Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non–Clear Cell Renal Cell Carcinoma

Gupta, Ruby; Ornstein, Moshe Chaim; Li, Hong; Allman, Kimberly D; Wood, Laura S.; Gilligan, Timothy D.; García, Jorge A.; Merveldt, Dendra Von; Hammers, Hans J.; Rini, Brian I.

doi:10.1016/j.clgc.2019.11.012

Cited by 48 publications

(51 citation statements)

References 17 publications

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“…Recently, the efficacy of ICIs in metastatic non-clear-cell RCC patients has been reported. 6 Indeed, our data also showed a tendency for improved survival due to nivolumab therapy, compared to that with mTTs (Fig. S2b).…”

supporting

confidence: 58%

Effect of improved systemic therapy on patient survival in metastatic non‐clear‐cell renal cell carcinoma

et al. 2021

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Non-clear-cell RCC accounts for up to 25% of all kidney cancers. 1 The survival rate of patients with metastatic non-clear-cell RCC has been reported to be worse than that of patients with metastatic clear-cell RCC. 2 Pivotal clinical trials have demonstrated the efficacy of mTTs or ICIs against metastatic clear-cell RCC, which has led to upgrading of systemic therapy strategies for such disease. 3 However, there is still a paucity of information on how these improved therapies affect survival in patients with metastatic non-clear-cell RCC. In the present study, therefore, we aimed to investigate the relationship between different time periods of initiation of systemic therapy strategies and the associated survival rates in such populations.We retrospectively analyzed 38 patients with metastatic non-clear-cell RCC treated with systemic therapy between January 2008 and December 2018 at two Japanese institutions. In all 38 patients, OS after the initiation of first-line therapy was 15.4 months (95% CI 12.4-23.8; Fig. S1). The objective response rate was 13% (n = 5; Table S1). The patients were divided into two groups based on the date of initiation of therapy; patients in whom therapy was initiated in the period 2008-2011 and those in whom therapy was initiated in 2012-2018 were categorized into an early (n = 12) and a late therapy initiation period group (n = 26), respectively. There was no significant difference in patient characteristics between the periods (all P > 0.05), except for lymph node metastasis status (P = 0.0336; Table S2). OS was significantly longer among the patients in the late therapy initiation period group than among those in the early group (P = 0.0009; Fig. 1a). Multivariate analysis showed further that systemic therapy initiation period was an independent factor for OS (P = 0.0067), together with the International Metastatic Renal Cell Carcinoma Database Consortium risk (P = 0.0198) and liver metastasis status (P = 0.0452; Table S3). The number of lines of therapy showed an increasing trend according to systemic therapy initiation period, and nivolumab was administered only in the late period (Table S4). Subsequent therapy and nivolumab administration appeared to improve OS (Fig. S2a: P = 0.0048; and Fig. S2b: P = 0.133, respectively). On comparing OS between the entire metastatic non-clear-cell RCC population and the metastatic clear-cell RCC population (n = 182), OS was significantly shorter in the metastatic non-clearcell RCC population (P = 0.0001; Fig. S1); this was consistent with the results of a previous study conducted in the mTT setting. 2 In the early therapy initiation period group, OS was significantly shorter in the metastatic non-clear-cell RCC population than in the metastatic clearcell RCC population (P < 0.0001; Fig. 1b), whereas the difference was statistically insignificant in the late therapy initiation period group (P = 0.104; Fig. 1c).This analysis demonstrates that advancements in systemic therapy in the last decade have positively influenced survival in patients ...

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confidence: 58%

Effect of improved systemic therapy on patient survival in metastatic non‐clear‐cell renal cell carcinoma

et al. 2021

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“…Five patients in our cohort had variant histology (non‐clear cell) RCC, which could have also contributed to the poor outcome. A recently published retrospective analysis of 18 patients with non‐clear cell mRCC treated with nivo/ipi showed a third of the patients achieving a PR and 16.7% achieving SD, with median PFS of 7.1 months and a 12‐month OS probability of 64.2% 20 …”

Section: Discussionmentioning

confidence: 99%

Outcomes of patients with intermediate‐risk or poor‐risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience

Alhalabi

Hasanov

Wilson³

et al. 2021

Intl Journal of Cancer

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Nivolumab plus ipilimumab (nivo/ipi) is an approved therapy for patients with intermediate-risk or poor-risk metastatic renal cell carcinoma (mRCC). Clinical factors that guide the selection of this regimen for patients with mRCC are urgently needed. We retrospectively analyzed medical records of patients with mRCC who were hospitalized at MD Anderson Cancer Center because of cancer-related symptoms and received their first cycle of nivo/ipi in the inpatient setting. Clinical parameters, including demographics, histology, clinical history, response, and survival, were collected. The 4-month survival probability, progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methods. Between November 2017 and 21 June 2020 patients were identified that fit the search: 19 patients (91%) had poor-risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score; 17 patients (81%) had ≥4 risk factors; and 9 patients (43%) had sarcomatoid features on histology. Shortness of breath (28%) and abdominal pain (19%) were the two most common reasons for hospitalization. Partial response was achieved in 14% (3/21) of patients.Median PFS for all patients was 1.7 months (95% CI 0-3.9); median OS for all patients was 1.7 months (95% CI 0-4.2); and the 4-month survival probability was 36% (95% CI 25%-47%). In this retrospective study, patients with intermediate-risk or poor-risk mRCC who are hospitalized at a large tertiary referral center for cancer-related symptoms derive limited clinical benefit from nivo/ipi when started in the inpatient setting. Alternative, more effective systemic therapies should be considered for these patients.

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“…With a median of 6.8 months at follow-up from the time of the first dose (range: 0.69-12.3 months), five patients were continuing treatment, with an ongoing response. An any-grade irAE occurred in 61% of patients, and a grade ≥3 toxicity was noted in 38% of patients [18]. The response rates and survival outcomes did not match those of CheckMate-214, but this patient population was heavily pretreated before the combination ICI challenge, which further complicates any comparison.…”

Section: Combination Immune Checkpoint Blockade: Ipilimumab and Nivolumabmentioning

confidence: 98%

“…Unfortunately, chromophobe tumors are considered immunologically cold, with very little tumor mutational burden, a weak PD-L1 expression, and a highly suppressive immune environment [9,26]. As such, the ICI efficacy is poor, with virtually no respondents in multiple retrospective studies looking at nivolumab or combination ipilimumab with nivolumab [13,15,18]. However, in CheckMate-374, 2 of the 7 patients with chromophobe RCC had a response, one of which had a complete response [16].…”

Section: Immune Checkpoint Blockade In Select Populations: Chromophobe and Translocation Subtypesmentioning

confidence: 99%

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

Zarrabi

Walzer

Zibelman

2021

Cancers

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Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

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Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non–Clear Cell Renal Cell Carcinoma

Cited by 48 publications

References 17 publications

Effect of improved systemic therapy on patient survival in metastatic non‐clear‐cell renal cell carcinoma

Effect of improved systemic therapy on patient survival in metastatic non‐clear‐cell renal cell carcinoma

Outcomes of patients with intermediate‐risk or poor‐risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

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