“PROBE”ing the Role of Cytoreductive Nephrectomy in Advanced Renal Cancer

The Southwest Oncology Group (SWOG)1931 trial, also known as PROBE (ClinicalTrials.gov Identifier: NCT04510597) is a phase III study evaluating the role of cytoreductive nephrectomy (CN) in metastatic renal cell cancer (RCC). Kidney cancer presenting with synchronous metastases has demonstrated shorter survival outcome compared to the patients relapsing with metastases after nephrectomy. Previously, CN has been associated with survival improvement when interferon-based systemic therapy was used. In the setting of antivascular therapy sunitinib, a prospective randomized clinical trial demonstrated no benefit of CN. Immune checkpoint-based combination therapy has now become the standard-of-care in the frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint-based systemic therapy. The sequence and optimal timing of nephrectomy is also not established. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in RCC within the context of immune checkpoint-based combination regimens. The study requires starting with systemic therapy; any one of the FDA approved immunotherapy-based regimens at the time the study was activated are permitted. The disease status and response are evaluated at 9–12 weeks of therapy and then consented patients are randomized 1:1 to receive CN or to continue systemic therapy. The patients who have rapid disease progression are considered ineligible for randomization as they need a switch in systemic therapy. Both groups should continue systemic therapy as long as they are tolerating the treatment and continuing to derive clinical benefit. Quality-of-life, tumor genomic testing, microbiome, radiomics and circulating tumor DNA assessments as predictive biomarkers are planned as study correlatives. The study hypothesis is that CN will improved OS in synchronous metastatic RCC when surgery is performed after starting systemic immune checkpoint-based combination therapy. A potential mechanism leading to improved survival is the broader antigen spread and higher neoantigen load enabled by the primary tumor enhancing the efficacy of the immune therapy. CN after initial systemic therapy would help select the patient subset most likely to benefit and will potentially enable eradication of immune resistant clones within the primary tumor.

Extended Disease Control with Unconventional Cabozantinib Dose Increase in Metastatic Renal Cell Carcinoma

BACKGROUND: Cabozantinib is among the most potent tyrosine kinase inhibitors (TKIs) FDA-approved for metastatic renal cell carcinoma (mRCC). Effective treatments after progression on cabozantinib salvage therapy are limited. Dose escalation for other TKIs has been shown to afford added disease control. OBJECTIVE: We sought to evaluate whether dose escalation of cabozantinib (Cabometyx®) from conventional doses in selected patients with limited treatment options offered additional disease control. We asked how cabozantinib dose increases may affect circulating drug levels. METHODS: We identified patients with mRCC at the University of Texas Southwestern Medical Center who were treated with cabozantinib dose escalation to 80 mg after progressing on conventional cabozantinib 60 mg. We then queried leading kidney cancer investigators across the world to identify additional patients. Finally, we reviewed pharmacokinetic (PK) data to assess how higher doses impacted circulating levels by comparison to other formulations (Cometriq® capsules). RESULTS: We report six patients treated at two different institutions with cabozantinib-responsive disease and good tolerability, where cabozantinib was dose escalated (typically to 80mg, but as high as 120 mg) after progression on 60 mg, a strategy that resulted in added disease control (median duration, 14 months; 95% Confidence Interval [CI]: 8 –Not Estimable[NE]). Four patients (66.7%) had disease control lasting at least 1 year. No grade III/IV adverse events were identified. A comparison of PK data to FDA-approved cabozantinib 140 mg capsules suggest that cabozantinib 80 mg tablets results in comparable exposures. CONCLUSIONS: mRCC patients with cabozantinib responsive disease and reasonable tolerability may benefit from dose escalation at progression.

BRCA1-Associated Protein 1 (BAP-1) as a Prognostic and Predictive Biomarker in Clear Cell Renal Cell Carcinoma: A Systematic Review

BACKGROUND: The gene that encodes BRCA1-associated protein 1 (BAP1) has been reported to be dysregulated in several human cancers such as uveal melanoma, malignant pleural mesothelioma, hepatocellular carcinoma, thymic epithelial tumors, and clear-cell renal cell carcinoma (ccRCC). The gene is located on the human chromosome 3p21.3, encoding a deubiquitinase and acts as a classic two-hit tumor suppressor gene. BAP1 predominantly resides in the nucleus, where it interacts with several chromatin-associated factors, as well as regulates calcium signaling in the cytoplasm. As newer therapies continue to evolve for the management of RCC, it is important to understand the role of BAP1 mutation as a prognostic and predictive biomarker. OBJECTIVE: We aimed to systematically evaluate the role of BAP1 mutations in patients with RCC in terms of its impact on prognosis and its role as a predictive biomarker. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through March 2021. Titles and abstracts were screened to identify articles for full-text and then a descriptive review was performed. RESULTS: A total of 490 articles were initially identified. Ultimately 71 articles that met our inclusion criteria published between 2012–2021 were included in the analysis. Data were extracted and organized to reflect the role of BAP1 alterations as a marker of prognosis as well as a marker of response to treatments, such as mTOR inhibitors, VEGF tyrosine kinase inhibitors, and immune checkpoint inhibitors. CONCLUSIONS: Alterations in BAP1 appear to be uniformly associated with poor prognosis in patients with RCC. Knowledge gaps remain with regard to the predictive relevance of BAP1 alterations, especially in the context of immunotherapy. Prospective studies are required to more precisely ascertain the predictive value of BAP1 alterations in RCC.

Phase Ib/II trial of ibrutinib and nivolumab in patients with advanced refractory renal cell carcinoma1

Background: Although immune checkpoint inhibitor-based therapy has improved the outcomes of many patients with metastatic renal cell carcinoma (mRCC), most eventually develop disease progression. Newer agents that modulate immune response can possibly potentiate checkpoint inhibitor therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate immunotherapy. We conducted an investigator-initiated trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC patients, particularly in those previously exposed to immune checkpoint inhibitors. Methods: Eligible patients had mRCC of any histologic subtype, completed at least one line of prior systemic therapy which could have included prior immunotherapy, and had acceptable end-organ function with ECOG performance status of 0–2. Treatment consisted of nivolumab 240 mg intravenously every 2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade 3 or higher adverse event (AE) attributable to therapy. After identification of the recommended phase 2 dose (RP2D), up to 19 patients were enrolled to an expansion cohort to further evaluate toxicities and any early evidence of efficacy. The primary endpoints of the trial were establishment of RP2D and progression-free survival (PFS). Results: A total of 31 patients were enrolled, 6 to dose level 0, 7 (of which one was not evaluable for DLT) in dose level -1, and 18 in the expansion cohort. Median age was 60 years (range, 36–90), most had clear cell histology (n = 27; 87%), and most had prior immune checkpoint inhibitor therapy (n = 28; 90%). Three patients experienced one DLT each, all in dose level 0 (all Grade 3), namely elevated lipase, hypoalbuminemia, and nausea. No DLTs were seen in dose level –1 which was declared the RP2D. The most common Grade 3 or higher AEs include anemia (n = 5), lymphocyte count decrease (4), nausea (2), and hypotension (2). Of 28 patients evaluable for response, one patient (3.6%) had a complete response, 2 (7.1%) had a partial response, and 11 (39.2%) had stable disease, for an objective response rate of 10.7%(95%CI: 3.7%–27.2%) and a disease control rate of 50%(95%CI: 32.6%–67.4%). All responders had received prior immune checkpoint inhibitor therapy. Median PFS was 2.5 months (95%CI, 1.9 –4.8) while median OS was 9.1 months (95%CI, 6.6 –19.0). Conclusions: Ibrutinib at a dose of 420 mg orally once daily in combination with nivolumab 240 mg IV every 2 weeks is feasible and tolerable in mRCC patients. No unique immune-related AEs were observed. Anti-tumor activity was seen in patients previously exposed to PD-1 targeted therapy.

Prognostic Impact of Lymphnode Metastases in Patients with Metastatic Renal Cell Carcinoma

BACKGROUND: Lymphnode metastases (LMN) in metastatic renal cell carcinoma (mRCC) has been associated with an unfavourable prognosis. However, the prognostic impact of LNM in mRCC in context of other solid organ metastases and throughout subsequent therapeutic lines is not well-defined. OBJECTIVE: This retrospective single-center analysis was designed to elucidate the impact of LNM in the context of other solid organ metastases and throughout subsequent therapeutic lines. METHODS: mRCC patients (pts) at our center were analysed (observation period, 04/00-03/16). Primary endpoint was overall survival (OS) and the impact of line of therapy as a co-variate. Pts were grouped into: with LNM [LNM(+)], without LNM [LNN(–)]. Subgroup analyses of LNM(+) was performed including the subgroup LNM(+) and other solid organ metastases [LNM(+) other] and LNM(+) without other solid organ metastases [LMN(+) only]. RESULTS: 383/401 mRCC pts were eligible. 318 (83.2%), 230 (60.1%) and 154 (40.5%) pts received 1stL, 2ndL and 3rdL medical treatment, respectively. In the overall population OS was 40.1 months (95%CI: 32.7–47.4), with superior OS in LNM(–) compared to LNM(+) pts (log rank, HR 1.7, 95%-CI 1.3-2.2, p < 0.001). This effect was maintained across lines of therapies. LNM(+) only had a similar risk of death as LNM(–) pts (HR 1.2, 95%-CI 0.8–2.0, p = 0.4), while the risk of death was significantly increased for LNM(+) other compared to LNM(–) (HR 1.9, 95%-CI 1.5–2.6, p < 0.001). CONCLUSION: LNM(+) in mRCC is associated with a poor OS. However, impaired OS in LNM(+) might be associated with the presence of other solid organ metastases rather than with the existence of LNM alone. Further studies are warranted to support this hypothesis.

Sarcomatoid Renal Cell Carcinoma: The Present and Future of Treatment Paradigms

Sarcomatoid renal cell carcinoma (sRCC) is an aggressive form of kidney cancer that is associated with poor prognosis. It can arise from any histologic type of renal cell carcinoma. The majority of cases will present with advanced or metastatic disease requiring systemic therapy. Nephrectomy is the treatment of choice in locally resectable disease. The therapeutic options for sRCC have evolved in the past decade. Cytotoxic chemotherapy and monotherapy with targeted therapy (VEGF and mTOR) have historically shown poor response rates and survival in the treatment of metastatic sRCC. The use of checkpoint inhibitors and their combination with targeted therapy against VEGF has changed the landscape and outcomes for renal cell carcinoma. Given the rarity of sRCC most of the data on treatment is from small cohorts or extrapolation from larger clinical trials. The benefit from the combination of checkpoint inhibitors and targeted therapy to VEGF has shown promise in the sRCC population in post hoc analysis of large clinical trials. Future research focusing on further characterizing the unique biologic and clinical features of sRCC is critical in advancing the knowledge and developing effective therapy to improve clinical outcomes and survival.

Retrospective Study of Real-World Treatment Patterns and Outcomes in Advanced/Metastatic Renal Cell Carcinoma Patients Receiving Lenvatinib/Everolimus after Heavy Pretreatment1

BACKGROUND: Lenvatinib with everolimus (“Len/Eve”) is approved for advanced/metastatic RCC following one antiangiogenic therapy. OBJECTIVE: This study evaluated patient characteristics, treatment patterns and overall survival (OS) with second-line or later (2L+) Len/Eve for advanced/metastatic RCC. METHODS: A retrospective observational study was conducted using electronic health records. Adult patients who initiated 2L+ Len/Eve for advanced/metastatic RCC from May 13, 2016 to July 31, 2019 were included. Patient characteristics and treatment patterns were assessed across the overall population and by post-immuno-oncology (IO) and post-tyrosine kinase inhibitors (TKI) groups. OS was estimated from Len/Eve initiation (i.e., index date) using Kaplan-Meier. RESULTS: Among the study population (n = 152), 44.1%received 2L/3L Len/Eve and median number of prior therapies was 3 (range:1–8). Median age was 63.2 years, 78.9%were Caucasian, 73.7%were male, and 56.6%had ECOG performance status 0/1. At initial diagnosis, 65.8%had stage IV disease. At index, 53.3%had an International Metastatic RCC Database Consortium risk score of intermediate/poor, 15.1%favorable, and 31.6%missing score. Sixty-five (42.8%) received IO-based regimens and 49.3%received TKIs directly before index. Median OS from index was 13.9 (95%CI: 9.5–16.5) months and 2L/3L and 4L+ were 12.1 (95%CI: 8.4–17.0) and 14.8 (95%CI: 8.9–22.5) months, respectively. Median OS for Len/Eve post-IO and post-TKI were 13.9 (95%CI: 8.4–21.3) and 14.8 (95%CI: 7.8–16.5) months, respectively. Conclusion: This study suggested that 2L+ Len/Eve has clinical effectiveness for advanced/metastatic RCC in a US community oncology setting. Future studies are needed to confirm the association of improved survival with 2L+ Len/Eve.

First-Line Immune-Oncology Combinations for Metastatic Clear Cell Renal Cell Carcinoma (mRCC): A Systematic Review of Phase III Clinical Trials

BACKGROUND: The introduction of immune checkpoint inhibitors rapidly changed treatment for patients with metastatic clear cell renal cell carcinoma (mRCC). First-line treatment now includes multiple immuno-oncology (IO) combinations that were approved over a short time period and were not directly compared in randomized clinical trials. Thus, clinicians face a challenge in individualizing first-line treatment to optimize clinical outcomes. OBJECTIVE: We sought to systematically review clinical outcomes for first-line IO combinations for patients with mRCC. METHODS: Literature reporting outcomes from phase III clinical trials that evaluated first-line IO combination therapies was identified through a search of the PubMed electronic database following PRISMA guidelines. Abstracts were screened to identify manuscripts that fit the search criteria, and then, a descriptive review was performed. RESULTS: Our literature search identified 2,229 abstracts that met the initial search criteria, and then, it was narrowed to 431 abstracts using filters for “clinical trial” and a “ten year” time window. After review of the abstracts, six manuscripts were selected for data extraction and subsequent review. CONCLUSION: When compared to sunitinib, four IO combinations improved overall survival as first-line treatment, and five improved progression free survival for patients with mRCC. These IO combination therapies have unique characteristics, so clinicians should take into account patient and cancer factors to individualize treatment recommendations.