The Survival Outcomes of the Metastatic Nonclear Cell Renal Cell Carcinoma in the Immunotherapy Era: Princess Margaret Cancer Centre Experience

Immunotherapy (IO) with or without targeted therapy (TT) is the standard treatment for patients with metastatic clear cell renal cell carcinoma (RCC). The evidence supporting their use in metastatic nonclear cell renal cell carcinoma (nccRCC) subtypes is based on small prospective trials and retrospective analyses. Here, we report survival outcomes for patients with metastatic nccRCC treated with IO and/or TT at the Princess Margaret Cancer Centre, Toronto, ON, Canada. Demographics, disease characteristics, and survival outcomes were collected retrospectively. Overall (OS), progression-free survival (PFS), and objective response rates (ORR) were calculated. We identified 69 patients with metastatic nccRCC treated with IO and/or TT as the first-line treatment, and 36 (52.1%) patients as the second-line treatment. Median OS of the first line IO recipients (n = 12) and non-IO recipients (n = 57) was not reached (NR) and 17.2 months (95% confidence interval (95% CI): 7.3–27.0; P = 0.23), respectively. Median PFS of first-line IO recipients and non-IO recipients was NR and 4.7 months (95% CI: 3.7–5.6; P = 0.019), respectively. The ORR of IO recipients versus non-IO recipients was 50% versus 12.3% (P = 0.007). Median OS of the second-line IO recipients (n = 8) and non-IO recipients (n = 28) was NR and 6.3 months (95% CI: 3.2–9.3; P = 0.003), respectively. Median PFS of second-line IO recipients and non-IO recipients was 4.8 months (95% CI: 2.7–6.8) and 2.8 months (95% CI: 1.8–3.7; P = 0.014), respectively. ORR of IO recipients and non-IO recipients was 37.5% and 3.5%, respectively; P = 0.028. While the number of patients included in our retrospective review was small, our analysis suggested that patients with nccRCC have improved survival outcomes with IO treatment. Validation of prospective dataset is required before widespread clinical utilization.

these subgroups were difficult to ascertain.Currently, the role of IO in the treatment of advanced nccRCC patients is based on smaller prospective trials and retrospective analyses with different survival outcomes, posing a challenge to oncologists to treat and counsel such patients (16).Therefore, real-world data on the efficacy of IO-based treatments for these rare subtypes is essential for treatment planning and counseling.A phase III randomized trial comparing the IO combination (nivolumab + ipilimumab) versus sunitinib in nccRCC is ongoing (NCT03075423).
Herein, we report a real-world experience of the survival outcomes of patients with nccRCC treated at the Princess Margaret Cancer Centre, Toronto, ON, Canada with IO and/ or TT in the first-and second-line treatment settings.

Patients and data collection
Patients with metastatic nccRCC treated with IO and/or TT at our cancer center from July 2002 to July 2021 were included in this study to permit sufficient follow-up.The study received ethics approval from University Health Network, Research Ethics Board (REB #17-6284.7).Patient demographics and disease characteristics were obtained from the electronic health records.Baseline variables, such as age, gender, eastern cooperative oncology group performance status (ECOG PS), International Metastatic Renal cell carcinoma database consortium (IMDC) score, date of nephrectomy, baseline lactate dehydrogenase (LDH) level, and sites of distant metastasis, were collected.Pathological reports were carefully reviewed to determine the histological subtypes and presence of sarcomatoid or rhabdoid features.We also collected data on first-and second-line treatment settings, response to treatment (which was defined according to RECIST 1.1) (17), date of progression, and date of death were collected for survival analysis.

Statistical analysis
Baseline demographics, and clinical and laboratory characteristics were described using absolute numbers and proportions for categorical variables and medians with interquartile ranges reported for continuous variables.For survival calculations, time from the start of treatment to the event of interest was used for PFS (disease progression) and OS (death

Introduction
Kidney cancer is the 14th most common cancer worldwide with an estimated 430,000 new cases and 179,368 deaths in 2020 (1).It was estimated that 8100 persons in Canada would be diagnosed with kidney cancer, and 1950 in Canada would die from it in 2022 (2).Renal cell carcinoma (RCC) is the most common kidney tumor in adults.The predominant histological subtype of RCC is clear cell type (ccRCC), accounting for approximately 70-90% of cases.This is followed by nonclear cell subtypes (nccRCC), including papillary (10-15%) and chromophobe (3-5%) subtypes (3).XP11.2 translocation RCC is a relatively uncommon and aggressive variant of nccRCC, comprising 0.72-1.6% of adult RCC patients.It is distinguished by chromosomal rearrangements involving the TFE3 gene (4).Unclassified RCC refers to renal tumors that do not conform to any established subtypes.These tumors account for 2-6% of all RCC patients (5).NccRCC subtypes exhibit notable differences in terms of their biological characteristics, clinical behavior, and prognostic outcomes, compared to ccRCC (6).Many studies have documented superior survival rates and a more favorable prognosis in patients with localized nccRCC, compared to ccRCC (7).On the contrary, inferior survival outcomes have been reported in patients who have metastatic papillary type II and XP11.2 translocation (8).
The management of ccRCC with combination immunotherapy (IO) and IO-TT combination approaches is based on a number of randomized clinical trials comparing these treatments with sunitinib (11)(12)(13)(14)(15).However, only a small number of patients with nccRCC were included in these studies, and definite conclusions about the efficacy of these regimens in significance.IBM SPSS Statistics v28 (IBM; Armonk, NY, USA) was used to conduct statistical analyses.
All patients (n = 69) received first-line treatment, with either IO-containing regimens (17.4%) or TT only (82.6%).Most commonly used regimens in the IO treatment group and the TT group were a combination of nivolumab + ipilimumab and sunitinib, respectively.We identified 36 (52%) patients who received the subsequent treatment.Of these, 8 (11.6%) patients received an IO-containing regimen, with nivolumab being the most often used treatment, and 28 (40.6%)patients received a TT, mostly everolimus (Table 2).

Discussion
Advanced nccRCC tumors are uncommon with diverse histological subtypes and variable prognosis (18).The study population included in our analysis was a representative of the patients with advanced nccRCC encountered in the realworld oncology practice.The majority of patients had either papillary, chromophobe, or unclassified nccRCC, consistent with the nccRCC literature's reported epidemiology (3).
Given the rarity of these tumors and the lack of prospective phase III trials to guide management, treatment decisions are extrapolated from the trials of ccRCC leading to increasing use of IO-and IO-TT-based combination approaches (11)(12)(13)(14)(15)19).In the present single-center retrospective analysis, we found that IO-containing regimens were the effective treatment options for nccRCC in both first-and second-line treatment settings, compared to TT.The efficacy was higher in terms of better response rates and PFS (statistically significant), OS (statistically significant in second-line treatment setting).
Preliminary results of the phase II KEYNOTE-B61 study were presented at the European Society for Medical Oncology 2022.The study showed an ORR of 47.6% with an IO-TT regimen (pembrolizumab and Lenvatinib) (n = 82) in patients with advanced nccRCC.Median OS and PFS were not reached in this study (22).Lee et al. reported ORR for cohort 1, which included patients with papillary, unclassified, or translocation-associated RCC (23).The cohort had cabozantinib + nivolumab (n = 40) at 47.5% (95% CI: 31.5-63.9),with a median PFS of 12.5 months (95% CI: 6.3-16.4)and median OS of 28 months (95% CI: 16.3-not evaluable) (23).nccRCC (24).The trial included 165 patients from the phase II KEYNOTE-427 study (cohort B).The authors reported an ORR of 26.7% for all patients.ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified RCC.ORR was 35.3% and 12.1% for PDL1 CPS ≥ 1 and CPS < 1 status, respectively.Median PFS was 4.2 months (95% CI: 2.9 to 5.6); and median OS was 28.9 months (95% CI: 24.3 months-not evaluable) (24).Metastatic RCC with Xp11.2 translocation/transcription factor E3 (TFE3) gene fusion is a rare distinct RCC subtype with aggressive behavior.It is now included in the classification of Microphthalmia-associated Transcriptional factor (MiT) family translocation RCC based on the World Health Organization (WHO) 2016 classification (3).Approximately 10% of patients had high PD-L1 expression (≥ 5% tumor cell membrane staining) (25).A multi-institutional study reported the efficacy of IO therapy in 43 patients with nccRCC, including three patients with metastatic RCC with XP translocation.The response was notable for one patient with PR, one patient with SD, and one patient with progressive disease (PD) (26).In our analysis, we identified one patient with metastatic XP translocation RCC, who received pembrolizumab in the first-line treatment setting and achieved complete remission that lasted for 46 months.During the course of IO therapy, he underwent cytoreductive nephrectomy that showed no viable tumor.AREN1721 is an ongoing phase II randomized clinical trial (NCT03595124) conducted in the United States, enrolling patients with metastatic RCC and an XP translocation to either a combination of nivolumab and axitinib or nivolumab alone to explore the role of IO therapy in this rare disease.

McDermott et al. assessed the efficacy and safety of first-line pembrolizumab for the treatment of advanced
In the present study, we observed better efficacy of IO, compared to TT in the second-line treatment setting (n = 36) in patients who had progressed on previous TT (ORR 37.5% versus 3.5%) with a statistically significant P-value.Significant improvements were also noted in median PFS and OS with IO-based treatments.The most common IO therapy used in our study was nivolumab.
Nivolumab was approved to treat patients with metastatic ccRCC who failed antiangiogenic therapy based on the CheckMate-025 trial.This trial excluded patients with nccRCC (27).The efficacy of nivolumab in patients with advanced nccRCC who had undergone at least one prior treatment in the metastatic setting was demonstrated in a prospective trial conducted by Vogelzang et al. (28).This trial included a cohort of 44 patients from the phase IIIb/ IV CheckMate 374 trial.The cohort had a median follow-up duration of 11 months, ranging from 0.4 to 27 months.The ORR was found to be 13.6% (95% CI: 5.2-27.4).The median PFS was determined as 2.2 months (95% CI:1.8-5.4).Additionally, the median OS was observed as 16.3 months (95% CI: 9.2-not evaluable) (28).Koshkin et al. reported the first retrospective analysis for the survival outcomes of 41 patients with nccRCC treated with nivolumab after the failure of TT (29).Among those patients, 16 (39%) had papillary RCC, 5 (12%) had chromophobe RCC, and 14 (34%) had unclassified RCC.With a median follow-up time of 8.5 months, 7 (20%) had PR and 10 (29%) had SD.Responses were observed in 14% papillary RCC and 36% in unclassified RCC.In the entire cohort, the median PFS was 3.5 months, and the median OS was NR (29).These results suggested that patients who do not receive IO in the first-line treatment setting should be offered IO in the second-line treatment setting.
We acknowledge several limitations in this study.First, it was a nonrandomized, retrospective analysis evaluating a small number of patients with heterogeneous characteristics because of the rarity of the disease.Therefore, the survival benefit shown in this study could be related to other unidentified variables.In addition, this study could not analyze the effectiveness of IO combinations versus IO with TT because of the small number of patients enrolled.Second, the benefit of IO therapy appeared to be driven predominantly by the papillary subgroup, and the effectiveness in other smaller subgroups remained inconclusive.Third, in the last decade, significant advancements have been observed in the treatment of advanced RCC.This is primarily due to the introduction of novel targeted treatments, innovative immunotherapies, and improved supportive care.Half of our cohort received treatment prior to 2015.Consequently, this could have an impact on their survival outcomes.Finally, sunitinib was the most commonly administered TT in the present study group.Cabozantinib, a treatment that showed recently significant prolongation of PFS in papillary RCC patients, compared to sunitinib, was not used in the first-line treatment setting.The absence of cabozantinib could impact the survival outcomes of the TT arm.

Conclusions
While the number of patients included in the present retrospective review was small, our analysis suggested that advanced nccRCC with variable histological subtypes showed potential responsiveness to IO-containing regimens.The outcomes of our study could assist clinicians in selecting the treatment approach for these rare tumors while waiting for more conclusive prospective randomized data.

Supplementary
Table S1: Best response to first-and second-line treatment settings based on histopathological subtype.

Figure 1 :
Figure 1: Kaplan-Meier survival curves of progression-free survival (PFS) and overall survival (OS) of the entire cohort in the first-line treatment.IO: immunotherapy.

Figure 2 :
Figure 2: Kaplan-Meier survival curves of progression free survival (PFS) and overall survival (OS) of the entire cohort in the second-line treatment.IO: immunotherapy.
; CR: complete response; PR: partial response; ORR: overall response rate; SD: stable disease; PD: progressive disease.* No chromophobe patients were identified in the IO group in the first-line treatment setting.

Table 1 :
Patients and disease characteristics.

Table 2 :
Summary of key treatment regimens.

Table 3 :
Response rate in the first-and second-line treatment settings.