Sarcomatoid Renal Cell Carcinoma: The Present and Future of Treatment Paradigms
Abstract
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.
Phase Ib/II trial of Ibrutinib and Nivolumab in Patients with Advanced Refractory Renal Cell Carcinoma 1
Abstract
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.
Retrospective Study of Real-World Treatment Patterns and Outcomes in Advanced/Metastatic Renal Cell Carcinoma Patients Receiving Lenvatinib/Everolimus after Heavy Pretreatment 1
Abstract
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.
Prognostic Impact of Lymphnode Metastases in Patients with Metastatic Renal Cell Carcinoma
Abstract
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.
First-Line Immuno-Oncology Combinations for Metastatic Clear Cell Renal Cell Carcinoma (mRCC): A Systematic Review of Phase III Clinical Trials
Abstract
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.
Clinical Trials Corner: Reimagining RADICAL
Abstract
A Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients with Advanced Renal Cell Carcinoma with Bone Metastasis (RADICAL).
Status: Recruiting
Clinicaltrials.gov identifier: NCT04071223
Sponsor: Alliance for Clinical Trials in Oncology/National Cancer Institute Enrollment: 210
Rationale: Roughly a third of patients with metastatic RCC have bone metastases, with the prevalence higher in patients with intermediate or poor risk disease. This leads to increased morbidity in these patients due to skeletal related events (SREs), and data suggest that these patients also have decreased survival. In the Phase III METEOR trial, cabozantinib appeared to particularly benefit the subset of patients with bone metastases compared to everolimus, both in terms of clinical endpoints as well as in changes in bone turnover markers. Radium-223, an alpha emitting radioisotope and calcium-mimetic, has been shown to decrease SREs in patients with metastatic castration resistant prostate cancer. An exploratory Phase I trial of Radium-223 combined with either sorafenib or pazopanib in patients with mRCC with at least one bone metastasis demonstrated significant declines in bone turnover markers. Given these findings suggesting combination activity of tyrosine kinase inhibitors with Radium-223, and the evidence suggesting benefit of cabozantinib in patients with bone involvement, this Phase II study evaluates whether there is benefit to addition of Radium-223 to cabozantinib.
Study Design: This Phase II randomized trial enrolls patients with advanced RCC of any histologic subtype with at least 1 metastatic bone lesion that has not been previously irradiated. Patients may have had any number of prior lines of systemic therapy, but cannot have previously received cabozantinib. Prior Radium-223 dichloride treatment is also an exclusion criteria. Patients will be randomized to receive either Radium-223 dichloride every 28 days with cabozantinib 40 mg every day, or cabozantinib 40 mg every day. Patients in the combination arm will be treated with 6 treatments of Radium-223 dichloride and cabozantinib until disease progression or unacceptable toxicity; patients in the cabozantinib arm will be treated until disease progression or unacceptable toxicity.
Endpoints: The primary endpoint of this trial is symptomatic skeletal event (SSE)-free survival of the combination of Radium-223 and cabozantinib compared to cabozantinib alone. Secondary endpoints include SSE-free survival in predefined subgroups, progression free survival (PFS), overall survival (OS), time to first SSE, toxicity and objective response rate (ORR). The effect on markers of bone turnover will be examined as a correlative endpoint.
