Gastrointestinal stromal tumor Like RCC, GIST does not generally respond to standard chemotherapy or radiation. Imatinib was the first cancer agent proven effective for metastatic GIST and represented a major development in the treatment of this rare but challenging disease. However, approximately 20% of patients do not respond to imatinib (early or primary resistance), and among those who do respond initially, 50% develop secondary imatinib resistance and disease progression within two years. Prior to<unk> , patients had no therapeutic option once they became resistant to imatinib.<unk>  offers patients with imatinib-resistant GIST a new treatment option to stop further disease progression and, in some cases, even reverse it. This was shown in a large, Phase III clinical trial in which patients who failed imatinib therapy (due to primary resistance, secondary resistance, or intolerance) were treated in a randomized and blinded fashion with either<unk>  or placebo. The study was unblinded early, at the very first interim analysis, due to the clearly emerging benefit of<unk> . At that time, patients receiving placebo were offered to switch over to<unk> . In the primary endpoint of this study, median time to tumor progression (TTP) was more than four-fold longer with<unk>  (27 weeks) compared with placebo (six weeks, P<.0001). These are based on the assessments of an independent radiology lab assessment. The benefit of<unk>  remained statistically significant when stratified for a multitude of prespecified baseline factors. Among the secondary endpoints, the difference in progression-free<unk> rvival (PFS) was similar to that in TTP (24 weeks vs six weeks, P<.0001). Seven percent of<unk>  patients had significant tumor shrinkage (objective response) compared with 0% of placebo patients (P=.006). Another 58% of<unk>  patients had disease stabilization vs. 48% of patients receiving placebo. The median time to response with<unk>  was 10.4 weeks.<unk>  reduced the relative risk of disease progression or death by 67%, and the risk of death alone by 51%. The difference in<unk> rvival benefit may be diluted because placebo patients crossed over to<unk>  upon disease progression, and most of these patients<unk> bsequently responded to<unk> .<unk>  was relatively well tolerated. About 83% of<unk>  patients experienced a treatment-related adverse event of any severity, as did 59% of patients who received placebo. Serious adverse events were reported in 20% of<unk>  patients and 5% of placebo patients. Adverse events were generally moderate and easily managed by dose reduction, dose interruption, or other treatment. Nine percent of<unk>  patients and 8% of placebo patients discontinued therapy due to an adverse event. Fatigue is the adverse event most commonly associated with<unk>  therapy. In this study, 34% of<unk>  patients reported any grade of fatigue, compared with 22% for placebo. The incidence of grade 3 (severe) fatigue was similar between the two groups, and no grade 4 fatigue was reported. Meningioma<unk>  is being studied for treatment of meningioma which is associated with neurofibromatosis. Pancreatic neuroendocrine tumors In November 2010,<unk> tent gained approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'. In May 2011, the USFDA approved<unk>  for treating patients with 'progressive neuroendocrine cancerous tumors located in the pancreas that cannot be removed by<unk> rgery or that have spread to other parts of the body (metastatic)'. Renal cell carcinoma<unk>  is approved for treatment of metastatic RCC. Other therapeutic options in this setting are pazopanib (Votrient), sorafenib (Nexavar), temsirolimus (Torisel), interleukin-2 (Proleukin), everolimus (Afinitor), bevacizumab (Avastin), and aldesleukin. RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNα) or interleukin-2. However, these agents demonstrated low rates of efficacy (5%-20%). In a phase III study, median progression-free<unk> rvival was significantly longer in the<unk>  group (11 months) than in the IFNα group (five months), a hazard ratio of 0.42. In the secondary endpoints, 28% had significant tumor shrinkage with<unk>  compared to 5% with IFNα. Patients receiving<unk>  had a better quality of life than IFNα. An update in 2008 showed that the primary endpoint of median progression-free<unk> rvival (PFS) remained<unk> perior with<unk> : 11 months versus 5 months for IFNα, P<.000001. Objective response rate also remained<unk> perior: 39-47% for<unk>  versus 8-12% with IFNα, P<.000001.<unk>  treatment trended towards a slightly longer overall<unk> rvival, although this was not statistically significant. * Median overall<unk> rvivability was 26 months with<unk>  vs 22 months for IFNα regardless of stratification (P-value ranges from .051 to .0132, depending on statistical analysis). * The first analysis includes 25 patients initially randomized to IFNα who crossed over to<unk>  therapy, which may have confounded the results; in an exploratory analysis that excluded these patients, the difference becomes more robust: 26 vs 20 months, P=.0081. * Patients in the study were allowed to receive other therapies once they had progressed on their study treatment. For a "pure" analysis of the difference between the two agents, an analysis was done using only patients who did not receive any post-study treatment. This analysis demonstrated the greatest advantage for<unk> : 28 months vs 14 months for IFNα, P=.0033. The number of patients in this analysis was small and this does not reflect actual clinical practice and is therefore not meaningful. Hypertension (HTN) was found to be a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with<unk> . Patients with mRCC and<unk> -induced hypertension had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval CI = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all).
Sunitinib
Ceritinib
Axitinib
Gilteritinib
Abrocitinib
Erdafitinib
Oclacitinib
Upadacitinib