Real-World Efficacy of First-Line Nivolumab Plus Ipilimumab and Its Practical Predictive Biomarkers in Advanced Renal Cell Carcinoma: First Analysis from RENOIR Study (KCSG GU22-13)

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J Korean Cancer Assoc. 2025;.crt.2025.846

Publication date (electronic) : 2025 October 13

doi : https://doi.org/10.4143/crt.2025.846

Jwa Hoon Kim¹, Sang Joon Shin², Woo Kyun Bae³, Se Hyun Kim⁴, Jin Young Kim⁵, Hyeon-Su Im⁶, In-Ho Kim⁷, Il Hwan Kim⁸, Kwonoh Park⁹, Eo Jin Kim¹⁰, Mihong Choi¹¹, Joo Han Lim¹², Hyunho Kim¹³, Kyoungmin Lee¹⁴, Hyo-Jeong Kim¹⁵, Jungmin Jo¹⁶, Hyo Jin Lee¹⁷, Dalyong Kim¹⁸, Byeong Seok Sohn¹⁹, Inkeun Park²⁰, Ji Hyun Park^,21

¹Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

²Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

³Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea

⁴Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

⁵Division of Hemato-Oncology, Keimyung University Dongsan Hospital, Daegu, Korea

⁶Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea

⁷Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

⁸Division of Hemato-Oncology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

⁹Division of Medical Oncology and Hematology, Department of Internal Medicine, Hanyang University Seoul Hospital, Hanyang University College of Medicine, Seoul, Korea

¹⁰Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

¹¹Department of Medical Oncology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu,

¹²Department of Hematology/Oncology, Inha University School of Medicine, Incheon, Korea

¹³Division of Medical Oncology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea

¹⁴Division of Hematology/Oncology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea

¹⁵Division of Hematology-Oncology, Department of Internal Medicine, Maryknoll Hospital, Busan, Korea

¹⁶Department of Medical Oncology, Ewha Womans University Mokdong Hospital, Seoul, Korea

¹⁷Department of Hemato-Oncology, Chungnam National University College of Medicine, Daejeon, Korea

¹⁸Division of Hematology and Medical Oncology, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea

¹⁹Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, Korea

²⁰Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²¹Department of Hemato-oncology, KonKuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea

Correspondence: Ji Hyun Park, Department of Hemato-oncology, Konkuk University Medical Center, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea Tel: 82-2-2030-7852 E-mail: irvineusa@hanmail.net, veropark@kuh.ac.kr

Received 2025 August 8; Accepted 2025 October 11.

Abstract

Introduction

The treatment landscape for advanced renal cell carcinoma (aRCC) has remarkably evolved with the introduction of immune checkpoint inhibitors (ICIs). Several pivotal phase 3 clinical trials [1-5] have demonstrated improved survival outcomes using ICI-based therapies, including double blockade of programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4), or combinations of ICI and tyrosine kinase inhibitor (TKI), compared with sunitinib TKI. Since the CheckMate 214 (CM-214) trial with a long-term follow-up [1,6-8], nivolumab (anti–PD-1 inhibitor) plus ipilimumab (anti–CTLA-4 inhibitor) (NI) has been the first-line standard treatment in the International mRCC Database Consortium (IMDC) [9] intermediate- or poor-risk patients. Various combinations of ICI plus TKI, including nivolumab plus cabozantinib [2], pembrolizumab plus axitinib [3], pembrolizumab plus lenvatinib [4], and avelumab plus axitinib [5], have also been widely used as first-line treatment in patients with aRCC, regardless of IMDC risk groups.

Meanwhile, there have been no studies directly comparing which first-line treatment is better for patients with aRCC. Combinations of ICI and TKI can generally offer rapid tumor shrinkage with a high objective response rate (ORR) while facing substantial toxicity. In contrast, NI as a double ICIs showed a higher ratio of complete response (CR) among responders (11.8/42.4%), a long duration of response (DoR), and long-tail survival with good tolerability in the CM-214 trial [1,8]. However, with NI, approximately 20% of intermediate- or poor–risk patients experience initial disease progression and progression-free survival (PFS) is relatively modest compared with other combination treatment [1,8]. Given that no biomarkers have been currently established to predict and allocate the optimal first-line treatment for each patient with RCC, this study aimed to evaluate the real-world efficacy of first-line NI and to identify patients with aRCC who would more benefit from first-line NI.

Materials and Methods

Results

1. Patients and treatment

The data cut-off for this study was March 2025. The characteristics of the 466 patients are summarized in Table 1. Most patients (92.3%) showed clear-cell histology, whereas 16.3% harbored sarcomatoid components. Most patients were classified into the IMDC intermediate-(62.0%) and poor-(35.8%) risk groups, whereas 2.1% were in the favorable risk group. The most common site of metastasis was the lungs (73.4%).

Table 1.

Baseline characteristics

Approximately one-quarter of the patients (25.4%) had a family history of RCC or other malignancies, and there were various comorbidities. Antibiotics were administered to 166 patients (35.6%) before NI treatment (S1 Table).

The median number of NI treatment cycles was 10 (range, 1 to 134). Approximately 11% of the patients (n=50) completed 2 years of NI treatment and 11 (2.4%) continued nivolumab maintenance beyond 2 years.

2. Efficacy

In the cohort, the ORR was 44.8%, including 5.2% complete response (n=24), and the disease control rate was 74.9%. Progressive disease was identified as the best response in 17.6% of patients (Table 2). For responders, median DoR was 39.8 months (95% confidence interval [CI], 26.1 to 53.6) (Fig. 1A). About a quarter of patients (n=113, 24.2%) obtained DoR ≥ 1 year, and nearly half of them sustained it over 2 years. With a median follow-up duration of 23.7 months (95% CI, 21.7 to 25.7), median PFS and OS were 11.5 months (95% CI, 9.1 to 13.9) and 44.2 months (95% CI, 34.4 to 54.0), respectively (Fig. 2A and B).

Table 2.

Clinical response with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma

Fig. 1.

Kaplan-Meier curves for duration of response (DoR) (A) and DoR according to the achievement of complete response (CR) (B). PR, partial response.

Fig. 2.

Kaplan-Meier curves for progression-free survival (PFS) (A), overall survival (OS) (B), and OS according to the duration of response (DoR) (C). CI, confidence interval; F/U, follow-up; mOS, median overall survival; mPFS, median progression-free survival.

3. Potential predictors of treatment outcomes

1) Response

After multivariate analysis, male sex (vs. female) (odds ratio [OR], 1.9; p=0.02) and lung metastasis (vs. no) (OR, 1.8; p=0.02), were significant independent predictors of achieving an objective response (Table 3). Although it did not reach statistical significance, a trend toward a higher rate of objective response was observed in patients with prior nephrectomy (vs. no) (OR, 1.5; p=0.06) (Table 3).

Table 3.

Multivariate analysis for PFS, OS, and ORR

2) PFS and overall survival

After multivariate analysis, full exposure to 4 cycles of ipilimumab (vs. no) (hazard ratio [HR], 0.3; p < 0.01) was identified as independent predictive factors for better PFS. In terms of OS, durable response (≥ 2 years vs. 1-2 years vs. < 1 year [reference]) (HR, 0.1 and 0.1; p < 0.01 and p < 0.01) as well as full exposure to 4 cycles of ipilimumab (vs. no) (HR, 0.6; p=0.01) were two independent predictors for better OS. Fig. 2C shows that the longer the DoR, the better was the OS (p=0.01). However, IMDC poor risk (vs. intermediate risk) (HR, 1.5; p=0.02), multiple metastatic sites (≥ 4) (HR, 2.0; p=0.01), and sarcomatoid component (vs. no) (HR, 1.8; p=0.01) were significantly associated with inferior OS (Table 3).

3) Durable responders and treatment duration

A summary of the 58 durable responders, who sustained objective response over 2 years, is listed in S2 Table. There were no clinically significant differences in the baseline characteristics between durable and non-durable responders, except for a marginally higher proportion of sarcomatoid components in durable responders than in non-durable responders (27.6% vs. 15.3%, p=0.05). Most patients (86.2%) achieved partial response as their best response, while eight patients achieved CR. In this cohort, achievement of CR was significantly associated with longer DoR (p=0.03) (Fig. 1B). Among durable responders, approximately 40% completed 2 years of NI treatment, but there was no significant difference in survival outcomes according to treatment duration.

There were 50 patients who completed 2 years of NI treatment in the cohort, and 11 (2.4%) continued nivolumab maintenance beyond 2 years. Notably, patients who sustained nivolumab treatment beyond 2 years had numerically longer PFS and OS outcomes, with no deaths reported in this group to date, compared to those who discontinued treatment within 2 years (S3 Fig.). Despite no significant difference in PFS, OS was marginally better in patients who received nivolumab treatment beyond 2 years than in those who discontinued nivolumab treatment at the time of 2 years (p=0.09) (S3 Fig.).

Discussion

RENOIR, the first real-world study for the efficacy and practical biomarkers of first-line NI in Korean patients with mRCC shows 44.8% of ORR, 39.8 months of DoR, 11.5 and 44.2 months of median PFS and OS, which is consistent with those of the pivotal CM-214 trial [1,6-8]. We suggest several practical clinical factors which can help predict enriched benefit of first-line NI treatment in our daily practice.

It is noteworthy that a durable response extended the survival that longer DoR over 2 years significantly improved OS in multivariate analysis, while achieving CR could predict longer DoR. Given that post-ICI anti-tumor responses, which activate and proliferate cytotoxic T cells rather than directly killing cancer cells, may be sustained and are associated with better OS in various cancers [10,11], achieving a longer response may serve as an early indicator of long-term survival in the era of immunotherapy.

Accordingly, identifying candidates who might be durable responders is practically important. Of note, male sex was a significant predictor of response in the study. Clinical evidence has shown that sex-based differences are involved in immunological responses in various cancers [12,13]. A multicenter study of 1,827 patients with mRCC receiving first-line NI or other ICI-TKI treatment reported that females showed inferior OS compared to males in a subgroup of patients with clear cell RCC, sarcomatoid differentiation, or < 50 years of age [14]. The higher frequency of PBRM1 alteration [15,16] or androgen-mediated immune cell dysfunction [14] supported the association of male sex with favorable response to ICI. Nonetheless, further studies are necessary to investigate more scientific rationale whether sex could affect the efficacy of immunotherapy. Lung metastasis was also associated with response achievement. Disparities in ICIs response according to metastatic sites have been reported [17], and the presence of lung metastasis has been considered a predictor of good responses to PD-1 immunotherapy in various cancers. It is because lungs are more immunogenic with increased immune cell infiltration [17]. Regarding prior nephrectomy, showing a trend toward better response, it was also associated with better PFS and all of CR cases were found in patients who underwent prior nephrectomy in our cohort, supported by CM-214 which similarly reported numerically higher ORR in patients with prior nephrectomy (42.5% vs. 38.1%) [1].

In the study, number of metastatic sites (≥ 4) and IMDC poor risk (vs. intermediate) were two independent predictors of poorer OS. The median sum of the diameters of targeted lesions (≥ 64 mm) concordantly showed a negative impact on OS in CM-214 trial, which could also reflect tumor burden similar to the number of metastatic sites [6]. However, IMDC risk assessment was not significant prognostic factor in the CM-214 trial, which highlights the need for further comprehensive validation of IMDC risk factors in the current immunotherapy era.

Interestingly, full exposure to 4 cycles of ipilimumab was significantly associated with better PFS and OS in this study. Although several recent studies have attempted to minimize the induction exposure of ipilimumab when applying NI combination because of the concern about its relatively more toxicity and intolerability than nivolumab [18,19], our result may raise the concern that too low or infrequent dosing of ipilimumab can sacrifice essential therapeutic benefit of NI treatment [19]. Ipilimumab contributes to enhancing earlier immune response and inducing optimal synergy through combined CTLA-4 and PD-1 blockades. And it may be decisively responsible for the durable and deep response with higher CR/PR ratio which define the salience of NI treatment compared to other ICI plus TKI combination in aRCC.

As NI exerts its durability of response in responders, whether to continue ICI after 2-year completion gives another conflicting question outside the trial. Indefinite-duration of ICIs might bring higher rates of treatment-related adverse events than 1-year fixed-duration ICIs in patients with lung cancer [20,21], and financial toxicity is also an obstacle [21]. However, nivolumab maintenance beyond 2 years exerted a marginally positive impact on OS in current study, and all patients are still alive. Thus, the optimal duration of immunotherapy, in terms of maintenance, should be defined in larger series balancing therapeutic benefit and toxicities.

This study has some clear limitations. First, because this was a retrospective study, selection bias may have influenced the results. Second, tumor PD-L1 or complex genomic analyses were not performed to identify potential predictors. Third, although prior studies have suggested that recent antibiotic exposure may modulate ICI efficacy through microbiome alterations, our exploratory analysis—defining antibiotic use within 4 weeks before NI initiation—did not demonstrate a consistent association with outcomes in this cohort. However, the main strength of the study is that the results were inferred from a large cohort of 21 tertiary referral hospitals made by the nationwide Korea Cancer Study Group (KCSG), and additional series with long-term follow-up would be expected.

Collectively, current study confirmed a comparable and competent real-world efficacy of front-line NI treatment in Korean patients with aRCC. Male sex and lung metastasis may serve as clinical predictors of response achievement, and durable response could confer survival benefit. Full exposure to 4 cycles of ipilimumab could independently predict better PFS and OS outcomes, whereas IMDC poor risk and multiple metastatic sites (≥ 4) adversely affect OS. With these results, clinical clues could be added for navigating expanded therapeutic benefit from first-line NI treatment, and defining optimal candidates of the treatment.

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