Background
Patients and methods
Japanese patient subgroup
Preplanned sample size for Japanese patients
Unadjusted analyses
Preplanned analyses
Post hoc analyses
Exploratory analyses to evaluate deviation of patient prognosis
Safety
Results
Patients
FISH result | IHC score | ||||
---|---|---|---|---|---|
IHC 0 | IHC 1+ | IHC 2+ | IHC 3+ | Total | |
FISH-positive, n
| 14 | 19 | 36 | 37 | 106 |
FISH-negative, n
| 155 | 57 | 14 | 1 | 227 |
NE, n
| 48 | 12 | 8 | 8 | 83 |
Total, n
| 217 | 88 | 58 | 46 | 409 |
Characteristic | Japanese | Non-Japanese | ||
---|---|---|---|---|
Trastuzumab plus XP (n = 51) | XP/FP (n = 50) | Trastuzumab plus XP (n = 243) | XP/FP (n = 240) | |
Sex | ||||
Male, n
| 40 (78.4%) | 40 (80.0%) | 186 (76.5%) | 178 (74.2%) |
Median age, years (range) | 63.0 (29–76) | 63.5 (45–81) | 60.0 (23–83) | 59.0 (21–82) |
Extent of disease | ||||
Locally advanced, n
| 0 (0.0%) | 1 (2.0%) | 10 (4.1%) | 9 (3.8%) |
Metastatic, n
| 51 (100.0%) | 49 (98.0%) | 233 (95.9%) | 231 (96.3%) |
Primary tumor site | ||||
Stomach, n
| 49 (96.1%) | 44 (88.0%) | 187 (77.0%) | 198 (82.5%) |
Gastroesophageal junction, n
| 2 (3.9%) | 6 (12.0%) | 56 (23.0%) | 42 (17.5%) |
Measurability of disease | ||||
Measurable, n
| 45 (88.2%) | 41 (82.0%) | 224 (92.2%) | 216 (90.0%) |
Nonmeasurable, n
| 6 (11.8%) | 9 (18.0%) | 19 (7.8%) | 24 (10%) |
ECOG performance status | ||||
0–1, n
| 51 (100.0%) | 50 (100.0%) | 213 (87.7%) | 213 (88.7%) |
2, n
| 0 (0.0%) | 0 (0.0%) | 30 (12.3%) | 27 (11.3%) |
Chemotherapy regimen | ||||
XP, n
| 51 (100%) | 50 (100%) | 205 (84.4%) | 205 (85.4%) |
FP, n
| 0 (0.0%) | 0 (0.0%) | 38 (15.6%) | 35 (14.6%) |
Number of lesions | (n = 242) | |||
1–4, n
| 16 (31.4%) | 18 (36.0%) | 112 (46.3%) | 98 (40.8%) |
>4, n
| 35 (68.6%) | 32 (64.0%) | 130 (53.7%) | 142 (59.2%) |
Median value (range) | 6 (1–15) | 6 (1–15) | 5 (1–20) | 5 (1–16) |
Number of metastatic sites | (n = 242) | |||
1–2, n
| 28 (54.9%) | 32 (64.0%) | 124 (51.2%) | 114 (47.5%) |
>2, n
| 23 (45.1%) | 18 (36.0%) | 118 (48.8%) | 126 (52.5%) |
Median value (range) | 2 (1–5) | 2 (1–5) | 2 (1–7) | 3 (1–8) |
Type of gastric cancer (central review)a
| (n = 242) | (n = 237) | ||
Intestinal type, n
| 37 (72.5%) | 42 (84.0%) | 188 (77.7%) | 171 (72.2%) |
Diffuse type, n
| 5 (9.8%) | 4 (8.0%) | 21 (8.7%) | 21 (8.9%) |
Mixed type, n
| 9 (17.6%) | 4 (8.0%) | 33 (13.6%) | 45 (19.0%) |
Visceral metastasis (liver or lung) | ||||
Yes, n
| 35 (68.6%) | 33 (66.0%) | 134 (55.1%) | 139 (57.9%) |
No, n
| 16 (31.4%) | 17 (34.0%) | 109 (44.9%) | 101 (42.1%) |
History of treatment for gastric cancer | ||||
Prior gastrectomy, n
| 8 (15.7%) | 13 (26.0%) | 62 (25.5%) | 49 (20.4%) |
Prior chemotherapy, n
| 1 (2.0%) | 0 (0.0%) | 26 (10.7%) | 12 (5.0%) |
HER2 status | ||||
IHC 0/FISH-positive, n
| 3 (5.9%) | 9 (18.0%) | 20 (8.2%) | 29 (12.2%) |
IHC 1+/FISH-positive, n
| 10 (19.6%) | 7 (14.0%) | 28 (11.5%) | 25 (10.4%) |
IHC 2+/FISH-positive, n
| 18 (35.3%) | 13 (26.0%) | 62 (25.5%) | 66 (27.5%) |
IHC 3+/FISH-positive, n
| 16 (31.4%) | 17 (34.0%) | 115 (47.3%) | 108 (45.0%) |
IHC 3+/FISH-negative, n
| 1 (2.0%) | 0 (0.0%) | 8 (3.3%) | 6 (2.5%) |
IHC unknown/FISH-positive, n
| 0 (0.0%) | 0 (0.0%) | 5 (2.1%) | 2 (0.8%) |
IHC 3+/FISH unknown, n
| 3 (5.9%) | 4 (8.0%) | 5 (2.1%) | 4 (1.7%) |
Region of origin | ||||
Japanese, n
| 51 (100%) | 50 (100%) | 0 (0.0%) | 0 (0.0%) |
Non-Japanese, n
| 0 (0.0%) | 0 (0.0%) | 243 (100%) | 240 (100%) |
Efficacy
Unadjusted analyses
Trastuzumab plus XP (n = 51) | XP (n = 50) | |
---|---|---|
Number of events (%) | 28 (54.9) | 27 (54) |
Median OS, months (95% CI) | 15.9 (12–25) | 17.7 (12–24) |
Survival rate (%) | ||
6 months | 92 | 92 |
12 months | 68 | 64 |
18 months | 48 | 49 |
24 months | 41 | 35 |
Hazard ratio (95% CI) | 1.00 (0.59–1.69) |
Preplanned analyses
Hazard ratio (95% CI) |
P value | ||
---|---|---|---|
Trastuzumab plus XP versus XP | 0.68 | (0.36–1.27) | 0.2251 |
Sex (male vs. female) | 0.16 | (0.07–0.41) | <0.0001 |
Age (<60 vs. ≥60) | 1.07 | (0.54–2.13) | 0.8382 |
Extent of disease (locally advanced vs. metastatic) | 0.00 | (0.00–.) | 0.9902 |
Primary tumor site (stomach vs. gastroesophageal junction) | 0.68 | (0.25–1.87) | 0.4559 |
Measurability of disease (measurable vs. nonmeasurable) | 0.95 | (0.29–3.05) | 0.9268 |
ECOG performance status | – | – | – |
Chemotherapy regimen | – | – | – |
Number of lesions (1–4 vs. >4) | 0.49 | (0.22–1.09) | 0.0818 |
Number of metastatic sites (1–2 vs. >2) | 0.79 | (0.41–1.50) | 0.4695 |
Type of gastric cancer | |||
Diffuse type versus intestinal type | 3.24 | (1.08–9.70) | 0.0356 |
Mixed type versus intestinal type | 0.91 | (0.30–2.71) | 0.8644 |
Visceral metastasis (yes vs. no) | 1.15 | (0.48–2.74) | 0.7510 |
Prior gastrectomy (yes vs. no) | 0.22 | (0.06–0.75) | 0.0159 |
Prior chemotherapy (yes vs. no) | 27.72 | (1.11–694.38) | 0.0432 |
HER2 status | |||
IHC 0/FISH-positive versus IHC 3+/FISH-positive | 5.31 | (1.29–21.86) | 0.0208 |
IHC 1+/FISH-positive versus IHC 3+/FISH-positive | 4.87 | (1.73–13.70) | 0.0027 |
IHC 2+/FISH-positive versus IHC 3+/FISH-positive | 1.53 | (0.73–3.18) | 0.2578 |
IHC 3+/FISH-negative versus IHC 3+/FISH-positive | 25.66 | (1.72–382.49) | 0.0186 |
Region of origin | – | – | – |
Post hoc analyses
Exploratory analyses to evaluate deviation of patient prognosis
Number of covariates | Covariates included in the model |
---|---|
4 | HER2 expression (low/high), sex (male/female), prior gastrectomy (yes/no), number of lesions (1–4/>4) |
5 | HER2 expression (low/high), sex (male/female), prior gastrectomy (yes/no), number of lesions (1–4/>4), type of gastric cancer (diffuse/intestinal) |
6 | HER2 expression (low/high), sex (male/female), prior gastrectomy (yes/no), number of lesions (1–4/>4), type of gastric cancer (diffuse/intestinal), number of metastatic sites (1–2/>2) |
Safety
Trastuzumab plus XP (n = 51) | XP (n = 50) | |||
---|---|---|---|---|
All grade n (%) | Grade ≥3 n (%) | All grade n (%) | Grade ≥3 n (%) | |
Total | 51 (100) | 43 (84) | 50 (100) | 36 (72) |
Gastrointestinal disorders | ||||
Nausea | 44 (86) | 7 (14) | 44 (88) | 7 (14) |
Vomiting | 33 (65) | 1 (2) | 28 (56) | 2 (4) |
Constipation | 24 (47) | 1 (2) | 24 (48) | – |
Diarrhoea | 23 (45) | 4 (8) | 24 (48) | 2 (4) |
Stomatitis | 29 (57) | – | 16 (32) | 1 (2) |
Blood and lymphatic system disorders | ||||
Neutropenia | 30 (59) | 18 (35) | 34 (68) | 20 (40) |
Thrombocytopenia | 11 (22) | 1 (2) | 8 (16) | 3 (6) |
Anemia | 15 (29) | 13 (25) | 11 (22) | 8 (16) |
Febrile neutropenia | 5 (10) | 5 (10) | 3 (6) | 3 (6) |
Skin and subcutaneous tissue disorders | ||||
Palmar–plantar erythrodysaesthesia syndrome | 21 (41) | – | 23 (46) | 1 (2) |
Alopecia | 12 (24) | – | 9 (18) | – |
Skin hyperpigmentation | 6 (12) | – | 5 (10) | – |
Rash | 10 (20) | – | 5 (10) | – |
Pigmentation disorder | 10 (20) | – | 7 (14) | – |
Nail disorder | 5 (10) | – | 5 (10) | – |
Metabolism and nutrition disorders | ||||
Anorexia | 43 (84) | 12 (24) | 46 (92) | 10 (20) |
Dehydration | 3 (6) | 1 (2) | 6 (12) | 1 (2) |
General disorders and administration site conditions | ||||
Fatigue | 31 (61) | 4 (8) | 26 (52) | 4 (8) |
Pyrexia | 19 (37) | 1 (2) | 12 (24) | – |
Chill | 7 (14) | – | 0 (0) | – |
Edema | 19 (37) | – | 23 (46) | – |
Nervous system disorders | ||||
Peripheral neuropathy | 16 (31) | 1 (2) | 10 (20) | – |
Dysgeusia | 13 (25) | – | 8 (16) | – |
Peripheral sensory neuropathy | 2 (4) | – | 11 (22) | – |
Dizziness | 5 (10) | 1 (2) | 5 (10) | – |
Respiratory, thoracic, and mediastinal disorders | ||||
Hiccups | 21 (41) | – | 16 (32) | – |
Epistaxis | 5 (10) | – | 3 (6) | – |
Renal and urinary disorders | ||||
Renal impairment | 32 (63) | 2 (4) | 27 (54) | – |
Vascular disorders | ||||
Hypertension | 4 (8) | 1 (2) | 3 (6) | – |
Investigations | ||||
Weight decreased | 27 (53) | 2 (4) | 13 (26) | 1 (2) |
Weight increased | 10 (20) | 1 (2) | 9 (18) | – |
Psychiatric disorders | ||||
Insomnia | 11 (22) | – | 8 (16) | – |
Infections and infestations | ||||
Nasopharyngitis | 18 (35) | – | 6 (12) | – |
Musculoskeletal and connective tissue disorders | ||||
Back pain | 5 (10) | – | 1 (2) | – |