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      The efficacy of VEGFR TKI therapy after progression on immune combination therapy in metastatic renal cell carcinoma

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          Abstract

          BACKGROUND

          The outcome of patients who progress on front-line immune-based combination regimens (IC) including immune checkpoint inhibitors (CPI) and receive subsequent systemic therapy is unknown.

          Methods

          Retrospective analysis of consecutive patients with clear-cell mRCC who progressed on one of seven clinical trials investigating an IC and received ≥1 line of subsequent VEGFR TKI therapy.

          Results

          Thirty-three patients [median age 57 (37–77), 85% male, 73% ECOG 0] were included. For evaluable patients ( N = 28), the best response to first subsequent therapy was 29% partial response, 54% stable disease, and 18% progressive disease. The median PFS (mPFS) for first subsequent therapy was 6.4 months (95% CI, 4.4–8.4); no difference in mPFS by prior type of IC (VEGFR TKI-CPI vs. CPI-CPI) was noted ( p = 0.310). Significant AEs were observed in 30% of patients, more frequently transaminitis (9%).

          Conclusions

          VEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.

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          Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.

          Daniel Heng, Wanling Xie, Meredith Regan … (2009)
          There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy. Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS. The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73. This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.
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            Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.

            Robert Motzer, Bernard Escudier, Piotr Tomczak … (2013)
            In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. Median overall survival was 20.1 months (95% CI 16.7-23.4) with axitinib and 19.2 months (17.5-22.3) with sorafenib (hazard ratio [HR] 0.969, 95% CI 0.800-1.174; one-sided p=0.3744). Median investigator-assessed PFS was 8.3 months (95% CI 6.7-9.2) with axitinib and 5·7 months (4.7-6.5) with sorafenib (HR 0.656, 95% CI 0.552-0.779; one-sided p<0.0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20.7 months (95% CI 18.4-24.6) versus 12.9 months (10.1-20.4) in the axitinib group (p=0.0116), and 20.2 months (17.1-32.0) versus 14.8 months (12.0-17.7) in the sorafenib group (one-sided p=0.0020). Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. Pfizer Inc. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206.

              Brian I Rini, Susan Halabi, Jonathan E Rosenberg … (2008)
              Bevacizumab is an antibody that binds to vascular endothelial growth factor (VEGF) and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN) is a historic standard first-line treatment for RCC. A prospective, randomized phase III trial of bevacizumab plus IFN versus IFN monotherapy was conducted. Patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or the same dose and schedule of IFN monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Between October 2003 and July 2005, 732 patients were enrolled. The prespecified stopping rule for OS has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P < .0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P < .0001). Bevacizumab plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% [95% CI, 9.5% to 17.3%]; P < .0001). Overall toxicity was greater for bevacizumab plus IFN, including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%). Bevacizumab plus IFN produces a superior PFS and ORR in untreated patients with metastatic RCC as compared with IFN monotherapy. Toxicity is greater in the combination therapy arm.
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                Author and article information

                Contributors
                Brian I. Rini: +216-444-9567 , rinib2@ccf.org
                Journal
                Journal ID (nlm-ta): Br J Cancer
                Journal ID (iso-abbrev): Br. J. Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Electronic): 24 May 2018
                Publication date (Print): 17 July 2018
                Volume: 119
                Issue: 2
                Pages: 160-163
                Affiliations
                [1 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Department of Hematology and Medical Oncology, Taussig Cancer Institute, , Cleveland Clinic, ; Cleveland, OH USA
                [2 ]Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary of London, London, UK
                Article
                Publisher ID: 104
                DOI: 10.1038/s41416-018-0104-z
                PMC ID: 6048048
                PubMed ID: 29795307
                SO-VID: c6dc7411-8db3-47bc-a4d7-abc5cb2d56b2
                Copyright © © Cancer Research UK 2018
                License:

                Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

                History
                Date received : 12 December 2017
                Date revision received : 4 April 2018
                Date accepted : 12 April 2018
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Cancer Research UK 2018

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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