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

Abstract

575 Background: Immune checkpoint inhibitors (ICI) are being increasingly utilized in front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) VEGFR-TKI therapy after 1L ICI therapy. 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 RECIST v1.1. Descriptive statistics and Kaplan-Meier method were utilized. Results: 70 patients were included in the analysis. Median age at mccRCC diagnosis was 59 years old; 8 patients (11%) had IMDC favorable-risk score, 48 (69%) had intermediate-risk score, and 14 (20%) had poor-risk score. As 1L therapy, 12 patients (17%) received anti-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 remission (CR), 27 patients (39.7%) a partial response (PR), and 36 patients (52.9%) stable disease (SD), adding to a 94% disease control rate (DCR). Median progression-free survival (mPFS) was 13.2 months (95% CI: 10.1, NA). Estimated 1-yr overall survival (OS) probability was 79.6% (95% CI: 70.2 – 90.3). Median duration of 2L TKI therapy was 10.1 months. In total, 45.7% of subjects required a dose reduction, and 27% of patients discontinued treatment due to toxicity. Conclusions: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy following 1L ICI, we observed 2L antitumor activity and tolerance comparable to historical data for first-line TKI. Further studies are needed to evaluate optimal strategies and sequencing of therapies in mccRCC.

Combination antiangiogenic tyrosine kinase inhibition and anti‐PD1 immunotherapy in metastatic renal cell carcinoma: A retrospective analysis of safety, tolerance, and clinical outcomes

“…8,22 The METEOR trial and Checkmate 025, investigating cabozantinib and nivolumab after TKI failure, respectively, both reported an ORR of 21%, 23,24 while a pooled analysis of patients treated with second-line TKI monotherapy after IO at MDACC and Memorial Sloan Kettering Cancer Center revealed an ORR of 41.2%. 25 In our heavily pretreated mRCC cohort, combination TKI-IO achieved comparable, if not superior, response rates in reference to these monotherapy strategies. As further support for salvage TKI-IO use, one exceptional responder underwent consolidative cytoreductive nephrectomy following second-line TKI-IO exposure.…”

“…Despite 77.1% of patients in receiving at least two lines of prior systemic therapy, our observed ORR of 51% was similar to that of prospective first‐line TKI–IO trials 1,2 as well as previously published phase 1 data for nivolumab–pazopanib and nivolumab–cabozantinib in the salvage setting—45% and 36% respectively 8,22 . The METEOR trial and Checkmate 025, investigating cabozantinib and nivolumab after TKI failure, respectively, both reported an ORR of 21%, 23,24 while a pooled analysis of patients treated with second‐line TKI monotherapy after IO at MDACC and Memorial Sloan Kettering Cancer Center revealed an ORR of 41.2% 25 . In our heavily pretreated mRCC cohort, combination TKI–IO achieved comparable, if not superior, response rates in reference to these monotherapy strategies.…”

Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies

“…Limited trial data exist on the efficacy of VEGFR-TKIs or cabozantinib after progression on ICIs. In three real-world studies, second-line VEGFR-TKIs, including cabozantinib, had similar or improved efficacy after disease progression on ICIs, compared with the post-VEGFR-TKI setting [18][19][20]. Cabozantinib is a multitarget TKI that inhibits VEGFR1-3, MET, AXL, RET, ROS1, TYRO3, MER, KIT, and FLT3 and is approved in the first-line and subsequent-line settings for mRCC based on results from the CABOSUN and METEOR trials, respectively [21][22][23][24].…”

Pazopanib after Nivolumab-Induced Tumor Lysis Syndrome in a Patient with Metastatic Clear-Cell Renal Cell Carcinoma

“…In contrast, a durable response to ICI has previously been reported [6], and in our case, the combination of pazopanib and the prolonged effect of nivolumab may have cause TLS, similar to TKI/ICI combination therapy. Previous reports on second-line TKI after ICI are summarized in Table 2 [14,15]. Each treatment has a certain level of therapeutic effect and AEs.…”

“…Each treatment has a certain level of therapeutic effect and AEs. Shah et al [15] reported that 8 of 19 (42%) patients treated with pazopanib after ICI discontinued treatment due to its toxicity, and the most frequent reason (5 of 8, 63%) was transaminitis. The discontinuation rate of pazopanib was higher than that of other TKIs (13% for axitinib, 17% for sunitinib, 0% for cabozantinib).…”