Clinical outcomes of checkpoint inhibitors in metastatic non-clear cell renal cell carcinoma and clear cell renal cell carcinoma with variant features.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17065-e17065
Author(s):  
Guy vin Chang ◽  
Moataz Ellithi ◽  
Radowan Elnair ◽  
Jonathan Bleeker
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cell Renal Cell Carcinoma ◽  
Durable Response ◽  
Rhabdoid Features

e17065 Background: Checkpoint inhibitors (CPI) are a well-established treatment option for advanced clear cell renal cell carcinoma (ccRCC); however, there is a paucity of data on efficacy of CPI on advanced non-clear cell renal cell carcinoma (nccRCC) and ccRCC with variant (sarcomatoid or rhabdoid) features. Recently, small series have demonstrated benefit for CPI in these entities. Methods: We performed a retrospective review of patients with metastatic nccRCC or ccRCC with variant features, who received a single agent CPI (nivolumab or pembrolizumab) or combination therapy (nivolumab and ipilimumab) between Feb 2016 – Oct 2019 at our integrated community-based health system. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). We used Kaplan-Meier survival analysis for PFS and OS. Results: A total of 26 patients met eligibility criteria; 11 patients with nccRCC (papillary n = 6, chromophobe n = 1, unclassified n = 4), 12 patients with sarcomatoid ccRCC, 2 patients with rhabdoid ccRCC, and 1 patient with both sarcomatoid and rhabdoid features. Sixteen patients received nivolumab, 3 received pembrolizumab, and 7 received a combination of nivolumab and ipilimumab. CPI was halted in 4 patients due to adverse effects including arthralgia, hyperthyroidism, hepatitis, and colitis. Among these 26 patients, 5 patients (19.2%) achieved complete response (CR), 3 patients (11.5%) achieved partial response (PR), and 10 patients (38.5%) had stable disease (SD). All patients who achieved CR or PR had a durable response throughout the follow-up period. At the median follow-up of 16.4 months, median PFS was 14.3 months, and median OS was not reached. Conclusions: In this retrospective series, the ORR of CPI in metastatic nccRCC and ccRCC with variant features was 30.7%, and disease control rate was 69.2%. These findings suggest that CPI may provide significant clinical benefit in patients with nccRCC and ccRCC with sarcomatoid and/or rhabdoid features. Sample size may limit inference and additional studies are needed.

UNISON - nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma (ANZUP 1602): Part 1—Nivolumab monotherapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 325-325
Author(s):  
Craig Gedye ◽  
David William Pook ◽  
Laurence Eliot Miles Krieger ◽  
Carole A. Harris ◽  
Jeffrey C. Goh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cell Renal Cell Carcinoma ◽  
Papillary Type

325 Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses; the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I; 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .

scholarly journals Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma

2018 ◽  
Vol 5 (4) ◽  
pp. 6-13 ◽  
Author(s):  
Juan Chipollini ◽  
Mounsif Azizi ◽  
Charles C Peyton ◽  
Dominic H Tang ◽  
Jasreman Dhillon ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Type I ◽  
Cell Renal Cell Carcinoma ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Papillary Type

The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort. PD-L1 expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) specimens from 45 non-ccRCC patients with available tissue. PD-L1 positivity was defined as ?1% of staining. Histopathological characteristics and oncological outcomes were correlated to PD-L1 expression. Cancer-specific survival (CSS) and recurrence-free survival (RFS) stratified by PD-L1 status were estimated using the Kaplan–Meier method. Median age was 58 years and median follow-up was 40 months. Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14). PD-L1 positivity was noted in nine (20%) patients. PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043). Five-year CSS was 73.2 and 83% for PD-L1 positive and negative tumors, respectively (P = 0.47). Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58). PD-L1 was expressed in a fifth of non-ccRCC cases and was associated with adverse histopathologic features. Expression of biomarkers such PD-L1 may help better risk-stratify non-ccRCC patients to guide treatment decisions and follow-up strategies.

Clinical activity of PD1/PDL1 inhibitors in metastatic non-clear cell renal cell carcinoma (nccRCC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 482-482 ◽  
Author(s):  
Raphael Brandao Moreira ◽  
Rana R. McKay ◽  
Wanling Xie ◽  
Daniel Yick Chin Heng ◽  
Guillermo de Velasco ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Clinical Activity ◽  
Significant Activity ◽  
Cell Renal Cell Carcinoma ◽  
Treatment Naïve ◽  
Retrospective Multicenter Study

482 Background: PD1/PDL1 inhibitors have shown significant activity in the treatment of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC), but their activity in nccRCC is poorly characterized. Methods: We conducted a retrospective multicenter study of pts with metastatic nccRCC treated with PD1/PDL1 inhibitors. Baseline clinical parameters, overall response rate (ORR) by RECIST, time-to-treatment failure (TTF), and overall survival (OS) were summarized. Results: We identified 40 pts across 8 academic institutions. Fourteen (35%) had papillary histology, 10 (25%) chromophobe, 3 (8%) translocation, and 7 (18%) unclassified. Six (16%) had ccRCC with a sarcomatoid component > 30%. 20% had International Metastatic RCC Database Consortium (IMDC) favorable-risk disease, 60% intermediate, and 20% poor-risk. Ten (25%) were treatment-naïve and the majority received PD1/PDL1 monotherapy (n=30, 75%), while the remaining received a combination of PD1/PDL1 with anti-VEGF(R) or anti-CTLA4 therapy. ORR for the total cohort was 18% and 10% for PD1/PDL1 monotherapy pts (Table). With a median follow-up of 5.6 months, the overall median TTF was 4.7 months (2.9-15.9) and six-month OS was 81% (60-91%). Conclusions: PD1/PDL1 blockade resulted in some activity in pts with various nccRCC histologies. In the absence of available clinical trials, this data may support the use of PD1/PDL1 blocking agents in pts with nccRCC. [Table: see text]

scholarly journals Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC)

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4401
Author(s):  
María Armesto ◽  
Maitane Marquez ◽  
María Arestin ◽  
Peio Errarte ◽  
Ane Rubio ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Gene Networks ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Cell Renal Cell Carcinoma ◽  
Angiogenic Therapy ◽  
Resistant Cells

The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance.

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