Abstract
Background/Aim: CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC. Patients and Methods: Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy. Results: The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR. Conclusion: Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.
The CheckMate 214 study revealed that nivolumab plus ipilimumab (Nivo+Ipi) combination therapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to sunitinib (SUN) in patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk/poor-risk advanced renal cell carcinoma (aRCC) (1). Such survival prolongation may be due to the durable effect of Nivo+Ipi in patients with complete or partial response (CR or PR); the ongoing response rates were 83.7% and 62.5% in patients with CR and PR among intermediate-risk/poor-risk patients at a minimum follow-up of 42 months in the CheckMate 214 study (2).
The exclusion criteria were as follows: patients with non-clear cell RCC, brain metastasis, and poor performance status. Among both the Nivo+Ipi and SUN arms, 79% and 21% of patients had intermediate or poor risk, respectively, and approximately 80% of patients underwent previous nephrectomy before systemic treatment. These strict criteria were important for maintaining internal validity and patient homogeneity within the clinical trial. However, patients treated in routine practice have heterogeneous clinical characteristics. In fact, about half of patients with aRCC had IMDC poor risk, and 10% of them had brain metastasis at the initial diagnosis in the present cases.
Until recently, in the era of molecular targeted therapy (MTT), cytoreductive nephrectomy (CN) has been the standard of care in aRCC, supported by randomized trials and large retrospective studies (3-7). Among prospective trials, the SURTIME trial (NCT01099423) showed longer overall survival with deferred CN than prior CN, despite poor recruitment of eligible candidates (8), and the CARMENA trial (NCT00930033) showed that SUN alone was not inferior to CN followed by SUN (CN-SUN) in patients with aRCC at the Memorial Sloan Kettering Cancer Center (MSKCC); intermediate-risk/poor-risk: 55.6%/44.4% in the CN-SUN group and 58.5%/41.5% in the SUN alone group, respectively (9). Based on these results, deferred CN came to be preferred to prior CN for aRCC patients with poorer risk.
The aim of this retrospective study of actual clinical patients at our single institution was (i) to review the efficacy and safety of Nivo+Ipi and (ii) to investigate the clinical impact of CN following Nivo+Ipi.
Patients and Methods
Ethics. This retrospective study was approved by the Institutional Review Board of Saitama Medical University International Medical Center (SIMC, approval #: 14-049).
Patients. Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 (date of approval for use of Nivo+Ipi in SIMC) and August 2021. In Table I, sixty-one patients with IMDC intermediate-risk/poor-risk were treated by Nivo+Ipi, and 10 of these patients underwent CN following Nivo+Ipi. The therapeutic strategy for each case was selected according to each physician’s judgment based on a clinical discussion.
Patient characteristics.
Routine examination and follow-up. Laboratory values were standardized according to the institutional upper and lower limits of the normal values. Radiological evaluations using computed tomography (CT) and/or magnetic resonance imaging (MRI) were performed every two to three months, while additional CT and elective bone scans were performed when clinically indicated.
Clinical outcome. OS was defined as the time from initiation of first-line therapy to the date of death from any cause or date of censorship from the last follow-up. PFS was defined as the time between the initiation of first-line therapy and radiological progression or cancer-related death. We evaluated the radiological effect based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) (10). Pathological and radiological findings were reviewed by two pathologists (YM and MY) and four radiologists (HT, YO, KN, and YU).
Statistical analyses. The variables of the different groups were compared using the chi-square test or the Mann-Whitney U-test, as appropriate. Laboratory values were standardized according to the institutional upper and lower limits of the normal values. Values are presented as medians and interquartile ranges (IQRs) or confidence intervals (CIs) for continuous variables and as frequencies with percentages for categorical variables. Survival curves were constructed using the Kaplan–Meier method and compared using the log-rank test. The level of significance was set at p<0.05. The above analyses were performed using the Statistical Package for the Social Sciences version 23.0.
Results
Clinical outcomes of patients with aRCC who were treated with Nivo+Ipi in SIMC. The characteristics of the 61 patients with aRCC who started Nivo+Ipi from October 2018 to August 2021 at our single institution are shown in Table I. The median follow-up duration was 13.9 months (IQR=1.3-39.2). RCC patients with a non-clear cell component accounted for 13.1% and those with brain metastases at the time of start treatment accounted for 11.5% of the Nivo+Ipi group. The percentage of patients with IMDC poor risk was 47.5% and those who underwent prior nephrectomy before Nivo+Ipi accounted for 37.7%.
The median OS were not reached (50.2% at 30 months) and the median PFS was 15.9 months (95% CI=7.4-24.4), respectively (Figure 1A and Figure 1B). The objective response rate was 50.8%; 9.8% of patients had a CR (Table II), and the median time to objective response was 3.2 (range=1.3-19.7) months. All patients who achieved CR underwent nephrectomy before Nivo+Ipi. The estimated percentage of patients who sustained an objective response at 30 months was 73.0% (Figure 1C).
Kaplan–Meier curves showing overall survival (A), progression-free survival (B), duration of response (C), and overall survival (D: with or without severe irAEs) of patients treated with nivolumab plus ipilimumab therapy at our institution between October 2018 and August 2021. severe irAE: Immune-related adverse event of grade 3 or higher; NR: not reach; NA: not available.
Clinical outcome.
The immune-related adverse events (irAEs) were of grade 3 or higher in 59.0%; these events due to any cause led to discontinuation of Nivo+Ipi in 37.7% (Table II). OS of the patients with severe irAEs tended to be longer than those without severe irAEs [median (95% CI)=not reached vs. 21.9 (11.3-32.5), p=0.052, Figure 1D]. Twenty-three patients (74%) in the CR/PR group, 11 patients (52%) in the SD group, and two patients (22%) in the PD group had irAEs of grade 3 or higher, respectively (p=0.015). Among severe irAEs, the common irAEs were adrenal insufficiency (14 cases), skin disorders (6 cases), and hepatic disorders (6 cases), respectively. Fortunately, no patient died due to irAEs.
Clinical outcomes of patients treated with CN following Nivo+Ipi. Table III demonstrates the clinical outcomes of the 10 patients who underwent CN following Nivo+Ipi. Histology in most patients was clear cell RCC, and six patients had poor risk. The best responses with Nivo+Ipi included PR in seven cases and SD in three cases. We performed laparoscopic surgery for patients who achieved dramatic shrinkage of the primary tumor (Figure 2A-D and Figure 3A-B). Although all patients safely underwent laparoscopic nephrectomy without conversion to open surgery, surgery was difficult in many cases because of severe adhesion in the renal hilum or with surrounding organs (red arrowhead in Figure 2A).
Clinical outcome of patients who treated with cytoreductive nephrectomy following Nivo+Ipi.
Case 1: Contrast-enhanced CT images and pathological images at initial diagnosis (A, B and E) and after nivolumab plus ipilimumab treatment (C, D, F and G). Red arrow heads indicate invasion to the left psoas muscle of the primary tumor. Yellow arrow heads indicate multiple lung metastases. Blue arrow heads indicate lesions with contrast enhancement within the tumor. Green arrow heads probably indicate lesions consistent with the lesions with contrast enhancement in the CT image (blue arrow heads). fib: Fibrosis.
Case 2: contrast-enhanced CT images and pathological images at initial diagnosis (A and C) and after nivolumab plus ipilimumab treatment (B, D, and E). Yellow arrow heads indicate a left renal tumor. Blue arrowhead indicates lesions with contrast enhancement within the tumor. Red arrow heads probably indicate lesions consistent with the lesions with contrast enhancement in the CT image (blue arrow heads).
All patients underwent pathologically curative nephrectomy; the cancer cells within the specimens were remaining in seven patients (Figure 2E-G), and three patients achieved pathological CR (Figure 3C-E). Four radiologists blindly re-evaluated the radiological responses and predicted the pathological responses considering the change in tumor size based on the RECIST criteria, as well as the change in the enhancement pattern in the tumor. Primary tumors radiologically showed remaining focal enhancement in all cases (blue arrowheads in Figure 2C and Figure 3B); therefore, pathological CR could not be predicted. Only two patients had residual lesions on the image after deferred CN; the remaining patients achieved radiological CR.
Discussion
We reported clinical outcomes of patients with aRCC who were treated with Nivo+Ipi at our Institution, and 10 patients who were treated with nephrectomy after Nivo/Ipi, of whom three cases achieved pathological CR. Consequently, most patients achieved radiological CR due to deferred CN.
Most clinical trials, including the CheckMate 214 trial, have strict eligibility criteria for safety and maintain validity in heterogeneous cohorts with poorer PS, non-specific histologic type, and brain metastases. A retrospective study based on 2,210 patients with aRCC treated with MTT showed that trial-ineligible patients had worse outcomes than eligible patients (11). In the present study, 47.5% of the patients had IMDC poor risk, 13.1% had a non-clear cell component, and 11.5% had brain metastases at initial metastatic diagnosis. However, contrary to our expectations, they gained a clear benefit and results were similar to the clinical outcome in the CheckMate 214 trial, suggesting that Nivo+Ipi treatment could be applicable to a wide variety of aRCC patients. We are looking forward to the results of the CheckMate 920 trial, which included subjects with poorer PS, non-clear cell RCC, and non-active brain metastases (NCT02982954). Unfortunately, approximately 15% of patients showed no response to Nivo+Ipi. Adequate sequential MTT should be administered to the patients within a reasonable period.
Regarding irAEs due to Nivo+Ipi, the CheckMate 214 trial showed that irAEs did not negatively affect long-term OS (2). Our data revealed that the response in patients with irAEs was better than that in those without irAEs during Nivo+Ipi, and that the OS of the patients with severe irAEs tended to be longer than those without severe irAEs. On the other hand, only two of nine non-responders had irAEs of grade 3 or higher: type 1 diabetes mellitus and pituitary adrenal insufficiency in one, and salivary gland inflammation in the other case. We should always strive to detect irAEs earlier for patients treated with immunotherapy, and with Nivo+Ipi in particular.
The CheckMate 214 trial revealed that the clinical benefits of Nivo+Ipi were consistent regardless of the number of IMDC risk factors, whereas no complete responses were observed even in the Nivo+Ipi patients with 4 or more risk factors (12). We basically recommend performing surgery following Nivo+Ipi for patients whose metastatic lesions can be controlled. In the present cohort, only two patients had residual lesions on the image after deferred CN. Consequently, the radiological CR rate achieved was 23% (14 patients including four patients with four or more risk factors). Meanwhile, there are some important issues regarding perioperative management. First, we have to be very careful when deciding the operative procedure because the images at initial diagnosis are more important than after ICI treatment to predict adhesion of the tumor and surrounding tissues due to immunotherapy. Second, our previous report demonstrated an autopsy case of delayed irAE after nivolumab monotherapy for aRCC (13), suggesting that great care should be taken when assessing delayed irAE, even after surgery following immunotherapy.
Some reports have shown that aRCC patients who underwent CN after ICI achieved pathological CR (14, 15). The clinical benefit may be clarified by SWOG 1931, a phase III trial of immunotherapy-based combination therapy with or without CN. Singla et al. reported 10 cases of CN with or without metastasectomy, concluding that nephrectomy following ICI for aRCC was safe and technically feasible with favorable surgical outcomes and pathologic responses (16). Interestingly, among these cases, only one patient (10%) exhibited CR to ICI in the primary tumor, while three of four cases with metastasectomy (75%) had no viable cancer cells. Although the cause of the differences in effectiveness of ICI between primary tumors and metastatic tumors has not been clarified, we also encountered some cases with metastatic lesions that sustainably shrank or disappeared with Nivo+Ipi, but in whom the primary tumor was radiologically visible. Pathologically reviewing the case with pathological CR in Figure 3E, we assumed that a huge primary tumor did not completely disappear because a necrotic or hyalinized lesion in the capsule surrounding the tumor remained, even if some priming lymphocytes infiltrated the tumor.
Pathologically, most of the remaining primary tumors after ICI treatment may contain viable malignant cells, and it is often difficult to diagnose these pathological findings using existing radiological methods. The radiological response assessment of cytotoxic tumor therapies with RECIST, which mainly evaluates the change in tumor size, has been successfully validated in numerous clinical studies (10). Concerning TKI-targeted vascular endothelial growth factor receptor (VEGFR), perfusion CT could predict initial changes in discriminating patients with aRCC as responders and non-responders to sunitinib (17), and use of the apparent diffusion coefficient (ADC) measurement on MRI could be useful to reliably predict responders to systemic treatment with pazopanib (18). To the best of our knowledge, there are few reports indicating whether imaging modalities could evaluate the treatment response to RCC after receiving Nivo+Ipi treatment (19). Further studies are needed to develop methods, including radiological modalities and liquid biopsies, in order to precisely diagnose the response to immunotherapy.
The clinical strengths of this study are that (i) this cohort included the patients with poorer PS, non-clear cell component and/or brain metastases based on the real-world data and (ii) our results showed the clinical impact of CN following Nivo+Ipi as multimodal treatment, not only the clinical benefit of Nivo+Ipi. However, the present study has several limitations. First, it was limited by its retrospective nature, as well as by its short median follow-up, and a limited number of Japanese patients. Furthermore, a systematic therapeutic strategy, such as surgical procedures (open or laparoscopic) and radiotherapy (for bone or brain), has not been standardized by various physicians.
In conclusion, based on our empirical findings, the prognosis of real-world patients with aRCC with intermediate-risk/poor-risk has improved since the approval of ICI. Even in the era of ICI, deferred CN after ICI treatment could be useful for limited cases of aRCC. We suggest that the clinical impact of deferred CN for patients with aRCC might be emphasized by the superior response and longer durability for metastatic lesions delivered by ICI regimens including Nivo+Ipi. We are looking forward to the day when “CN” will mean “curative nephrectomy,” not just “cytoreductive nephrectomy”.
Footnotes
Authors’ Contributions
Conception and design of study, Suguru Shirotake and Koshiro Nishimoto. Collection and assembly of data, Suguru Shirotake and Daisuke Igarashi. Analysis and interpretation of data, Suguru Shirotake, Yu Miyama, Hiroyuki Tajima, Yoshitaka Okada, Ken Nakazawa, and Yoko Usami. Drafting of the article, Suguru Shirotake and Koshiro Nishimoto. Critical revision of the article for important intellectual content, Yasutaka Baba, Masanori Yasuda, Go Kaneko, Kent Kanao, and Masafumi Oyama. Final approval of the article, Suguru Shirotake. All Authors read and approved the version submitted for publication.
Conflicts of Interest
All Authors declare that they have no conflicts of interest regarding this study.
- Received January 29, 2022.
- Revision received February 23, 2022.
- Accepted March 22, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
