Nivolumab improves the prognosis of lung cancer, but its use can cause immune-related adverse events (irAEs). However, patients with irAEs are reported to have a longer progression free survival (PFS). We previously reported an association between Programmed death ligand 1 (PD-L1) single nucleotide polymorphisms (SNPs) and PFS following nivolumab treatment. We hypothesized that the irAEs were associated with PFS and the SNPs of Programmed death l (PD-1) and PD-L1.
Between January 2016 and June 2017, a total of 79 consecutive patients who were diagnosed with non-small lung cancer (NSCLC) and who had not undergone definitive operation were treated with nivolumab at Kyoto University Hospital. Of these 79 patients, 68 participated in this study. We retrospectively analyzed patients to evaluate the relationship between adverse events and PFS, and to assess the relationship between these adverse events and the PD-1/PD-L1 SNPs.
The response rate was 13% and the median PFS was 61 days. A significantly longer PFS was observed in patients with the adverse event of hypothyroidism than without hypothyroidism (56 days vs. N.R.; P = 0.016). Occurence of hypothyroidism, which is defined as the low free T4 level, was associated with the SNPs of PD-L1; rs1411262 and rs822339. Hypothyroidism developed in patients with the T/T and C/T genotypes of rs1411262 (P = 0.0269) and with the A/A and A/G genotypes of rs822339 (P = 0.0216). A significantly longer PFS was also associated with the T/T genotype than with the C/T and C/C genotypes of rs1411262 (P = 0.031) and the A/A genotype than the A/G and G/G genotypes of rs822339 (P = 0.017).
Patients with advanced NSCLC who developed hypothyroidism after nivolumab treatment had a significantly longer PFS when compared with those without hypothyroidism, and patients with the T allele of rs1411262 and the A allele of rs822339 tended to develop hypothyroidism. The T/T genotype of rs1411262 and the A/A genotype of rs822339 were significantly associated with longer PFS. The SNPs of PD-L1 might be associated with maintained functioning of the PD-1 and PD-L1 pathway following nivolumab treatment.
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T. Hirai: Chugai Pharmaceutical Co., Ltd Y.H. Kim: Supported: Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K. (Japan), Ono Pharmaceutical Co., Ltd. (Japan), Bristol-Myers Squibb K.K. (Japan), Boehringer Ingelheim Japan, Inc. (Japan), Eli Lilly Japan K.K (Japan) as honorarium recipient. All other authors have declared no conflicts of interest.