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The New England Journal of Medicine Mar 2021The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.
METHODS
In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.
RESULTS
Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.
CONCLUSIONS
Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Renal Cell; Female; Humans; Intention to Treat Analysis; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Progression-Free Survival; Proportional Hazards Models; Pyridines; Quality of Life; Receptor Protein-Tyrosine Kinases; Sunitinib; Survival Analysis
PubMed: 33657295
DOI: 10.1056/NEJMoa2026982 -
The Lancet. Oncology Jul 2022In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib... (Randomized Controlled Trial)
Randomized Controlled Trial
Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial.
BACKGROUND
In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18·1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety.
METHODS
This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177.
FINDINGS
Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4-35·9]), median overall survival was 37·7 months (95% CI 35·5-not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0-not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55-0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8-19·8) versus 8·3 months (7·0-9·7; HR 0·56 [95% CI 0·46-0·68], p<0·0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death).
INTERPRETATION
With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma.
FUNDING
Bristol Myers Squibb and Ono Pharmaceutical.
Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Renal Cell; Follow-Up Studies; Humans; Kidney Neoplasms; Nivolumab; Pyridines; Sunitinib
PubMed: 35688173
DOI: 10.1016/S1470-2045(22)00290-X -
Journal of Hematology & Oncology Jan 2021Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The majority of GISTs harbor gain of function mutations in... (Review)
Review
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The majority of GISTs harbor gain of function mutations in either KIT or PDGFRα. Determination of the GIST molecular subtype upon diagnosis is important because this information informs therapeutic decisions in both the adjuvant and metastatic setting. The management of GIST was revolutionized by the introduction of imatinib, a KIT inhibitor, which has become the standard first line treatment for metastatic GIST. However, despite a clinical benefit rate of 80%, the majority of patients with GIST experience disease progression after 2-3 years of imatinib therapy. Second and third line options include sunitinib and regorafenib, respectively, and yield low response rates and limited clinical benefit. There have been recent FDA approvals for GIST including ripretinib in the fourth-line setting and avapritinib for PDGFRA exon 18-mutant GIST. This article aims to review the optimal treatment approach for the management of patients with advanced GIST. It examines the standard treatment options available but also explores the novel treatment approaches in the setting of imatinib refractory GIST.
Topics: Animals; Antineoplastic Agents; Disease Management; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Neoplasm Metastasis; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Sunitinib
PubMed: 33402214
DOI: 10.1186/s13045-020-01026-6 -
Cancer Jun 2022Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years.
METHODS
Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed.
RESULTS
The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age.
CONCLUSIONS
Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Ipilimumab; Kidney Neoplasms; Male; Nivolumab; Sunitinib
PubMed: 35383908
DOI: 10.1002/cncr.34180 -
The Journal of Clinical Endocrinology... Nov 2022Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but... (Review)
Review
Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but remain difficult to treat. This mini-review provides an overview of established molecular targeted therapies in present use, and perspectives on those currently under development and evaluation in clinical trials. Recently published research articles, guidelines, and expert views on molecular targeted therapies in PPGLs are systematically reviewed and summarized. Some tyrosine kinase inhibitors (sunitinib, cabozantinib) are already in clinical use with some promising results, but without formal approval for the treatment of PPGLs. Sunitinib is the only therapeutic option which has been investigated in a randomized placebo-controlled clinical trial. It is clinically used as a first-, second-, or third-line therapeutic option for the treatment of progressive metastatic PPGLs. Some other promising molecular targeted therapies (hypoxia-inducible factor 2 alpha [HIF2α] inhibitors, tumor vaccination together with checkpoint inhibitors, antiangiogenic therapies, kinase signaling inhibitors) are under evaluation in clinical trials. The HIF2α inhibitor belzutifan may prove to be particularly interesting for cluster 1B-/VHL/EPAS1-related PPGLs, whereas antiangiogenic therapies seem to be primarily effective in cluster 1A-/SDHx-related PPGLs. Some combination therapies currently being evaluated in clinical trials, such as temozolomide/olaparib, temozolomide/talazoparib, or cabozantinib/atezolizumab, will provide data for novel therapy for metastatic PPGLs. It is likely that advances in such molecular targeted therapies will play an essential role in the future treatment of these tumors, with more personalized therapy options paving the way towards improved therapeutic outcomes.
Topics: Humans; Pheochromocytoma; Sunitinib; Temozolomide; Paraganglioma; Adrenal Gland Neoplasms; Randomized Controlled Trials as Topic
PubMed: 35973976
DOI: 10.1210/clinem/dgac471 -
ESMO Open Nov 2020To report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC).
METHODS
Patients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomised to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favourable-risk disease (FAV; exploratory).
RESULTS
Overall, 1096 patients were randomised (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favourable with NIVO+IPI vs SUN.
CONCLUSION
After long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety.
TRIAL REGISTRATION DETAILS
ClinicalTrials.gov identifier: NCT02231749.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Follow-Up Studies; Humans; Ipilimumab; Kidney Neoplasms; Nivolumab; Sunitinib
PubMed: 33246931
DOI: 10.1136/esmoopen-2020-001079 -
Drug Resistance Updates : Reviews and... Mar 2023Currently, renal cell carcinoma (RCC) is the most prevalent type of kidney cancer. Targeted therapy has replaced radiation therapy and chemotherapy as the main treatment... (Review)
Review
Currently, renal cell carcinoma (RCC) is the most prevalent type of kidney cancer. Targeted therapy has replaced radiation therapy and chemotherapy as the main treatment option for RCC due to the lack of significant efficacy with these conventional therapeutic regimens. Sunitinib, a drug used to treat gastrointestinal tumors and renal cell carcinoma, inhibits the tyrosine kinase activity of a number of receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, rearranged during transfection (RET) and fms-related receptor tyrosine kinase 3 (Flt3). Although sunitinib has been shown to be efficacious in the treatment of patients with advanced RCC, a significant number of patients have primary resistance to sunitinib or acquired drug resistance within the 6-15 months of therapy. Thus, in order to develop more efficacious and long-lasting treatment strategies for patients with advanced RCC, it will be crucial to ascertain how to overcome sunitinib resistance that is produced by various drug resistance mechanisms. In this review, we discuss: 1) molecular mechanisms of sunitinib resistance; 2) strategies to overcome sunitinib resistance and 3) potential predictive biomarkers of sunitinib resistance.
Topics: Humans; Biomarkers; Carcinoma, Renal Cell; Indoles; Kidney Neoplasms; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sunitinib; Vascular Endothelial Growth Factor A; Drug Resistance, Neoplasm
PubMed: 36739809
DOI: 10.1016/j.drup.2023.100929 -
Lancet (London, England) Feb 2021MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic... (Randomized Controlled Trial)
Randomized Controlled Trial
A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.
BACKGROUND
MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.
METHODS
We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.
FINDINGS
Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.
INTERPRETATION
Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.
FUNDING
National Institutes of Health and National Cancer Institute.
Topics: Aged; Anilides; Canada; Carcinoma, Renal Cell; Crizotinib; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazines; Pyridines; Sunitinib; Triazines; United States
PubMed: 33592176
DOI: 10.1016/S0140-6736(21)00152-5 -
Cancer Cell Dec 2020Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical...
Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Prognosis; Randomized Controlled Trials as Topic; Sequence Analysis, RNA; Sunitinib; Treatment Outcome; Unsupervised Machine Learning
PubMed: 33157048
DOI: 10.1016/j.ccell.2020.10.011 -
Journal of Clinical Oncology : Official... Dec 2022Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501).
PATIENTS AND METHODS
Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by / mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures.
RESULTS
Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib ( exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the exon 11 ITT population (23.9% 14.6%, nominal = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% 65.6%, nominal < .0001), and better scores on patient-reported outcome measures of tolerability.
CONCLUSION
Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.
Topics: Humans; Gastrointestinal Stromal Tumors; Imatinib Mesylate; Sunitinib; Pyrroles; Indoles; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Mutation; Antineoplastic Agents; Proto-Oncogene Proteins c-kit
PubMed: 35947817
DOI: 10.1200/JCO.22.00294