Mismatch repair proficiency/deficiency and microsatellite instability
Cancer type | MSI-H (%) | Cancer type | MSI-H (%) | Cancer type | MSI-H (%) | Cancer type | MSI-H (%) |
---|---|---|---|---|---|---|---|
UCEC | 17.00–31.37 | BRCA | 0.00–1.53 | PRAD | 0.60–3.00 | KICH | 0.00 |
COAD | 6.00–19.72 | KIRC | 1.47 | LUAD | 0.53–1.00 | KIRP | 0.00 |
STAD | 9.00–19.09 | OV | 1.37–2.00 | BLCA | 0.49 | LAML | 0.00 |
READ | 5.73 | CHOL | 1.35–3.00 | NBL | 0.45 | NPC | 0.00 |
ACC | 4.35 | THYM | 0.81 | LGG | 0.39 | PAAD | 0–2.00 |
UCS | 3.00–3.51 | LIHC | 0.80–3.00 | CLL | 0.30 | PCPG | 0.00 |
CESC | 2.62–4.00 | HNSC | 0.78 | GBM | 0.25 | TGCT | 0.00 |
WT | 2.44 | SARC | 0.78 | AML | 0.00 | THCA | 0.00–3.00 |
MESO | 2.41 | SKCM | 0.00–0.64 | CTCL | 0.00 | UVM | 0.00–2.00 |
ESCA | 1.63 | LUSC | 0.60 | DLBC | 0.00 |
The relationship between MMR and multiple tumors
The predictive value of dMMR/MSI-H in multiple tumors
dMMR/MSI-H predicts the efficacy of anti-PD-1/PD-L1 immunotherapy
Author/year | Cancer type |
N
| Protocol | Results | PFS | OS |
---|---|---|---|---|---|---|
Le DT [65] 2015 | dMMR CRC | 41 | Pembrolizumab 10 mg/kg, q14d, 20 weeks | ORR 40% | 20-week PFS, 78%; mPFS: NR | mOS: NR |
pMMR CRC | ORR 0% | 20-week PFS, 11%; mPFS: 2.2 months | mOS, 5.0 months | |||
dMMR non-CRC | ORR 71% | 20-week PFS, 67%; mPFS: 5.4 months | mOS: NR | |||
pMMR CRC | 25 | ORR 0% DCR16% | mPFS, 2.4 months | mOS, 6 months | ||
Le DT [30] 2017 | 12 tumors with dMMR | 86 | Pembrolizumab 10 mg/kg, q14d, 2 years | ORR 53% DCR 66% | 12-month PFS, 64% 24-month PFS, 53%;mPFS: NR | 12-month OS, 76% 24-month OS, 64%;mOS: NR |
Diaz LA [66] 2017 | Multiple types of solid tumors | 77 | Pembrolizumab 200 mg, q3w, 35 cycles | ORR 38% DCR 58% | 6-month PFS, 45% mPFS, 4.3 months | 6-month OS, 73%;mOS: NR |
D Le [67] 2018 | MMR/dMMR CRC | 63 | Pembrolizumab 200 mg, q3w, 35 cycles | ORR 28% DCR 51% | 6-month PFS, 43% 12-month PFS, 41%;mPFS, 4.1 months | 6-month OS, 87% 12-month OS, 76%;mOS: NR |
Overman MJ [68] 2017 | dMMR/MSI-H mCRC | 74 | Nivolumab 3 mg/kg, q2w, until PD | ORR 31% DCR 69% (≥ 12 weeks) | 12-month PFS, 50% mPFS, 14.3 months | 12-month OS, 73%;mOS: NR |
Overman MJ [71] 2018 | dMMR/MSI-H mCRC | 119 | Nivolumab 3 mg/kg + ipilimumab 1 mg/kg, q3w, 4 doses, followed by nivolumab 3 mg/kg, q2w, until PD | ORR 55% DCR 80% | 9-month PFS, 76% 12-month PFS, 71%;mPFS: NR | 9-month OS, 87% 12-month OS, 85%;mOS: NR |
H-J J Lenz [72] 2018 | dMMR/MSI-H mCRC | 45 | Nivolumab 3 mg/kg, q2w + ipilimumab 1 mg/kg, q6w, until PD (as first-line treatment) | ORR 60% DCR 84% | 12-month PFS, 78%;mPFS: NR | 12-month OS: 83%;mOS: NR |
M Chalabi [73] 2018 | dMMR early-stage CC pMMR early-stage CC | 7 8 | Nivolumab 3 mg/kg, d1, d15 + ipilimumab 1 mg/kg, d1 | mPR 100% mPR 0% | NA | NA |
Clinical trial | Phase | Drug treatment | Drugs | Tumor type | Current status |
---|---|---|---|---|---|
NCT03150706 | II | Avelumab | Anti-PD-L1 mAb | Previously treated dMMR/MSI-H or POLE-mutated mCRC | Ongoing |
NCT03435107 | II | Durvalumab | Anti-PD-L1 mAb | Previously treated dMMR/MSI-H or POLE-mutated mCRC | Ongoing |
NCT02983578 | II | Durvalumab (MEDI4736) + AZD9150 | Anti-PD-L1 mAb + Antisense STAT3 | dMMR CRC, NSCLC, and advanced pancreatic cancer | Ongoing |
NCT02997228 | III | Atezolizumab + mFOLFOX6 + bevacizumab versus mFOLFOX6 + bevacizumab versus atezolizumab | Anti-PD-L1 mAb | dMMR mCRC | Ongoing |
NCT02912559 | III | Atezolizumab + standard chemotherapy* versus standard chemotherapy* | Anti-PD-L1 mAb | dMMR stage III resected CRC | Ongoing |
NCT03257163 | II | Pembrolizumab + capecitabine + radiation therapy | Anti-PD-1 mAb | dMMR and Epstein-Barr virus positive GC | Ongoing |
NCT02563002 | III | Pembrolizumab versus standard therapy** | Anti-PD-1 mAb | dMMR/MSI-H stage IV CRC | Not recruiting |
NCT03236935 | Ib | Pembrolizumab + L-NMMA | Anti-PD-1 mAb + nitric oxide synthase inhibitor | dMMR/MSI-H cancer, melanoma, NSCLC, HNSCC, classic HL, and urothelial carcinoma | Ongoing |
NCT03607890 | II | Nivolumab + relatlimab | Anti-PD-1 mAb + anti-LAG-3 mAb | MSI-H solid tumors refractory to prior PD-(L)1 therapy | Not recruiting |
NCT02992964 | I/II | Nivolumab | Anti-PD-1 mAb | Pediatric patients with hypermutant cancers, including biallelic MMR syndrome | Ongoing |
NCT03241745 | II | Nivolumab | Anti-PD-1 mAb | dMMR/MSI-H/hypermutated uterine cancer | Ongoing |
NCT02060188 | II | Nivolumab versus nivolumab + ipilimumab or nivolumab + ipilimumab + cobimetinib or nivolumab + BMS-986016 or nivolumab + daratumumab | Anti-PD-1 mAb + Anti-CTLA-4 mAb + MEK inhibitor + anti-LAG-3 mAb + anti-CD38 mAb | dMMR/pMMR/MSI-H/MSI-L/MSS CRC | Ongoing |
Relationship between dMMR/MSI-H and other immune biomarkers
Author/year | Tumor |
N
| PD-L1+ (%) | dMMR (%) | PD-L1+ in dMMR tumors (%) | PD-L1+ in pMMR tumors (%) |
P
| The impact of PD-L1 or dMMR on survival |
---|---|---|---|---|---|---|---|---|
Gatalica Z [74] 2014 | CC | 87 | 20.7 | 31.0 | 38.0 | 13.0 | 0.02 | NA |
Inaguma S [83] 2016 | CRC | 506 | NA | NA | 44.7 | 6.8 | < 0.01 | NA |
Inaguma S [83] 2016 | GC | 180 | NA | NA | 46.7 | 12.1 | < 0.01 | NA |
Kim ST [82] 2017 | Advanced GI, GU, and others | 430 | 16.5 in all, 28.6 in melanoma, 22.4 in GC, 20.9 in CRC, 12.5 in BTC, 7.1 in GU, 6.7 in HCC, 0.0 in pancreatic cancer and sarcoma | 4.5 in all 7.1 in GC 6.7 in HCC 4.4 in CRC | 38.9 | 15.2 | < 0.01 | P = 0.535 in GC P = 0.231 in mCRC P = 0.508 in sarcoma |
Mills AM [26] 2018 | Breast carcinoma | 245 | 12.0 in all 32.0 in TNDC | 0.04 | 100.0 | NA | NA | NA |
Wang L [84] 2018 | GC | 550 | 37.3 | 8.2 | 60.0 | 35.2 | < 0.01 | NA |
Clinical trial | Phase | Drug | TMB (mut/Mb) | Tumor |
N
| Response | PFS | OS |
---|---|---|---|---|---|---|---|---|
CheckMate026 [88] | III | Nivolumab | H ≥ 243 | NSCLC | 47 | ORR 47% | *mPFS, 9.7 moths | 1-year OS, 64%; mOS, 18.3 months |
Platinum-based CT | 60 | ORR 28% | *mPFS, 5.8 months | 1-year OS, 60%; mOS, 18.8 months | ||||
Nivolumab | L 0 to 99 and M 100 to 242 | 111 | ORR 23% | mPFS, 4.1 months | 1-year OS, 54%; mOS, 12.7 months | |||
Platinum-based CT | 94 | ORR 33% | mPFS, 6.9 months | 1-year OS, 53%; mOS, 13.2 months | ||||
CheckMate568 [89] | II | Nivolumab + ipilimumab | < 5, 5–10, 10–15, ≥ 15 | NSCLC | 288 | ORR 4%, ORR 10%, ORR 44%, ORR 39% | NA | NA |
CheckMate227 [90] | III | Nivolumab + ipilimumab | ≥ 10 | NSCLC | 139 | ORR 45.3% 1-year DoR 68% | *1-year PFS, 42.6% *mPFS, 7.2 months | NA |
Platinum doublet CT | 160 | ORR 26.9% 1-year DoR 25% | *1-year PFS, 13.2% *mPFS, 5.5 months | |||||
Nivolumab + ipilimumab | < 10 | mPFS, 3.2 months | ||||||
Platinum doublet CT | mPFS, 5.5 months | |||||||
CheckMate 032 [91] | Exploratory | Nivolumab + ipilimumab | H ≥ 248 | SCLC | 26 | ORR 46.2% | 1-year PFS, 30.3% mPFS, 7.8 months | 1-year OS, 62.4%; mOS, 22.0 months |
Nivolumab | 47 | ORR 21.3% | 1-year PFS, 21.2% mPFS, 1.4 months | 1-year OS, 35.2%; mOS, 5.4 months | ||||
Nivolumab + ipilimumab | M 143 to 247 | 25 | ORR 16.0% | 1-year PFS, 8.0% mPFS, 1.3 months | 1-year OS, 19.6%; mOS, 3.6 months | |||
Nivolumab | 44 | ORR 6.8% | 1-year PFS, 3.1% mPFS, 1.3 months | 1-year OS, 26.0%; mOS, 3.9 months | ||||
Nivolumab + ipilimumab | L 0 to 143 | 27 | ORR 22.2% | 1-year PFS, 6.2%; mPFS, 1.5 months | 1-year OS, 23.4%; mOS, 3.4 months | |||
Nivolumab | 42 | ORR 4.8% | 1-year PFS, NC;mPFS, 1.3 months | 1-year OS, 2.1%; mOS, 3.1 months | ||||
POPlAR [92] | Training | Atezolizumab | H-bTMB ≥ 16 | NSCLC | 25 | NA | *mPFS, 4.2 months | *mOS, 13.0 months |
Docetaxel | 38 | *mPFS, 2.9 months | *mOS, 7.4 months | |||||
OAK [92] | Validation | Atezolizumab | H-bTMB ≥ 16 | NSCLC | 77 | ORR 21% | *PFS (HR 0.65, 95% CI 0.47–0.92; P = 0.013) | *mOS, 13.5 months |
Docetaxel | 81 | ORR 10% | *mOS, 6.8 months | |||||
Atezolizumab | bTMB < 16 | NSCLC | 216 | ORR 13% | PFS (HR 0.98, 95% CI 0.80–1.2) | OS (HR 0.65, 95% CI 0.52–0.81) | ||
Docetaxel | 209 | ORR 12% | ||||||
Zhijie W et al. [96] | Anti-PD-1/PD-L1 therapies | bTMB ≥ 6 bTMB < 6 | NSCLC | 28 22 | *ORR 39.3% *ORR 9.1% | *mPFS: NR *mPFS, 2.9 months |