Original ResearchOutcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors☆
Introduction
The incidence of kidney cancer worldwide in 2018 was greater than 400,000 cases; in the metastatic setting, this disease is typically incurable [1], [2]. Clear-cell renal cell carcinoma (ccRCC) is primarily associated with mutations in the VHL gene, which has led to the development of vascular endothelial growth factor–receptor tyrosine kinase inhibitors (VEGFR-TKIs) as anticancer therapies in ccRCC [3], [4], [5], [6]. From 2006 to 2017, the standard of care in metastatic ccRCC (mccRCC) shifted in the front-line setting to VEGF-targeted therapies [7], [8], [9]. In second and subsequent lines of therapy, VEGFR-TKIs, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors (ICIs) have been frequently used [10], [11], [12].
Nivolumab, a monoclonal antibody targeting programmed death-1 (PD-1), was the first ICI to be approved in advanced RCC, showing overall survival (OS) benefit over everolimus [13]. More recently, in CheckMate 214, a pivotal randomised phase 3 trial, nivolumab and ipilimumab demonstrated statistically superior median OS and higher objective response rate (ORR), in patients with international metastatic database consortium (IMDC) intermediate- and poor-risk disease compared with sunitinib [14], [15]. These results led to the US Food and Drug Administration approval of combination nivolumab and ipilimumab in the front-line setting for treatment of mccRCC.
The mccRCC treatment landscape is further rapidly changing with the exploration of combinations of ICI and anti-VEGF therapies. The results of the IMmotion-151 were recently reported, and the combination of atezolizumab, an anti–PD-L1 antibody, with bevacizumab, an anti-VEGF therapy, was superior to sunitinib in terms of progression-free survival (PFS) (11.2 vs. 7.7 months, hazard ratio [HR] 0.74, p = 0.02) and ORR (43% vs. 35%) in PD-L1 positive patients, per investigator assessment [16], opening the possibility of another non-TKI–containing ICI-based regimen in the frontline. The JAVELIN Renal 101 Phase 3 trial has now been reported as a TKI/ICI registration trial meeting (one of) its primary end-points, demonstrating superior PFS for the combination of axitinib and avelumab over sunitinib in PD-L1–positive patients (13.8 vs. 7.2 months, HR 0.61) [17]. In addition, the KEYNOTE-426 trial has demonstrated both PFS and OS advantage of axitinib plus pembrolizumab over sunitinib (median PFS [mPFS] 15.1 months vs. 11.1 months, HR 0.69), which may lead to further approvals in the first-line landscape [18].
With front-line approval of the combination of nivolumab and ipilimumab and upcoming data on anti-VEGF/ICI combination therapy, understanding responses of subsequent therapies is needed. This retrospective study of patients with mccRCC reports on ORR, PFS, safety of second line (2L) VEGFR-TKI and OS after progressive disease (PD) with front-line (1L) ICI-based non-TKI–containing therapy.
Section snippets
Patients and methods
We conducted this retrospective, multicenter study after Institutional Review Board (IRB) approval was obtained at the two participating centres. A combined deidentified secure database was constructed of 70 patients with mccRCC treated from December 2015 to February 2018 at MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center with a 2L VEGFR-TKI after PD with 1L ICI. All patients had previously received 1L ICI in the setting of clinical trials (nivolumab vs.
Patient characteristics
Among the 70 patients, 50 (71%) were male. The median age at diagnosis with metastatic involvement of RCC was 59 years (range 44–75). Forty-three patients (61%) initially presented with stage IV disease. At the time of 2L TKI therapy initiation, 8 patients (11%) had IMDC favourable-risk disease, 48 patients (69%) had intermediate-risk disease and 14 patients (20%) had poor-risk disease by IMDC criteria. Sixty patients (86%) had previously undergone nephrectomy. All patients included in this
Discussion
The landscape of mccRCC treatment has shifted dramatically in the last year with the introduction of ICI therapy in 1L treatment, particularly in intermediate- and poor-risk disease by IMDC [15]. Furthermore, evolving data with ICI-VEGF–directed combination therapies in the 1L setting may well lead to further approvals in this area in the near future [16], [20]. With ICI therapy moving up in the treatment paradigm of mccRCC, TKIs previously developed in and approved for the first- and
Conclusion
In this retrospective study, we observed a high ORR of 41%, mPFS of 13.2 months and 1-yr survival probability of 79.6% in patients with mccRCC treated with 2L TKI after 1L ICI. Very few patients had outright PD on 2L TKI after 1L ICI. Tolerance was comparable with prior experience with these approved agents. Further studies are needed to evaluate optimal combination strategies and sequencing of therapies in mccRCC.
Disclaimers
None.
Research support
None
Conflict of interest statement
A.Y.S. received research funding to employer for clinical trial support from BMS, Eisai and EMD Serono; honoraria from Eisai and Roche; reimbursement for travel expenses from BMS. P.M. is supported by a Young Investigator Award by the Kidney Cancer Association and by a Department of Defense Kidney Cancer Concept Award. J.G. was a part of consulting in Guidepoint Global and AstraZeneca and advisory committee member of Jounce. M.T.C. was a member of advisory boards of/ received honoraria from
References (28)
- et al.
Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial
Lancet Oncol
(2013) - et al.
Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial
Lancet Oncol
(2016) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009) - et al.
Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma
Eur J Cancer
(2015) - et al.
Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma
Eur J Cancer
(2019) - et al.
Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma
Ann Oncol
(2016) - et al.
Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial
Lancet
(2011) Global cancer statistics for the most common cancers
(2018)Cancer stat facts: kidney and renal pelvis cancer
(2017)- et al.
Systemic therapy for metastatic renal-cell carcinoma
N Engl J Med
(2017)
Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors
Clin Cancer Res
Comprehensive molecular characterization of clear cell renal cell carcinoma
Nature
The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer
Nat Rev Canc
Sunitinib versus interferon alfa in metastatic renal-cell carcinoma
N Engl J Med
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Data Presented: Oral presentation at KCA Conference Nov 2018 (Miami, FL) and poster presentation at GU ASCO February 2019 (San Francisco, CA).