Efficacy and safety of subsequent molecular targeted therapy after immuno-checkpoint therapy, retrospective study of Japanese patients with metastatic renal cell carcinoma (AFTER I-O study)

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Abstract

Objectives

Guidelines for treatment of mRCC recommend nivolumab monotherapy (NIVO) for treated patients, and nivolumab plus ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor-risk mRCC patients. Although molecular-targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their efficacy and safety remain unclear.

Methods

Outcome of Japanese patients with mRCC who received TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator-assessed ORR of the first TT after either NIVO or NIVO+IPI. Secondary endpoints included TFS, PFS, OS and safety of TTs.

Results

Twenty six patients in CheckMate 025 and 19 patients in CheckMate 214 from 20 centers in Japan were analyzed. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most frequently treated regimen for both CheckMate 025 (54%) and CheckMate 214 (47%) patients. The ORRs of TT after NIVO and NIVO+IPI were 27 and 32% (all risks), and median PFSs were 8.9 and 16.3 months, respectively. During the treatment of first TT after either NIVO or NIVO+IPI, 98% of patients experienced treatment-related adverse events, including grade 3–4 events in 51% of patients, and no treatment-related deaths occurred.

Conclusions

TTs have favorable antitumor activity in patients with mRCC after ICI, possibly via changing the mechanism of action. Safety signals of TTs after ICI were similar to previous reports. These results indicate that sequential TTs after ICI may contribute for long survival benefit.

Abstract

Outcome of targeted molecular therapies after discontinuation of nivolumab or nivolumab and ipilimumab in patients with mRCC was retrospectively analyzed. Efficacy was favorable, and safety was similar to previous reports.

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Most cited references 44

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Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Suzanne Topalian, F. Stephen Hodi, Julie Brahmer … (2012)

Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006). Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).

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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Megan Wind-Rotolo, Sergio Bracarda, Howard Gurney … (2018)

Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.

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Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

Robert Motzer, Bernard Escudier, David F McDermott … (2016)

Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.

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Author and article information

Contributors

Yoshihiko Tomita:

ORCID: https://orcid.org/0000-0002-7465-9591

Go Kimura:

ORCID: https://orcid.org/0000-0003-0088-9324

Satoshi Fukasawa:

ORCID: https://orcid.org/0000-0002-4759-4999

Kazuyuki Numakura:

ORCID: https://orcid.org/0000-0002-5899-1738

Yutaka Sugiyama:

ORCID: https://orcid.org/0000-0001-7620-0269

Kazutoshi Yamana:

ORCID: https://orcid.org/0000-0002-8858-1027

Sei Naito:

ORCID: https://orcid.org/0000-0002-6104-4344

Koki Kabu:

ORCID: https://orcid.org/0000-0003-2753-4259

Yohei Tajima:

ORCID: https://orcid.org/0000-0002-2048-4263

Mototsugu Oya

Journal

Journal ID (nlm-ta): Jpn J Clin Oncol

Journal ID (iso-abbrev): Jpn J Clin Oncol

Journal ID (publisher-id): jjco

Title: Japanese Journal of Clinical Oncology

Publisher: Oxford University Press

ISSN (Print): 0368-2811

ISSN (Electronic): 1465-3621

Publication date Collection: June 2021

Publication date (Electronic): 17 February 2021

Publication date PMC-release: 17 February 2021

Volume: 51

Issue: 6

Pages: 966-975

Affiliations

Department of Urology , Molecular Oncology, Graduate School of Medicine and Dental Sciences , Niigata, Japan

Department of Urology , Nippon Medical School Hospital , Tokyo, Japan

Prostate Center and Division of Urology , Chiba, Japan

Department of Urology , Akita University School of Medicine , Akita, Japan

Department of Urology , Graduate School of Medical Sciences , Kumamoto, Japan

Department of Urology , Molecular Oncology, Graduate School of Medicine and Dental Sciences , Niigata, Japan

Department of Urology , Yamagata University Faculty of Medicine , Yamagata, Japan

Bristol-Myers Squibb , Shinjuku-ku, Tokyo, Japan

Ono Pharmaceutical Co. Ltd. , Osaka-shi, Japan

Department of Urology , Keio University School of Medicine , Tokyo, Japan

Author notes

For reprints and all correspondence: Department of Urology, Niigata University, Asahimachi 1-757, Niigata 951-8510, Japan. E-mail: ytomita@ 123456med.niigata-u.ac.jp

Author information

Yoshihiko Tomita https://orcid.org/0000-0002-7465-9591

Go Kimura https://orcid.org/0000-0003-0088-9324

Satoshi Fukasawa https://orcid.org/0000-0002-4759-4999

Kazuyuki Numakura https://orcid.org/0000-0002-5899-1738

Yutaka Sugiyama https://orcid.org/0000-0001-7620-0269

Kazutoshi Yamana https://orcid.org/0000-0002-8858-1027

Sei Naito https://orcid.org/0000-0002-6104-4344

Koki Kabu https://orcid.org/0000-0003-2753-4259

Yohei Tajima https://orcid.org/0000-0002-2048-4263

Article

Publisher ID: hyaa266

DOI: 10.1093/jjco/hyaa266

PMC ID: 8163064

PubMed ID: 33594427

SO-VID: a8e6522e-bbcb-4fca-85f6-b238711b800b

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 4 August 2020

Date: 20 December 2020

Date accepted : 22 December 2020

Page count

Pages: 10

Funding

Funded by: Ono Pharmaceutical Co., Ltd., DOI 10.13039/501100013170;

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Efficacy and safety of subsequent molecular targeted therapy after immuno-checkpoint therapy, retrospective study of Japanese patients with metastatic renal cell carcinoma (AFTER I-O study)

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Karger: Oncology

Most cited references 44

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

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