Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial

Choueiri, Toni K.; Larkin, James; Pal, Sumanta K.; Motzer, Robert J.; Rini, Brian I.; Venugopal, Balaji; Alekseev, Boris; Miyake, Hideaki; Gravis, Gwénaëlle; Bilen, Mehmet Asım; Subramanian, Hariharan; Chudnovsky, A.; Ching, Keith A.; Mu, Xinmeng Jasmine; Mariani, Mariangela; Robbins, Paul B.; Huang, Bo; Pietro, Alessandra di; Albigès, Laurence

doi:10.1016/j.esmoop.2021.100101

Cited by 29 publications

(22 citation statements)

References 50 publications

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“…The administration of immune checkpoint inhibitors (ICI) has become an accepted standard of care for patients with many tumor types [ 12 ]. Subgroup analyses of sRCC in the first line setting in recent phase 3 clinical trials confirmed the efficacy of ICI-based regimens compared to sunitinib [ 13 , 14 , 15 , 16 ]. In a post hoc analysis of the phase III CheckMate 214 trial, anti-PD-1 therapy with nivolumab plus anti-CTLA4 therapy with ipilimumab showed an impressive overall response rate (ORR) and OS benefit in comparison with sunitinib in treatment-naive sRCC patients with intermediate and poor-risk prognosis [ 13 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

et al. 2022

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Background: Renal cell carcinoma with sarcomatoid dedifferentiation represents a rare histological entity characterized by aggressive behavior, limited efficacy of tyrosine kinase inhibitors or mTOR inhibitors, and poor outcome. The immune checkpoint inhibitor therapy regimen combining ipilimumab with nivolumab represents a new standard of care for this patient population due to a hitherto unprecedented response rate and overall survival. On the other hand, the role of cytoreductive nephrectomy in metastatic renal cell carcinoma, in particular, with sarcomatoid histology, remains controversial. Patient and Methods: In the present case series, we report six patients with locally advanced or synchronous metastatic sarcomatoid renal cell carcinoma and intermediate or poor International Metastatic RCC Database Consortium (IMDC) risk score, five of whom were successfully subjected to cytoreductive nephrectomy. Results: All six patients received the combination regimen of ipilimumab with nivolumab. Five of these patients underwent upfront cytoreductive nephrectomy followed by systemic treatment without any significant delay, with a durable treatment outcome. Notably, two patients with poor prognostic features achieved a long-term major partial response to therapy. We also performed a review of the literature on optimal treatment strategies for patients with sarcomatoid renal cell carcinoma. Conclusion: Herein, we highlight the feasibility of performing cytoreductive nephrectomy in patients with intermediate/poor prognosis metastatic renal cell carcinoma with sarcomatoid dedifferentiation followed by immunotherapy with ipilimumab and nivolumab. To enhance the chances of immunotherapy success, cytoreductive nephrectomy should also be considered for patients presenting with a disease with adverse prognostic parameters.

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Section: Introductionmentioning

confidence: 99%

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

et al. 2022

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“…However, PBRM1-mutant patients tended to have a higher TMB and might evoke immunotherapy sensitivity (24). Furthermore, Malouf et al detected genomic profiling, underpinning renal cell carcinoma with sarcomatoid dedifferentiation, and identified TP53 (42.3%), VHL (34.6%), CDKN2A (26.9%), and NF2 (19.2%) as the most frequently altered genes for sRCC (12,25). Approaches and strategies are needed for other malignancies driven by the loss of CDKN2 and NF2, as revealed by genomic features in the course of clinical management for patients with sRCC.…”

Section: Discussionmentioning

confidence: 99%

“…For example, with over 42 months of median follow-up, RCC patients with sarcomatoid histology who received nivolumab plus ipilimumab still had median overall survival that was not yet reached [(25.2–not estimable); n = 74] versus those who received sunitinib [14.2 months (9.3–22.9); n = 65; P = 0.0004] ( 11 ). Meanwhile, the JAVELIN Renal 101 trial enrolled 108 RCC patients with sarcomatoid histology (47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm), and patients with sRCC in the combination arm had improved efficacy outcomes versus those in the sunitinib arm ( 12 ). The median progression-free survival (PFS) was 7.0 months (95% CI, 5.3–13.8 months) versus 4.0 months (95% CI, 2.7–5.7 months), respectively.…”

Section: Introductionmentioning

confidence: 99%

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

Anwaier

Liu

et al. 2022

Front. Immunol.

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Sarcomatoid differentiation is a highly aggressive pathological characteristic of renal cell carcinoma (RCC) and is characterized by susceptibility to progression and extremely poor prognosis. In this study, we included all genomic alteration events that led to a loss of protein function of MTAP and CDKN2A, and enrolled 5,307 RCC patients with genomic sequencing data from Western and Chinese cohorts. Notably, MTAP/CDKN2AMUT occurred in the Chinese population ~2 times more frequently than in the Western cohort and showed significant co-mutation trends. We found significantly higher proportions of sarcomatoid-positive patients with MTAPMUT or CDKN2AMUT compared with MTAP/CDKN2A wild-type (WT) patients (P < 0.001). Of the 574 RCC samples from the FUSCC cohort and 3,563 RCC samples from 17 independent cohorts, the MTAP/CDKN2AMUT significantly predicted extremely poor outcomes (P < 0.0001). The Western cohort suggested a concordant relationship between MTAP/CDKN2AMUT and sarcomatoid differentiation in RCC. Moreover, although MTAP/CDKN2AMUT RCC may be insensitive to targeted therapy, the high degree of tumor heterogeneity and higher PD-L1 and CXCL13 expression characterizations reflected that MTAP/CDKN2A-deficient features could benefit from immunotherapy for patients with RCC. This study utilized RCC samples from large-scale, global, multicenter sequencing cohorts and first proved that MTAP/CDKN2A deficiency significantly correlates with sarcomatoid differentiation in RCC and predicts aggressive progression, poor prognosis, and primary resistance to targeted therapy and potential favorable responses to immune checkpoint blockade. Unlike conventional targeted therapies, emerging drugs such as immunotherapies or synthetic lethal PRMT5 inhibitors may become novel therapeutic options for patients with MTAP/CDKN2AMUT RCC.

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“…The TKIs improve immune cell response to tumor cells and reduce immunosuppressive effects. In their analysis of 108 sRCC patients, the authors noted improved ORR (46.8 vs. 21.3%) and PFS (HR 0.57, 95 CI 0.325-1.003) among those receiving avelumab-axinitib [58].…”

Section: Systemic Therapy Updates In Sarcomatoid Renal Cell Carcinomamentioning

confidence: 97%

The roaring 2020s: a new decade of systemic therapy for renal cell carcinoma

Srivastava

Doppalapudi

Patel

et al. 2022

Current Opinion in Oncology

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Purpose of reviewThe genomic and immunologic profiling of renal cell carcinoma (RCC) has provided the impetus for advancements in systemic treatments using combination therapy --either with immune check point inhibitor (ICI) þ ICI or with ICI þ targeted therapy. This approach has been examined in several landmark trials, treating both clear cell (ccRCC) and nonclear cell (nccRCC) histologies. In this review, we highlight systemic therapy advancements made in this new decade, the 2020s. Recent findingsTargeting the programmed death receptor 1/PD-L1 pathway has created more tolerable and effective immunotherapy regimens, expanding the applications of ICIs. These new applications, paired with trial data, include ICI monotherapy in nccRCC and adjuvant pembrolizumab in resected, high-risk RCC. In addition, ICI þ ICI and ICI þ TKI combination therapy have demonstrated oncologic efficacy in advanced ccRCC and sarcomatoid RCC. Similar progress has been noted regarding new targeted therapies. Along the hypoxia inducible factor pathway, belzutifan has received FDA approval in von Hippel-Lindauassociated RCC. In addition, in papillary RCC, agents such as cabozantinib target the MET protooncogene pathway and have demonstrated impressive oncologic outcomes.

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Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial

Cited by 29 publications

References 50 publications

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

The roaring 2020s: a new decade of systemic therapy for renal cell carcinoma

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