Use of Second-line Immunotherapy in Control Arms of Randomized Clinical Trials in Kidney Cancer

Key Points Question In randomized clinical trials for first-line advanced kidney cell carcinoma (KCC) comparing combination immunotherapy regimens (defined as anti–programmed death ligand 1 antibody plus an additional agent) with the tyrosine kinase inhibitor sunitinib, what is the proportion of patients in the control arm who received postprotocol immunotherapy treatment? Findings In this systematic review examining 5478 patients enrolled in 6 trials for first-line advanced KCC comparing combination immunotherapy treatment with the sunitinib, 45.0% of the patients in the control arm who discontinued control arm treatment received postprotocol immunotherapy. Meaning In this systematic review, use of postprotocol immunotherapy among patients in the control arm was low, which may be associated with an overestimation of the clinical benefit of the combination immunotherapy regimen.


Introduction
In 2020, kidney cell carcinoma (KCC) was diagnosed in more than 70 000 adults in the US. 1 While the 5-year overall survival (OS) rate has improved in the last several decades from nearly 50% to 75.2% in 2020, 2 the prognosis of advanced stage disease remains stable, with a 5-year survival rate of only 13%. 3 This is based partly on the fact that KCC is resistant to chemotherapy; consequently, a relatively limited number of treatments are known to be effective. With the development of agents other than cytotoxic chemotherapies, options for advanced KCC treatment have increased. Sunitinib, an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor has been a cornerstone of first-line treatment for metastatic KCC after longer progression-free survival (PFS) and OS compared with cytokine-based therapy was reported. 4,5 Immunotherapy (anti-programmed death ligand 1 antibody treatment) has shown efficacy, with nivolumab receiving US Food and Drug Administration approval in the second-line setting after the CheckMate 025 trial reported an OS benefit. 6,7 Recent trials [8][9][10][11][12] in advanced KCC have sought to combine immunotherapy agents with other treatments, frequently TKIs, in the firstline setting.
When the number of effective therapies is limited, proper sequencing is important to maximize clinical outcomes for patients, such as survival and quality of life. By combining 2 effective therapeutic agents in a single line of therapy, as recent trials in advanced KCC have done, toxic effects increase and subsequent treatment options are reduced. [13][14][15] Thus, the relevant question facing the clinician is whether the combination of therapies is superior to the same therapies in sequence, particularly in terms of OS. Testing this hypothesis requires appropriate administration of postprotocol therapy in the patients in the control arm. 16 We report on recent trials in first-line advanced KCC comparing combination immunotherapy regimens with the current standard of care TKI, sunitinib, and the proportion of patients in the control arm that receive postprotocol immunotherapy.

Overview
This study followed the relevant sections of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. We sought to determine the proportion of patients who received postprotocol immunotherapy treatment in the control arms of studies comparing combination immunotherapy with sunitinib in first-line advanced KCC. We searched PubMed for clinical trials for treatment of first-line advanced KCC comparing a combination immunotherapy regimen, using 1 immunotherapy agent and either an additional immunotherapy agent or a TKI, to sunitinib in the first-line setting that were published between January 1, 2015, and February 28, 2021. We then analyzed the published articles, protocols, and supplementary materials to determine the total number of patients in the control arm, the number of patients in the control arm undergoing any form of postprotocol therapy, and the number of patients in the control arm receiving postprotocol immunotherapy, specifically, and report these figures as percentages. When available, updated results from subsequently published analyses were used.

Study Selection
We performed a PubMed search using the terms renal cell cancer and first-line, and applied the filter clinical trial. Trials published between January 1, 2015, and February 28, 2021, were considered.
Abstracts were manually reviewed to find phase 3 trials with an intervention group of combination immunotherapy regimens and a control group of sunitinib as well as a primary outcome of PFS or OS.
We excluded trials that were phase 1 or 2, subgroup analyses of other trials, not in the first-line setting, and studies other than clinical trials (cost-effectiveness, biomarker expression analysis, epidemiologic, and imaging-based studies). Each abstract was manually reviewed for inclusion or exclusion by one of us (J.S.).
to each treatment arm, the primary outcome of the trial, PFS and OS data, treatment status of patients at last data cutoff (ie, still receiving treatment or received postprotocol therapy), the number of patients in the control arm receiving postprotocol immunotherapy, and the number of patients in the control arm receiving any postprotocol therapy.

Status of Patients in the Control Arm at Data Close
Trial articles and supplementary materials were reviewed and CONSORT diagrams and tables summarizing postprotocol treatment were analyzed for each trial. Patients were categorized as (1) still receiving control arm therapy, (2) having received postprotocol anticancer therapy, or (3) having received no postprotocol anticancer therapy (including deceased). The patients who received postprotocol anticancer therapy were further categorized as receiving immunotherapy or receiving other anticancer therapy.

Rate of Postprotocol Immunotherapy Administration in Control Groups
The total number of patients in the control arm who received postprotocol immunotherapy was divided by the total number of patients who discontinued control arm treatment to provide an estimate of the proportion of patients in the control arm receiving postprotocol immunotherapy. In addition, we divided the total number of patients in the control arm who received postprotocol immunotherapy by the total number of patients in the control arm who received any form of postprotocol anticancer therapy in each trial. We then performed aggregate calculations using the same process but including all patients in all control arms across all trials considered.

Countries of Enrollment and Proportion of Patients
Trial figures and tables and supplementary materials were reviewed for total number of patients enrolled in each country participating in trial enrollment. Because detailed breakdowns of enrollment by country were not available in most supplements, the number of patients enrolled in each geographic region was recorded. Owing to slight heterogeneity in method of reporting across trials, we recorded patients as being enrolled in either United States/Canada/Western Europe or rest of the world.

Statistical Analysis
We sought to provide a descriptive estimate of the proportion of patients in the control arm who received postprotocol immunotherapy after first-line treatment with sunitinib for advanced KCC.
Analysis was performed using Microsoft Excel (Microsoft Corp).

Results
A total of 106 studies met our search criteria. The reasons studies were excluded included that they involved phase 1 or 2 trials (37), cancer other than KCC (18), subgroup analysis of other trial (7), no immunotherapy component (13), not first-line setting (2), and study type other than clinical trial (20).
Several studies met more than one exclusion criteria. We identified 6 clinical trials and 3 updated analyses comparing immunotherapy combination regimens with sunitinib in first-line advanced KCC that were published between January 1, 2015, and February 28, 2021. One trial, CLEAR, had a second intervention arm of lenvatinib and everolimus but because this regimen did not include an immunotherapy agent, this group of patients was not included in our analysis. All trials used identical control arm treatments of sunitinib (50 mg once a day with identical dose reduction schemes). Three trials, KEYNOTE-426, 11 CheckMate 214, 17 and JAVELIN Renal 101, 9 had subsequently published analyses that were used. Figure 1 summarizes our search strategy. The Table summarizes the studies we considered in our analysis. [8][9][10][11][12]17

Multinational Trials
All 6 trials were conducted in the multinational setting. In total, 4872 patients were enrolled (our analysis does not consider the 357 patients randomized to lenvatinib or everolimus in CLEAR). Of these patients, 2759 (56.6%) were enrolled in the US, Canada, or Western Europe. A total of 2113

Discussion
In trials comparing immunotherapy combination regimens with sunitinib in first-line advanced KCC, we found that 45.0% of patients who discontinued control arm treatment received postprotocol immunotherapy. We additionally found that, of patients in the control arm who received postprotocol therapy of any kind, only 66.4% received immunotherapy.
To our knowledge, this is the first investigation of control arm postprotocol immunotherapy administration after first-line treatment in advanced KCC. This is a notable area of inquiry because there are limited proven effective therapies for this disease, and appropriate use of lines of therapy is essential to provide the best outcomes for patients. While providing combination immunotherapy regimens in the first-line setting has been reported to improve PFS in each of these trials, a relevant clinical question is whether the strategy of using multiple agents in a single treatment line, and thus depleting subsequent treatment options, is associated with improved OS compared with sequential therapy.
While median OS had not been reached at the time of publication in any of the 6 trials we considered, 8,9 4 of the trials report that combination immunotherapy was associated with a statistically significant improvement in OS. [10][11][12]17 In published subsequent analyses, [18][19][20]   Third, we recognize that the binary geographic groupings of US/Canada/Western Europe and rest of the world lacks sufficient specificity to provide a more nuanced discussion regarding local availability of postprotocol immunotherapy. We report these data in this manner because more granular country-by-country data on patient enrollment were not uniformly available in the articles or supplements. We believe the multinational nature of these trials likely affects the availability of postprotocol immunotherapy and have attempted to quantify how much this may have affected the results we observed, but without more detailed data being uniformly available, we acknowledge that future studies are needed to validate this hypothesis.

Conclusions
Advanced KCC remains a challenging disease to treat with a limited number of effective therapies.
While recent trials comparing combination immunotherapy regimens with the TKI sunitinib in the first-line setting have reported positive, if preliminary, OS results, interpretation of these figures must be informed by the rate of appropriate postprotocol immunotherapy in patients in the control arm.
We found that the proportion of patients in the control arm receiving postprotocol immunotherapy, which has a proven mortality benefit, is low. This raises the question of how much of the benefit of first-line combination immunotherapy regimens is associated with superior efficacy of the combination regimen compared with a lack of postprotocol immunotherapy treatment in the control arm.