Abstract
Background/Aim: Immuno-oncology (IO) combination therapy has become the standard of treatment for advanced renal cell carcinoma (RCC). In this retrospective study, we compared the efficacy of first-line molecular targeted therapy (MTT), administered as monotherapy, and IO combination therapy using real-world data of Japanese patients. Patients and Methods: The clinical information of 202 patients with RCC who received MTT (n=144) or IO combination therapy (n=58) at the Kurume University Hospital from May 2008 to May 2022 was collected and retrospectively analyzed. The Cox proportional hazards model was used for univariate and multivariate analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated. Results: The patients treated with IO combination therapy had a prolonged progression-free survival (PFS) compared with those treated with MTT (p=0.0038). IO combination therapy was significantly associated with a better PFS in patients with intermediate (p=0.0072) and poor risk (p=0.0411) but not in those with favorable risk (p=0.5434). Furthermore, overall survival with IO combination therapy was significantly better in patients at poor risk (p=0.0335). Multivariate analyses suggested that prior nephrectomy (HR=1.501, 95%CI=1.048-2.150, p=0.0268) and first-line therapy (HR=1.962, 95%CI=1.288-2.986, p=0.0017) were independent prognostic factors for PFS. Conclusion: IO combination therapy significantly improved the PFS of patients with advanced RCC, especially those with intermediate- and poor-risk disease. Further investigations focusing on the improvement of survival are warranted.
Since 2008, several molecular targeted agents, such as vascular endothelial growth factor (VEGF) pathway inhibitors and mammalian target of rapamycin (mTOR) inhibitors, have been approved for the treatment of advanced renal cell carcinoma (aRCC) in Japan. Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have further improved the prognosis of aRCC. Following clinical trials, immuno-oncology (IO) combination therapy, such as IO + IO therapy or IO therapy + tyrosine kinase inhibitors (TKIs), has become the standard of treatment for aRCC in Japan (1-5). These regimens have allowed the possibility of long-term survival of patients with aRCC. However, few studies have evaluated the changes in outcomes of patients treated with IO combination therapy using real-world population data. Real-world data include patients with a relatively poor performance status (PS) and comorbidities who are excluded from clinical trials. These differences are known to affect patient outcomes, and real-world data are needed to evaluate the therapeutic effects of IO combinations.
In the present study, we performed a retrospective analysis to compare the efficacy of molecular targeted therapy (MTT) and IO combination therapy as first-line treatments using real-world data of Japanese patients.
Patients and Methods
Study design and patients. The clinical information of 202 patients with RCC who received MTT, administered as monotherapy, or IO combination therapy at the Kurume University Hospital from May 2008 to May 2022 was collected and retrospectively analyzed. Pretreatment assessments of clinical characteristics and blood data were performed immediately before the initiation of first-line therapy. Progression-free survival (PFS) was measured from the time of first-line treatment initiation to clinical or radiographic progression of the disease or death from any cause. Overall survival (OS) was measured from the time of first-line treatment initiation to death from any cause.
Statistical analyses. Kaplan–Meier survival analysis with the log-rank test was performed to compare the PFS and OS between the MTT and IO combination groups. In addition, survival curves were compared using the International Metastatic RCC Database Consortium (IMDC) risk classification. The Cox proportional hazards model was used for univariate and multivariate analyses, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Variables with p-values <0.05 identified by univariate analyses were selected for multivariate analyses. All statistical analyses were performed using JMP version 16 (SAS Institute, Inc., Cary, NC, USA). All p-values were two-sided, and statistical significance was set at p<0.05.
Ethical approval. This study was conducted in accordance with the principles of the World Medical Association Declaration of Helsinki and was independently reviewed and approved by the Ethics Review Committee at the Kurume University School of Medicine. Informed consent was not obtained from the patients because this study was retrospective. All patient data were processed anonymously and deidentified prior to analysis.
Results
Patient characteristics. The clinicopathological characteristics of the 202 study participants are summarized in Table I. The median age of the patients was 67 (range=21-91 years). The majority of the patients were males (78.2%). According to the IMDC classification, at the initiation of first-line therapy, 32 (15.8%), 112 (55.4%), and 58 (28.7%) patients were classified as favorable, intermediate, and poor risk, respectively. The clinicopathological characteristics of the patients treated with MTT and those treated with IO combination therapy were compared before first-line treatment initiation. The histopathology results and absence or presence of prior nephrectomy were significantly different between the patients with first-line MTT or IO combination therapy. However, there were no significant differences in the age, sex, PS, IMDC risk classification, frequency of lung, bone, liver, and brain metastasis, pretreatment C-reactive protein (CRP) level, and neutrophil-to-lymphocyte ratio (NLR). The median follow-up was 21.37 (range=0.03-164.43 months) for all patients. Table II shows the regimens administered as first-line MTT and IO combination therapy, which most frequently included sunitinib (48.6%) and nivolumab + ipilimumab (NIVO + IPI; 74.1%), respectively.
Clinical course according to first-line therapy. Figure 1A and B shows the estimated PFS and OS curves, respectively, according to the first-line treatment. The patients treated with IO combination therapy had a prolonged PFS compared with those treated with MTT (17.6 vs. 6.4 months, respectively, p=0.0038). However, there was no significant difference in OS between the two groups (p=0.2351). Comparison of the survival curves according to the IMDC risk classification showed that IO combination therapy was significantly associated with a better PFS in the intermediate- (p=0.0072) and poor-risk (p=0.0411) groups but not in the favorable-risk group (p=0.5434) (Figure 2A-C). In terms of OS, IO combination therapy was significantly better than MTT for patients at poor risk (p=0.0335) (Figure 2F). However, no significant differences were observed between the treatments in favorable- (p=0.5680) and intermediate-risk (p=0.5014) patients (Figure 2D and E).
Univariate and multivariate analyses of survival. Univariate and multivariate analyses were performed to identify the prognostic factors associated with the PFS and OS (Table III and Table IV). Univariate analysis showed that prior nephrectomy (HR=1.382, 95%CI=1.000-1.909, p=0.0498), PS (HR=1.602, 95%CI=1.068-2.403, p=0.0228), bone metastasis (HR=1.418, 95%CI=1.016-1.979, p=0.0400), and first-line therapy (HR=1.818, 95%CI=1.204-2.743, p=0.0044) were significant factors that affected PFS. Multivariate analyses suggested that prior nephrectomy (HR=1.501, 95%CI=1.048-2.150, p=0.0268) and first-line therapy (HR=1.962, 95%CI=1.288-2.986, p=0.0017) were independent prognostic factors for PFS. In the OS-related univariate analysis, prior nephrectomy (HR=1.551, 95%CI=1.067-2.255, p=0.0216), PS (HR=2.951, 95%CI=1.908-4.563, p<0.0001), IMDC risk classification (intermediate: HR=1.146, 95%CI=0.699-1.879, p=0.5884; poor: HR=2.696, 95%CI=1.553-4.678, p=0.0004), bone metastasis (HR=1.840, 95%CI=1.268-2.672, p=0.0013), CRP level (HR=2.130, 95%CI=1.486-3.052, p<0.0001), and NLR (HR=2.129, 95%CI=1.488-3.044, p<0.0001) were significant factors. Furthermore, multivariate analyses suggested that PS (HR=2.009, 95%CI=1.217-3.315, p=0.0064) was an independent prognostic factor for OS.
Discussion
In the present study, we compared the survival of real-world patients with aRCC who were treated with first-line MTT or IO combination therapy. The patients treated with IO combination therapy had a significantly prolonged PFS compared with those treated with MTT. To our knowledge, this is the first study that used real-world data to evaluate the improvement in aRCC outcomes with first-line IO combination therapy in Japan. Our study showed that IO combination therapy as a first-line treatment was an independent prognostic predictor of the PFS, but not OS, in multivariate analysis. The IO combination group had a short follow-up period, resulting in insufficient data on OS. However, previous reports have shown that the duration of first-line therapy is also reflected in the OS (6, 7). Furthermore, some researchers have demonstrated that TKIs have favorable antitumor activity in patients with aRCC after ICIs (8-10). Therefore, IO combination therapy is expected to further prolong the survival of patients with aRCC.
In this study, compared with MTT, IO combination therapy significantly prolonged the PFS in intermediate- and poor-risk groups of patients based on the IMDC risk classification. However, there was no significant difference in PFS between the treatments in the favorable-risk group of patients. Pivotal clinical trials have reported that IO combination therapy results in better survival outcomes than sunitinib in intermediate- and poor-risk patients (1-5). On the other hand, some of these reports have not shown a significant difference in PFS between the two treatments in favorable-risk patients (3, 4). Meanwhile, long-term disease control and survival have been observed in favorable-risk patients treated with MTT (11).
The National Comprehensive Cancer Network treatment guideline recommends some IO combination therapies and MTT as equally preferred regimens in favorable-risk patients (12). However, the Society for Immunotherapy of Cancer recommends I-O combination therapy for patients who are candidates for immunotherapy (13). This controversy regarding whether patients with favorable-risk aRCC should be treated with MTT or IO combination therapy warrants further analysis.
In this study, IO combination therapy resulted in a significantly better OS in poor-risk patients, but not in intermediate-risk patients. Rini et al. (14) reported that the median PFS with first-line sunitinib in patients with IMDC poor-risk RCC was 2.4 months. Heng et al. (15) showed that the median OS of IMDC poor-risk patients was 7.8 months. In a Japanese cohort, Naito et al. (16) reported that the median PFS and OS with first-line MTT were 4.9 and 11.5 months, respectively. In the present study, the median OS in the MTT and IO combination therapy poor-risk groups was 15.2 and 22.9 months, respectively, with NIVO + IPI used in the majority of patients at poor risk. The CheckMate 214 trial showed that NIVO + IPI significantly prolonged the survival in IMDC intermediate- and poor-risk patients (17), which is consistent with our results.
Recent studies have reported that the PD-L1 and PD-L2 positivity, tumor mutation burden, and circulating inflammatory markers, such as the NLR, monocyte-to-lymphocyte ratio, CRP levels, neutrophil counts and absolute lymphocyte counts, are useful predictive factors in patients with aRCC who are treated with ICIs (1, 18-24). In this study, no significant correlations were found between the therapeutic effects of the IO combination and inflammatory biomarkers, such as the NLR and CRP levels (Data not shown). Prior nephrectomy seems to be associated with a better PFS outcome. However, the significance of cytoreductive nephrectomy in the IO combination therapy is still controversial (25-27). Therefore, further studies are needed to validate the usefulness of cytoreductive nephrectomy in aRCC and find useful biomarkers for the therapeutic efficacy of IO combination therapy.
The present study has several limitations. First, this was a retrospective study from a single institution, and thus, there is a possibility of selection bias. Second, the number of patients, especially those at favorable risk, was limited. Third, a relatively short follow-up time in the IO combination group made interpreting the OS results difficult. A previous report has shown a treatment duration effect of NIVO + IPI and the need for a long-term follow-up to accurately determine the OS (28). Further confirmation of these findings in larger and more diverse populations will be required.
In conclusion, our real-world data showed that IO combination therapy significantly improved the PFS of patients with aRCC, especially those with intermediate- and poor-risk disease. There was no statistically significant difference in OS between first-line MTT and IO combination therapy because of a short follow-up period. Further investigations focusing on the improvement of survival are warranted.
Footnotes
Authors’ Contributions
KU drafted the manuscript. SS contributed to the manuscript. KU, HK, NI and NO have contributed to data collection. KU, SS, HK, TH, KC, KE, KU, MN, KN and MM have performed the clinical follow-up. KU, SS and TI were responsible for the conception and design of this study, interpretation of the data, and critical revision of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare that there are no conflicts of interest in relation to this study.
- Received July 5, 2022.
- Revision received July 19, 2022.
- Accepted July 20, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
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