Introduction
Methods
Eligibility criteria
Search strategy
Study selection
Data extraction
Study risk of bias assessment
Statistical analysis
Results
Overview of included studies and risk of bias assessment
Trial name | Trial characteristics | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Phase of trial | Anti-EGFR mAb therapy | Treatment line | Background therapy | Bevacizumab in control arm? | ITT, N | RAS status, N (%) of ITT | RAS wt, N (%) | Biomarker analysis | ||
III | Panitumumab | 3rd | BSC | No | 463 | KRAS codons 12, 13, and 61 | 288 (62) | 153 (53) | BRAF, PIK3CA, PTEN, EGFR GCN | |
20050181 [38] | III | Panitumumab | 2nd | FOLFIRI | No | 1186 | KRAS and NRAS exons 2, 3, 4 | 1014 (85) | 421 (42) | BRAF |
20100007 [39] | III | Panitumumab | 2nd | BSC | No | 377 | KRAS and NRAS exons 2, 3, 4 | 377 (100) | 270 (72) | BRAF |
III | Cetuximab | 1st | FOLFIRI | No | 1198 | KRAS exon 2 | 1063 (89) | 666 (63) | BRAF, EGFR | |
OPUS [40] | II | Cetuximab | 1st | FOLFOX4 | No | 337 | KRAS exon 2 | 315 (93) | 179 (57) | BRAF |
PRIME [10] | III | Panitumumab | 1st | FOLFOX4 | No | 1183 | KRAS and NRAS exons 2, 3, 4 | 1060 (90) | 512 (48) | BRAF |
III | Cetuximab | 2nd | BSC | No | 572 | KRAS exon 2 | 394 (69) | 230 (58) | BRAF, PIK3CA, PTEN, EREG | |
III | Cetuximab | 1st | FOLFOX4 | No | 393 | KRAS and NRAS exons 2, 3, 4 | 393 (100) | 393 (100) | EGFR | |
III | Panitumumab | 2nd | Irinotecan | No | 696 | KRAS codons 12, 13, and 61 | 523 (75) | 523 (100) | BRAF, PIK3CA, KRAS/NRAS/BRAF/PIK3CA, EGFR CN, EREG/AREG, EREG, AREG, HER3, MiR 31-3p | |
III | Cetuximab | 1st | Oxaliplatin and fluoropyrimidine | No | 2445 | KRAS codons 12, 13, and 61 | 1949 (80) | 1125 (58) | BRAF, PIK3CA, EGFR, EREG/AREG | |
NORDIC-VII [55] | III | Cetuximab | 1st | FLOX | No | 566 | KRAS and NRAS exons 2, 3, 4 | 457 (81) | 247 (54) | BRAF |
CAPRI-GOIM [56] | II | Cetuximab | 2nd | FOLFOX | No | 153 | KRAS exon 2 | 153 (100) | 153 (100) | KRAS/NRAS/BRAF/PIK3CA |
CALGB 80203 [57] | II | Cetuximab | 1st | FOLFOX or FOLFIRI | No | 238 | KRAS exon 2 | 103 (43) | 55 (53) | EGFR, EREG, AREG, HER2, HER3, HER4 |
III | Cetuximab | 1st | FOLFIRI | Yes | 592 | KRAS and NRAS exons 2, 3, 4 | 515 (87) | 343 (67) | BRAF, MiR 31-3p, MiR-21 | |
CALGB/SWOG 80405 [60] | III | Cetuximab | 1st | mFOLFOX6 or FOLFIRI | Yes | 2326 | KRAS exon 2 | 843 (36) | 600 (71) | BRAF |
PEAK [61] | II | Panitumumab | 1st | mFOLFOX6 | Yes | 285 | KRAS and NRAS exons 2, 3, 4 | 250 (88) | 170 (68) | BRAF |
III | Cetuximab | 1st | Oxaliplatin/irinotecan plus fluorouracil | Yes | 257 | KRAS codons 12, 13, and 61 | 257 (100) | 257 (100) | MiR 31-3p | |
VISNÚ-2 [64] | II | Cetuximab | 1st | FOLFIRI | Yes | 240 | KRAS exons 2 and 3 | 240 (100) | 240 (100) | BRAF/ PIK3CA |
Markers downstream of EGFR
BRAF Mutations
Subgroup | PFS | P value for interaction* | OS | P value for interaction* | ORR | P value for interaction* | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
N Trials | Interaction Hazard Ratio (95% CI) | Interaction P value | N Trials | Interaction Hazard Ratio (95% CI) | Interaction P value | N Trials | Interaction Odds Ratio (95% CI) | Interaction P value | ||||
Anti-EGFR drug | 0.55 | 0.56 | 0.33 | |||||||||
Cetuximab | 7 | 1.44 (1.11, 1.87) | < 0.01 | 6 | 1.10 (0.82, 1.46) | 0.52 | 3 | 0.66 (0.23, 1.89) | 0.44 | |||
Panitumumab | 6 | 1.26 (0.88, 1.80) | 0.21 | 5 | 1.26 (0.88, 1.79) | 0.21 | 1 | 2.93 (0.18, 46.88) | 0.45 | |||
Line of therapy | 0.88 | 0.88 | ||||||||||
First | 8 | 1.36 (1.06, 1.74) | 0.02 | 7 | 1.10 (0.84, 1.43) | 0.50 | 3 | 0.80 (0.30, 2.13) | 0.65 | - | ||
≥ Second | 5 | 1.41 (0.94, 2.11) | 0.10 | 4 | 1.16 (0.60, 2.25) | 0.65 | 0 | - | ||||
Bevacizumab in control arm? | 1.00 | 0.60 | 0.33 | |||||||||
Yes | 3 | 1.37 (0.87, 2.16) | 0.18 | 3 | 1.29 (0.81, 2.06) | 0.28 | 3 | 0.66 (0.23, 1.89) | 0.44 | |||
No | 10 | 1.37 (1.08, 1.75) | < 0.01 | 8 | 1.12 (0.87, 1.44) | 0.38 | 1 | 2.93 (0.18, 46.88) | 0.45 |
PIK3CA Mutations
Subgroup | PFS | P value for interaction* | OS | P value for interaction* | ||||
---|---|---|---|---|---|---|---|---|
N Trials | Interaction Hazard Ratio (95% CI) | Interaction P value | N Trials | Interaction Hazard Ratio (95% CI) | Interaction P value | |||
Anti-EGFR drug | 0.53 | 0.70 | ||||||
Cetuximab | 2 | 1.26 (0.77, 2.04) | 0.36 | 2 | 1.00 (0.59, 1.70) | 0.99 | ||
Panitumumab | 2 | 1.71 (0.75, 3.92) | 0.21 | 1 | 1.21 (0.53, 2.77) | 0.66 | ||
Line of therapy | 0.59 | 0.87 | ||||||
First | 1 | 1.50 (0.86, 2.60) | 0.15 | 1 | 1.10 (0.58, 2.06) | 0.77 | ||
≥ Second | 3 | 1.19 (0.62, 2.26) | 0.60 | 2 | 1.02 (0.55, 1.91) | 0.95 |
Prognostic and Predictive role of Non-functional PTEN
Prognostic and predictive role of multiple biomarkers
EGFR and its ligands
Prognostic and predictive role of EGFR
Study | Biomarker | Subgroup | N | PFS | OS | ORR | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Median, months | HR (95% CI) | P value | Median, months | HR (95% CI) | P value | Rate, % | Odds ratio (95% CI) | P value | ||||
COIN | ||||||||||||
EGFR membrane staining cells | Cetuximab ± oxaliplatin and fluoropyrimidine (N = NR) | 1.25 (1.05–1.50) | 0.015 | NR | NR | NR | NR | |||||
< 10% | NR | NR | NR | NR | ||||||||
≥ 10% | NR | NR | NR | NR | ||||||||
CALGB 80203 | ||||||||||||
EGFR mRNAa | Cetuximab + FOLFOX or FOLFIRI (N = 26) | 0.77 (0.50–1.21) | NR | 1.07 (0.77–1.46) | NR | NR | NR | |||||
high | NR | NR | NR | NR | ||||||||
low | NR | NR | NR | NR | ||||||||
FOLFOX or FOLFIRI (N = 29) | 1.04 (0.63–1.73) | NR | 1.21 (0.69–2.11) | NR | NR | NR | ||||||
high | NR | NR | NR | NR | ||||||||
low | NR | NR | NR | NR | ||||||||
20,020,408 and 194b | ||||||||||||
EGFR GCN | Panitumumab + BSC (N = 58) | NR | 0.039 | NR | 0.015 | NR | 0.0009c | |||||
≥ 2.5 copies/nucleus | 19 | NR | NR | 30 | ||||||||
< 2.5 copies/nucleus | 39 | NR | NR | 0 | ||||||||
BSC (N = 34) | 0.635 | NR | NR | NR | NR | |||||||
≥ 2.5 copies/nucleus | 8 | NR | NR | NR | ||||||||
< 2.5 copies/nucleus | 26 | NR | NR | NR | ||||||||
EGFR chromosome 7 polysomy | Panitumumab + BSC (N = 58) | NR | 0.029 | NR | 0.014 | 31.6 | NR | 0.0007c | ||||
≥ 40% | 22 | NR | NR | |||||||||
< 40% | 36 | NR | NR | 0 | ||||||||
PICCOLO | ||||||||||||
EGFR CN | Panitumumab + Irinotecan (N = NR) | NR | NR | NR | NR | 0.01 | ||||||
> 2 copies | NR | NR | NR | NR | 45.3 | |||||||
2 copies | NR | NR | NR | NR | 18.7 | |||||||
Irinotecan (N = NR) | NR | 0.98 | NR | 0.97 | NR | 1.0 | ||||||
> 2 copies | NR | NR | NR | 13.3 | ||||||||
2 copies | NR | NR | NR | 12.9 |
Prognostic and Predictive role of EGFR Ligands
Biomarker | Study | Subgroup | N | PFS | OS | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Median, months | HR (95% CI) | P value | Interaction P | Median, months | HR (95% CI) | P value | Interaction P | ||||
EREG/AREG | |||||||||||
PICCOLO | Irinotecan (N = NR) | 1.03 (0.70, 1.50) | 0.89 | 0.81 (0.55, 1.19) | 0.29 | ||||||
High (either EREG or AREG in top tertile) | NR | NR | |||||||||
Low (neither EREG nor AREG in top tertile) | NR | NR | NR | ||||||||
PICCOLO* | Irinotecan (N = 140) | 1.11 (0.77, 1.62) | 0.57 | 0.93 (0.65, 1.34) | 0.70 | ||||||
High (> 50% AREG or > 50% EREG) | 66 | NR | NR | ||||||||
Low (≤ 50% AREG and ≤ 50% EREG) | 74 | NR | NR | ||||||||
EREG | |||||||||||
CO.17 | BSC (N = 111) | 0.80 (0.59, 1.09) | 0.16 | 0.82 (0.58, 1.15) | 0.24 | ||||||
High (prespecified threshold (ΔCt = 6.27)) | 73 | NR | NR | ||||||||
Low (prespecified threshold (ΔCt = 6.27)) | 38 | NR | NR | ||||||||
CALGB 80203 | Cetuximab + FOLFOX or FOLFIRI (N = 26) | 0.84 (0.67, 1.00) | NR | 0.41 | 0.91 (0.74, 1.08) | NR | 0.70 | ||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
FOLFOX or FOLFIRI (N = 29) | 0.87 (0.71, 1.05) | NR | 0.79 (0.66, 0.94) | NR | |||||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
CO.17 | Cetuximab + BSC (N = 114) | 0.88 (0.99, 0.79) | 0.03 | 0.08 | 0.88 (0.99, 0.79) | 0.04 | 0.30 | ||||
Continuous variable | 114 | NR | NR | ||||||||
BSC (N = 111) | NR | 0.48 | 0.85 (0.96, 0.76) | 0.01 | |||||||
Continuous variable | 111 | NR | NR | ||||||||
PICCOLO | Panitumumab + Irinotecan (N = NR) | 0.85 (0.79, 0.93) | 0.0003 | 0.08 | 0.86 (0.79, 0.93) | 0.0005 | 0.72 | ||||
Log EREG | NR | NR | NR | ||||||||
Irinotecan (N = NR) | 0.95 (0.86, 1.04) | 0.27 | 0.87 (0.79, 0.95) | 0.002 | |||||||
Log EREG | NR | NR | NR | ||||||||
PICCOLO* | Panitumumab + Irinotecan (N = 134) | 0.93 (0.87, 0.98) | 0.009 | 0.01 | 0.91 (0.86, 0.96) | 0.001 | 0.17 | ||||
Continuous variable | 134 | NR | NR | ||||||||
Irinotecan (N = 140) | 1.02 (0.96, 1.07) | 0.57 | 0.96 (0.91, 1.02) | 0.19 | |||||||
Continuous variable | 140 | NR | NR | ||||||||
AREG | |||||||||||
CALGB 80203 | Cetuximab + FOLFOX or FOLFIRI (N = 26) | 0.88 (0.67, 1.18) | NR | 0.84 | 0.96 (0.70, 1.30) | NR | 0.66 | ||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
FOLFOX or FOLFIRI (N = 29) | 0.87 (0.71, 1.07) | NR | 0.84 (0.68, 1.03) | NR | |||||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
PICCOLO | Panitumumab + Irinotecan (N = NR) | 0.79 (0.72, 0.87) | < 0.0001 | 0.008 | 0.85 (0.77, 0.93) | 0.0006 | 0.07 | ||||
Log AREG | NR | NR | NR | ||||||||
Irinotecan (N = NR) | 0.96 (0.85, 1.07) | 0.47 | 0.95 (0.85, 1.06) | 0.37 | |||||||
Log AREG | NR | NR | NR | ||||||||
PICCOLO* | Panitumumab + Irinotecan (N = 134) | 0.95 (0.89, 1.02) | 0.18 | 0.06 | 0.94 (0.88, 1.01) | 0.09 | 0.43 | ||||
Continuous variable | 134 | NR | NR | ||||||||
Irinotecan (N = 140) | 1.04 (0.97, 1.10) | 0.27 | 0.98 (0.92, 1.05) | 0.53 | |||||||
Continuous variable | 140 | NR | NR |
Prognostic and Predictive role of other members of the HER family
Biomarker | Study | Subgroup | N | PFS | OS | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Median, months | HR (95% CI) | P value | Interaction P | Median, months | HR (95% CI) | P value | Interaction P | ||||
HER2 mRNA | |||||||||||
CALGB 80203 | Cetuximab + FOLFOX or FOLFIRI (N = 26) | 0.67 (0.42, 1.08) | NR | 0.77 | 0.86 (0.55, 1.33) | NR | 0.62 | ||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
FOLFOX or FOLFIRI (N = 29) | 0.66 (0.39, 1.10) | NR | 0.65 (0.39, 1.10) | NR | |||||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
HER4 mRNA | |||||||||||
CALGB 80203 | Cetuximab + FOLFOX or FOLFIRI (N = 26) | 0.63 (0.33, 1.16) | NR | 0.076 | 0.77 (0.42, 1.37) | NR | 0.07 | ||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
FOLFOX or FOLFIRI (N = 29) | 1.27 (0.79, 2.04) | NR | 1.52 (0.95, 2.39) | NR | |||||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
HER3 mRNA | |||||||||||
CALGB 80203 | Cetuximab + FOLFOX or FOLFIRI (N = 26) | 0.98 (0.71, 1.36) | NR | 0.20 | 1.15 (0.81, 1.62) | NR | 0.029 | ||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
FOLFOX or FOLFIRI (N = 29) | 0.69 (0.43, 1.12) | NR | 0.48 (0.27, 0.87) | NR | |||||||
High (≥ the median) | NR | NR | NR | ||||||||
Low (< the median) | NR | NR | NR | ||||||||
PICCOLO | Irinotecan (N = 115) | 0.98 (0.63, 1.52) | 0.92 | 0.93 (0.60, 1.44) | 0.74 | ||||||
High (> 66th centile) | 33 | NR | NR | ||||||||
Low (< 66th centile) | 82 | NR | NR | ||||||||
Panitumumab + Irinotecan (N = 94) | 0.71 (0.61, 0.82) | < 0.001 | 0.003 | 0.73 (0.64, 0.83) | < 0.001 | 0.01 | |||||
Log2 HER3 | 94 | NR | |||||||||
Irinotecan (N = 115) | 0.91 (0.77, 1.07) | 0.25 | 0.90 (0.80, 1.01) | 0.07 | |||||||
Log2 HER3 | 115 | NR | NR |
Prognostic and Predictive role of MicroRNA
Biomarker | Study | Subgroup | N | PFS | OS | ORR | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Median, months | HR (95% CI) | P value | Median, months | HR (95% CI) | P value | Rate, % | Odds ratio (95% CI) | P value | ||||
MiR-31-3p | ||||||||||||
PICCOLO | ||||||||||||
Panitumumab ± Irinotecan (N = 188) | 0.018 | 0.0012 | NR | |||||||||
Int: Low | NR | NR | 1.60 | NR | 1.58 | NR | NR | |||||
High: Low | NR | NR | 1.60 | NR | 2.03 | NR | NR | |||||
FIRE-3 | ||||||||||||
Cetuximab/Bevacizumab ± FOLFIRI (N = 340) | 1.11 (0.85, 1.45) | 0.43 | 1.43 (1.05, 1.96) | 0.02 | NR | NR | ||||||
High (≥ a prespecified cutoff (1.36)) | 111 | 7.8 | 20.3 | NR | ||||||||
Low (< a prespecified cutoff (1.36)) | 229 | 11.1 | 30.3 | NR | ||||||||
Cetuximab/Bevacizumab ± FOLFIRI (N = 340) | ||||||||||||
Log miR-31-3p | 340 | NR | 1.15 (1.05, 1.25) | < 0.01 | NR | 1.26 (1.13, 1.40) | < 0.01 | NR | NR | NR | ||
New EPOC | ||||||||||||
Cetuximab + oxaliplatin/irinotecan plus fluorouracil (N = 78) | 2.00 (1.00, 4.20) | 0.50 | 1.10 (0.40, 3.00) | 0.85 | 0.92 (0.33, 2.54) | 0.874 | ||||||
Mid + High (mid + high tertiles) | 51 | 12.3 | NR | 68.6 | ||||||||
Low (low tertile) | 27 | 20.3 | NR | 70.4 | ||||||||
Oxaliplatin/irinotecan plus fluorouracil (N = 71) | 0.90 (0.40, 2.00) | 0.79 | 0.70 (0.20, 2.90) | 0.62 | 0.69 (0.25, 1.92) | 0.473 | ||||||
Mid + High (mid + high tertiles) | 48 | NR | NR | 56.3 | ||||||||
Low (low tertile) | 23 | NR | NR | 65.2 | ||||||||
Cetuximab + oxaliplatin/irinotecan plus fluorouracil (N = 62) | 1.20 (0.98, 1.48) | 0.035 | NR | NR | NR | NR | ||||||
Log2 miR-31-3p | 62 | NR | NR | NR | ||||||||
Oxaliplatin/irinotecan plus fluorouracil (N = 63) | 0.96 (0.75, 1.23) | 0.36 | NR | NR | NR | NR | ||||||
Log2 miR-31-3p | 63 | NR | NR | NR |