Prior to the approval of nivolumab, a monoclonal antibody targeting programmed death-1 (PD-1), vascular endothelial growth factor-receptor tyrosine kinase inhibitors (VEGFR-TKIs), specifically pazopanib and sunitinib, were the standard of care in the front-line setting for metastatic clear cell renal cell carcinoma (mccRCC). CheckMate 025, a randomized, open label, phase 3 study comparing nivolumab to everolimus in previously treated mccRCC, reported an objective response (ORR) rate of 25% with nivolumab as compared to 5% in the everolimus arm.1  These results led to the US Food and Drug Administration (FDA) approval of nivolumab for patients with previously treated mccRCC, ushering in a new era in the treatment of mccRCC with immune checkpoint inhibition (ICI).

More recently, ICI has been introduced in the front line, with the recent FDA approvals of the VEGF-ICI combination axitinib + pembrolizumab as well as avelumab + axitinib, and ICI-ICI combination nivolumab + ipilimumab.2,3,4  With these new approvals, TKIs previously developed and approved in the first and second-line space, will now shift and be used in the second line and beyond following progression on ICI therapy. There has been a paucity of prospective data reporting the efficacy of TKI after progression on front-line ICI-based therapy; therefore, we report retrospective data assessing outcomes of patients treated with TKIs after first-line ICI, to provide insight in this setting given the shifting standard of care.5

This analysis included 70 patients, all with mccRCC. The most common sites of metastatic disease were lung in 61 patients (87%), lymph nodes in 48 patients (69%) and bone in 35 patients (50%). All patients had previously received first line ICI-based therapy in the context of clinical trial, where 12 patients (17%) received single-agent ICI (either nivolumab or atezolizumab), 33 (47%) received combination ICI (ipilimumab + nivolumab) followed by single agent nivolumab maintenance therapy, and 25 (36%) received combination ICI + VEGFR therapy (nivolumab + bevacizumab or atezolizumab + bevacizumab). Second-line TKIs utilized included pazopanib in 19 patients (27%), sunitinib in 6 patients (9%), axitinib in 25 patients (26%) and cabozantinib in 20 patients (28%).

Median progression-free survival (mPFS) on the second-line TKI was 13.2 months (95% CI 10.1-NA) and median overall survival (OS) was not reached. Patient previously treated with first-line ICI monotherapy (n=12) had a mPFS of 7.5 months on second-line TKI, those previously treated with first-line nivolumab + ipilimumab (n=33) had a mPFS of 11.9 months on second-line TKI, and those treated with ICI + bevacizumab (n=25) had a mPFS of 20.8 months on second-line TKI. Objective response rate (ORR) was 41% where 1 patient (1.5%) achieved a complete response (CR) and 27 patients (39.7%) had a partial response. Thirty-six patients (52.9%) had stable disease, with a disease control rate of 94%.

A limitation in interpreting these numbers is the small sample size and the retrospective nature of this work. However, with that caveat in mind, it is intriguing, and replicated in other studies, that the mPFS and ORR of second-line TKI hereafter first-line ICI parallels historic outcomes with front line TKI.6,7 These data can help in counseling our patients as they come off of front-line ICI therapy and can also help inform new trial design in 2L and 3L therapy in mccRCC.

With the recent approvals of combination ICI + VEGFR-TKI as well as previously approved nivolumab + ipilimumab, both in the first-line setting, appreciating the response to second-line TKI is important to determine optimal treatment sequencing in mccRCC. Our reported data is encouraging, suggesting a robust response to second-line TKIs, and this will hopefully lead to more prospective data.

Written by: Emily A. Lemke, DNP, AGPCNP-BC, AOCNP1, and Amishi Y. Shah, MD2
1. Medical College of Wisconsin, Department of Medicine – Hematology/Oncology, Milwaukee, Wisconsin
2. UT MD Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, Texas

1. Motzer, R.J., et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med, 2015. 373(19): p. 1803-13.
2. Motzer, R.J., et al., Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med, 2018. 378(14): p. 1277-1290.
3. Rini, B.I., et al., Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med, 2019. 380(12): p. 1116-1127.
4. Motzer, R.J., et al., Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med, 2019. 380(12): p. 1103-1115.
5. Shah, A.Y., et al., Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors. Eur J Cancer, 2019. 114: p. 67-75.
6. Albiges, L., et al., Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma. Eur J Cancer, 2015. 51(17): p. 2580-6.
7. Auvray, M., et al., Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma. Eur J Cancer, 2019. 108: p. 33-40.  

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