There are few molecular markers driving treatment selection in later lines of advanced colorectal cancer patients, despite a growing commitment toward molecular characterization aimed at treatment personalization. |
Regorafenib, trifluridine/tipiracil, fruquintinib, and the combination of trifluridine/tipiracil (TFD/TPI) with bevacizumab demonstrated effectiveness in third-/fourth-line of therapy in randomized, phase III studies, irrespective of molecular characterization. |
The vast majority of patients progressing after first- and second-line therapy undergo chemotherapy regardless of molecular data. |
We aimed to assess the prognostic and predictive effects of specific RAS mutations on overall survival of patients receiving regorafenib, trifluridine/tipiracil, or both. |
1 Introduction
2 Patients and Methods
2.1 Patients
2.2 Treatment Details
2.3 Endpoints and Statistical Analysis
3 Results
3.1 Patients
RAS mutation | Patients (%) |
---|---|
No mutation (all wild-type) | 270 (46.3) |
Kras Codon 12 | 212 (36.4) |
G12D | 63 (10.8) |
G12V | 53 |
G12C | 17 (2.9) |
G12R | 3 |
G12S | 9 |
G12A | 14 |
G12V/D/A | 19 |
G12X | 34 |
Kras Codon 13 | 49 (8.4) |
G13D | 40 |
G13C | 1 |
G13A | 1 |
G13X | 7 |
Rare mutations | 51 (8.7) |
Kras A146X | 8 |
Kras A146T | 6 |
Kras A146V | 1 |
Kras G61X | 2 |
Kras Q61K | 1 |
Kras K117X | 2 |
Kras A146G | 1 |
Kras A59T | 1 |
Kras Q22K | 1 |
Kras codon 61 not further specified | 3 |
Nras G12A | 3 |
Nras G61L | 3 |
Nras Q61H | 3 |
Nras Q61X | 4 |
Nras Q61L | 2 |
Nras Q61R | 2 |
Nras Q61K | 2 |
Nras G61A | 2 |
Nras A117X | 2 |
Nras G61C | 1 |
Nras A11P | 1 |
WT [n = 174] | Codon 12 [n = 89] | Codon 13 [n = 29] | Rare [n = 30] | G12C [n = 10] | G12D [n = 31] | |
---|---|---|---|---|---|---|
Median age, years | 64.6 | 66.4 | 67.2 | 66.9 | 62.8 | 65.1 |
(p = 0.99) | ||||||
Sex [M/F] (p = 0.75) | 100/74 | 57/32 | 14/15 | 18/12 | 7/3 | 19/12 |
ECOG PS (p = 0.22) | ||||||
0 | 50 (28.7) | 23 (25.8) | 4 (13.7) | 8 (26.6) | 4 (40.0) | 10 (32.2) |
1 | 98 (56.3) | 58 (65.1) | 24 (82.7) | 16 (53.3) | 5 (50.0) | 19 (61.2) |
2 | 26 (14.9) | 8 (8.9) | 1 (3.4) | 6 (20.1) | 1 (10.0) | 2(6.4) |
Primary tumor location (p = 0.62) | ||||||
Right | 47 (27.0) | 33 (37.0) | 10 (34.4) | 9 (30.0) | 2 (20.0) | 11 (35.5) |
Left | 99 (57.0) | 43 (48.4) | 16 (55.2) | 18 (60.0) | 5 (50.0) | 13 (41.9) |
Rectum | 28 (16.0) | 13 (14.6) | 3 (10.4) | 3 (10.0) | 3 (30.0) | 7 (22.6) |
Metastatic synchronous disease (p = 0.28) | ||||||
145 (83.3) | 70 (78.6) | 20 (68.9) | 25 (83.3) | 6 (60.0) | 25 (80.6) | |
Site of metastatic disease (p = 0.16) | ||||||
Liver only | 19 (10.9) | 6 (6.7) | 5 (17.2) | – | 2 (20.0) | 4 (12.9) |
Liver + other | 86 (49.5) | 46 (51.6) | 18 (62.2) | 19 (63.3) | 7 (70.0) | 17 (54.8) |
Other sites | 69 (39.7) | 37 (41.5) | 6 (20.6) | 11 (36.7) | 1 (10.0) | 10 (32.3) |
Previous lines of therapy (p < 0.004) | ||||||
2 | 69 (39.6) | 56 (62.9) | 16 (55.1) | 20 (66.6) | 7 (70.0) | 18 (58.0) |
3 | 63 (36.2) | 14 (15.7) | 6 (20.6) | 3 (10.0) | 2 (20.0) | 10 (32.2) |
4 | 19 (10.9) | 4 (4.4) | 2 (6.8) | 2 (6.6) | 1 (10.0) | 3 (9.6) |
>4 | 23 (13.2) | 15 (16.8) | 5 (17.2) | 5 (16.6) | – | – |
Previous drugs administered (p < 0.001; p = 0.99 [excluding anti-EGFRs]) | ||||||
Fluoropyrimidine | 131 (75.2) | 65 (73.0) | 21 (72.4) | 23 (76.6) | 7 (70.0) | 25 (80.6) |
Oxaliplatin | 127 (72.9) | 58 (65.1) | 22 (75.8) | 22 (73.3) | 7 (70.0) | 23 (74.1) |
Irinotecan | 119 (68.3) | 52 (58.4) | 23 (79.3) | 20 66.6) | 6 (60.0) | 22 (70.9) |
Bevacizumab | 125 (71.8) | 59 (66.2) | 19 (65.5) | 17 (56.6) | 7 (70.0) | 23 (74.1) |
Anti-EGFRs | 129 (74.1) | – | – | – | – | – |
Immunotherapy | 4 (2.2) | 1 (1.1) | 1 (3.4) | – | – | – |
Aflibercept | 12 (6.8) | 7 (6.8) | 2 (6.8) | 6 (20.0) | 2 (20.0) | 4 (12.9) |
Unknown | 43 (24.7) | 22 (24.7) | 8 (27.5) | 7 (23.3) | 2 (20.0) | 6 (19.3) |
Receiving TFD/TPI | 79 (45.4) | 47 (52.8) | 17 (58.6) | 16 (53.3) | 6 (60.0) | 19 (61.2) |
(p = 0.88) | ||||||
Before rego | 46 (26.4) | 26 (29.2) | 8 (27.5) | 10 (33.3) | 4 (40.0) | 9 (29.0) |
After rego | 33 (18.9) | 21 (23.5) | 9 (31.0) | 6 (20.0) | 2 (20.0) | 10 (32.2) |
WT [n = 177] | Codon 12 [n = 90] | Codon 13 [n = 38] | Rare [n = 37] | G12C [n = 14] | G12D [n = 52] | |
---|---|---|---|---|---|---|
Median age, years | 66.8 | 68.0 | 68.6 | 69.0 | 66.0 | 68.3 |
(p = 0.99) | ||||||
Sex [M/F] (p = 0.13) | 97/80 | 55/35 | 16/22 | 17/20 | 11/3 | 27/25 |
ECOG PS (p = 0.29) | ||||||
0 | 48 (27.1) | 26 (28.8) | 7 (18.4) | 12 (32.4) | 4 (28.5) | 9 (17.3) |
1 | 102 (57.6) | 56 (62.2) | 29 (76.3) | 18 (48.6) | 9 (64.2) | 34 (65.3) |
2 | 27 (15.2) | 8 (8.8) | 2 (5.2) | 7 (18.9) | 1 (7.1) | 9 (17.3) |
Primary tumor location (p = 0.82) | ||||||
Right | 47 (26.5) | 26 (28.8) | 14 (36.8) | 15 (40.5) | 4 (28.5) | 13 (25.0) |
Left | 90 (50.8) | 41 (45.5) | 16 (42.1) | 14 (37.8) | 8 (57.1) | 27 (51.9) |
Rectum | 40 (22.5) | 23 (25.5) | 8 (21.0) | 8 (21.6) | 2 (14.2) | 12 (23.1) |
Synchronous metastatic disease (p = 0.59) | ||||||
130 (73.4) | 64 (71.1) | 23 (60.5) | 29 (78.3) | 10 (71.4) | 39 (75.0) | |
Site of metastatic disease (p = 0.65) | ||||||
Liver only | 22 (12.4) | 11 (12.2) | 6 (15.7) | 3 (8.1) | 3 (21.4) | 6 (11.5) |
Liver + other | 89 (50.2) | 46 (51.1) | 19 (51.3) | 23 (62.1) | 8 (57.1) | 34 (65.3) |
Other sites | 66 (37.2) | 33 (36.6) | 13(34.2) | 11 (29.7) | 3 (21.4) | 12 (23.0) |
Previous lines of therapy (p = 0.0001) | ||||||
2 | 77 (43.5) | 61 (67.7) | 16 (42.1) | 19 (51.3) | 9 (64.2) | 26 (50.0) |
3 | 71 (40.1) | 18 (20.0) | 12 (31.5) | 8 (21.6) | 4 (28.5) | 17 (32.6) |
4 | 9 (5.0) | 2 (2.2) | 2 (5.2) | 3 (8.1) | 1 (7.1) | 9 (17.3) |
>4 | 20 (11.2) | 9 (10.0) | 8 (21.0) | 7 (18.9) | – | – |
Previous drugs administered (p < 0.0001; p = 0.91 [with exclusion of anti-EGFRs]) | ||||||
Fluoropyrimidine | 173 (97.7) | 86 (95.5) | 36 (94.7) | 36 (97.2) | 14 (100.0) | 52 (100.0) |
Oxaliplatin | 165 (93.2) | 81 (90.0) | 32 (84.2) | 34 (91.8) | 13 (92.8) | 43 (82.6) |
Irinotecan | 166 (93.7) | 82 (91.1) | 35 (92.1) | 34 (91.8) | 14 (100.0) | 45 (86.5) |
Bevacizumab | 95 (53.6) | 75 (83.3) | 28 (73.6) | 28 (75.6) | 9 (64.2) | 42 (80.7) |
Anti-EGFRs | 154 (87.0) | – | – | – | – | – |
Immunotherapy | 2 (1.1) | 2 (2.2) | 2 (5.2) | – | – | – |
Aflibercept | 9 (5.0) | 12 (13.3) | 6 (15.7) | 12 (32.4) | 4 (28.5) | 8 (15.3) |
Unknown | 4 (2.2) | 3 (3.3) | 2 (5.2) | 1 (2.7) | – | – |
Receiving rego | 80 (45.1) | 49 (54.4) | 17 (44.7) | 16 (43.2) | 7 (50.0) | 19 (36.5) |
(p = 0.65) | ||||||
Before TFD/TPI | 32 (18.0) | 19 (21.1) | 9 (23.6) | 5 (13.5) | 2 (14.2) | 10 (19.2) |
After TFD/TPI | 48 (27.1) | 30 (33.3) | 8 (21.0) | 11 (29.7) | 5 (35.7) | 9 (17.3) |