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免疫チェックポイント阻害剤とPPIの関係(追加)

またしてもICIに PPIは有害伝説が1つ…。

IMpower150試験(非小細胞肺癌でCBDCA+PTXにatezo,bev,atezo+bevのいずれか)の事後解析でPPIと免疫チェックポイント阻害剤の好ましからぬ関連を示唆する報告がまたひとつ増えました。このBr J cancerの報告によると、肺癌のCBDCA+PTXに上乗せするアテゾリズマブの有効性を評価したとき、PPIを使っている人はOS HR 1.53、PFS HR 1.34と生命予後が悪い傾向が見られたようです。

Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150 - British Journal of Cancer
Proton pump inhibitors (PPIs) are commonly used concomitant to cancer treatment and they induce gut microbiota changes. It is increasingly apparent that gut dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). However, little is known about PPI effects on outcomes with ICIs, particularly in combination, ICI approaches. Post hoc, Cox proportional hazard analysis of phase III trial, IMpower150 was conducted to assess the association between PPI use and overall survival (OS) and progression-free survival (PFS) in chemotherapy-naive, metastatic non-squamous non-small cell lung cancer participants randomised atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation. Of 1202 participants, 441 (37%) received a PPI. PPI use was independently associated with worse OS (n = 748; hazard ratio (HR) [95% confidence interval (CI)] = 1.53 [1.21–1.95], P < 0.001) and PFS (1.34 [1.12–1.61], P = 0.002) in the pooled atezolizumab arms (ACP plus ABCP). This association was not apparent for BCP (n = 368; OS 1.01 [0.73–1.39], P = 0.969; PFS 0.97 [0.76–1.25], P = 0.827). The observed OS treatment effect (HR 95% CI) of the atezolizumab (ACP plus ABCP) arms vs BCP was 1.03 (0.77–1.36) for PPI users compared to 0.68 (0.54–0.86) for non-users (P [interaction] = 0.028). A similar association was noted for ABCP vs BCP (PPI users 0.96 [0.68–1.35]; PPI non-users 0.66 [0.50–0.87]; P [interaction] = 0.095). PPI use was a negative prognostic marker in patients treated with ACP or ABCP, but not BCP. The analysis suggests that PPIs negatively influence the magnitude of ICI efficacy.
https://www.nature.com/articles/s41416-021-01606-4

この手の論文では「PPIを使っている人は他に消化器疾患があったり、抗血栓薬を服用しなければならない心疾患があったり、そういう併存症の交絡因子があるのでは?」という反論がなされがちです。しかしIMpower150試験はCBDCA+PTXにアテゾリズマブではなくベバシズマブを上乗せする群もあり、この群ではPPIによりOSやPFSが悪化する様子は見られなかったようです。これを考えると、PPIで予後が悪化するという現象は免疫チェックポイント阻害剤に特有の現象と言えそうです。

1年ほど前にはこういう記事も書いていました。

プロトンポンプ阻害剤が免疫チェックポイント阻害剤(ICI)の有効性に悪影響を及ぼすかもしれないと言う報告が出てきました。これまでにも抗菌薬の投与はICIの有効性を落とすということが言われていましたが、ICIとプロトンポンプ阻害剤の関係についての報告が出て注目を集めています。PPIの使用はアテゾリズマブ投与患者の死亡リスク上昇に関与する

こちらの報告もアテゾリズマブ。どれも再現性を持ってPPI投与患者はICIの治療予後が悪いが細胞障害性化学療法では予後に差がないという結果で一貫していて、PPIが腫瘍免疫環境に何らかの影響を与えているのは間違いなさそうです。

Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab
Purpose: Emerging evidence indicates that gut microbiota dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). Proton pump inhibitors (PPI) are known to induce gut microbiota changes. However, little is known on the effects of PPIs on outcomes with ICI therapy, and it has not been explored in urothelial cancer treatment. Experimental Design: Individual–participant data from the advanced urothelial cancer trials, IMvigor210 (single-arm atezolizumab trial, n = 429) and IMvigor211 (phase III randomized trial of atezolizumab vs. chemotherapy, n = 931) were pooled in a Cox proportional hazard analysis assessing the association between PPI use and overall survival (OS) and progression-free survival (PFS). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation. Results: Of the 1,360 participants, 471 (35%) received a PPI within the 60-day window. PPI use was associated with significantly worse OS [HR (95% confidence interval (CI)) = 1.52 (1.27–1.83), P < 0.001] and PFS [1.38 (1.18–1.62), P < 0.001] with atezolizumab, but not chemotherapy ( P > 0.05). In the randomized cohort of IMvigor211, the OS treatment effect [HR (95% CI)] of atezolizumab versus chemotherapy was 1.04 (0.81–1.34) for PPI users, compared with 0.69 (0.56–0.84) for PPI nonusers ( P interaction = 0.013). Similar associations were noted in the PD-L1 IC2/3 population. Conclusions: This study indicates PPI use is a negative prognostic marker in advanced urothelial carcinoma treated with ICI therapy, but not chemotherapy. Furthermore, the analysis suggests PPIs influence the magnitude of ICI efficacy, and this warrants further investigation.
https://clincancerres.aacrjournals.org/content/26/20/5487.abstract

それにしても、PPIと免疫チェックポイント阻害剤の関連の研究が報告されてるのはIMvigor210試験、IMvigor211試験、あるいはPOPLAR試験といずれもアテゾリズマブ関係が多いのはなんでしょうね。。。


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更新日:2021-11-04 閲覧数:693 views.