Real-World Utilization of Oral Anticancer Agents and Related Costs in Older Adults with Metastatic Renal Cell Carcinoma in the United States
Abstract
BACKGROUND:
Substantial racial and socioeconomic disparities in metastatic RCC (mRCC) have persisted following the introduction of targeted oral anticancer agents (OAAs). The relationship between patient characteristics and OAA access and costs that may underlie persistent disparities in mRCC outcomes have not been examined in a nationally representative patient population.
METHODS:
Retrospective SEER-Medicare analysis of patients diagnosed with mRCC between 2007–2015 over age 65 with Medicare part D prescription drug coverage. Associations between patient characteristics, OAA receipt, and associated costs were analyzed in the 12 months following mRCC diagnosis and adjusted to 2015 dollars.
RESULTS:
2,792 patients met inclusion criteria, of which 32.4%received an OAA. Most patients received sunitinib (57%) or pazopanib (28%) as their first oral therapy. Receipt of OAA did not differ by race/ethnicity or socioeconomic indicators. Patients of advanced age (> 80 years), unmarried patients, and patients residing in the Southern US were less likely to receive OAAs. The mean inflation-adjusted 30-day cost to Medicare of a patient’s first OAA prescription nearly doubled from $3864 in 2007 to $7482 in 2015, while patient out-of-pocket cost decreased from $2409 to $1477.
CONCLUSION:
Race, ethnicity, and socioeconomic status were not associated with decreased OAA receipt in patients with mRCC; however, residing in the Southern United States was, as was marital status. Surprisingly, the cost to Medicare of an initial OAA prescription nearly doubled from 2007 to 2015, while patient out-of-pocket costs decreased substantially. Shifts in OAA costs may have significant economic implications in the era of personalized medicine.
Bim Expression in Peritumoral Lymphocytes is Associated with Survival in Patients with Metastatic Clear Cell Renal Cell Carcinoma
Abstract
BACKGROUND:
Bim (BCL-2-interacting mediator of cell death) is a downstream pro-apoptotic signaling molecule activated by the PD-1 pathway.
OBJECTIVE:
We sought to determine if Bim expression in peritumoral T-lymphocytes (PTLs) is associated with survival in patients with metastatic clear cell renal cell carcinoma (ccRCC).
METHODS:
Immunohistochemistry staining for Bim was performed on paraffin-embedded tumor tissue blocks from patients with metastatic ccRCC who underwent nephrectomy between 1990-2004. Associations of Bim expression with cancer-specific survival (CSS) and overall survival (OS) from date of metastasis were evaluated using multivariable Cox regression models, adjusting for age, sex, and metastases-score.
RESULTS:
525 patients with metastatic ccRCC, of whom 169 (32%) had metastases at time of nephrectomy were studied. After multivariable adjustment, high Bim expression remained associated with worse CSS (HR = 1.31; 95% CI 1.07–1.59; p = 0.008) and OS (HR = 1.28; 95% CI 1.06–1.55; p = 0.01). The interaction between Bim and PD-L1 was not statistically significant for CSS (p = 0.68) or OS (p = 0.57), suggesting that the associations between Bim and survival outcomes were not significantly different based on tumor PD-L1 expression.
CONCLUSION:
High Bim expression in PTLs at nephrectomy is prognostic of worse CSS and OS in patients with metastatic ccRCC, irrespective of tumor PD-L1 expression. The role of earlier PD-1/PD-L1-directed therapy warrants evaluation in these patients.
Defining the Optimal Management Strategy for Small Renal Masses
Abstract
Small renal masses are typically defined as solid, contrast enhancing kidney tumors under 4cm in size, corresponding to American Joint Cancer Commission TNM stage T1a. They are most commonly asymptomatic and incidentally discovered, a classic by-product of increasing use of cross-sectional imaging for any variety of unrelated abdominal symptoms. The risk that a small renal mass represents a malignancy is closely tied to size with nearly 20% of tumors under 4cm being benign. [1] Also, of the small renal masses that are kidney cancer, the majority have indolent histology with prolonged natural history. In this issue of the journal, Drs. Ellis and Messing provide a comprehensive review of the management of small renal masses [2]. They conclude that “short and intermediate-term data demonstrate that active surveillance with the option for delayed intervention is a safe management approach with similar survival outcomes to primary intervention (PI) at 2 and 5 years, is cost effective, and prevents overtreatment, especially in patients with significant comorbidities”.
Active Surveillance of Small Renal Masses: A Systematic Review
Abstract
BACKGROUND:
Our goal is to review current literature regarding active surveillance (AS) of small renal masses (SRMs) and identify trends in survival outcomes, factors that predict the need for further intervention, and quality of life (QOL).
METHODS:
We performed a comprehensive literature search in PubMed and EMBASE and identified 194 articles. A narrative summary was performed in lieu of a meta-analysis due to the heterogeneity of selected studies.
RESULTS:
Seventeen articles were chosen to be featured in this review. Growth rate (GR) was not an accurate predictor of malignancy, although it was the characteristic most commonly used to trigger delayed intervention (DI). The mean 5-year overall survival (OS) of all studies was 73.6% ±1.7% for AS groups. The combined cancer specific survival (CSS) for AS is 97.1% ±0.6%, compared to 98.6% ±0.4% for the primary intervention (PI) groups, (p = 0.038).
CONCLUSIONS:
Short and intermediate-term data demonstrate that AS with the option for DI is a management approach whose efficacy (in terms of CSS) approaches that of PI at 5 years, is cost effective, and prevents overtreatment, especially in patients with significant comorbidities.
First-Line Immunotherapy Combinations in Advanced Renal Cell Carcinoma: A Rapid Review and Meta-Analysis
Abstract
BACKGROUND:
Combination or multi-agent therapy including immune checkpoint inhibitors has shifted the landscape of the treatment of advanced/metastatic renal cell carcinoma. There are several approved immune checkpoint inhibitor (ICI) combinations featuring antibodies against programmed cell death protein 1 (PD-1) receptor or its ligand 1 (PD-L1) combined with other immune checkpoint inhibitors, multi-targeted tyrosine kinase inhibitors (TKIs), or other agents active in renal cell carcinoma.
OBJECTIVE:
This study aims to compile the evidence of available first-line combination therapies compared to sunitinib monotherapy in advanced renal cell carcinoma.
METHODS:
A systematic literature search was conducted according to the PRISMA statement to identify all randomized Phase III clinical trial data in previously untreated metastatic renal cell carcinoma featuring an immune checkpoint inhibitor combination compared against sunitinib. A two-stage selection process was utilized to determine eligible studies. Of a total of 124 studies and 94 additional abstracts, 6 studies were considered for final analysis. These studies were evaluated for progression free survival (PFS), overall survival (OS), Grade III or higher adverse events (AEs), objective response rate (ORR), and complete response rate (CRR).
RESULTS:
6 studies with 5,121 patients met our search criteria. For OS, ICI combination therapy was favored over sunitinib with an estimated combined hazard ratio of 0.74 (0.67–0.81 95% CI). For PFS, ICI combination therapy was favored over sunitinib with an estimated combined hazard ratio of 0.65 (0.52–0.82, 95% CI). The combination of nivolumab and ipilimumab had the longest duration of response and less incidence of grade III or higher adverse events compared to the combination of anti-PD-1/PD-L1 with TKI. The combination of anti-PD-1/PD-L1 with TKI had higher rates of overall response and longer PFS than the combination of nivolumab/ipilimumab.
CONCLUSIONS:
This meta-analysis supports the recommendation of immune checkpoint inhibitor combination therapy over sunitinib monotherapy for previously untreated advanced renal cell carcinoma by virtue of improved PFS and OS. The choice of which ICI combination therapy to use may be guided by patient-specific characteristics including IMDC risk status, adverse effect profile, and need for early response.
Clinical Trials Corner: Contact After the First Round
Abstract
A Phase III, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Atezolizumab Given in Combination With Cabozantinib Versus Cabozantinib Alone in Patients With Inoperable, Locally Advanced, or Metastatic Renal Cell Carcinoma Who Experienced Radiographic Tumor Progression During or After Immune Checkpoint Inhibitor Treatment.
Status: Recruiting
Clinicaltrials.gov identifier: NCT04338269
Sponsor: Hoffmann-La Roche
Enrollment: 500
Rationale: In recent years, combination immune checkpoint inhibitor (ICI) therapy has become standard first-line treatment of mRCC. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib and nivolumab plus cabozantinib are all combinations that have been approved for use based on randomized trials in which these combinations demonstrated an overall survival benefit compared to sunitinib, regardless of risk stratification. Nivolumab plus ipilimumab has also demonstrated overall survival benefit in patients with intermediate- or poor-risk disease as compared to sunitinib, and thus is also an option for first-line treatment in select patients. Clinical data on sequencing further treatment after progression on initial immune checkpoint-based therapy is limited, and in particular whether there is further benefit to combining immune checkpoint inhibitor therapy with VEGF-directed therapies remains unclear. This trial seeks to interrogate that question..
Study Design: This Phase III randomized trial enrolls patients with histologically proven clear cell or non-clear cell metastatic RCC, though those with chromophobe subtype must have sarcomatoid differentiation. Patients must have radiographic evidence of disease progression during or following treatment with an anti-PD-L1 or anti-PD1 antibody (including atezolizumab, avelumab, pembrolizumab, or nivolumab). Patients may not have received prior cabozantinib, or more than one anti-PD-L1 or anti-PD-1 therapy prior to enrollment. They also may not have received more than two prior lines of therapy in the locally advanced or metastatic setting. While brain metastases are not an exclusion, patients with symptomatic, untreated or actively progressing CNS metastases or leptomeningeal disease are not permitted on study. Patients enrolled to study will be randomized to receive either atezolizumab (1200 mg IV every 3 weeks) plus cabozantinib (60 mg PO daily) or cabozantinib 60 mg PO daily, until unacceptable toxicity or disease progression.
Endpoints: The co-primary endpoints of this trial progression free survival (PFS) and overall survival (OS). The secondary outcomes include investigator-assessed PFS, investigator-assessed objective response rate (ORR), independently reviewed ORR, investigator-assessed duration of response (DOR) and independently reviewed DOR, as well as percentage of patients with adverse events.
