(UroToday.com) The Society of Urologic Oncology (SUO) annual winter meeting included a kidney cancer session and a presentation by Dr. Ari Hakimi discussing clinical and genomic updates in sarcomatoid renal cell carcinoma (RCC). Dr. Hakimi started by noting that sarcomatoid dedifferentiation is seen in ~5% of all kidney cancer, and ~20% of patients with metastatic disease. This is associated with an aggressive de-differentiated state with a very poor prognosis in which, historically, surgery and systemic therapies were ineffective.
Bulky disease is usually present at initial presentation, commonly requiring radical nephrectomy for complete resection. However, ~80% of patients who receive nephrectomy with curative intent for localized sarcomatoid RCC recur within 2 years. Furthermore, ~60-80% of patients with sarcomatoid RCC present with metastatic disease, whereby cytoreduction can be appropriate in selected patients, although historical 5-year survival is a dismal ~6%.
In 2020, Dr. Hakimi’s group published a comprehensive review of the biology, natural history, and management of sarcomatoid RCC.1 Historically, systemic therapy for sarcomatoid RCC has included chemotherapy regimens, primarily doxorubicin-based treatment with objective response rates ranging from 0%-20%. Targeted therapy studies have reported overall partial response rates of 11.1–19%, with progression of disease observed in 33–57% of patients within 1 year, as summarized in the following table:
More recently, immunotherapy is ushering in a new paradigm for sarcomatoid RCC. As of 2020, 5 prospective studies have investigated different forms of immune checkpoint blockade therapy in sarcomatoid RCC, which continues to show the strongest improvement in outcomes compared with any previous systemic therapy for this disease. The results of these trials are summarized in the following table:
At the 2021 GU ASCO annual meeting, Dr. Motzer presented results of the CheckMate 9ER trial (nivolumab + cabozantinib versus sunitinib), specifically among patients with sarcomatoid histology. In this analysis, sarcomatoid histology was identified in 75 patients (11.5%), not identified in 557 (84.6%), and was unavailable in 19 (2.9%). Among these 75 patients, 34 were randomized to nivolumab and cabozantinib and 41 were randomized to sunitinib. Patients treated with nivolumab and cabozantinib had significantly improved progression-free survival (HR 0.39, 95%CI 0.22-0.70), overall survival (HR 0.36, 95% CI 0.16-0.82), and objective response rates (55.9%, 95% CI 37.9-72.8%), compared with sunitinib. Further, this relative benefit, compared to sunitinib, was even larger in patients with sarcomatoid histology compared to those without sarcomatoid histology.
From a genomic standpoint, Bi et al.2 performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 patients, of which sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs 63 SSNVs, p = 4.0 × 10(-4)), and the most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known clear cell RCC genes including VHL, PBRM1, SETD2, and PTEN. Sarcomatoid elements acquired biallelic TP53 mutations in 32% of tumors. Furthermore, mutations in known cancer drivers ARID1A and BAP1 were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. Using multiple clinical trial and real-world cohorts of sarcomatoid and rhabdoid RCC to characterize molecular features, clinical outcomes, and immunologic characteristics, Bakouny and colleagues3 found that these tumors harbor distinctive molecular features that may account for their aggressive behavior. These include BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs.
Previous work has also assessed PD-L1 and tumor-infiltrating lymphocyte (TIL) status among patients with sarcomatoid RCC. Among 118 sarcomatoid RCC patients and 92 non-sarcomatoid clear cell renal cell carcinoma patients, Kawakami et al.4 estimated overall survival, and comparisons were made between PD-L1-positive and PD-L1-negative groups, as well as TIL-high and TIL-low groups. This study showed that the PD-L1 H-score of sarcomatoid RCC (mean, 3.7; range, 0-192.1) was significantly higher than the score of grade 4 clear cell RCC (p = .001), and 41.3% of sarcomatoid RCC cases showed a PD-L1 H-score ≥ 10. Additionally, the intratumoral CD8-positive cell density was significantly higher in sarcomatoid RCC versus clear cell RCC.
Dr. Hakimi’s lab has also recently established an immunocompetent sarcomatoid RCC cell line, summarized as follows:
Dr. Hakimi concluded his presentation discussing sarcomatoid RCC with the following take-home messages:
- Sarcomatoid histology is a highly aggressive form of RCC
- It appears to be highly sensitive to immunotherapeutic strategies, which has implications for cytoreduction (cytoreductive nephrectomy not favored)
- Sarcomatoid histology has distinct genomic features (CDKN2A loss, TP53) and has upregulation of immune checkpoints (ie. PDL1) and Tregs
Presented by: A. Ari Hakimi, MD, Memorial Sloan Kettering Cancer Center, New York, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 Society of Urologic Oncology (SUO) Winter Annual Meeting, Orlando, FL, Wed, Dec 1 – Fri, Dec 3, 2021.
References:
- Blum KA, Gupta S, Tickoo SK, et al. Sarcomatoid renal cell carcinoma: Biology, natural history and management. Nat Rev Urol. 2020 Dec;17(12):659-678.
- Bi M, Zhao S, Said JW, et al. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. Proc Natl Acad Sci USA. 2016 Feb 23;113(8):2170-2175.
- Bakouny Z, Braun DA, Shukla SA, et al. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma. Nat Commun 2021;12:808.
- Kawakami F, Sircar K, Rodriguez-Canales J, et al. Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation. Cancer 2017 Dec 15;123(24):4823-4831.