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学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.

Journal Club : Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy.

Journal Club : Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy

www.ncbi.nlm.nih.gov

 

今週のプレゼンターは、呼吸器内科のボスです。

 

2017年3月JCOに発表された、2カ国2施設における抗PD-1/PD-L1抗体の投与に関連した肺臓炎の報告。

 

 

 

ABSTRACT

Purpose

 

Pneumonitis is an uncommon but potentially fatal toxicity of anti–programmed death-1 (PD-1)/ programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and path- ologic features are poorly described.

 

Methods

 

Patients who received anti–PD-1/PD-L1 monotherapy or in combination with anti–cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher’s exact test as were associations between pneumonitis features and outcomes.

 

Results

 

Of 915 patients who received anti–PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P , .01). In- cidence was similar in patients with melanoma and non–small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [P = 1.0]; combination, 11 of 115 v four of 57 [P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse.

 

Conclusion

 

Pneumonitis associated with anti–PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti–PD-1/PD-L1 mAbs are combined with anti–cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/ resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immuno- suppression, and may result in infection and/or death.

 

Fig and Tab 

 

f:id:akinohanayuki:20170614150436p:plain

 

f:id:akinohanayuki:20170614150448p:plain

 

f:id:akinohanayuki:20170614150512p:plain

Fig 1. Time from first dose of anti– programmed death-1/programmed death ligand 1 therapy to date of pneumonitis event stratified by grade, with interquartile range and median values shown.

 

Median time to onset of pneumonitis was 2.8 months, with a wide range (9 days to 19.2 months). 

 

f:id:akinohanayuki:20170614150521p:plain

 

f:id:akinohanayuki:20170614150539p:plain

f:id:akinohanayuki:20170614150554p:plain

 

 参加者からの意見

  • この論文は、Pseudo progressionに触れていない。
  • 現在、Pseudo progressionか肺臓炎の判断ができないため、抗PD-1/PD-L1抗体の投与継続は難しい。
  • もし再投与となれば、Pembrolizumab → irAE → CDDP+Pem → PD → Nivoの流れになるのか...。しかし、最終ラインNIVOは、効果はどうなのか。

感想

  • Grade3と5に対して、infliximab と cyclophosphamideの併用症例があり、一つの選択肢になり得ることがわかった。
  • 抗PD-1/PD-L1抗体投与患者 915人→ 肺臓炎 43人 (5%)→ 併用 抗CTLA4抗体 (10%) > 単剤 (3%) であった。
  • 抗PD-1と抗PD-L1抗体における肺臓炎の差は、以下の通りであった。統計的な差ないが、抗PD-L1抗体の方が、肺臓炎に対する注意が必要であろう。(抗PD-1 vs 抗PD-L1抗体 : monotherapy, 22 of 564 [4%] v two of 152 [1%], P = .13; combination, 18 of 178 [10%] v one of 21 [5%], P = .70)

 

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