Factor Receptor-tyrosine Kinase Inhibitor Therapy Research Articles

Epidermal growth factor receptor mutations and their correlation with epidermal growth factor receptor-tyrosine kinase inhibitor therapy and association with the characteristics of patients with non-small-cell lung cancer: A meta-analysis.

Many studies have demonstrated that epidermal growth factor receptor (EGFR) mutation is associated with the response to therapy with single agent EGFR-tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients, but the extent of the effect is varied. We carried out a meta-analysis to assess the association between EGFR mutation and the efficacy of EGFR-TKI therapy and the independent predictor of EGFR mutation in order to identify who would be likely to benefit from this kind of therapy. All literature relating to EGFR mutation and EGFR-TKI therapy was researched and carefully selected. Related variables were abstracted and the pooled odds ratio calculated after a heterogeneity test with the software, State 10. Publication bias was evaluated at the same time. Seventeen studies were included according to the selection criteria. We found a statistically significant higher probability of response in patients with an EGFR mutation versus wild-type (19.33, 95% CI, 13.61-27.46, P < 0.0001). Furthermore, the pooled odds ration of susceptibility to EGFR mutation among female patients compared with male patients was 3.01 (95% confidence interval (CI), 2.34-3.88 P < 0.0001), adenocarcinoma patients compared with non-adenocarcinoma patients was 5.40 (95% CI, 2.55-11.40 P < 0.0001), and non-smoker patients compared smoker patients was 19.33 (95% CI:,13.61-27.46 P < 0.0001). The publication bias analysis had no statistically significant results. Female, adenocarcinoma and non-smoker are independent predictors for the EGFR mutation. Efficacy of EGFR-TKI therapy favors patients with an EGFR mutation. Without the gene mutational analysis, patients selected for EGFR-TKI therapy should be female non-smokers with adenocarcinoma.

An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy

Background and objectivesThe RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. Patients and methodsREACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. ResultsA total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. ConclusionEverolimus is well tolerated in patients with mRCC and demonstrates a favourable risk–benefit ratio.

Third-line or fourth-line chemotherapy in non-small-cell lung cancer patients with relatively good performance status

Background Our aim here was to explore treatment efficacy of pemetrexed and docetaxel in non-small-cell lung cancer patients who had failed previous chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Methods We retrospectively reviewed clinical data of our non-small-cell lung cancer patients who received third- or fourth-line chemotherapy with pemetrexed or docetaxel in our institution from January 2006 to December 2009. Results One hundred and twenty-three patients received treatment, including 85 patients with pemetrexed treatment and 38 patients with docetaxel treatment. There was no difference in tumor response rate and toxicity profiles when using pemetrexed as third- or fourth-line treatment, neither was there difference in docetaxel treatment of third- versus fourth-line treatment. There was also no difference between docetaxel and pemetrexed in response rate and control rate when they were used as fourth-line treatment. However, docetaxel used in fourth-line treatment had higher incidence of neutropenia and more frequent need of granulocyte colony-stimulating factor support compared with pemetrexed in fourth-line treatment. Median progression-free survivals (PFSs) were 2.6 months and 3.8 months when using pemetrexed as third- and fourth-line treatment, respectively ( p = 0.417). Median PFSs were 3.8 months and 4.8 months when using docetaxel as third- and fourth-line treatment, respectively ( p = 0.882). There was also no difference in PFS between pemetrexed and docetaxel, both in third- and fourth-line treatment. Median survivals were 13.4, 12.2, 13.2, and 13 months for pemetrexed in third-line, fourth-line, and docetaxel in third-line and fourth-line treatment, respectively. Conclusion This retrospective study of pemetrexed and docetaxel showed relatively safe toxicity profile, reasonable response rate, and long survival when used as third- and fourth-line chemotherapy. Thus, it is reasonable to give good performance status patients third- and fourth-line chemotherapy. A phase III randomized trial is needed for better clarification of these issues.

Phase III, randomized, placebo-controlled study of everolimus in patients with metastatic renal cell carcinoma (mRCC): Subgroup analysis of patients intolerant of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy.

312 Background: In the RECORD-1 phase III study, the mammalian target of rapamycin (mTOR) inhibitor everolimus (ClinicalTrials.gov: NCT00410124 ) prolonged progression-free survival (PFS) versus placebo (median PFS 4.9 vs 1.9 months) in patients with mRCC whose disease progressed during or within 6 months of VEGFr-TKI (sunitinib and/or sorafenib) therapy. In this retrospective analysis, we evaluated the effect of everolimus on PFS in the subgroup of patients who discontinued prior VEGFr-TKI therapy because of adverse events. Methods: In the randomized, double-blind RECORD-1 trial, patients with mRCC who had prior VEGFr-TKI therapy were randomized (2:1) to receive everolimus 10 mg/day (n = 277) or placebo (n = 139) plus best supportive care. Results: Patients who were intolerant of prior VEGFr-TKI therapy included 50 patients (sunitinib = 26; sorafenib = 24) in the everolimus group and 13 patients (sunitinib = 5; sorafenib = 8) in the placebo group. The median PFS in the sunitinib group was 5.13 mo (95% confidence interval [CI]: 3.71, not available [NA]) in patients receiving everolimus vs 2.81 mo (95% CI: 1.87, 3.71) in those receiving placebo (HR: 0.28; 95% CI: 0.07, 1.18; p = 0.033). In the sorafenib subgroup, median PFS was 5.59 mo (95% CI: 3.78, NA) versus 1.91 mo (95% CI: 1.68, 3.48), respectively (HR: 0.29; 95% CI: 0.09, 0.91; p = 0.012). Conclusions: Everolimus prolonged PFS in a subgroup of patients with mRCC who were intolerant of prior VEGFr-TKI therapy. These results suggest that mTOR inhibition with everolimus was active in patients with mRCC who were intolerant of a previous VEGFr-TKI. [Table: see text]

Open-label phase II trial of everolimus monotherapy in patients with recurrent metastatic and/or unresectable renal cell carcinoma (RCC).

TPS233 Background: Until recently, patients with metastatic renal cell carcinoma (mRCC) had few treatment options given the low response rate associated with chemotherapy and cytokine treatment. An improved understanding of the molecular basis of RCC has led to the development of targeted therapies that have shown clinical benefit in patients with metastatic disease. Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR), a key regulator of cell growth and proliferation, cellular metabolism, and angiogenesis that is aberrantly activated in RCC. In the pivotal RECORD-1 study, everolimus monotherapy prolonged progression-free survival (PFS) vs placebo in patients with clear cell mRCC whose disease had progressed on vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy, and everolimus is now approved for this indication. The EVERMORE (Everolimus as Monotherapy Treatment for Patients with Metastatic Recurrent and/or Unresectable Renal Cell Carcinoma) trial will evaluate the efficacy and safety of everolimus monotherapy in patients with metastatic recurrent and/or unresectable RCC without prior systemic therapy other than cytokine therapy. Methods: EVERMORE is an open-label, multicenter, single-arm phase II trial. Up to 80 adult patients with metastatic, recurrent, or unresectable RCC of any MSKCC prognosis and histologic or cytologic confirmation of clear cell or non-clear cell RCC, ≥1 measurable baseline lesion as per RECIST criteria, Karnofsky performance status ≥70%, and adequate liver, renal, and bone marrow function are targeted for enrollment. Patients who have received prior systemic RCC therapy (sunitinib, sorafenib, bevacizumab, sirolimus, temsirolimus, everolimus, deferolimus) other than cytokine therapy are excluded. Everolimus 10 mg/d will be administered orally until disease progression, unacceptable toxicity, or study discontinuation for any other reason. The primary study endpoint is PFS. Overall survival, disease control rate, objective response rate and duration, and safety will also be assessed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis

7135 Effects of renal impairment on the pharmacokinetics and safety of sorafenib

The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC.REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10 mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3 months for the first year and every 6 months thereafter.A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14 weeks.Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk–benefit ratio.

7155 Overall survival among metastatic renal cell carcinoma (MRCC) patients corrected for crossover using a rank preserving structural failure time (RPSFT) model: analyses from the everolimus phase III trial

The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC.REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10 mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3 months for the first year and every 6 months thereafter.A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14 weeks.Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk–benefit ratio.