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 ... -  《-》

Cabozantinib real-world effectiveness in the first-through fourth-line settings for the treatment of metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Cabozantinib is approved for metastatic renal cell carcinoma (mRCC) based on the METEOR and CABOSUN trials. However, real-world effectiveness and dosing patterns of cabozantinib are not well characterized. Patients with mRCC treated with cabozantinib between 2011 and 2019 were identified and stratified using the International mRCC Database Consortium (IMDC) risk groups. First- (1L), second- (2L), third- (3L), and fourth-line (4L) overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were analyzed. Dose reduction rates and their association with TTF and OS were determined. A total of 413 patients were identified. The ORRs across 1L to 4L were 32%, 26%, 25%, and 29%, respectively, and the median TTF rates were 8.3, 7.3, 7.0, and 8.0 months, respectively. The median OS (mOS) rates in 1L to 4L were 30.7, 17.8, 12.6, and 14.9 months, respectively. For patients treated with 1L PD(L)1 combination agent (n = 31), 2L cabozantinib had ORR of 22%, median TTF of 5.4 months, and mOS of 17.4 months. About 50% (129/258) of patients required dose reductions. The TTF and mOS were significantly longer for patients who required dose reduction vs. patients who did not, with an adjusted hazard ratio of 0.37 (95% CI 0.202-0.672, p < 0.01) and 0.46 (95% CI 0.215-0.980, p = 0.04), respectively. Limitations include the retrospective study design and the lack of central radiology review. The ORR and TTF of cabozantinib were maintained from the 1L to 4L settings. Dose reductions due to toxicity were associated with improved TTF and OS. Cabozantinib has clinical activity after 1L Immuno-oncology combination agents.

Gan CL ，Dudani S ，Wells JC ，Donskov F ，Pal SK ，Dizman N ，Rathi N ，Beuselinck B ，Yan F ，Lalani AA ，Hansen A ，Szabados B ，de Velasco G ，Tran B ，Lee JL ，Vaishampayan UN ，Bjarnason GA ，Subasri M ，Choueiri TK ，Heng DYC ... -  《Cancer Medicine》

Cabozantinib with immune checkpoint inhibitor versus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

Gebrael G ，Jo Y ，Mathew Thomas V ，Li H ，Sayegh N ，Tripathi N ，Srivastava A ，Nordblad B ，Dal E ，Narang A ，Brundage J ，Campbell P ，Galarza Fortuna G ，Hage Chehade C ，Maughan BL ，Agarwal N ，Swami U ... -  《-》

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 ... -  《-》

Activity of cabozantinib after immune checkpoint blockade in metastatic clear-cell renal cell carcinoma.

Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1-based ICBs. We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated. Eighty-six patients were included in the analysis; the median age was 63 years (range 33-84) and the median number of prior therapies was 2 (range 1-10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26-47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3-8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41-66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%). Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies.

McGregor BA ，Lalani AA ，Xie W ，Steinharter JA ，E Bakouny Z ，Martini DJ ，Fleischer JH ，Abou-Alaiwi S ，Nassar A ，Nuzzo PV ，Kaymakcalan MD ，Braun DA ，Wei XX ，Harshman LC ，Bilen MA ，Choueiri TK ... -  《-》