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Everolimus as second-line therapy for metastatic renal cell carcinoma: a ‘real-life’ study Mimma Rizzo*,1,2, Gaetano Facchini2,3, Clementina Savastano2,3, Giuseppe Di Lorenzo2,4, Luigi De Lucia2,5, Luigi Maiorino2,6, Beniamino Casale2,7, Giuseppe Grimaldi2,8, Roberta Formato2,9, Antonio Febbraro2,10 & Giacomo Cartenì1,2 ABSTRACT Aims: This study, conducted in a ‘field-practice’ scenario, investigates the effectiveness and safety of everolimus in the second-line treatment of metastatic renal cell carcinoma (mRCC) patients. Patients & methods: mRCC patients, who started everolimus 10 mg/day after failure of first-line VEGF receptor-targeted tyrosine kinase inhibitor, were included in this study. Study end points were treatment response, progression-free survival and tolerability. Results: In total, 100 patients were assessed; the median duration of everolimus treatment was 7.1 months (95% CI: 5.7–8.5). A total of 19% of patients experienced a partial response and 62% of patients reached a stable disease. Median progression-free survival was 8 months (95% CI: 6.7–9.3). A total of 75% of patients experienced adverse events; no grade 4 adverse events were reported. Conclusion: These findings, obtained in a ‘field-practice’ scenario, support the use of everolimus for mRCC patients who failed one VEGF receptor-targeted tyrosine kinase inhibitor. Everolimus is a rapamycin derivative that inhibits the mTOR kinase [1] . The mTOR pathway has a major role in several cellular processes, including cell cycle control and cellular proliferation [2–4] . In addition, mTOR is a downstream target of the PI3K/phosphatase and tensin homolog/AKT axis, often impaired in human tumors [5,6] . Therefore, the inhibition of mTOR with everolimus represents an effective strategy for the therapy of a number of solid tumors, including metastatic renal cell carcinoma (mRCC), neuroendocrine tumors of pancreatic origin and hormone receptor-positive, HER2-negative breast cancer in combination with exemestane [7] . In the mRCC setting, everolimus has been approved for the treatment of patients who failed treatment with tyrosine kinase inhibitors (TKIs) targeting the VEGF receptor (VEGFR), such as sunitinib, sorafenib or pazopanib [8,9] . In the multicenter, randomized, double-blind, Phase III RECORD-1 trial, everolimus 10 mg/day prolonged progression-free survival (PFS) when compared with placebo in patients with mRCC who had failed previous therapy with sunitinib and/or sorafenib [10] . Of note, only a small percentage of patients enrolled in the RECORD-1 study actually received a second-line treatment with everolimus, while approximately 79% of them were undergoing a third-line or further-line treatment after failure of VEGFR-targeted TKIs [11] . Moreover, the safety population of this trial included less
KEYWORDS
• everolimus • mRCC • observational studies • second-line therapy
Cardarelli Hospital, Naples, Italy S Giovanni di Dio e Ruggi d’Aragona Hospital, Salerno, Italy 3 National Tumor Institute Pascale, Naples, Italy 4 Federico II University, Naples, Italy 5 S Sebastiano e S Anna Hospital, Caserta, Italy 6 S Gennaro Hospital, Naples, Italy 7 Ospedale dei Colli, Naples, Italy 8 Umberto I Hospital, Nocera Inferiore, Italy 9 S Maria delle Grazie Hospital, Pozzuoli, Italy 10 Osp. Fatebenefratelli, Benevento * Author for correspondence: [email protected] 1 2
10.2217/FON.14.170 © 2015 Future Medicine Ltd
part of
Future Oncol. (2015) 11(2), 219–224
ISSN 1479-6694
219
Research Article Rizzo, Facchini, Savastano et al. than 300 patients. Thus, the external validity of RECORD-1 randomized controlled trial needs improvement. It is widely accepted that a large gap exists between registrative randomized studies and daily clinical practice [12] . Therefore, welldesigned observational studies conducted in a ‘field-practice’ setting can provide valuable clinical information about the safety and effectiveness of cancer therapies and represent an additional, real-world source of clinical information. A number of observational studies have been conducted to investigate everolimus in the treatment of mRCC [13–15] . However, additional evidence is required to further elucidate its effectiveness and safety in daily practice. This study, conducted in an Italian ‘fieldpractice’ scenario, investigates the effectiveness and safety of everolimus in the second-line treatment of mRCC patients. Patients & methods
●●Patients
Consecutive adult patients with histologically confirmed mRCC and failure of a prior VEGFR-targeted therapy were included in this study. Owing to the ‘field-practice’ nature of this study, no other inclusion or exclusion criteria were applied. ●●Study treatment
All patients received everolimus 10 mg/day until disease progression or unacceptable toxicity. Doses could be delayed or reduced to 5 mg/day if patients presented clinically relevant adverse events that were deemed related to everolimus. Determination of disease progression and follow-up of the patients were performed according to the routine medical practice of the treating center. No other oncological treatments were allowed; however, supportive care and other concomitant treatments for the treatment of comorbidities were permitted.
●●Study setting & design
●●Study end points & data analysis
This observational, retrospective cohort study was conducted at ten oncological centers in the Campania region (southern Italy) from 31 January 2011 to 31 January 2013. The study was conducted in accordance with the Helsinki Declaration and its protocol was approved by the local ethical committees. All patients signed an informed consent before inclusion.
Study end points were response to everolimus therapy according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (as assessed by the referring radiologist), PFS (defined as time from the first administration of everolimus to progression or death for any cause) and tolerability, with adverse event type and grade defined according to the Common
Table 1. Baseline characteristics of the study cohort (n = 100). Variable
Number
Males Median age at diagnosis; range (IQR), years Time from RCC diagnosis; range (IQR), months KPS: – 80–100 – 70–79 –
Everolimus as second-line therapy for metastatic renal cell carcinoma: a ‘real-life’ study Mimma Rizzo*,1,2, Gaetano Facchini2,3, Clementina Savastano2,3, Giuseppe Di Lorenzo2,4, Luigi De Lucia2,5, Luigi Maiorino2,6, Beniamino Casale2,7, Giuseppe Grimaldi2,8, Roberta Formato2,9, Antonio Febbraro2,10 & Giacomo Cartenì1,2 ABSTRACT Aims: This study, conducted in a ‘field-practice’ scenario, investigates the effectiveness and safety of everolimus in the second-line treatment of metastatic renal cell carcinoma (mRCC) patients. Patients & methods: mRCC patients, who started everolimus 10 mg/day after failure of first-line VEGF receptor-targeted tyrosine kinase inhibitor, were included in this study. Study end points were treatment response, progression-free survival and tolerability. Results: In total, 100 patients were assessed; the median duration of everolimus treatment was 7.1 months (95% CI: 5.7–8.5). A total of 19% of patients experienced a partial response and 62% of patients reached a stable disease. Median progression-free survival was 8 months (95% CI: 6.7–9.3). A total of 75% of patients experienced adverse events; no grade 4 adverse events were reported. Conclusion: These findings, obtained in a ‘field-practice’ scenario, support the use of everolimus for mRCC patients who failed one VEGF receptor-targeted tyrosine kinase inhibitor. Everolimus is a rapamycin derivative that inhibits the mTOR kinase [1] . The mTOR pathway has a major role in several cellular processes, including cell cycle control and cellular proliferation [2–4] . In addition, mTOR is a downstream target of the PI3K/phosphatase and tensin homolog/AKT axis, often impaired in human tumors [5,6] . Therefore, the inhibition of mTOR with everolimus represents an effective strategy for the therapy of a number of solid tumors, including metastatic renal cell carcinoma (mRCC), neuroendocrine tumors of pancreatic origin and hormone receptor-positive, HER2-negative breast cancer in combination with exemestane [7] . In the mRCC setting, everolimus has been approved for the treatment of patients who failed treatment with tyrosine kinase inhibitors (TKIs) targeting the VEGF receptor (VEGFR), such as sunitinib, sorafenib or pazopanib [8,9] . In the multicenter, randomized, double-blind, Phase III RECORD-1 trial, everolimus 10 mg/day prolonged progression-free survival (PFS) when compared with placebo in patients with mRCC who had failed previous therapy with sunitinib and/or sorafenib [10] . Of note, only a small percentage of patients enrolled in the RECORD-1 study actually received a second-line treatment with everolimus, while approximately 79% of them were undergoing a third-line or further-line treatment after failure of VEGFR-targeted TKIs [11] . Moreover, the safety population of this trial included less
KEYWORDS
• everolimus • mRCC • observational studies • second-line therapy
Cardarelli Hospital, Naples, Italy S Giovanni di Dio e Ruggi d’Aragona Hospital, Salerno, Italy 3 National Tumor Institute Pascale, Naples, Italy 4 Federico II University, Naples, Italy 5 S Sebastiano e S Anna Hospital, Caserta, Italy 6 S Gennaro Hospital, Naples, Italy 7 Ospedale dei Colli, Naples, Italy 8 Umberto I Hospital, Nocera Inferiore, Italy 9 S Maria delle Grazie Hospital, Pozzuoli, Italy 10 Osp. Fatebenefratelli, Benevento * Author for correspondence: [email protected] 1 2
10.2217/FON.14.170 © 2015 Future Medicine Ltd
part of
Future Oncol. (2015) 11(2), 219–224
ISSN 1479-6694
219
Research Article Rizzo, Facchini, Savastano et al. than 300 patients. Thus, the external validity of RECORD-1 randomized controlled trial needs improvement. It is widely accepted that a large gap exists between registrative randomized studies and daily clinical practice [12] . Therefore, welldesigned observational studies conducted in a ‘field-practice’ setting can provide valuable clinical information about the safety and effectiveness of cancer therapies and represent an additional, real-world source of clinical information. A number of observational studies have been conducted to investigate everolimus in the treatment of mRCC [13–15] . However, additional evidence is required to further elucidate its effectiveness and safety in daily practice. This study, conducted in an Italian ‘fieldpractice’ scenario, investigates the effectiveness and safety of everolimus in the second-line treatment of mRCC patients. Patients & methods
●●Patients
Consecutive adult patients with histologically confirmed mRCC and failure of a prior VEGFR-targeted therapy were included in this study. Owing to the ‘field-practice’ nature of this study, no other inclusion or exclusion criteria were applied. ●●Study treatment
All patients received everolimus 10 mg/day until disease progression or unacceptable toxicity. Doses could be delayed or reduced to 5 mg/day if patients presented clinically relevant adverse events that were deemed related to everolimus. Determination of disease progression and follow-up of the patients were performed according to the routine medical practice of the treating center. No other oncological treatments were allowed; however, supportive care and other concomitant treatments for the treatment of comorbidities were permitted.
●●Study setting & design
●●Study end points & data analysis
This observational, retrospective cohort study was conducted at ten oncological centers in the Campania region (southern Italy) from 31 January 2011 to 31 January 2013. The study was conducted in accordance with the Helsinki Declaration and its protocol was approved by the local ethical committees. All patients signed an informed consent before inclusion.
Study end points were response to everolimus therapy according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (as assessed by the referring radiologist), PFS (defined as time from the first administration of everolimus to progression or death for any cause) and tolerability, with adverse event type and grade defined according to the Common
Table 1. Baseline characteristics of the study cohort (n = 100). Variable
Number
Males Median age at diagnosis; range (IQR), years Time from RCC diagnosis; range (IQR), months KPS: – 80–100 – 70–79 –
