoSmithKline, EpizymeTravel, Accommodations, Expenses: Adaptimmune Aimee M. CragoStock and Other Ownership Interests: Gilead SciencesHonoraria: Wolters Kluwer, WebMDConsulting or Advisory Role: Springworks TherapeuticsPatents, Royalties, Other Intellectual Property: Patent assigned to MSKCC for a companion diagnostic to CDK4 inhibitors—Patent number 9,889,135 (Inst) Sam YoonStock and Other Ownership Interests: Attis Lab Gary UlanerConsulting or Advisory Role: GE Healthcare, ImaginAbSpeakers' Bureau: GE HealthcareResearch Funding: Sanofi, Genentech, Puma Biotechnology, GE Healthcare, Lantheus Medical ImagingExpert Testimony: GE Healthcare Michael F. BergerConsulting or Advisory Role: Lilly, PetDxResearch Funding: GrailPatents, Royalties, Other Intellectual Property: Provisional patent pending for Systems and Methods for Detecting Cancer via cfDNA Screening Yu ChenStock and Other Ownership Interests: ORIC PharmaceuticalsHonoraria: MerckPatents, Royalties, Other Intellectual Property: Invention related to glucocorticoid inhibitors for treatment of prostate cancer (SK2013-045), Invention related to glucocorticoid inhibitors for treatment of prostate cancer (SK2013-045) William D. TapLeadership: Certis Oncology Solutions, Atropos, Innova TherapeuticsStock and Other Ownership Interests: Certis Oncology Solutions, AtroposConsulting or Advisory Role: EMD Serono, Lilly, Daiichi Sankyo, Deciphera, C4 Therapeutics, Mundipharma, Adcendo, Ayala Pharmaceuticals, Kowa Pharmaceutical, Servier, Bayer, Epizyme, Cogent, Medpacto, Foghorn Therapeutics, AmgenResearch Funding: Novartis, Lilly, Plexxikon, Daiichi Sankyo, TRACON Pharma, Blueprint Medicines, Immune Design, BioAtla, DecipheraPatents, Royalties, Other Intellectual Property: Companion Diagnostic for CDK4 inhibitors—14/854,329, Enigma and CDH18 as companion Diagnostics for CDK4 inhibition SKI2016-021-03No other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT flow diagram of patients in the phase II study of imatinib in combination with binimetinib (September 15, 2014-November 15, 2020, data cutoff). EORTC, European Organisation for Research and Treatment of Cancer.

FIG 2.

Response rates (RECIST1.1, Choi, and EORTC) and duration of response. (A) Best objective responses by RECIST1.1 (n = 42), Choi responses (n = 41) around 8 weeks (end of cycle 2, first post-treatment scan), and EORTC responses (n = 35) by PET at 4 weeks (end of cycle 1) on combination imatinib and binimetinib treatment. The best RECIST1.1 responses are shown as % of change from baseline for patients who received the combination of imatinib and binimetinib and with at least one postbaseline scan. The known associated primary driver mutations in KIT, PDGFRA, and others are shown. The best ORR was 69.0% (29 of 42 confirmed PR), two-sided 95% CI: 52.9 to 82.4. (B) Duration of the response. AE, adverse events; CMR, complete metabolic response; EORTC, European Organisation for Research and Treatment of Cancer; mut, mutant; ORR, objective response rate; PD, progression of disease; PET, positron emission tomography; PMD, progressive metabolic disease; PMR, partial metabolic response; PR, partial response; SD, stable disease; SMD, stable metabolic response.

FIG 3.

Kaplan-Meier estimates of PFS and OS: (A) PFS by RECIST1.1 and (B) OS. Median PFS is based on a Kaplan-Meier estimate of PFS, per investigator assessment. The median PFS was 29.9 months (95% CI, 24.2 to NE). The median OS was not reached (95% CI, 50.4 to NE). NE, not estimable; OS, overall survival; PFS, progression-free survival.

FIG 4.

Pathologic responses. (A) Comparison of pathologic and RECIST1.1 response. (B) Representative images of KIT IHC (top left) and H&E (top right) of a patient with rectal GIST (KIT exon 11 pE554_K558del) pretreatment samples demonstrating 100% viable tumor tissue, and representative H&E images of post-treatment H&Es (bottom left: lower magnification image; bottom right: calcified scar) demonstrating 99% treatment effect. H&E, hematoxylin and eosin; IHC, immunohistochemistry.

FIG 5.

Genomic analysis of resistant disease. (A) Oncogenic driver mutations and concurrent genetic alterations in pretreatment patient samples (n = 35). *Indicates patients who consented to germline testing. (B) Comparison of frequency of common genetic alteration events in pretreatment samples of patients who have progressed on imatinib and binimetinib combination treatment (POD, n = 12) and of those without disease progression (nonPOD, n = 23). P = .047 for CDKN2A by Fisher's exact test. Comparison of (C) VAF of mutation and (D) CNA of paired pretreatment and post-treatment biopsy samples from patients with (POD, n = 12) and without (nonPOD, n = 4) disease progression. (E) Comparison of FGA and TMB changes of paired pretreatment and post-treatment tumor samples from POD and nonPOD patients. P values were calculated using Student's paired-samples t-test. RECIST response: on the basis of best RECIST1.1 response. CNA, copy-number alteration; FGA, fraction of genome altered; nonPD, nonprogression of disease; PD, progression of disease; PR, partial response; SD, stable disease; TMB, tumor mutational burden; Tx, treatment; VAF, variant allele frequency.

FIG A1.

Association of CDKN2A genetic alteration with PFS by the Kaplan-Meier estimates. Log-rank P = .14. mut, mutation; PFS, progression-free survival; WT, wild-type.

FIG A2.

Examples of changes in CNA comparing pretreatment and post-treatment samples. Each dot represents a probe set, and the values on the y-axis show the log2 transformed ratio of tumor versus normal. Red dots denote fold changes ≥ 2. (A) Patient 04 is a nonPOD patient; there was a deep deletion of CDKN2A in the pretreatment samples (tumor purity approximately 70%, sequence coverage 577×), which was lost in the post-treatment sample because of low tumor purity (approximately 10%) and low sequence coverage (95×) and high background noise. (B and C) CNA changes in POD patients demonstrating loss of RB1 deep deletion and emergence of (B) CDKN2A deep deletion in patient 07 resistant tumor samples, and (C) emergence of RB1 deep deletion in patient 25 resistant tumor samples (C). CNA, copy-number alteration; POD, progression of disease.

FIG A2.

Examples of changes in CNA comparing pretreatment and post-treatment samples. Each dot represents a probe set, and the values on the y-axis show the log2 transformed ratio of tumor versus normal. Red dots denote fold changes ≥ 2. (A) Patient 04 is a nonPOD patient; there was a deep deletion of CDKN2A in the pretreatment samples (tumor purity approximately 70%, sequence coverage 577×), which was lost in the post-treatment sample because of low tumor purity (approximately 10%) and low sequence coverage (95×) and high background noise. (B and C) CNA changes in POD patients demonstrating loss of RB1 deep deletion and emergence of (B) CDKN2A deep deletion in patient 07 resistant tumor samples, and (C) emergence of RB1 deep deletion in patient 25 resistant tumor samples (C). CNA, copy-number alteration; POD, progression of disease.