Background
Methods
Study design
Ethics
Patients
Study drug administration
Tumor response and safety assessments
Definition of dose-limiting toxicity (DLT)
Pharmacokinetic assessments
Biomarker assessments
Statistical considerations
Results
Patients
Characteristic | Cohort 1 N = 2 | Cohort 2 N = 20 | Cohort 3 N = 13 | Overall N = 35 |
---|---|---|---|---|
Age, median (range), years | 52.5 (42, 63) | 62.0 (35, 75) | 49.0 (33, 77) | 60.0 (33, 77) |
Sex, n (%) | ||||
Male | 0 | 0 | 1 (7.7) | 1 (2.9) |
Female | 2 (100) | 20 (100) | 12 (92.3) | 34 (97.1) |
ECOG score, median (range) | 0.5 (0, 1) | 0 (0, 1) | 0 (0, 1) | 0 (0, 1) |
ER-positivity of primary tumor, no. of patients (%) | 1 (50.0) | 16 (80.0) | 12 (92.3) | 29 (82.9) |
ER-positivity of recurrent tumor, no. of patients (%) | 1 (50.0) | 11 (55.0) | 9 (75.0) | 21 (61.8) |
Previous lines of chemotherapy for MBC, median (range) | 0.5 (0, 1) | 1 (0, 5) | 0 | 0 (0, 5) |
No. of cycles, median (range) | ||||
Paclitaxel | 2 (2, 2) | 3.5 (1, 7) | 6 (1, 10) | – |
Pertuzumab | 2 (2, 2) | 5 (1, 23) | 5 (1, 19) | – |
Lumretuzumab | 2 (2, 2) | 5.5 (1, 23) | 7 (1, 19) | – |
Safety
Adverse event | No. of patients having an adverse event (%) | |||||||
---|---|---|---|---|---|---|---|---|
Cohort 1 N = 2 | Cohort 2 N = 20 | Cohort 3 N = 13 | All patients N = 35 | |||||
All grades | Grade ≥ 3 | All grades | Grade ≥ 3 | All grades | Grade ≥ 3 | All grades | Grade ≥ 3 | |
Diarrhea | 2 (100) | 2 (100) | 20 (100) | 10 (50.0) | 13 (100) | 4 (30.8) | 35 (100) | 16 (45.7) |
Nausea | 1 (50.0) | 0 | 16 (80.0) | 0 | 7 (53.8) | 0 | 24 (68.6) | 0 |
Hypokalemia | 2 (100) | 1 (50.0) | 13 (65.0) | 11 (55.0) | 5 (38.5) | 2 (15.4) | 20 (57.1) | 14 (40.0) |
Weight loss | 1 (50.0) | 0 | 13 (65.0) | 4 (20.0) | 4 (30.8) | 0 | 18 (51.4) | 4 (11.4) |
Alopecia | 0 | 0 | 8 (40.0) | 0 | 9 (69.2) | 0 | 17 (48.6) | 0 |
Decreased appetite | 1 (50.0) | 0 | 12 (60.0) | 1 (5.0) | 2 (15.4) | 1 (7.7) | 15 (42.9) | 2 (5.7) |
Rash | 0 | 0 | 9 (45.0) | 1 (5.0) | 4 (30.8) | 0 | 13 (37.1) | 1 (2.9) |
Asthenia | 2 (100) | 1 (50.0) | 7 (35.0) | 1 (5.0) | 3 (23.1) | 1 (7.7) | 12 (34.3) | 3 (8.6) |
Hypomagnesemia | 1 (50.0) | 1 (50.0) | 8 (40.0) | 0 | 3 (23.1) | 0 | 12 (34.3) | 1 (2.9) |
Vomiting | 0 | 0 | 6 (30.0) | 0 | 6 (46.2) | 0 | 12 (34.3) | 0 |
Urinary tract infection | 0 | 0 | 6 (30.0) | 0 | 4 (30.8) | 1 (7.7) | 10 (28.6) | 1 (2.9) |
Mucosal inflammation | 1 (50.0) | 0 | 4 (20.0) | 0 | 5 (38.5) | 0 | 10 (28.6) | 0 |
Dygeusia | 0 | 0 | 7 (35.0) | 0 | 3 (23.1) | 0 | 10 (28.6) | 0 |
Fatigue | 0 | 0 | 4 (20.0) | 0 | 5 (38.5) | 0 | 9 (25.7) | 0 |
Pyrexia | 1 (50.0) | 0 | 6 (30.0) | 0 | 2 (15.4) | 0 | 9 (25.7) | 0 |
Nasopharyngitis | 0 | 0 | 3 (15.0) | 0 | 6 (46.2) | 0 | 9 (25.7) | 0 |
ALT increased | 0 | 0 | 7 (35.0) | 4 (20.0) | 1 (7.7) | 0 | 8 (22.9) | 4 (11.4) |
Infusion-related reaction | 0 | 0 | 5 (25.0) | 0 | 3 (23.1) | 0 | 8 (22.9) | 0 |
Neurotoxicity | 0 | 0 | 4 (20.0) | 3 (15.0) | 3 (23.1) | 1 (7.7) | 7 (20.0) | 4 (11.4) |
AST increased | 0 | 0 | 6 (30.0) | 2 (10.0) | 1 (7.7) | 0 | 7 (20.0) | 2 (5.7) |
Abdominal pain | 1 (50.0) | 0 | 5 (25.0) | 0 | 1 (7.7) | 0 | 7 (20.0) | 0 |
Anemia | 1 (50.0) | 0 | 3 (15.0) | 0 | 3 (23.1) | 0 | 7 (20.0) | 0 |
Hypophosphatemia | 1 (50.0) | 1 (50.0) | 2 (10.0) | 1 (5.0) | 3 (23.1) | 3 (23.1) | 6 (17.1) | 5 (14.3) |
Epistaxis | 0 | 0 | 2 (10.0) | 0 | 4 (30.8) | 0 | 6 (17.1) | 0 |
Headache | 0 | 0 | 3 (15.0) | 0 | 3 (23.1) | 0 | 6 (17.1) | 0 |
Polyneuropathy | 0 | 0 | 5 (25.0) | 0 | 1 (7.7) | 0 | 6 (17.1) | 0 |
Flatulence | 0 | 0 | 3 (15.0) | 0 | 3 (23.1) | 0 | 6 (17.1) | 0 |
Lymphopenia | 0 | 0 | 1 (5.0) | 0 | 3 (23.1) | 2 (15.4) | 4 (11.4) | 2 (5.7) |
Constipation | 0 | 0 | 2 (10.0) | 1 (5.0) | 3 (23.1) | 0 | 5 (14.3) | 1 (2.9) |
Edema peripheral | 0 | 0 | 2 (10.0) | 0 | 3 (23.1) | 0 | 5 (14.3) | 0 |
Hypocalcemia | 1 (50.0) | 0 | 2 (10.0) | 0 | 2 (15.4) | 0 | 5 (14.3) | 0 |
Dry mouth | 0 | 0 | 4 (20.0) | 0 | 0 | 0 | 4 (11.4) | 0 |
Stomatitis | 0 | 0 | 2 (10.0) | 0 | 2 (15.4) | 0 | 4 (11.4) | 0 |
Neuropathy peripheral | 0 | 0 | 2 (10.0) | 0 | 2 (15.4) | 0 | 4 (11.4) | 0 |
Acne | 0 | 0 | 2 (10.0) | 0 | 2 (15.4) | 0 | 4 (11.4) | 0 |
Erythema | 0 | 0 | 3 (15.0) | 0 | 1 (7.7) | 0 | 4 (11.4) | 0 |
Onycholysis | 0 | 0 | 2 (10.0) | 0 | 2 (15.4) | 0 | 4 (11.4) | 0 |
Pruritus | 0 | 0 | 3 (15.0) | 0 | 1 (7.7) | 0 | 4 (11.4) | 0 |
Back pain | 0 | 0 | 2 (10.0) | 0 | 2 (15.4) | 0 | 4 (11.4) | 0 |
Pain in extremity | 0 | 0 | 3 (15.0) | 0 | 1 (7.7) | 0 | 4 (11.4) | 0 |
Pharmacokinetic analysis
Cohort | Descriptive statistic | Cmax (μg/mL) | AUClast (day x μg/mL) | Vd (mL) | Total CL (mL/day) | t1/2 (day) |
---|---|---|---|---|---|---|
Lumretuzumab | ||||||
1 |
N
| 2 | 2 | 2 | 2 | 2 |
Mean | 448 | 3180 | 3370 | 253 | 10.1 | |
CV% | 8.52 | 27 | 4.1 | 44.6 | 40.9 | |
2 |
N
| 19 | 18 | 18 | 18 | 18 |
Mean | 188 | 1430 | 4040 | 275 | 11 | |
CV% | 18.6 | 23.3 | 25.7 | 32.3 | 34.5 | |
3 |
N
| 10 | 8 | 9 | 9 | 9 |
Mean | 161 | 1160 | 4330 | 295 | 10.9 | |
CV% | 18.8 | 10.8 | 26.7 | 26.6 | 40.7 | |
Pertuzumab | ||||||
1 |
N
| 2 | 1 | ND | ND | ND |
Mean | 155 | 2160 | ND | ND | ND | |
CV% | 15.1 | ND | ND | ND | ND | |
2 |
N
| 13 | 7 | 10 | 10 | 10 |
Mean | 256 | 2560 | 4920 | 229 | 15.6 | |
CV% | 35 | 34.1 | 36.5 | 35.7 | 33.5 | |
3 |
N
| 10 | 4 | 10 | 10 | 10 |
Mean | 157 | 1260 | 4440 | 240 | 13.5 | |
CV% | 12.7 | 27.2 | 31.4 | 33.8 | 27.2 |
Biomarker analysis
Gene | Prevalence (n) | Total mutations | Mutations (n) |
---|---|---|---|
PIK3CA | 40.6% (13) | 15 | H1047R (4), E542K (3), E545K (3), E545A (1), E365Q (1), P124L (1), N1068 fs*3+ (1), G106-E109del (1) |
TP53 | 34.4% (11) | 11 | Q52H (1), V157E (1), V173 M (1), R175M (1), L194R (1), Y220C (1), S241F (1), R248Q (1), R248W (1), R280T (1), L194R (1) |
GATA3 | 28.1% (9) | 12 | P191H (1), H237fs*29 (1), H282_Y283 > QHY (1), M357I (2), S402 fs*45+ (1), P409fs*38+ (1), S427 fs*20+ (1), T441 fs*6+ (1), M443 fs*4+ (1), A70D (1), P42L (1) |
MLL3 | 18.8% (6) | 9 | R2296H (1), K2797 fs*26 (1), N2990 fs*4 (1), E4049* (1), R4595G (1), R4139* (1), E1748K (1), E1746* (1), C438Y (1) |
ESR1 | 18.8% (6) | 7 | D538G (3), S118P (1), T496 N (1), L536P (1), L549P (1) |
BRCA2 | 15.6% (5) | 6 | R1190W (1), I1859fs*3 (1), R2027K (1), K2404 fs*7 (1), R2502H (1), K3326* (1) |
LRP1B | 15.6% (5) | 5 | A960V (1), E2998K (1), R2443H (1), R2777* (1), H112Y (1), S3586 T (1) |
SPEN | 12.5% (4) | 9 | R187W (1), T838R (1), I1159fs*28 (1), N2072 fs*51 (1), E2176* (1), T3104 M (1), A3169V (1), E2260K (1), S2120F (1) |
ARID1A | 12.5% (4) | 6 | S1138 fs*55 (1), G1711A (1), V1834A (1), D1850fs*33 (1), Q2176fs*48 (1), Splice site 3406 + 1G > T (1) |
JAK1 | 12.5% (4) | 6 | G319 W (1), Q834* (1), R839Q (1), K860 fs*16 (1), E1051* (1), splice site 2404-1G > A (1) |
Number of patients (%) with respective assessment | ||||
---|---|---|---|---|
Cohort 1 N = 2 | Cohort 2 N = 20 | Cohort 2a N = 9 | Cohort 3 N = 13 | |
Complete response | 0 | 1 (5.0) | 1 (11.1) | 0 |
Partial response | 0 | 5 (25.0) | 4 (44.4) | 5 (38.5) |
Stable disease | 2 (100) | 9 (45.0) | 2 (22.2) | 5 (38.5) |
Progressive disease | 0 | 4 (20.0) | 1 (11.1) | 2 (15.4) |
Lost to follow up | 0 | 1 (5.0) | 1 (11.1) | 1 (7.7) |
Objective response rate | 0 | 6 (30.0) | 5 (55.5) | 5 (38.5) |
Disease control rate | 2 (100) | 15 (75.0) | 7 (77.7) | 10 (76.9) |