The Trouble with Doublets: Making Sense of Combination Strategies in Advanced Kidney Cancer
Abstract
On November 10, 2020, the topline results of the Phase III CLEAR/Keynote 581 trial were announced in a press release [1]. In that trial, the combination of pembrolizumab, a PD-1 immune checkpoint inhibitor, plus lenvantinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI), as well as the combination of lenvantinib plus the mTOR inhibitor everolimus, were evaluated versus sunitinib for the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). Both combinations were reported to demonstrate enhanced efficacy when compared to sunitinib. The pembrolizumab/lenvantinib arm met the trial’s primary endpoint of significantly prolonging progression-free survival (PFS). In addition, there was statistically significant improvement in the secondary endpoints of overall survival (OS) and response rate (ORR). The lenvantinib/everolimus doublet also met the trial’s primary endpoint of PFS and the secondary endpoint of ORR.
A Shared Decision-Making Model for Management of Small Renal Masses: Optimizing the Patient Experience
Abstract
Background:
The finding of a small renal mass (SRM) on radiological imaging and the potential of a cancer diagnosis is anxiety provoking in most patients. The decision-making process often occurs in the absence of any framework regarding the nature and treatment outcomes. This project aimed to educate patients newly diagnosed with a SRM, implement a shared decision-making (SDM) model, and assess the educational attainment and effect on a SDM intervention.
Methods:
This project assessed the educational attainment and its effect on a SDM intervention using a pre-and post- intervention survey, an educational video [Urology Care Foundation, “What is a renal mass?], and a structured provider discussion. The survey incorporated eight knowledge questions and two questions which addressed anxiety related to diagnosis and confidence in decision-making.
Results:
Fifty surveys were completed. The post intervention score showed a significant increase in patient knowledge. Wilcoxon signed rank test (P = <0.001; 2.0; CI 95% (1.54–2.46)). Thirty-nine demonstrated improvement in knowledge with a mean of 2.0, 9 were unchanged and 2 decreased. Approximately 42% of patients reported a decrease in anxiety rating by a mean of 40%. When confidence in decision-making improved, it improved by a mean of 45%.
Conclusions:
A significant improvement in understanding of SRMs was demonstrated. This model showed improved knowledge, alleviation of anxiety and improved confidence and denotes the feasibility of implementing a SDM model in newly diagnosed patients. Results should encourage providers who aspire to incorporate a SDM as a Best Practice.
Long-Term Outcomes in Clear-Cell Renal Cell Carcinoma Patients Treated with Complete Metastasectomy
Abstract
Background:
Complete metastasectomy is routinely performed in selected patients with metastatic clear-cell renal cell carcinoma (ccRCC).
Objectives:
To assess (1) outcomes after first and repeat metastasectomy, (2) outcomes on targeted therapy in patients who underwent previous metastasectomy and (3) compare outcomes with and without metastasectomy after correction for selection bias.
Methods:
Metastatic ccRCC patients treated with or without metastasectomy at University Hospitals Leuven were included from prospective databases. We calculated disease-free survival (DFS), time to systemic therapy and cancer-specific survival (CSS) after metastasectomy, and progression-free survival (PFS) and CSS on 1st line sunitinib/pazopanib. We calculated propensity scores to estimate a patient’s likelihood to undergo metastasectomy.
Results:
We included 113 patients who underwent complete metastasectomy and 139 who did not. (1) Median DFS after complete metastasectomy was 18 mo, time to systemic therapy was 73 mo and CSS was 101 mo. 20% did not relapse during long-term follow-up. Outcomes remained favorable after repeat metastasectomy. (2) PFS and CSS on 1st line sunitinib/pazopanib were 15 mo and 35 mo. (3) The propensity scores of patients who did and did not undergo metastasectomy showed no overlap, indicating that correction for selection bias is impossible and comparison of outcomes unreliable.
Conclusions:
Complete metastasectomy and repeat metastasectomy can result in excellent outcomes in highly selected patients, even when its causal benefit cannot be formally assessed. Previous metastasectomy does not impair outcomes on targeted therapies.
Individualised Predictions of the Survival Benefit Due to Adjuvant Therapy in a Randomised Trial of Sorafenib after Nephrectomy for Localised Renal Cell Carcinoma
Abstract
BACKGROUND:
Little has been published regarding how doctors think and talk about prognosis and the potential benefits of adjuvant therapy.
OBJECTIVE:
We sought predictions of survival rates and survival times, for patients with and without adjuvant therapy, from the clinicians of patients participating in a randomised trial of adjuvant sorafenib after nephrectomy for renal cell carcinoma.
METHODS:
A subset of medical oncologists and urologists in the SORCE trial completed questionnaires eliciting their predictions of survival rates and survival times, with and without adjuvant sorafenib, for each of their participating patients. To compare predictions elicited as survival times versus survival rates, we transformed survival times to survival rates. To compare predicted benefits elicited as absolute improvements in rates and times, we transformed them into hazard ratios (HR), a measure of relative benefit.We postulated that a plausible benefit in overall survival (OS) should be smaller than that hypothesized for disease–free survival (DFS) in the trials original sample size justification (i.e. HR for OS should be ≥ 0.75).
RESULTS:
Sixty–one medical oncologists and 17 urologists completed questionnaires on 216 patients between 2007 and 2013. Predictions of survival without adjuvant sorafenib were similar whether elicited as survival rates or survival times (median 5–year survival rate of 61% vs 60%, p = 0.6). Predicted benefits of sorafenib were larger when elicited as improvements in survival rates than survival times (median HR 0.76 vs 0.83, p < 0.0001). The proportion of HR for predicted OS with sorafenib that reflected a plausible benefit (smaller effect of sorafenib on OS than hypothesized on DFS, i.e. HR ≥ 0.75) was 51% for survival rates, and 65% for survival times.
CONCLUSIONS:
The predicted benefits of adjuvant sorafenib were larger when elicited as improvements in survival rates than as survival times, and were often larger than the sample size justification for the trial. These potential biases should be considered when thinking and talking about individual patients in clinical practice, and when designing clinical trials.
Tissue Based Biomarkers for Metastatic Clear Cell Renal Carcinoma: A Systematic Review
Abstract
Background:
Treatments for metastatic clear cell renal carcinoma (mccRCC) are evolving with multiple targeted and immune therapy drugs currently approved by regulatory agencies as single agents or in combination. Developing predictive biomarkers to determine which patients derive a differential benefit from a particular treatment is an area of ongoing clinical research.
Objective:
We sought to systematically evaluate the role of tumour tissue-based biomarkers that assist in selection of therapy for mccRCC.
Methods:
Literature addressing the role of biomarkers in mccRCC was identified through a search of the electronic databases MEDLINE, Embase, and the Web of Science and a hand search of major conference abstracts (from Jan 2010 –Sep 2020). Abstracts were screened to identify papers meriting full-text review. Studies with a comparison arm were included to assess biomarker relevance. A narrative review of studies was performed.
Results:
The literature search yielded 6784 potentially relevant articles. 133 articles met criteria for full text review, and 10 articles were identified by scanning bibliographies of relevant studies. A total of 33 articles (involving 13 studies) were selected for data extraction and subsequent review.
Conclusions:
Predictive biomarkers for immediate use in the clinic are lacking, and embedding their evaluation and validation in future clinical trials is needed to refine practice and patient selection.
Clinical Trials Corner: Healthy Competition
Abstract
A Randomized, Double-Blind, Controlled Phase 3 Study of Cabozantinib in Combination with Nivolumab and Ipilimumab versus Nivolumab and Ipilimumab in Subjects with Previously Untreated Advanced or Metastatic Renal Cell Carcinoma of Intermediate or Poor Risk.
Status: Recruiting
Clinicaltrials.gov identifier: NCT03937219
Sponsor: Exelixis
Enrollment: 676
Rationale: The combination of nivolumab and ipilimumab was demonstrated to be superior to sunitinib in the treatment of patients with intermediate or poor risk advanced RCC in the CheckMate-214 trial, and thus has become an established therapy for these patients. Recently, the CheckMate 9ER trial demonstrated that the combination of nivolumab with cabozantinib was tolerated and was superior in radiographic progression free survival (PFS) and objective response rate (ORR) to sunitinib.
Study Design: This Phase III randomized trial enrolls patients with advanced RCC with a clear-cell component, who must be intermediate- or poor-risk by International Metastatic RCC Database Consortium (IMDC) criteria. Patients may not have had previous systemic therapy in the locally advanced or metastatic setting, and will be excluded if they have underlying, recent autoimmune disorders requiring systemic treatment. Patients will be randomized to receive either cabozantinib + nivolumab + ipilimumab (with nivolumab + ipilimumab received for 4 doses) followed by cabozantinib + nivolumab (experimental arm) or placebo + nivolumab + ipilimumab (for 4 doses) followed by placebo + nivolumab (control arm). Patients will be treated until disease progression or unacceptable toxicity.
Endpoints: The primary endpoint of this trial is duration of PFS. The secondary outcome measure is duration of overall survival (OS).
