Elsevier

European Journal of Cancer

Volume 114, June 2019, Pages 67-75
European Journal of Cancer

Original Research
Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors

https://doi.org/10.1016/j.ejca.2019.04.003Get rights and content

Highlights

  • Immunotherapy (ICI) is moving to front-line treatment in metastatic RCC for intermediate- and poor-risk patients.

  • Little data exists on responses to second-line (2L) TKI after front-line (1L) ICI.

  • Our data showed that 2L VEGFR-TKI have ORR 41% and DCR 94% after 1L ICI–containing regimen.

  • Median PFS on 2L VEGFR-TKI after 1L ICI in metastatic clear-cell RCC was 13.2 mo.

  • Safety and tolerability of 2L VEGFR-TKI after 1L ICI is typical of class effects.

Abstract

Background

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor–receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy.

Patients and methods

This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan–Meier method were used.

Results

Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti–programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti–PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity.

Conclusions

In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

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

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