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. 2023 Jun;72(6):1903-1915.
doi: 10.1007/s00262-023-03367-w. Epub 2023 Feb 2.

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial

Masaki Shiota  1 , Hideaki Miyake  2 , Masayuki Takahashi  3 , Mototsugu Oya  4 , Norihiko Tsuchiya  5 , Naoya Masumori  6 , Hideyasu Matsuyama  7 , Wataru Obara  8 , Nobuo Shinohara  9 , Kiyohide Fujimoto  10 , Masahiro Nozawa  11 , Kojiro Ohba  12 , Chikara Ohyama  13 , Katsuyoshi Hashine  14 , Shusuke Akamatsu  15 , Tomomi Kamba  16 , Koji Mita  17 , Momokazu Gotoh  18 , Shuichi Tatarano  19 , Masato Fujisawa  20 , Yoshihiko Tomita  21 , Shoichiro Mukai  22 , Keiichi Ito  23 , Tokiyoshi Tanegashima  24 , Shoji Tokunaga  25 , Masatoshi Eto  24 ; SNiP-RCC investigators
Affiliations

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial

Masaki Shiota et al. Cancer Immunol Immunother. 2023 Jun.

Abstract

Background: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC.

Methods: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated.

Results: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment.

Conclusion: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

Keywords: Anti-PD-1 antibody; Genome-wide association study; Nivolumab; Renal cell carcinoma; Single nucleotide polymorphism.

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Conflict of interest statement

Hideaki Miyake received honoraria from Ono Pharmaceutical. Masayuki Takahashi received honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. Mototsugu Oya received honoraria from Pfizer, Novartis, Bayer, MSD, Eisai, Ono Pharmaceutical, Bristol-Myers Squibb, Takeda Pharmaceutical and Merck Biopharma. Norihiko Tsuchiya received honoraria from Pfizer, Novartis, MSD, Eisai, Bristol-Myers Squibb, Takeda Pharmaceutical and Merck Biopharma, and support for attending meetings from Merck Biopharma. Naoya Masumori received honoraria from MSD, Bristol-Myers Squibb, Takeda Pharmaceutical and Ono Pharmaceutical. Hideyasu Matsuyama received grants from Janssen Pharma, Takeda Pharmaceutical, Baxter, KyowaKirin and Sanofi, and honoraria from Janssen Pharma, AstraZeneca, Merck Biopharma, Bayer, Astellas Pharma and Chugai. Wataru Obara received honoraria from Ono Pharmaceutical, Merck Biopharma, Takeda Pharmaceutical and Astellas Pharma. Nobuo Shinohara received grants from Ono Pharmaceutical, honoraria from Ono Pharmaceutical and Bristol-Myers Squibb, and support for attending meetings from Ono Pharmaceutical and Bristol-Myers Squibb. Masahiro Nozawa received honoraria from Takeda Pharmaceutical. Shusuke Akamatsu received grants from Astellas Pharma, AstraZeneca and Tosoh, and honoraria from Janssen Pharma, AstraZeneca, Bayer, Astellas Pharma, Sanofi and Takeda Pharmaceutical. Tomomi Kamba received honoraria from AstraZeneca and Merck Biopharma. Masatoshi Eto received from grants from Ono Pharmaceutical, and honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. All other authors declare no conflicts of interests to the current manuscript.

Figures

Fig. 1
Fig. 1
Manhattan plot of genome-wide significance in the development set. Plot of − log10 P-values from allelic chi-squared tests for the association of each single nucleotide polymorphism with CR/PR versus SD/PD after nivolumab treatment. The blue line indicates a threshold suggestive to be significant (= − log10 (1.0 × 10−5))
Fig. 2
Fig. 2
Objective response after nivolumab treatment according to genotype in rs643896 (A), rs685736 (B), rs4527932 (C), and rs4740819 (D)
Fig. 3
Fig. 3
Prediction of outcomes of nivolumab treatment by genetic risk category. Objective response (A), radiographic progression-free survival (B), and grade ≥ 3 adverse events (C) after nivolumab treatment according to risk stratification by genetic risk category are indicated
See this image and copyright information in PMC

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