備考

1. ミスマッチ修復機能欠損を有する固形がん患者に対する免疫チェックポイント阻害薬の国内外の承認状況(2019年2月時点)

本邦およびFDA での承認状況を以下に示す(表1表2)。

表1. 本邦での承認状況

薬剤 適応の詳細
ペムブロリズマブ
(商品名:キイトルーダ)
【効能・効果】

がん化学療法後に増悪した進行・再発の高頻度マイクロサテライト不安定性(MSI-H)を有する固形癌(標準的な治療が困難な場合に限る)

効能・効果に関連する使用上の注意
  1. (1)十分な経験を有する病理医又は検査施設における検査により、MSI-High が確認された進行・再発の固形癌患者に投与すること。検査にあたっては、承認された体外診断薬を用いること。
  2. (2)結腸・直腸癌の場合、フッ化ピリミジン系抗悪性腫瘍剤、オキサリプラチン及びイリノテカン塩酸塩水和物による治療歴のない患者における本剤の有効性及び安全性は確立していない。
  3. (3)結腸・直腸癌以外の固形癌の場合、本剤の1次治療における有効性及び安全性は確立していない。また、2次治療において標準的な治療が可能な場合にはこれらの治療を優先すること。
  4. (4)本剤の手術の補助療法における有効性及び安全性は確立していない。
  5. (5)臨床試験に組み入れられた患者の癌腫等について、「臨床成績」の項の内容を熟知し、本剤の有効性及び安全性を十分に理解した上で、本剤以外の治療の実施についても慎重に検討し、適応患者の選択を行うこと。
用法・用量

通常、成人には、ペムブロリズマブ(遺伝子組換え)として、1 回200 mg を3 週間間隔で30 分間かけて点滴静注する。

表2. FDAでの承認状況

薬剤 適応の詳細
ペムブロリズマブ
(商品名:キイトルーダ)
INDICATIONS AND USAGE

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

DOSAGE AND ADMINISTRATION
  • MSI-H Cancer: 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for children.

Administer KEYTRUDA as an intravenous infusion over 30 minutes.

ニボルマブ
(商品名:オプジーボ)
INDICATIONS AND USAGE
  • OPDIVO, as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  • OPDIVO, in combination with ipilimumab, is indicated for the treatment of adults and pediatric patients 12 years and older with MSI-H or dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION
  • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer
    ✓ OPDIVO 240 mg every 2 weeks.

OPDIVO 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then OPDIVO 240 mg every 2 weeks.

イピリムマブ
(商品名:ヤーボイ)
INDICATIONS AND USAGE

YERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION
  • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer:
    ✓ Nivolumab 3 mg/kg followed by YERVOY 1 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks.

2. 各ガイドラインでの推奨

2.1 NCCNガイドライン(2019年2月時点)

それぞれのがんの種類に対するガイドライン内での検査に対する推奨、抗PD-1/PD-L1抗体薬に対する推奨、臓器特異的に抗PD-1/PD-L1抗体薬が承認されているかを以下に示す(表3)。

表3. NCCN ガイドラインにおけるMSI 検査/IHC 検査推奨

Guideline Version. Year Testing Immunotherapy Indication Organ-specific approval
Anal carcinoma 2.2018 MSI/MMR testing is not required. Subsequent therapy*+ No
Bladder cancer 1.2019 - Subsequent therapy* +‡†# Yes
Bone cancer 1.2019 - Systemic therapy for MSI-H/ MMR-D tumors* No
Breast cancer 4.2018 - - No
CNS cancer 2.2018 - - No
Cervical cancer 3.2019 Consider MMR/MSI testing or PD-L1 testing for patients with recurrent, progressive, or metastatic disease. 2nd line for MSI-H/ MMR-D tumors* No
Colon cancer 4.2018 Universal MMR or MSI testing is recommended in all patients with a personal history of colon or rectal cancer. MSI-H/ MMR-D tumors*+ No
Rectal cancer 3.2018 Universal MMR or MSI testing is recommended in all patients with a personal history of colon or rectal cancer. MSI-H/ MMR-D tumors*+ No
Esophageal cancer 2.2018 MMR or MSI testing should be considered on locally advanced, recurrent, or metastatic esophageal adenocarcinoma or EGJ in patients who are candidates for treatment with PD-1 inhibitors. 2nd line or subsequent therapy for MSI-H/ MMR-D tumors* No
Gastric cancer 2.2018 MMR or MSI testing should be considered on locally advanced, recurrent, or metastatic esophageal adenocarcinoma or EGJ in patients who are candidates for treatment with PD-1 inhibitors. For 2nd line or subsequent therapy for MSI-H/ MMR-D tumors*, for 3rd line or subsequent therapy for PD-L1 positive adenocarcinoma* Yes
Head and neck cancer 2.2018 - 2nd line or subsequent therapy* Yes
Hepatobiliary cancer 1.2019 - MSI-H/ MMR-D tumors*
2nd line for patients with HCC who progressed on sorafenib+
Yes, but HCC Only
Kidney cancer 3.2019 - 1st line (favorable risk) other recommebdation regimen+
1st line (poor/ intermediate risk) preferred regimen+
Yes
Malignant pleural mesothelioma 1.2019 - Subsequent therapy+ No
Melanoma 1.2019 - 1st line therapy-*+ Yes
Neuroendocrine and adrenal tumors 4.2018 Adrenocortical carcinoma: Consider MSI or MMR testing Pembrolizumab should be considered for dMMR or MSI-H unresectable/metastatic adrenocortical tumors that have progressed following prior treatment and have no satisfactory alternative treatment options. No
Non-small cell lung cancer 3.2019 - 1st line therapy-*+‡ Yes
Occult primary 2.2019 The population of patients with MSI-High/MMR-deficient occult primary tumors is low. Use IHC for MMR or PCR for MSI, which are different assays measuring the same biological effect. - No
Ovarian cancer 2.2018 - MSI-H/ MMR-D tumors* No
Pancreatic cancer 1.2019 Consider microsatellite instability (MSI) testing and/or mismatch repair (MMR) testing on available tumor tissue 2nd line for MSI-H/ MMR-D tumors* No
Penile cancer 1.2019 - Subsequent therapy for metastatic/recurrent disease preferred regimen: MSI-H/ MMR-D tumors* No
Prostate cancer 4.2018 Consider microsatellite instability (MSI) testing and/or mismatch repair (MMR) testing Subsequent therapy for MSI-H/ MMR-D tumors* No
Small cell lung cancer 1.2019 - Subsequent therapy*+ Yes
Soft tissue sarcoma 2.2019 - Systemic therapy agents and regimens:
Alveolar soft part sarcoma and UPS
No
Testicular cancer 1.2019 MSI testing if progression after high-dose chemotherapy or 3rd line therapy Palliative therapy for MSI-H/ MMR-D tumors* No
Thymomas and thymic carcinomas 1.2019 - 2nd line systemic therapy (thymic carcinomas only) No
Thyroid carcinoma 2.2018 - - No
Uterine neoplasms 3.2019 For recurrent endometrial cancer, NCCN recommends MSI-H or dMMR testing if not previously done. Useful in certain circumstances (for MSI-H/ MMR-D tumors)* No
Vulvar cancer 2.2019 Consider MMR/MSI testing for patients with recurrent, progressive, or metastatic disease Chemotherapy for advanced, recurrent/metastatic disease: useful in certain circumstances (2nd line therapy for PD-L1 positive or MSI-H/dMMR tumors)* No
Merkel cell carcinoma 2.2019 - Disseminated disease*+# Yes

*Pembrolizumab, +Nivolumab, ‡Atezolizumab, †Durvalumab, #Avelumab, - No statement

2.2 ESMOガイドライン
2.2.1 ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer
Recommendation: MSI testing

  • MSI testing in the metastatic disease setting can assist clinicians in genetic counselling.
  • MSI testing has strong predictive value for the use of immune check-point inhibitors in the treatment of patients with mCRC.

2.2.2 Pan-Asian Adapted ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer
Recommendation: Tumour mismatch repair(MMR)testing

  • Immunohistochemistry(IHC)tests for MMR proteins or PCR tests for microsatellite instability (MSI) in the metastatic disease setting can assist clinicians in genetic counselling.
  • Tumour MMR testing has strong predictive value for the use of immune check-point inhibitors in the treatment of patients with mCRC.

2.3 国内ガイドラインでの記載

「大腸癌治療ガイドライン」「遺伝性大腸癌診療ガイドライン」「大腸がん診療における遺伝子関連検査のガイダンス」、「産婦人科診療ガイドライン(外来編)」にリンチ症候群、スクリーニングについて記載あり。(大腸癌関連ガイドラインには抗PD-1 抗体薬についても記載あり。)「がん免疫療法ガイドライン」では免疫療法・irAE の管理・各癌腫に対する(dMMR 固形がんも含む)免疫療法のエビデンスについて記載されている。