A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy

Abstract

Background:

Cytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy.

Objective:

To evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy.

Materials and methods:

A multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality.

Results:

The study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2–79.8) compared to the ST alone group (19.1 months IQR 12.8–23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS.

Conclusions:

CN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.

1. Introduction

The last 2 decades have ushered in a paradigm shift in the treatment of metastatic renal cell carcinoma (mRCC). In the early 2000s, treatments for metastatic disease primarily consisted of cytokine-based therapies including interleukin-2 (IL-2) and interferon-alfa (IFN-alfa) [1]. The approval of tyrosine kinase inhibitor (TKI) therapies in 2004 rapidly supplanted these agents, becoming the standard of care over the following decade [2]. More recently, immune checkpoint inhibitor (ICI) therapy alone or in combination with TKIs have demonstrated superior efficacy and have been adopted as front-line systemic therapy (ST) [3–6].

Cytoreductive nephrectomy (CN) has long been utilized as an adjunct to ST in the treatment of mRCC, however the research supporting CN has not been able to keep pace with the rapid development of new ST modalities. The role of CN was initially supported by 2 randomized controlled trials which evaluated the efficacy of CN in patients receiving IFN-alpha [7,8]. Metanalysis of these trials demonstrated that CN+IFN alpha conferred an overall survival (OS) advantage of 5.8 months compared to IFN alpha therapy alone [9]. Based on these findings, and supported by multiple retrospective studies, CN continued to be incorporated into the treatment of mRCC well into the targeted therapy era [10–13]. The CARMENA and SURTIME trials in 2018 initially upended this thinking, although their generalizability and validity have since been queried given that both trials struggled with timely recruitment and the population ultimately studied in CARMENA had a disproportionate number of patients with poor risk disease [11,14–17].

The questions of who should receive CN and when surgery should occur in the immunotherapy era are critical to answer in a timely fashion with well-designed trials before ST research surpasses the field again. The PROBE trial (NCT04510597) is recruiting patients to evaluate outcomes of immunotherapy-based treatment with or without CN, but is not estimated to report out data regarding its primary end-point until 2033.

Currently, data regarding the utility of CN in patients with mRCC treated with ICI is sparse. A retrospective cohort analysis of the National Cancer Database reported an improved OS among patients treated with CN+ICI therapy compared to patients who received ICI therapy alone (median OS was not reached compared to 11.6 months in the ICI alone group) [18]. With prospective study conclusions years away, there is an urgent need for replication and extrapolation of these results.

In this multicenter retrospective cohort study, we sought to characterize the relative survival outcomes of patients in contemporary clinical practice who had received ICI therapy, comparing patients who received CN+ST vs. ST alone. We also specifically examined outcomes in a subgroup of patients who received immunotherapy as first-line therapy and examined the role that deferring CN after initiation of ST plays in survival. We hypothesized that CN+ST would confer a greater survival advantage compared to ST alone, regardless of when ICI therapy is employed during treatment.

2. Methods

2.1. Study design and patient cohort

A multicenter retrospective review of mRCC patients who received treatment at the Seattle Cancer Care Alliance and The Ohio State University between 2000 and 2020 was completed. Separate IRB approval was obtained at each institution. Treatment with ICI therapy at any point during a patient’s systemic therapy course was required for inclusion in this study. Findings are reported as per the STROBE guidelines.

Clinicopathological features including age, gender, race, dates of RCC and mRCC diagnosis, cancer histology type, metastatic burden and metastatic location were collected from patient charts. Patient risk was assessed using the International Metastatic RCC Database Consortium (IMDC) scale at time of metastatic diagnosis. Initial ICI therapy included treatment with ipilimumab + nivolumab or nivolumab monotherapy. Treatment data included nephrectomy and ST timing as well as ST type, outcome, and any associated grade 3 or above adverse effects. Patients were placed in the CN+ST group if they underwent surgery to remove their primary tumor after they were diagnosed with metastatic disease and also received ST. Patients were placed in the ST group if they did not undergo surgery during their treatment. Patients were coded as having undergone deferred-CN (dCN) if they underwent surgery at any time point after the initiation of ST. Adverse events during ST were determined by the Common Terminology Criteria for Adverse Events Version 5.0 guidelines. ST outcome was designated by the treating physician using formal RECIST v1.1 criteria as complete response (CR), partial response, stable disease, and progressive disease. All data was reviewed and confirmed for accuracy.

2.2. Statistical analyses

Statistical analyses were performed using JMP Pro Version 15.2 software and R Version 4.1.1. Continuous variables were reported as a median (interquartile range, IQR). Categorical variables were reported as a frequency count (percent, %). Either a Wilcoxon, Pearson, or Fisher Exact test was used to compare patients undergoing CN and patients who received ST alone. Kaplan-Meier curves were used to estimate OS. OS was calculated from time of metastatic diagnosis to death. Patients were censored if they were lost to follow up or were alive at last follow up. Multivariable Cox proportional hazards regression was performed to evaluate for predictors of OS and were summarized by the HR and 95% confidence intervals. This multivariable model assessed the association between CN +ST vs. ST alone and risk of all-cause mortality, and adjusted for age at metastasis diagnosis, clear cell vs. non-clear cell histology, total number of metastatic sites, presence of first line ICI therapy, and IMDC risk score. Confounders were selected according to clinicopathological differences between the 2 cohorts and for model parsimony. All hypothesis tests were 2 sided and P < 0.05 was considered statistically significant.

3. Results

We identified 735 patients diagnosed with mRCC between 2000 and 2020 who were subsequently treated with ICI therapy (Fig. 1). Of these, 325 had undergone radical nephrectomy prior to receiving a metastatic diagnosis and were excluded. An additional 43 patients were excluded for missing nephrectomy or ST timing data. Therefore, our final cohort consisted of 367 patients. Of these 135 patients were treated only with ST and 232 patients underwent CN in combination with ST. CN was deferred until after treatment with ST in 30 of these patients. ICI receipt was front line (1L) in 28.1%, second line (2L) in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Median follow-up among all survivors was 28.4 (IQR 13.2–59.7) months. Regardless of treatment group, patients were predominately male, white, and older, with a principle tumor histology subtype of clear cell carcinoma (Table 1). Patients in the CN+ST group were slightly younger (median age: 60 vs. 62, P = 0.02) and had an improved IMDC risk profile (Favorable/Intermediate 82.3% vs. 68.3%, P = 0.01) with fewer overall metastatic sites and fewer CNS and liver metastases. TKI monotherapy was utilized in 62.1% of CN+ST patients and 59.3% of ST alone patients. OS for the whole cohort comparing patients who received CN with ST vs. patients who received ST alone is shown in Fig. 2. Median survival in the CN+ST group was 56.3 months (IQR 50.2–79.8) and median survival in the ST alone group was 19.1 months (IQR 12.8–23.8). This difference in OS was maintained when the groups were stratified by IMDC risk group (Supplemental Figure 1A and B). On multivariable analysis CN was significantly associated with reduced all-cause mortality (hazard ratio [HR] 0.33, 95% confidence interval [95% CI] 0.24–0.45, Table 2). Significant predictors of mortality included non-clear cell histology and poor risk disease by the IMDC classification. Addition of metastatic site location into the multivariable model did not influence the primary outcome of risk of death with CN and was therefore not included in the final analysis to optimize model parsimony.

Fig. 1.

Selection of ST and CN+ST cohorts from all patients with mRCC who received treatment with ICI therapy.

Table 1.

Clinicopathological features of entire cohort comparing patients who received CN+ST to those who received ST alone.

Feature	Systemic therapy with cytoreductive nephrectomy n = 232 Median (IQR) or N (%)	Systemic therapy alone n = 135 Median (IQR) or N (%)	P value
Sex
Male	180 (77.6)	107 (79.3)
Female	52 (22.4)	28 (20.7)	0.71
Race
White	198 (85.3)	119 (88.2)
Black	10 (4.3)	6 (4.4)
Asian	6 (2.6)	1 (0.7)
Other	16 (6.9)	8 (5.9)
Unknown/Missing	2 (0.9)	1 (0.7)	0.74
Age at metastatic diagnosis	60 (52–66)	62 (56–68)	0.02
IMDC
Favorable	13 (5.6)	4 (2.9)
Intermediate	178 (76.7)	89 (65.4)
Poor	38 (16.4)	40 (29.4)
Unknown/Missing	3 (1.3)	2 (1.4)	0.01
RCC histology
Clear cell	159 (68.5)	97 (71.9)
Other	21 (9.1)	25 (18.5)
Unknown	52 (22.4)	13 (9.6)	0.001
Location of metastases
Lymph node	60 (25.9)	41 (30.4)	0.4
Lung	150 (64.7)	82 (60.7)	0.5
Liver	22 (9.5)	25 (18.5)	0.02
Bone	72 (31.0)	53 (39.3)	0.11
CNS	5 (2.2)	12 (8.9)	0.004
Muscle	6 (2.6)	2 (1.5)	0.72
Other kidney	1 (0.4)	3 (2.2)	0.14
Others	57 (24.7)	36 (26.7)	0.61
Number of sites of metastasis
One	115 (49.6)	47 (34.8)
2 or more	103 (44.4)	82 (60.7)
Unknown/Missing	14 (6.0)	6 (4.4)	0.01
Immunotherapy utilization
First-line	47 (20.3)	56 (41.4)
Second line	34 (14.7)	30 (22.2)
Third line or later	151 (65.1)	49 (36.3)	<0.0001
First-line therapy
TKI	103 (44.4)	56 (41.5)
ICI	47 (20.3)	56 (41.5)
Other	82 (35.3)	23 (17.0)	<0.0001
TKI monotherapy exposure in any therapy line
Yes	144 (62.1)	80 (59.3)
No	88 (37.9)	55 (40.7)	0.65
Time to starting systemic therapy (Median, IQR) mo	2.7 (2.0–4.1)	1.4 (0.9–4.1)	<0.0001
Time from diagnosis to nephrectomy (median, IQR) mo	0.9 (0.4–1.9)	NA
Time to ICI therapy (median, IQR) mo	11.6 (3.6–23.1)	2.8 (1.3–7.8)	<0.0001
Median follow-up among survivors (median, IQR) mo	39.9 (18.2–66.9)	13.1 (6.8–20.4)	<0.0001

Fig. 2.

Overall survival of entire cohort comparing patients who received CN+ST versus those who received ST alone.

Table 2.

Multivariable model evaluating risk of death among the entire patient cohort.

Feature	Hazard ratio	95% Confidence ratio	P Value
Cytoreductive nephrectomy	0.33	0.24–0.45	<0.0001
Histology
Clear cell	1.0 (reference)	-	-
Non-clear cell	2.08	1.37–3.15	0.001
Other/Unknown	1.61	1.08–2.39	0.02
Total metastatic sites
Only 1	1.0 (reference)	-	-
2 or more	1.09	0.81–1.47	0.6
Age at metastatic diagnosis	1.00	0.99–1.02	0.7
IMDC risk score
Favorable	1.0 (reference)	-	-
Intermediate	1.24	0.65–2.38	0.5
Poor	2.28	1.13–4.61	0.02
ICI utilization
First line	1.0 (reference)
Second line or later	1.03	0.7–1.53	0.9

Our subgroup analysis of patients who received immunotherapy as a first-line treatment included 103 patients. Of these, 56 (54.3%) were treated with ST only and 47 (45.6%) were treated with CN+ST. Subgroup demographics were similar to the larger cohort (Supplemental Table 1). Median follow-up among survivors in the ST group was 12.5 months (IQR 5.8–16.0) and 19.2 months (IQR 11.8–39.2) in the CN+ST group. Responses to first-line therapy varied significantly between the 2 groups (Table 3).

Table 3.

Systemic therapy response of patients who received first-line ICI therapy.

	CN+ST Median (IQR)	ST alone Median (IQR)	P value
Therapy type
Ipilimumab/Nivolumab	33 (70.2)	44 (78.6)
Nivolumab	14 (29.8)	12 (21.4)	0.33
Time to therapy start (median, IQR) d	80 (62–123)	48 (31–77)	<0.0001
Time on therapy (median, IQR) d	84 (63–174.5)	63 (34–85)	0.01
Best response (%)
CR	9 (19.2)	0 (0)
PR	13 (27.7)	15 (26.8)
SD	11 (23.4)	10 (17.9)
PD	9 (19.2)	18 (32.1)
Unknown	5 (10.6)	13 (23.2)	0.003
Grade 3–4 adverse events experienced (%)
Yes	15 (31.9)	13 (23.2)
No	32 (68.1)	43 (76.8)	.32

The CN+ST group stayed on first-line therapy for a longer duration and demonstrated an improved response profile compared to the ST alone group, with 19.2% of patients achieving CR. The 2 groups experienced similar rates of Grade 3 to 4 adverse events while receiving first-line treatment. The CN+ST group in this analysis again demonstrated an improved OS. The median OS was not reached (IQR 33.3-NR), compared to the ST alone group with a median OS of 14.9 months (IQR 10.9–22.8) (Fig. 3). Multivariable analysis showed that for patients who had received first-line ICI therapy CN was also significantly associated with a decreased risk of all-cause mortality (Table 4).

Fig. 3.

Overall survival of patients who received first-line ICI therapy comparing CN+ST to ST alone.

Table 4.

Multivariable analysis evaluating the risk of death among subgroup of patients who received first-line ICI therapy.

Feature	Hazard ratio	95% Confidence ratio	P Value
Cytoreductive nephrectomy	0.19	0.09–0.43	<0.0001
Histology
Clear cell	1.0 (reference)	-	-
Non-clear cell	3.18	0.65–15.5	0.15
Other/Unknown	1.57	0.73–3.38	0.25
Total metastatic sites
Only 1	1.0 (reference)	-	-
2 or more	1.84	0.87–3.90	0.11
Age at metastatic diagnosis	1.00	0.97–1.04	0.8
IMDC risk score
Favorable	1.0 (reference)	-	-
Intermediate	1.91	0.24–15.4	0.5
Poor	1.86	0.23–15.0	0.6

Of patients undergoing CN, 202 (87%) patients underwent upfront CN and 30 (23%) patients underwent deferred CN (dCN). Patients receiving dCN had a higher proportion of bone metastases at diagnosis but were otherwise similar to those who had upfront surgery (Supplemental Table 2). OS comparing upfront vs. dCN is shown in Fig. 4. Median OS was 72.0 months (IQR 56.3-NR) in the dCN group compared to 53.5 months (IQR 48.7–80.7) in the upfront CN group, however the difference between the 2 groups was not significant by log-rank test (P = 0.37).

Fig. 4.

Overall survival comparing patients who underwent upfront vs. deferred CN.

4. Discussion

In this paper we examined the role of CN for the treatment of mRCC in a multicenter cohort of patients treated with ICI therapy. We found that receipt of CN was independently associated with increased OS compared to treatment with ST alone. This relationship was maintained in a subgroup analysis of patients who received first-line ICI therapy following CN. We observed that patients who underwent CN+ST subsequently remained on first-line ST for a longer duration and had higher rates of CR, without significant differences in adverse events.

CN for mRCC has been theorized to confer several benefits. Surgery can reduce local symptoms and decrease the effects of paraneoplastic syndromes. It is also theorized to work as an adjunct to ST by optimizing the immune environment [19,20]. The immune hypothesis emerged in the 1990s with advances in our understanding regarding the immunogenicity of RCC [21,22]. Early studies with IL-2 demonstrated lower levels of response in patients with the primary tumor in situ compared to patients who had undergone upfront CN [23]. Furthermore, the benefit of cytoreductive surgery combined with ICI therapy has been described in other immunogenic cancers such as melanoma and lung cancer, lending support to its utilization in mRCC [24–26]. The first paper to examine CN in a cohort of mRCC patients who had received ICI therapy looked at 391 patients reported to the National Cancer Database (NCDB) between 2015 and 2016 [18]. Within this cohort, patients who underwent CN+ST had significantly increased OS compared to those who received ST alone (HR 0.23 [95% CI 0.15–0.37]). Median OS in the CN+ST group was not reached compared to the ST alone median OS of 11.6 months (P < 0.001). Our findings of CN+ST demonstrating a greatly increased OS compared to ST alone are consistent with the results from the NCDB.

Patient selection for CN is a crucial consideration as the discussion about increased survivability with CN+ST moves forward. The CARMENA trial was groundbreaking in suggesting that sunitinib alone is not inferior to sunitinib + CN, however the study had limited broader applicability to clinical practice due to a high proportion of poor risk patients, poor recruitment, and cross contamination of study arms [14,15]. The question has now shifted to evaluate how CN should be sequenced into this new immunotherapy landscape and how to best select patients for surgery to optimize survival. In our cohort, stratification by IMDC risk did not change survival outcomes, suggesting that more complicated factors go in to surgical selection. McIntosh et al. evaluated criteria for CN in patients treated with targeted therapy, identifying 9 preoperative risk factors associated with an increased risk of death within a modern cohort of patients with mRCC undergoing CN [27]. Future studies should continue to expand on this with a focus on first-line ICI therapy to best appreciate the post-surgical influence of the tumor immune environment.

Establishment of appropriate timing of CN in relation to ST continues to be an ongoing question. The SURTIME clinical trial was conducted contemporaneously with CARMENA [17]. The authors found that deferred CN did not improve the 28-week progression free rate and that a deferred approach was associated with a higher OS, although this was not statistically significant. We did not find significant differences in OS between patients who received upfront CN or dCN. This result is at odds with previous retrospective analyses which have suggested that dCN had significantly improved OS compared to upfront surgery [28]. Reasons for this are likely multifactorial. Foremost, only 30 patients within our cohort underwent deferred surgery, allowing for limited analytical power. It is also possible that while surgery did occur after ST initiation, performing CN prior to the introduction of ICI therapy would leave the benefits of immune activation still intact. A majority of the dCN patients in our cohort (61.1%) received surgery prior to starting ICI therapy. We also did not collect data as to indications for dCN which could confound survival results.

Our study is limited by several factors. Foremost is its retrospective design and observational nature with the attendant impacts of selection bias, unmeasured confounding, and variation in institutional and provider practice patterns over time which may influence both generalizability and impact the validity of the results. While we did note that associations between CN and reduced mortality were preserved after adjustments for the IMDC scores, our cohort also lacked sufficient comorbidity data to make granular analyses about patient selection. This lack of granular patient-level data and our modest cohort size precluded us from performing propensity score matching techniques in our analysis. The wide range of utilization of ICI across therapy lines and agents is likewise important to acknowledge. ICI therapy has become standard first-line therapy and has even been surpassed by ICI/TKI combinations. The majority of our cohort received immunotherapy as second line treatment or later. While our results are reflective of real-world data and generalizable to clinical practice, this heterogeneity has the potential to limit broader conclusions about direct benefit of CN in relation to ICI therapy. Our subgroup analysis of patients receiving first-line ICI was undertaken to mitigate this effect and demonstrated a stronger association between ST+CN and survival. We were not able to directly compare the relative beneficial effect of CN for patients receiving first-line vs. second-line or later ICI therapy given the progressive temporal nature of utilization of ICI therapy as a first-line treatment and substantial associated confounding.

Nevertheless, the findings presented here add to the emerging literature regarding optimal management of patients with mRCC in contemporary practice. The speed at which immunotherapy has surpassed targeted treatment has left guidance regarding surgery for mRCC unclear. Timely retrospective analyses offer crucial direction until knowledge gaps can be filled with large prospective clinical trials. This report supports previous research suggesting that CN has a strong role to play in the immunotherapy era. Future studies should seek to continue to elucidate optimal patient selection criteria and surgery timing strategies, with a focus on relationships to ICI therapy.

5. Conclusion

We evaluated a large multicenter cohort of patients with mRCC who had received ICI therapy to examine survival relationships among patients who underwent CN+ST vs. ST alone. On multivariable analyses, we observed that CN was associated with improvements in OS. Furthermore, we found that addition of CN to treatment generated much higher rates of CR following first-line ICI therapy without additional rates of grade 3 to 4 adverse events. Our data support the continued use of CN in carefully selected patients with mRCC undergoing treatment with contemporary immunotherapy.