Abstract
Background
Sequential systemic therapy after first-line discontinuation in metastatic renal cell carcinoma remains incompletely characterized in routine practice. We aimed to evaluate subsequent systemic therapy initiation in a Japanese real-world cohort and identify clinical factors associated with failure to initiate subsequent therapy.
Patients and methods
The primary analysis used real-world data from the Japanese AGEHA database (n = 518). In the real-world cohort, patient flow after first-line treatment was described, and subsequent systemic therapy initiation was evaluated primarily among patients with discontinuation due to progressive disease (PD) or adverse events (AEs). Multivariable logistic regression was carried out to identify factors associated with failure to initiate subsequent therapy.
Results
Among patients with PD- or AE-related discontinuation, subsequent systemic therapy was initiated in 66.7% of those receiving first-line tyrosine kinase inhibitor (TKI) monotherapy and 59.9% of those receiving immune-oncology (IO)-based regimens. Failure to initiate subsequent therapy was independently associated with poorer Eastern Cooperative Oncology Group performance status and receipt of IO-based first-line regimens, whereas discontinuation due to PD was associated with a higher likelihood of subsequent therapy initiation.
Conclusions
Failure to initiate subsequent therapy after first-line discontinuation was not uncommon in real-world practice, but its interpretation depended on the denominator definition and treatment context. In the immune checkpoint inhibitor era, lower rates of subsequent therapy initiation may not have the same clinical implications as in the TKI monotherapy era and should be interpreted cautiously.
Key words: immune-oncology, metastatic renal cell carcinoma, real-world data, subsequent therapy, treatment sequencing
Graphical abstract
Highlights
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Subsequent therapy rates after 1L discontinuation ranged from 44% to 76% in RCTs.
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In practice, 67% on TKI and 60% on IO-based regimens received subsequent therapy.
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Poor ECOG PS and IO-based 1L therapy were linked to no subsequent therapy.
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Subsequent therapy rates depended on denominator choice and treatment context.
Introduction
The treatment landscape for metastatic renal cell carcinoma (mRCC) has evolved substantially over the past decade, with immune-oncology (IO) agents and tyrosine kinase inhibitors (TKIs) establishing new standards of care in first-line therapy. Pivotal randomized controlled trials (RCTs) have demonstrated significant survival benefits with both IO–IO and IO–TKI combinations,1, 2, 3, 4, 5, 6, 7 leading to their widespread adoption in clinical practice.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 However, it is well recognized that RCT participants often differ from patients in real-world settings, as trial eligibility criteria tend to select younger individuals with better performance status and fewer comorbidities.20, 21, 22, 23, 24 These differences may influence not only the outcomes of first-line therapy but also the feasibility and frequency of subsequent treatment.
Despite the growing complexity of first-line treatment strategies in mRCC, the frequency with which patients proceed to subsequent systemic therapy after discontinuation of first-line treatment remains incompletely characterized in routine practice.25, 26, 27, 28 Although pivotal RCTs have reported subsequent therapy exposure to varying degrees, differences in study design, patient selection, and reporting standards limit direct comparison across trials and with real-world data.
In this study, we summarized reported rates of subsequent systemic therapy initiation in pivotal phase III RCTs as contextual background and carried out a retrospective real-world cohort analysis using the Japanese multicenter AGEHA database. Our primary aim was to evaluate subsequent therapy initiation after first-line discontinuation in real-world practice and to explore clinical factors associated with failure to initiate subsequent therapy.
Patients and methods
Study design and ethics statement
The primary analytic component of this study was a retrospective real-world cohort analysis using the Japanese multicenter AGEHA database to evaluate subsequent systemic therapy initiation after first-line treatment discontinuation in patients with mRCC. In addition, as an exploratory contextual component, we descriptively summarized reported rates of subsequent systemic therapy initiation, as well as discontinuation due to progressive disease (PD) or adverse events (AEs), in pivotal phase III RCTs. Because the RCT summary and the real-world cohort analysis differed substantially in study design, patient selection, and available data, the RCT findings were included for contextual interpretation only and are not intended for direct quantitative comparison with the real-world cohort.
Real-world cohort design and data collection
The real-world cohort analysis was conducted using the AGEHA database, a Japanese multicenter retrospective database including patients with genitourinary malignancies treated in routine clinical practice. For the present study, we identified patients with mRCC who received first-line systemic therapy during the study period at participating institutions. Patients with mRCC who initiated first-line systemic therapy between June 2008 and July 2025 were eligible.
Clinical data were collected retrospectively from medical records at each site using a predefined case report framework. Demographic and clinical variables collected included age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), International Metastatic RCC Database Consortium (IMDC) risk category, first-line regimen type (IO–IO, IO–TKI, or TKI monotherapy), histology (clear-cell or non-clear-cell), and reason for first-line discontinuation. IO-based regimens included nivolumab–ipilimumab, avelumab–axitinib, pembrolizumab–axitinib, nivolumab–cabozantinib, pembrolizumab–lenvatinib, and nivolumab–ipilimumab–cabozantinib. TKI monotherapy included axitinib, sunitinib, or cabozantinib. Because cabozantinib monotherapy was represented by only one case, it was included in the overall TKI monotherapy group but was not presented as a separate regimen-specific subgroup. Pazopanib was approved during the study period but not used in this cohort, whereas tivozanib was not approved as a first-line TKI monotherapy option in Japan during most of the study period.
Extracted variables included baseline demographic and clinical characteristics, first-line treatment regimen, reason for first-line discontinuation, and receipt of subsequent systemic therapy or best supportive care (BSC). Patients who discontinued first-line treatment for any reason were included in the descriptive real-world cohort summary. For the primary analysis of subsequent systemic therapy initiation, we focused on patients who discontinued first-line treatment due to PD or AEs, as these were considered the most clinically relevant settings in which transition to subsequent systemic therapy would generally be expected. In this dataset, discontinuation reasons other than PD or AEs were limited to death or local intervention. These cases were described separately in the real-world cohort but were not included in the primary analysis of subsequent systemic therapy initiation.
Exploratory summary of pivotal RCTs
As an exploratory contextual component, we identified pivotal phase III RCTs evaluating first-line systemic therapy for mRCC: CheckMate 214 (median follow-up, 99.1 months), COSMIC-313 (median follow-up, 17.7 months), JAVELIN Renal 101 (median follow-up, 73.6 months), KEYNOTE-426 (median follow-up, 67.2 months), CheckMate 9ER (median follow-up, 44 months), and CLEAR (median follow-up, 33 months). From the published primary or updated reports and supplementary materials, we descriptively extracted study characteristics, treatment arms, reported patient numbers, rates of subsequent systemic therapy initiation, and reported discontinuation due to PD or AEs when available. This component was intended as a descriptive evidence summary rather than as a formal systematic review or pooled comparative analysis.
Outcomes
The primary outcome was the proportion of patients in the real-world cohort who initiated subsequent systemic therapy after discontinuation of first-line treatment due to PD or AEs. Patients who discontinued first-line treatment for other reasons were summarized descriptively but were not included in the primary analysis. Secondary outcomes were identification of clinical factors associated with failure to initiate subsequent systemic therapy in the real-world cohort and descriptive characterization of reasons for first-line discontinuation. As an exploratory contextual analysis, we also summarized reported rates of subsequent systemic therapy initiation and reported discontinuation due to PD or AEs in pivotal RCTs.
Statistical analysis
Statistical analyses were carried out using BellCurve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan) and GraphPad Prism version 7.00 (GraphPad Software, San Diego, CA). In the real-world cohort, categorical variables were summarized as counts and percentages and compared using two-tailed Fisher’s exact test, as appropriate. Continuous variables were expressed as medians with interquartile ranges and compared between groups using the Mann–Whitney U test.
Descriptive statistics were used to summarize baseline clinical characteristics, reasons for first-line treatment discontinuation, and subsequent treatment exposure in the real-world cohort. Reported rates of subsequent systemic therapy initiation, as well as discontinuation due to PD or AEs in pivotal RCTs, were summarized descriptively and were not subjected to direct statistical comparison with the real-world cohort because of differences in study design, patient selection, and available data.
To evaluate factors associated with failure to initiate subsequent systemic therapy in the real-world cohort, multivariable logistic regression analyses were carried out among patients who discontinued first-line treatment due to PD or AEs. Covariates were selected based on prior knowledge and clinical relevance and included age, sex, IMDC risk category, first-line regimen type (IO-based or TKI monotherapy), histology (clear-cell or non-clear-cell), ECOG PS, and reason for first-line discontinuation. The model was designed as an exploratory transition-focused analysis and therefore included both baseline clinical variables and reason for discontinuation as a clinically relevant transition-related variable. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Potential effect modification between first-line regimen type and ECOG PS was explored by including an interaction term in the logistic regression model. Statistical significance was defined as a two-sided P value <0.05.
Results
Patient characteristics in the real-world cohort
A total of 518 patients with mRCC who received first-line systemic therapy were included in the real-world cohort. Of these, 184 received first-line TKI monotherapy and 334 received IO-based regimens (IO–IO or IO–TKI). Baseline characteristics are summarized in Table 1. Patients treated with IO-based regimens had a higher proportion of disease with favorable IMDC risk status than those receiving TKI monotherapy, whereas non-clear-cell histology was more frequent in the TKI monotherapy group. Age, sex, and ECOG PS were generally comparable between groups.
Table 1.
Baseline characteristics, first-line treatment status, and subsequent systemic therapy in the real-world AGEHA cohort
| All | PD or AE discontinuation |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| TKI |
IO–IO/IO–TKI |
||||||||||
| All TKI | Sunitinib | Axitinib | Cabozantinib | All IO combo | Ave + Axi | Nivo + Cabo | Nivo + Ipi | Pemb + Lenv | Pemb + Axi | ||
| No. of patients | 518 | 184 | 118 | 65 | 1 | 334 | 48 | 41 | 115 | 72 | 58 |
| Median age, years (IQR) | 69 (62-75) | 67 (60-74) | 64 (62-75) | 72 (64-78) | 84 (84-84) | 69 (63-75) | 72 (68-76) | 69 (63-74) | 68 (61-73) | 67 (61-75) | 72 (63-79) |
| Male | 380 (73) | 143 (78) | 95 (81) | 47 (72) | 1 (100) | 237 (71) | 34 (71) | 31 (76) | 84 (73) | 48 (67) | 40 (69) |
| ECOG PS | |||||||||||
| 0-1 | 439 (85) | 158 (86) | 102 (86) | 55 (85) | 1 (100) | 281 (84) | 41 (85) | 31 (76) | 89 (77) | 65 (90) | 55 (95) |
| >1 | 79 (15) | 26 (14) | 16 (14) | 10 (15) | 0 (0) | 53 (16) | 7 (15) | 10 (24) | 26 (23) | 7 (10) | 3 (5.2) |
| IMDC risk | |||||||||||
| Favorable | 101 (19) | 18 (10) | 12 (10) | 6 (9) | 0 (0) | 83 (25) | 12 (25) | 8 (20) | 23 (20) | 17 (24) | 23 (40) |
| Intermediate | 253 (49) | 98 (53) | 65 (55) | 32 (49) | 1 (100) | 155 (46) | 27 (56) | 16 (39) | 49 (43) | 37 (51) | 26 (45) |
| Poor | 164 (32) | 68 (37) | 41 (35) | 27 (42) | 0 (0) | 96 (29) | 9 (19) | 17 (41) | 43 (37) | 18 (25) | 9 (16) |
| Non-clear cell histology | 74 (14) | 38 (21) | 32 (27) | 6 (9) | 0 (0) | 36 (11) | 3 (6.3) | 8 (20) | 13 (11) | 7 (10) | 3 (5.2) |
| Status after first-line therapy | |||||||||||
| Still on first-line therapy | 115 (22) | 5 (2.7) | 2 (1.7) | 2 (3.1) | 1 (100) | 110 (33) | 13 (27) | 11 (27) | 34 (30) | 37 (51) | 15 (26) |
| Local intervention | |||||||||||
| Cytoreductive nephrectomy | 5 (1.0) | 3 (1.6) | 0 (0) | 3 (4.6) | 0 (0) | 2 (0.6) | 0 (0) | 2 (4.9) | 0 (0) | 0 (0) | 0 (0) |
| Radiofrequency ablation | 1 (0.2) | 1 (0.5) | 0 (0) | 1 (1.5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Death from other causes | 1 (0.2) | 1 (0.5) | 0 (0) | 1 (1.5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| PD or AE discontinuation | 396 (76) | 174 (95) | 116 (98) | 58 (89) | 0 (0) | 222 (66) | 35 (73) | 28 (68) | 81 (70) | 35 (49) | 43 (74) |
| PD discontinuation | 304 (59) | 117 (64) | 79 (67) | 38 (58) | 0 (0) | 187 (56) | 30 (63) | 23 (56) | 73 (63) | 29 (40) | 32 (55) |
| AE discontinuation | 92 (18) | 57 (31) | 37 (31) | 20 (31) | 0 (0) | 35 (10) | 5 (10) | 5 (12) | 8 (7.0) | 6 (8.3) | 11 (19) |
| Subsequent therapy among all patients | 247 (48) | 116 (63) | 81 (67) | 35 (54) | 0 (0) | 131 (39) | 20 (42) | 12 (29) | 54 (47) | 20 (28) | 25 (43) |
| Status of subsequent therapy | |||||||||||
| No. of patients with PD or AE discontinuation | 396 | 174 | 116 | 58 | 0 | 222 | 35 | 28 | 81 | 35 | 43 |
| Subsequent therapy among patients with PD or AE discontinuation | 249 (63) | 116 (66) | 81 (70) | 35 (60) | 0 (0) | 133 (60) | 20 (57) | 14 (50) | 54 (67) | 20 (57) | 25 (58) |
| Axitinib | 70 (18) | 25 (14) | 23 (20) | 2 (3.4) | 0 (0) | 45 (20) | 2 (2.5) | 9 (32) | 29 (36) | 3 (9) | 2 (4.7) |
| Sunitinib | 10 (2.5) | 9 (5.2) | 0 (0) | 9 (16) | 0 (0) | 1 (0.5) | 0 (0) | 1 (4) | 0 (0) | 0 (0) | 0 (0) |
| Temsirolimus | 11 (2.8) | 11 (6.3) | 5 (4.3) | 6 (10) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Sorafenib | 12 (3.0) | 12 (6.9) | 12 (10) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Nivolumab | 26 (6.6) | 15 (8.6) | 8 (6.9) | 7 (12) | 0 (0) | 11 (5.0) | 8 (9.9) | 0 (0) | 1 (1.2) | 1 (3) | 1 (2.3) |
| IL-2 | 1 (0.3) | 1 (0.6) | 1 (0.9) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| IFN-α | 7 (1.8) | 7 (4.0) | 7 (6.0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Everolimus | 28 (7.1) | 27 (16) | 25 (22) | 2 (3.4) | 0 (0) | 1 (0.5) | 0 (0) | 1 (4) | 0 (0) | 0 (0) | 0 (0) |
| Cabozantinib | 58 (15) | 2 (1.1) | 0 (0) | 2 (3.4) | 0 (0) | 56 (25) | 9 (11) | 1 (4) | 22 (27) | 10 (29) | 14 (33) |
| Pazopanib | 7 (1.8) | 7 (4.0) | 0 (0) | 7 (12) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| BSC | 116 (29) | 58 (33) | 35 (30) | 23 (40) | 0 (0) | 58 (26) | 12 (15) | 12 (43) | 13 (16) | 12 (34) | 9 (21) |
| Others | 7 (1.8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 7 (3.2) | 0 (0) | 1 (4) | 3 (3.7) | 1 (3) | 2 (4.7) |
| Unknown | 43 (11) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 43 (19) | 4 (4.9) | 3 (11) | 13 (16) | 8 (23) | 15 (35) |
Values are n (%) within each treatment subgroup unless otherwise indicated. Cabozantinib monotherapy was included in the overall TKI monotherapy group and is shown as a separate column in Table 1 for completeness, but was not treated as a separate regimen-specific subgroup in the main analyses because it was represented by only a single patient.
AE, adverse event; Avel, avelumab; Axi, axitinib; BSC, best supportive care; Cabo, cabozantinib; ECOG PS, Eastern Cooperative Oncology Group performance status; IFN-α, interferon-α; IL-2, interleukin 2; IMDC, International Metastatic RCC Database Consortium; IO, immune-oncology; Ipi, ipilimumab; IQR, interquartile range; Lenv, lenvatinib; Nivo, nivolumab; PD, progressive disease; Pemb, pembrolizumab; TKI, tyrosine kinase inhibitor.
Patient flow after first-line therapy in the real-world cohort
Patient flow after first-line therapy is shown in Figure 1. Among the 518 patients, 396 discontinued first-line treatment because of PD or AEs, including 174 in the TKI monotherapy group and 222 in the IO-based group. PD-related discontinuation occurred in 304 patients overall, whereas AE-related discontinuation occurred in 92 patients. In addition, 115 patients remained on first-line therapy at the time of data cutoff, while the remaining patients discontinued treatment because of death from other causes or local intervention.
Figure 1.
Patient flow and subsequent treatment disposition in the real-world AGEHA cohort. A total of 518 patients with mRCC who received first-line systemic therapy in the AGEHA database were included in the real-world cohort. Patients were categorized according to first-line treatment type as TKI monotherapy or IO-based therapy (IO–IO or IO–TKI). For each group, the numbers of patients with first-line discontinuation due to PD or AEs, as well as those who remained on first-line therapy, underwent local intervention, or died from other causes, are shown. Among patients who discontinued first-line therapy because of PD or AEs, subsequent management was classified as initiation of subsequent systemic therapy or BSC. AEs, adverse events; BSC, best supportive care; mRCC, metastatic renal cell carcinoma; PD, progressive disease; TKI, tyrosine kinase inhibitor.
Among patients with PD- or AE-related discontinuation, 249 proceeded to subsequent systemic therapy, whereas the remaining patients received BSC. In the TKI monotherapy group, 116 of 174 patients (66.7%) initiated subsequent therapy, compared with 131 of 222 patients (59.9%) in the IO-based group.
Regimen-specific rates of subsequent systemic therapy initiation in the real-world cohort
Regimen-specific rates of subsequent systemic therapy initiation among patients with PD- or AE-related discontinuation are shown in Figure 2A. The rate of subsequent initiation was 66.7% for first-line TKI monotherapy and 66.7% for nivolumab–ipilimumab, compared with 57.1% for avelumab–axitinib, 58.1% for pembrolizumab–axitinib, 57.1% for pembrolizumab–lenvatinib, and 50.0% for nivolumab–cabozantinib.
Figure 2.
Subsequent systemic therapy initiation and factors associated with failure to initiate subsequent therapy in the real-world cohort. (A) Regimen-specific rates of subsequent systemic therapy initiation among patients who discontinued first-line treatment because of PD or AEs. Cabozantinib monotherapy was included in the overall TKI monotherapy group but is not shown separately because it was represented by only one patient. (B) Multivariable logistic regression analysis of factors associated with failure to initiate subsequent systemic therapy among patients with PD- or AE-related discontinuation in the real-world cohort. ORs with 95% CIs are shown. Receipt of an IO-based first-line regimen and poorer ECOG PS were independently associated with a higher likelihood of failure to initiate subsequent therapy, whereas discontinuation due to PD was associated with a lower likelihood of failure to initiate subsequent therapy. No significant interaction was observed between first-line regimen type and ECOG PS. AEs, adverse events; Avel, avelumab; Axi, axitinib; Cabo, cabozantinib; CIs, confidence intervals; ECOG PS, Eastern Cooperative Oncology Group performance status; IMDC, International Metastatic RCC Database Consortium; IO, immune-oncology; Ipi, ipilimumab; Lenv, lenvatinib; Nivo, nivolumab; PD, progressive disease; Pemb, pembrolizumab; TKI, tyrosine kinase inhibitor.
Factors associated with failure to initiate subsequent systemic therapy
Multivariable logistic regression analysis among patients with PD- or AE-related discontinuation is shown in Figure 2B. Poorer ECOG PS and receipt of an IO-based first-line regimen were independently associated with failure to initiate subsequent systemic therapy. Specifically, IO-based first-line therapy was associated with a higher likelihood of failure to initiate subsequent therapy (OR 1.64, 95% CI 1.04-2.61, P = 0.035), and poorer ECOG PS was also associated with failure to initiate subsequent therapy (OR 1.32 per unit increase, 95% CI 1.02-1.70, P = 0.032). In contrast, discontinuation due to PD was associated with a higher likelihood of proceeding to subsequent therapy (OR 0.34 for failure to initiate, 95% CI 0.18-0.66, P = 0.001). No significant interaction was observed between first-line regimen type and ECOG PS (P for interaction = 0.88).
Impact of denominator definition on subsequent therapy initiation rates
The influence of denominator definition on subsequent therapy initiation is shown in Figure 3A. When all first-line treated patients were used as the denominator, the corresponding rates were 63.0% for first-line TKI monotherapy, 47.0% for nivolumab–ipilimumab, 43.1% for pembrolizumab–axitinib, 41.7% for avelumab–axitinib, 29.3% for nivolumab–cabozantinib, and 27.8% for pembrolizumab–lenvatinib. In contrast, when the denominator was restricted to patients with PD- or AE-related discontinuation, the corresponding rates ranged from 50.0% to 66.7%. The difference between these two definitions mainly reflected whether patients who were still receiving first-line therapy were included in the denominator.
Figure 3.
Influence of denominator definition and treatment status distribution on subsequent systemic therapy initiation in the real-world cohort. (A) Regimen-specific rates of subsequent systemic therapy initiation according to denominator definition. Bars show the proportion of patients who initiated subsequent systemic therapy when calculated either among all first-line treated patients or only among patients with PD- or AE-related discontinuation. The difference between the two bars mainly reflects whether patients still receiving first-line therapy are included in the denominator. (B) Distribution of treatment status after first-line therapy by regimen in the real-world cohort. Stacked bars show the proportions of patients with PD-related discontinuation, AE-related discontinuation, ongoing first-line therapy, local intervention, or death from other causes. These differences in treatment status distribution largely explain the discrepancy between subsequent therapy initiation rates calculated using the two denominator definitions. 1L, first-line; AE, adverse event; Avel, avelumab; Axi, axitinib; Cabo, cabozantinib; Ipi, ipilimumab; Lenv, lenvatinib; Nivo, nivolumab; PD, progressive disease; Pemb, pembrolizumab; TKI, tyrosine kinase inhibitor.
Reasons for first-line treatment discontinuation or continuation by regimen
The distribution of treatment status by regimen is shown in Figure 3B. PD-related discontinuation accounted for ∼40.3% to 66.9% of patients across regimens, whereas AE-related discontinuation ranged from 7.0% to 30.8%. The proportion of patients still receiving first-line therapy also varied substantially across regimens, ranging from 1.7% to 51.4%, and was highest in the pembrolizumab–lenvatinib group. These differences in ongoing first-line treatment largely explained the discrepancy between subsequent treatment rates calculated among all first-line treated patients and those calculated only among patients with PD- or AE-related discontinuation.
Exploratory contextual summary of pivotal RCTs
As an exploratory contextual analysis, reported rates of subsequent systemic therapy initiation in six pivotal phase III RCTs are summarized in Table 2 and Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2026.100733. Across these studies, the reported proportion of patients receiving subsequent systemic therapy ranged from 44.4% to 75.9%. Among experimental arms, reported rates were 66.7% for nivolumab–ipilimumab in CheckMate 214, 69.9% for nivolumab–ipilimumab–cabozantinib in COSMIC-313, 62.2% for pembrolizumab–axitinib in KEYNOTE-426, 69.6% for avelumab–axitinib in JAVELIN Renal 101, 44.4% for nivolumab–cabozantinib in CheckMate 9ER, and 55.5% for pembrolizumab–lenvatinib in CLEAR. Because these trial populations differed in eligibility criteria, follow-up duration, and reporting structure, these data were interpreted descriptively as contextual background rather than as directly comparable estimates (Table 2).
Table 2.
Reported rates of subsequent systemic therapy initiation and reasons for first-line discontinuation in pivotal phase III RCTs of mRCC
| Trial name | Publication | Trial arms | All | PFS or discontinuation events | Any subsequent systemic therapy | % | AE-related discontinuation (%) | PD-related discontinuation (%) | Other reasons for first-line discontinuation (%) |
|---|---|---|---|---|---|---|---|---|---|
| CheckMate 214 | Tannir et al.29 Ann Oncol. 2024 |
Nivo + Ipi | 550 | 478 | 319 | 66.7% | 26.0% | 47.7% | 16.6% |
| Sun | 546 | 513 | 381 | 74.3% | 13.3% | 66.3% | 17.8% | ||
| COSMIC-313 | Choueiri et al.5 N Engl J Med. 2023 |
Nivo + Ipi + Cabo | 428 | 186 | 130 | 69.9% | 29.6% | 45.8% | 12.2% |
| Nivo + Ipi | 427 | 216 | 136 | 63.0% | 21.4% | 53.1% | 10.3% | ||
| KEYNOTE-426 | Rini et al.6 Nat Med. 2025 |
Pemb + Axi | 432 | 381 | 237 | 62.2% | 12.1% | 21.0% | 7.9% |
| Sun | 429 | 406 | 300 | 73.9% | 13.4% | 33.2% | 10.4% | ||
| JAVELIN Renal 101 | Choueiri et al.1 Ann Oncol. 2025 |
Avel + Axi | 442 | 411 | 286 | 69.6% | NA | NA | NA |
| Sun | 444 | 434 | 319 | 73.5% | 14.6% | 59.9% | 23.2% | ||
| CheckMate 9ER | Powles et al.3 ESMO Open. 2024 |
Nivo + Cabo | 323 | 261 | 116 | 44.4% | 11.9% | 55.0% | 26.6% |
| Sun | 328 | 328 | 148 | 45.1% | 12.2% | 66.2% | 16.9% | ||
| CLEAR | Choueiri et al.4 Lancet Oncol. 2023 |
Pemb + Lenv | 355 | 238 | 132 | 55.5% | NA | 39.4% | NA |
| Sun | 357 | 291 | 221 | 75.9% | NA | 56.3% | NA |
Reported values were extracted descriptively from published primary reports, updated analyses, and supplementary materials. Because reporting of discontinuation categories and subsequent systemic therapy varied across trials, these data are presented as contextual background only and are not intended for direct quantitative comparison with the real-world AGEHA cohort. COSMIC-313 enrolled only patients with intermediate or poor risk disease.
AE, adverse event; Avel, avelumab; Axi, axitinib; Cabo, cabozantinib; Ipi, ipilimumab; Lenv, lenvatinib; mRCC, metastatic renal cell carcinoma; NA, not available; Nivo, nivolumab; PD, progressive disease; Pemb, pembrolizumab; PFS, progression-free survival; RCTs, randomized controlled trials; Sun, sunitinib.
Discussion
Subsequent systemic therapy after first-line discontinuation remains an important but incompletely characterized aspect of mRCC care in routine practice. In this Japanese multicenter real-world cohort, subsequent treatment was initiated in 66.7% of patients receiving first-line TKI monotherapy and 59.9% of those receiving IO-based regimens among patients who discontinued first-line therapy because of PD or AEs. Poorer ECOG PS and receipt of an IO-based first-line regimen were independently associated with failure to initiate subsequent therapy, whereas discontinuation due to PD was associated with a higher likelihood of subsequent treatment initiation. These findings suggest that barriers to subsequent therapy in routine practice are likely multifactorial and may include impaired general condition, treatment-related burden, and the clinical context of first-line treatment discontinuation. Together, these results indicate that transition from first-line to subsequent therapy is not uniform in real-world practice.
A key finding of this study is that the interpretation of subsequent treatment exposure depends strongly on the denominator used. When all patients who initiated first-line therapy were used as the denominator, subsequent treatment rates were lower overall than when the analysis was restricted to patients with PD- or AE-related discontinuation. This difference mainly reflects whether patients who were still receiving first-line therapy are included in the denominator. Thus, a lower proportion of subsequent therapy among all first-line treated patients does not necessarily indicate poorer treatment sequencing because it may also reflect longer disease control or prolonged continuation of first-line therapy. We therefore considered the PD/AE-focused framework more directly aligned with the clinical question of whether patients who reached a treatment-discontinuing event were able to proceed to subsequent systemic therapy.
However, the PD/AE-based denominator also requires careful interpretation. In the TKI monotherapy era, failure to proceed to subsequent treatment after first-line discontinuation may often have represented a relatively unfavorable course. In the immune checkpoint inhibitor era, however, the same observation may not carry identical clinical meaning. Some patients treated with IO-based regimens may experience durable disease control without an immediate need for subsequent systemic therapy even after discontinuation of first-line treatment. This concept is supported by recent real-world data from the IMDC cohort that demonstrated the clinical relevance of treatment-free survival in patients with mRCC receiving first-line therapy.30 Accordingly, lower rates of subsequent initiation after IO-based therapy may reflect not only barriers to treatment sequencing but also sustained benefit after first-line therapy in selected patients. This distinction could not be fully resolved in the present dataset and should be considered when interpreting lower rates of subsequent exposure in contemporary practice.
The finding that IO-based first-line regimens were associated with lower subsequent treatment initiation also warrants cautious interpretation. Treatment-related toxicity may affect the ability to proceed to subsequent therapy, and post-IO treatment sequencing may be less straightforward in some situations than sequencing after historical TKI monotherapy. Real-world physician decision making, patient preference, and institutional practice patterns may also contribute. In addition, durable responses after IO-based therapy may reduce the immediate need for subsequent treatment.30 Lower subsequent treatment exposure after IO-based regimens should therefore not be interpreted simply as inferior treatment delivery or reduced overall clinical benefit.
By contrast, discontinuation due to PD was associated with a higher likelihood of subsequent initiation. This is clinically plausible, as patients with progression often have a clear indication for treatment change, whereas those discontinuing because of toxicity may follow more heterogeneous trajectories. Some may later receive subsequent therapy, whereas others may remain untreated because of frailty, persistent toxicity, competing illness, or limited perceived benefit. This asymmetry between PD- and AE-related discontinuation is an important real-world feature of treatment sequencing and supports the value of distinguishing reasons for first-line discontinuation when evaluating subsequent exposure.
The exploratory summary of pivotal RCTs provided context, but these data should be interpreted descriptively. Reported rates of subsequent therapy initiation varied widely across the selected trials, which differed in eligibility criteria, follow-up duration, endpoint structure, reporting conventions, and treatment era. In addition, these were global studies conducted across multiple health care systems, and access to subsequent therapies may vary by region, reimbursement systems, drug availability, and local practice. Reported subsequent treatment rates in such trials may therefore not always reflect the feasibility of treatment sequencing in routine practice within a specific health care setting. For this reason, we treated the RCT data as contextual background rather than directly comparable estimates against the AGEHA cohort.
Clinically, our findings suggest that treatment sequencing feasibility deserves attention alongside first-line efficacy when selecting therapy for mRCC. In routine practice, the ability to proceed to subsequent treatment may be shaped by patient condition, tolerability, and the complexity of post-discontinuation management. At the same time, lower observed rates of subsequent initiation should not automatically be interpreted as evidence of treatment failure, particularly in the immune checkpoint inhibitor era. Rather, such rates should be interpreted in light of denominator definition, first-line treatment duration, reason for discontinuation, and the possibility of ongoing benefit without immediate retreatment.
This study has several limitations. Firstly, the real-world analysis was based on a retrospective multicenter Japanese database, and the findings may not be fully generalizable to other populations or health care systems. Secondly, although we evaluated patient flow after first-line treatment, the dataset did not allow detailed adjudication of all post-discontinuation clinical scenarios. In particular, we could not reliably distinguish patients who remained treatment-free because of durable disease control from those who did not receive subsequent therapy for other reasons. We also could not reliably assess patient characteristics at the time of first-line discontinuation, such as interval changes in performance status or cumulative treatment-related burden, which may have influenced the ability to proceed to subsequent therapy. Thirdly, the primary analysis focused on patients with PD- or AE-related discontinuation, which we considered clinically relevant for evaluating transition to subsequent therapy, although alternative denominator definitions may also be appropriate depending on the research question. To address this issue, we additionally presented descriptive analyses using all first-line-treated patients as the denominator. In addition, the multivariable model combined baseline variables with a discontinuation-related variable, which is clinically meaningful for evaluating treatment transition after first-line discontinuation but limits strict temporal interpretation of the regression coefficients. Fourth, the exploratory RCT summary was not a formal systematic review and was limited by heterogeneity in published reporting. Finally, unmeasured factors such as comorbidity, frailty, physician preference, and institutional barriers may also have influenced real-world treatment sequencing.
Conclusions
Subsequent systemic therapy initiation after first-line discontinuation in mRCC is not uniform in real-world practice, and its interpretation depends on denominator definition and treatment context. In the immune checkpoint inhibitor era, lower rates of subsequent initiation should be interpreted cautiously.
Acknowledgements
We thank Ikuya Iwabuchi, Kazuaki Yoshikawa, Hiroyuki Ito, Shoji Nishimura, Satoshi Narita, Hisao Saito, Fumitada Saito, Takaki Ichiyama, Hisashi Sakurai, Anna Yoneyama, Kyo Togashi, Sakae Konishi, Kazutaka Okita, Shogo Hosogoe, Toshikazu Tanaka, Daisuke Noro, Osamu Soma, Yuichiro Suzuki, Noriko Tokui, Kengo Imanishi, Yuki Fujita, and all the participants of the AGEHA Database for their help with data collection.
Informed consent
The study information was publicly disclosed in lieu of written informed consent, and patients could opt out of the study (opt-out approach).
Ethical approval
This study was conducted in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of the Hirosaki University School of Medicine (2021–158–2) and all the hospitals involved in the study.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Funding
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [grant number 25K02769].
Disclosure
SH received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, and Merck Biopharma Co., Ltd. and also received research funding support from Ferring Pharmaceuticals Co., Ltd., Kaneka Corporation, Nipro Corporation, and Oyokyo Kidney Research Institute (Public Interest Incorporated Association). SN received honoraria from Janssen Pharmaceutical K.K., Takeda Pharmaceutical Company Ltd., Astellas Pharma Inc., AstraZeneca K.K., Kyorin, Sysmex, and Bayer AG. TH received honoraria from Janssen Pharmaceutical K.K., Nippon Kayaku Co., LTD., Takeda Pharmaceutical Company Ltd., Astellas Pharma Inc., Daiichi Sankyo Company, Ltd., AstraZeneca K.K., Sanofi S.A., Novartis Pharmaceuticals, and Bayer AG and also received research funding from Mochida Pharmaceutical Co., Novartis Pharmaceuticals Co, Ltd., and Sysmex Co. The other authors have no conflicts of interest to declare.
Supplementary data
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.