Abstract
Aim: The objective of this study was to compare the efficacies of tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORI) as second-line molecular-targeted therapy in patients with poor-risk metastatic renal cell carcinoma (mRCC). Patients and Methods: This study included 89 consecutive patients with mRCC who were classified into a poor-risk group after the failure of first-line molecular-targeted agent and subsequently received second-line targeted therapy. Results: Of the 89 patients, 59 and 30 were treated with TKI and mTORI, respectively, as second-line targeted therapy, and no significant differences in the clinicopathological characteristics were noted between the TKI and mTORI groups. There was no significant difference in the response rate to the second-line agent between the TKI and mTORI groups; however, the proportion of patients with tumor shrinkage in the TKI group was significantly higher than that in the mTORI group. There was no significant difference in the progression-free survival between the TKI and mTORI groups, while the overall survival for the TKI group was significantly superior to that of the mTORI group (median of 15.0 vs. 7.6 months, respectively). Furthermore, the type of second-line agent (i.e. TKI vs. mTORI) was identified as an independent predictor of the OS, but not of PFS. Conclusion: Favorable disease control might be achieved by introducing TKI as second-line targeted therapy for patients with poor-risk mRCC.
- Second-line
- metastatic renal cell carcinoma
- poor-risk
- tyrosine kinase inhibitor
- mammalian target of rapamycin inhibitor
In recent years, several novel agents targeted against vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways have been introduced into clinical practice, and the use of these agents has resulted in marked improvement in the prognosis of patients with metastatic renal cell carcinoma (mRCC) (1). However, it is well-documented that the majority of patients with mRCC receiving molecular-targeted agents will eventually develop resistance to these drugs and subsequently experience disease progression (2). Accordingly, the strategy of sequencing one targeted agent after the failure of another has gained popularity, and is currently considered the standard approach in treating patients with mRCC (3).
To date, a number of prognostic factors for mRCC have been identified based on the findings of clinical trials as well as retrospective analyses in a routine clinical setting, resulting in the establishment of prognostic model systems classifying mRCC patients into favorable-, intermediate- and poor-risk categories according to the numbers of risk factors associated with poor prognostic outcomes (4-6). In the first-line setting for the treatment of patients with mRCC, the selection of agents is generally made considering the prognostic classification based on the recommendations by major models, such as the Memorial Sloan-Kettering Cancer Center (MSKCC) and International Renal Cell Carcinoma Database Consortium (IMDC) systems; however, the prognostic classification is not taken into account when determining the use of second-line targeted agents against mRCC (7, 8). In particular, data guiding optimal second-line targeted therapy for poor-risk mRCC following disease progression on a first-line agent are completely lacking (9).
Considering these facts, we retrospectively reviewed the data from a total of 89 consecutive patients who were diagnosed with poor-risk mRCC after the failure of first-line targeted-therapy and were subsequently treated with a second-line agent, and assessed the impact of the type of second-line targeted agent on the prognostic outcomes in this cohort of patients.
Paterials and Methods
Patients. This was carried out as a retrospective study analyzing clinicopathological data from a total of 89 consecutive Japanese patients with mRCC who were classified into a poor-risk group following the failure of treatment with the first-line molecular-targeted agent, and who subsequently received second-line targeted therapy between August 2011 and September 2015 in a routine clinical setting at our institutions. Eight patients for whom surgical therapy was not performed underwent needle biopsies of their primary tumors to determine the histological subtype; thus, all 89 patients were pathologically diagnosed with primary RCC. In this study, risk classification was conducted based on the MSKCC system for previously treated patients with mRCC, which considers the following prognostic factors: anemia, hypercalcemia and poor performance status (PS) (6). The design of this study was approved by the Institutional Research Ethics Committee (no. 1029), and informed consent for conducting it was obtained from all of the included patients.
Administration of molecular-targeted agents. In this series, either axitinib, sunitinib, sorafenib, everolimus, or temsirolimus was introduced as the second-line molecular-targeted agent. As a rule, these agents were initially administered according to the following standard schedules: axitinib: 5 mg orally, twice daily; sunitinib: 50 mg orally, once daily in repeated 6-week cycles consisting of 4 weeks on, followed by 2 weeks off; sorafenib: 400 mg orally, twice daily; everolimus: 10 mg orally, once daily; and temsirolimus: 25 mg intravenously, once weekly. Treatment with a targeted agent was continued until the development of disease progression or intolerable adverse events (AEs). Dose modification of each agent was generally performed based on the AE severity; that is, dose reduction was considered for grade 2 AEs that were poorly tolerated, and treatment was withheld in cases with AEs of grade 3 or more and restarted with a reduced dosing schedule after recovery to grade 2 or lower.
Evaluation. As baseline assessments at the initiation of second-line targeted therapy, the clinicopathological examinations and PS were evaluated according to the seventh edition of the Union for International Cancer Control TNM classification system (10) and Karnofsky PS scale (11), respectively. Prior to the start of the second-line targeted agent, radiological evaluations by computed tomography of the brain, chest and abdomen and/or radionuclide bone scan were performed for all patients. In general, tumor measurements were conducted by computed tomography before and every 6 to 12 weeks after the start of the second-line targeted therapy. Responses to targeted agents and AEs were evaluated using the Response Evaluation Criteria in Solid Tumors v.1.1 (12) and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (13), respectively, by the treating physician.
Statistical analysis. All statistical analyses were performed using Statview 5.0 software (Abacus Concepts, Inc., Berkley, CA, USA), and a value of p<0.05 was considered significant. Differences in the characteristics between the two groups were compared using the chi-square test. The progression-free survival (PFS) and overall survival (OS) rates were analyzed with the Kaplan–Meier method, and differences were determined by the log-rank test. The significance of certain parameters in the PFS and OS was assessed by the Cox proportional hazards regression model.
Results
Characteristics of patients with poor-risk mRCC according to type of second-line targeted agent. Of the 89 patients included in this study, 35 (39.3%), 20 (22.5%), 16 (18.0%), 14 (15.7%) and four (4.5%) received axitinib, sunitinib, everolimus, temsirolimus and sorafenib, respectively, as second-line targeted therapy. Therefore, as the second-line targeted agent, anti-VEGF receptor-tyrosine kinase inhibitors (TKIs), including axitinib, sunitinib and sorafenib, were introduced for 59 (66.3%), while mTOR inhibitors (mTORIs), including everolimus and temsirolimus, were administered to the remaining 30 (33.7%). Table I shows the major characteristics of the 89 patients according to the type of second-line targeted agents, and there were no significant differences in the characteristics examined in this study between the TKI and and mTORI groups.
Response to second-line targeted agent in patients with poor-risk mRCC. As the best response to the second-line targeted agent, despite the absence of any patient achieving a complete response in either group, four (6.8%), 38 (64.4%) and 17 (28.8%) in the TKI group, while two (6.7%), 15 (50.0%) and 13 (43.3%) in the mTORI group were judged as having partial response, stable disease and progressive disease, respectively. Therefore, no significant difference in the objective response rate (ORR) was noted between the TKI and mTORI groups. Furthermore, a degree of tumor shrinkage was achieved in 35 (59.3%) and six (20.0%) patients in the TKI and mTORI groups, respectively, and the difference in the proportion of patients with tumor shrinkage was significant. Figure 1 shows the maximum reduction from baseline of the target tumors in the 89 patients.
Prognosis in patients with poor-risk mRCC after introducing second-line targeted agent. PFS and OS after the initiation of second-line targeted therapy were evaluated. As shown in Figure 2, the median durations of PFS in the TKI and mTOR groups were 4.9 and 3.1 months, respectively, and there was no significant difference in the PFS between the two groups. In addition, the median durations of OS in the TKI and mTORI groups were 15.0 and 7.6 months, respectively, and the OS in the TKI group was significantly superior to that in the mTORI group.
The impact of several clinicopathological factors on PFS and OS in these 89 patients was then investigated (Table II). Univariate analyses identified the significant prognostic predictors as follows: prior nephrectomy, high C-reactive protein (CRP) level and liver metastasis for PFS, and prior nephrectomy, high CRP level, liver metastasis, sarcomatoid feature and use of mTORI as second-line agent for OS. Multivariate analyses of these significant prognostic predictors were performed, and the following factors were shown to have independent prognostic impacts: high CRP level for PFS, and high CRP level, liver metastasis and use of mTORI as second-line agent for OS. Furthermore, 29 (49.2%) and 8 (26.7%) patients in the TKI and mTOR groups, respectively, went on to receive third-line targeted therapy, and the difference in this proportion was significant.
Discussion
With the introduction of molecular-targeted agents into routine clinical practice, there has been marked progress in the treatment of patients with mRCC (1). In fact, most patients with mRCC currently experience prolonged disease control as well as acceptable quality of life due to the sequential use of multiple targeted agents (14). However, some patients are classified into a poor-risk group by several prognostic model systems, and the treatment of this category of patients, characterized by highly aggressive disease, is still challenging (9). In the first-line setting, the efficacy of temsirolimus in patients with poor-risk mRCC is well-recognized based on the outcome of a pivotal randomized clinical trial (15), whereas, to or knowledge, no data are available with respect to the selection of second-line targeted therapy for patients with poor-risk mRCC following disease progression on a first-line agent. For this reason, we conducted a retrospective study focusing on patients with poor-risk mRCC who were treated with a second-line targeted agent in order to elucidate the prognostic features in this cohort of patients in the era of molecular-targeted therapy.
Recently, Ko et al. reported that the IMDC prognostic model can be applied to patients previously treated with targeted therapy (16). In our study, however, despite being developed based on the data during the era of cytokine therapy, the MSKCC system for previously treated mRCC patients (6) was used for the risk classification for the following reasons: i) This system is simple, considering only three parameters: anemia, hypercalcemia and poor PS. ii) This system, rather than the IMDC model, has been used in several previous randomized clinical trials (17, 18), which makes it possible to compare the findings between the present and previous studies. As a result, we identified a total of 89 patients with poor-risk mRCC, consisting of 59 and 30 who received TKI and mTORI, respectively, as second-line targeted therapy at our institutions. Although the selection of targeted agents during sequential therapy was made based on the preference of each physician rather than strictly determined criteria in this series, no significant differences in the clinicopathological characteristics were noted between the TKI and mTORI groups. Therefore, the subsequent assessments were performed by comparing the findings between these two groups.
To date, several randomized clinical trials investigating the efficacy of targeted agents as second-line therapy for patients with mRCC revealed that the ORR for patients receiving TKI tends to be better than that for those receiving mTORI (17-22). For example, Rini et al. reported that the ORR in patients treated with second-line axitinib was 19% in the AXIS trial (17), while Motzer et al. showed an ORR of 5% in patients receiving everolimus in the CheckMate 025 trial (18). In this study, including only patients with poor-risk mRCC, the ORRs for the TKI and mTORI groups were similar (6.8 vs. 6.7%); however, the proportion of patients with tumor shrinkage in the TKI group was markedly greater than that in the mTORI group (59.3 vs. 20.0%). Compared with the findings of previous studies on second-line targeted therapies including overall mRCC populations (17-22), the ORR in the TKI group of this study was low, but the proportion of those achieving tumor shrinkage was comparable. Collectively, these findings suggest that TKI, but not mTORI, could induce a modest tumor response even in patients with mRCC classified into the poor-risk group.
We then assessed the prognostic outcomes of patients with poor-risk mRCC following the introduction of second-line targeted agents. In this series, although there was no significant difference in the PFS between the TKI and mTOR groups (median PFS of 4.9 versus 3.1 months), the OS for the TKI group appeared to be significantly superior to that forthe mTOR group (median OS of 15.0 versus 7.6 months; p=0.011). These prognostic outcomes were unfavorable compared with those in previous studies including patients with mRCC irrespective of their risk classification in order to assess the efficacies of second-line targeted therapies (17-22), except for the OS in the TKI group, which was just slightly inferior or similar to those in previous studies (17, 20, 22). In addition, despite being difficult to explain clearly, the inconsistent prognostic finding between the PFS and OS according to the type of second-line agent for poor-prognostic mRCC is of interest. In the INTORSECT trial as well, the second-line sorafenib-treated group was shown to have a significantly better OS than the second-line temsirolimus-treated group, whereas no significant difference in the PFS was noted between these two groups (20). Considering these findings, when introduced as a second-line agent, TKI may have a satisfactory impact on the improvement of at least OS in patients with mRCC, including those classified into the poor-risk group, compared with mTORI.
Another point of interest is the identification of parameters closely associated with the prognosis in patients with poor-risk mRCC following the introduction of a second-line agent. In this series, PFS was shown to be independently correlated with the CRP level, while the type of second-line agent, in addition to the CRP level and liver metastasis, were identified as independent predictors of the OS. To date, due to the lack of information on prognostic factors for patients with poor-risk mRCC receiving a second-line targeted agent, it would be difficult to draw a definitive conclusion on this topic based on the findings of this study alone. The current findings, however, confirmed that conventional prognostic indicators can also be applied to this cohort of patients, and furthermore suggest that the introduction of TKI, rather than that of mTORI, as a second-line agent may result in the prolongation of the OS in such patients. In fact, the TKI group was more significantly likely to receive subsequent third-line targeted therapy than the mTORI group (47.5 vs. 26.7%).
Here, we would like to describe several limitations of this study. Initially, this was a retrospective study including a comparatively small number of patients, particularly those receiving second-line mTORI. Secondly, albeit being classified into the same category, multiple agents with different pharmacological characteristics were used as second-line therapy in both groups, and the selection of these agents was made based on the preference of each physician. Thirdly, although this study used the inclusion criteria employing the MSKCC system for previously treated mRCC, a consensus regarding the optimal prognostic system for patients with mRCC receiving second-line targeted therapy has not been reached. Finally, prognostic outcomes according to risk classification in pivotal randomized clinical trials for second-line targeted agent remain unavailable, which makes is impossible to compare the present data with others.
Conclusion
To our knowledge, this is the first study assessing the prognostic features in patients with poor-risk mRCC treated with second-line targeted therapy, and the findings presented in this study indicate that despite the lack of a significant difference in the ORR and PFS between patients receiving TKI and mTORI, the TKI group had significantly better prognostic outcomes than the mTORI group in terms of the proportion of patients with tumor shrinkage and OS. Furthermore, the use of TKI as second-line targeted agent appeared to be independently associated with OS, but not PFS, suggesting the superiority of TKI for improving the survival of this cohort of patients. Although the findings of this study should be prospectively confirmed, the consideration of such information may help provide the rationale for the stratification of therapeutic strategies in patients with poor-risk mRCC treated with second-line targeted agents in routine clinical practice.
- Received December 27, 2016.
- Revision received February 20, 2017.
- Accepted February 21, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved