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

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. 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. 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. 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.

Shah AY ，Kotecha RR ，Lemke EA ，Chandramohan A ，Chaim JL ，Msaouel P ，Xiao L ，Gao J ，Campbell MT ，Zurita AJ ，Wang J ，Corn PG ，Jonasch E ，Motzer RJ ，Sharma P ，Voss MH ，Tannir NM ... -  《-》

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.

Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs. We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used. Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2-10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8-9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8-16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0-10.5), and OS was 11.7 months (95% CI, 7.9-16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity. Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs. As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.

Wiele AJ ，Bathala TK ，Hahn AW ，Xiao L ，Duran M ，Ross JA ，Jonasch E ，Shah AY ，Campbell MT ，Msaouel P ，Tannir NM ... -  《-》

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

Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches. We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1. We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event. To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO.

Laccetti AL ，Garmezy B ，Xiao L ，Economides M ，Venkatesan A ，Gao J ，Jonasch E ，Corn P ，Zurita-Saavedra A ，Brown LC ，Kao C ，Kinsey EN ，Gupta RT ，Harrison MR ，Armstrong AJ ，George DJ ，Tannir N ，Msaouel P ，Shah A ，Zhang T ，Campbell MT ... -  《Cancer Medicine》

Real-world Treatment Sequencing and Outcomes With Cabozantinib After First-line Immune Checkpoint Inhibitor-based Combination Therapy For Patients With Advanced Renal Cell Carcinoma: CARINA Study Results.

Real-world data are limited on treatment sequencing and outcomes after first-line (1L) immune checkpoint inhibitor (CPI)-based combination treatment of advanced renal cell carcinoma (aRCC). In this real-world, UK-based, retrospective study (CARINA; NCT04957160), data were obtained from hospital and electronic prescribing records. Patients were aged ≥ 18 years at aRCC diagnosis and had received 1L CPI-CPI or tyrosine kinase inhibitor (TKI)-CPI combination therapy before second-line (2L) therapy including cabozantinib. We describe treatment outcomes including 1L and 2L durations of treatment (DoT) and overall survival (OS). Data from April 2015 to June 2022 were collected on 281 patients from nine UK centres. Median 1L DoT was 2.3 months for CPI-CPI therapy (n = 171) and 5.0 months for TKI-CPI therapy (n = 58). After 1L CPI-CPI or TKI-CPI therapy, median 2L DoT was 5.8 versus 4.2 months, respectively, for cabozantinib (n = 163), and 3.8 versus 2.4 months for other therapies (n = 118); median 2L OS was 15.2 and 15.3 months, respectively, for cabozantinib, and 14.6 and 24.2 months for other therapies. DoT for 2L treatment was numerically better for cabozantinib than for other therapies, and after 1L CPI-CPI therapy than after 1L TKI-CPI therapy. Median OS was similar for 2L cabozantinib and other 2L therapies, and median OS for 2L cabozantinib was similar after both 1L therapy types. These results demonstrate the antitumour effect of 2L therapies, including cabozantinib, after 1L CPI-based combination treatment, regardless of whether 1L CPI-CPI or TKI-CPI therapy is used.

Nathan P ，Venugopal B ，Ali J ，Allison J ，Ceruso M ，Charnley N ，Griffiths R ，Michael A ，Moore K ，Perrot V ，Prendergast Á ，Sharma A ，Szabados B ，Larkin J ... -  《-》

Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma.

Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naïve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear. Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected. Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (≥6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade ≥3. This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.

Auvray M ，Auclin E ，Barthelemy P ，Bono P ，Kellokumpu-Lehtinen P ，Gross-Goupil M ，De Velasco G ，Powles T ，Mouillet G ，Vano YA ，Gravis G ，Mourey L ，Priou F ，Rolland F ，Escudier B ，Albiges L ... -  《-》