Edited by: Giovanni Li Volti, University of Catania, Italy
Reviewed by: Sheldon L. Holder, Penn State Milton S. Hershey Medical Center, United States; Franco Franco Morelli, Casa Sollievo della Sofferenza (IRCCS), Italy
*Correspondence: Gaetano Facchini
This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
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In metastatic renal cell carcinoma, complete response to first-line antiangiogenic agents is rare and resistance to therapy often develops. Protocols for sequential treatment with angiogenesis and mTOR inhibitors are under evaluation to improve outcomes. In this observational, real-world study, patients received a first-line therapy with pazopanib until discontinuation for disease progression or toxicity, then a second-line with everolimus. Primary endpoints were overall survival (OS) for sequence, progression free survival (PFS) for each agent, and safety. Thirty-one patients were included in the analysis: 73.3% of patients underwent nephrectomy before treatment, 25.8% had at least three comorbidities. At the beginning of therapy, the median age was 68 years, with more than 60% of patients older than 65 years. The median OS for sequence was 26.5 months (95% CI 17.4-nc); median PFS was 10.6 months (95% CI 6.3–12.1) with pazopanib and 5.3 months (95% CI 3.8–6.7) with everolimus. The median persistence in pazopanib therapy was 8.1 months (Interquartile Range IQR 5.3–12.7), with 31% of patients who required dose reduction, while persistence in everolimus was 4.4 months (IQR 3.4–6.5). Sequence was well tolerated with a different profile of adverse events for each agent. These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance.
Sequential treatment in metastatic renal cell carcinoma (mRCC) is of interest as a complete response to treatment with first-line antiangiogenic agents is rare and tyrosine kinase inhibitors usually do not produce long term remission: patients relapse when therapy is discontinued, or a resistance develops during treatment (Facchini et al.,
This retrospective, observational study would describe the clinical outcomes of the pazopanib and everolimus sequential therapy in unselected patients with mRCC.
This multi-centric, real-world, observational study included consecutive patients who were newly diagnosed with mRCC and received a sequential therapy with pazopanib followed by everolimus. Pazopanib treatment was continued until disease progression or discontinuation for toxicity; then, everolimus was given until discontinuation for toxicity, progression, or death. The study was approved by the Istituto Nazionale Tumori - IRCCS “Fondazione G. Pascale” ethical committees and a written informed consent was signed by all subjects, according to the Declaration of Helsinki (no trial registration number available).
The primary endpoints were OS for sequence and objective response rate (ORR), disease control rate (DCR), and PFS for each treatment. The safety profile for each agent was also evaluated for all patients who received at least one dose of drugs. The potential relationships between baseline characteristics and response were even explored. PFS was defined as the interval between the date of the first dose of drug (either pazopanib or everolimus) and the date of disease progression or death for any cause (Cecere et al.,
Data were shown as mean and standard deviation or as mean and 95% CI or as absolute (n) and relative frequency (%). Baseline characteristics and variables distribution were compared using a Chi-square test for categorical variables and a Student
From July 2012 to April 2016, 31 patients with mRCC started a sequential therapy with pazopanib and everolimus and were included in the analysis (Figure
Study overview.
Baseline characteristics.
Age | 68.0 (8.0) | 68.8 (7.9) | |
<65 | 12 (38.7) | 10 (32.3) | |
≥65 | 19 (61.3) | 21 (67.7) | |
0 | 17 (54.8) | 6 (19.4) | |
1 | 10 (32.3) | 22 (71.0) | |
2 | 4 (12.9) | 2 (6.4) | |
3 | – | 1 (3.2) | |
<80 | 7 (22.6) | 17 (54.8) | |
≥80 | 24 (77.4) | 11 (35.5) | |
Unknown | – | 3 (9.8) | |
Good | 6 (19.4) | 2 (6.5) | |
Intermediate | 21 (67.7) | 22 (71.0) | |
Poor | 4 (12.9) | 6 (19.4) | |
Unknown | – | 1 (3.2) | |
Good | 6 (19.4) | 2 (6.4) | |
Intermediate | 21 (67.7) | 22 (71.0) | |
Poor | 1 (3.2) | 3 (9.7) | |
Unknown | 3 (9.7) | 4 (6.4) | |
Lung | 20 (64.5) | 21 (67.7) | |
Liver | 7 (22.6) | 12 (38.7) | |
Kidney | 14 (45.1) | 9 (29.0) | |
Bone | 9 (29.0) | 8 (25.8) | |
Other | 13 (41.9) | 17 (54.8) |
The median duration of pazopanib treatment was 8.1 months (Interquartile Range IQR 5.3–12.7); nine patients (31%) required a dose reduction, due to toxicity in 7 cases. The main cause of discontinuation was disease progression (87.2%), followed by toxicity (6.4%). At the time of the analysis, everolimus treatment was still ongoing in 4 patients, the median treatment duration was 4.4 months (IQR 3.4–6.5); five patients needed dose reduction for toxicity. Again, disease progression was the main cause for discontinuation (77.8%), followed by toxicity (18.5%).
OS for sequence was 26.5 months (95% CI 17.4-nc; Figure
Kaplan-Meier estimates of Overall Survival for sequence.
During pazopanib treatment, fatigue (32.2%), hypertension (48.4%), diarrhea (16.1%), thyroid disorders (19.3%), and hematological disorders (16.1%), including thrombocytopenia, leukopenia and anemia, were reported (Table
Adverse events.
Fatigue | 10 (32.2) | – |
Hypertension | 15 (48.4) | – |
Diarrhea | 5 (16.1) | 4 (12.9) |
Thyroid disorders | 6 (19.3) | – |
Mucositis | 5 (16.1) | 7 |
Rash | 2 (6.5) | 3 |
Hematological disorders | 5 (16.1) | 10 (32.2) |
Thrombocytopenia | 3 | – |
Leukopenia | 1 | – |
Anemia | 1 | 10 |
Metabolic disease | – | |
Hyper-triglyceridemia | 5 (16.1) | |
Hyper-cholesterolemia | 7 (22.6) | |
Hyper-glycemia | 7 (22.6) |
During pazopanib treatment, the best response was a partial response, achieved in 7 (24.1%) patients; a stable disease was obtained in 17 patients (58.6%) and 5 patients (17.3%) experienced a disease progression. The median PFS was 10.6 months (95% CI 6.3–12.1; Figure
Kaplan-Meier estimates of Progression Free Survival on pazopanib treatment.
During everolimus treatment, two patients achieved a partial response, while 13 patients (44.8%) had a stable disease and 14 patients (48.3%) a progression disease. Median OS was 6.7 months (95% CI 4.33-nc; Figure
Kaplan-Meier estimates of Overall Survival on everolimus treatment.
Kaplan-Meier estimates of Progression Free Survival on everolimus treatment.
This observational study evaluated the clinical outcomes of a sequential treatment with pazopanib and everolimus in mRCC. As designed in real-world setting, the analysis included patients with poor performance status, comorbidities and metastases. Baseline characteristics of patients further worsened during the sequence, due to disease progression and deterioration of the global health status; for this reason, the direct comparison between pazopanib and everolimus treatment may be few informative. Other variables including age, risk status (both MDCC and IMDCC), and metastasis sites did not change.
The median duration of pazopanib treatment was similar to that reported in the phase III pivotal trial (7.4 months; Sternberg et al.,
The median OS (26.5 months) for sequence was longer than those reported in previous sequential studies, in the RECORD-1 study (14.4 months; Motzer et al.,
The adverse event profile of two treatments was quite different: hypertension, hypothyroidism, and fatigue were observed only with pazopanib, whereas anemia and metabolic disorders were commonly reported with everolimus. Thus, patients showing intolerance to pazopanib may preferentially switch to a mTOR inhibitor and avoid potential for cumulative toxicity associated with sequential VEGFR-TKI treatment (D'Aniello et al.,
When each treatment was separately considered, most patients responded to both treatment, showing partial response or stable disease as the best response. Median PFS with pazopanib was 10.6 months; other real-world studies reported 13.7 months in the MD Anderson Cancer Center study (Matrana et al.,
Everolimus treatment had a median PFS of 5.3 months, similar to those reported in the RECORD-1 study (5.5 months; Motzer et al.,
The main limitation of the study was the population size which limited the generalizability of results; however, our data were consistent and comparable with previous results reported in both randomized trials and real-world studies. Further analyses with a larger cohort will better elucidate the relationships between clinical and disease characteristics and outcomes of the sequential therapy.
These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance. Overall, the sequential therapy showed favorable clinical outcomes and a good safety profile, and may be feasible even for elderly patients or with multiple comorbidities. The choice of second-line treatment in the new therapeutic paradigm is dramatically changed with the approval of new drugs, such as nivolumab and cabozantinib. The next step in optimizing mRCC management would be the identification of new prognostic and predictive factors to detect a personalized sequence for each patient.
SR, CD, GI, MP, MB, SP, GF, and CC substantially contributed to the conception of the work, data acquisition and interpretation. All the authors revised the work for important intellectual content and approved the final version to be published. They agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Authors thanks Novartis Farma SpA (Origgio – IT) for unconditional support. Editorial support was provided by Content Ed Net, with the helpful contribution in drafting the test by Elisa Sala, Ph.D., Medical Writer.