Online Resource 1 Summary of studies included in the analysis (CRPC castration-resistant prostate cancer, EOI end of infusion, HRPC hormone-refractory prostate cancer, MBC metastatic breast cancer, NSCLC non-smallcell lung cancer)

Study / Phase / Patient group / Regimensa / Overall population (N) / PK population (N) / PK samples (N) / PK sampling schedule
Single-agent studies
TOC2297g / Ia / Advanced solid tumors / 0.5, 2.0, 5.0, 10.0, and 15 mg/kg / 21 / 21 / 372 / Cycle 1: Day 1 (pre-dose, EOI, 1.5, 4, and 8 h post-infusion), Days 2, 5, 8, 15
Cycle ≥2: Day 1 (pre-dose, EOI), Day 8
JO17076 / I / Advanced solid tumors / 5, 10, 15, and
25 mg/kg / 18 / 18 / 218 / Cycle 1: Day 1 (pre-dose, EOI, 4, and 8 h post-infusion), Days 2, 5, 8, 15, 22
Cycle 2: Day 1 (pre-dose, EOI, 4, and 8 h post-infusion), Days 8, 22
Cycle 3: Day 1 (pre-dose, EOI), Days 8, 22
TOC2689g / II / Advanced ovarian cancer / Cohort 1: 840/420mg
Cohort 2: 1050 mg / 123 / 123 / 966 / Cycles 1 and 2: Day 1 (pre-dose, EOI), Days 8, 15
Cycles 3, 5, 9, 13, 17: Day 1 (pre-dose, EOI)
BO16934 / II / MBC with low HER2 expression / Arm A: 840/420 mg
Arm B: 1050 mg / 78 / 78 / 779 / Cycles 1 and 2: Day 1 (pre-dose, EOI), Days 8, 15
Cycle ≥3: Day 1 (pre-dose, EOI)
BO17004 / II / HRPC, chemotherapy-naïve / Cohort 1: 840/420mg
Cohort 2: 1050 mg / 68 / 68 / 719 / Cycles 1 and 2: Day 1 (pre-dose, EOI), Days 8, 15
Cycle ≥3: Day 1 (pre-dose, EOI)
TOC2682g / II / CRPCpretreated with docetaxel / 840/420 mg / 41 / 41 / 343 / Cycles 1 and 2: Day 1 (pre-dose, EOI), Days 8, 15
TOC2572g / II / Advanced, recurrent NSCLC / 840/420 mg / 43 / 43 / 281 / Cycles 1 and 2: Day 1 (pre-dose, EOI), Days 8, 15
Cycles 3, 5, 9, 13, 17: Day 1 (pre-dose, EOI)
Combination therapy studies
BO17003 / Ib / Advanced solid tumors / Pertuzumab: 1050mg q3w
Capecitabine: 825, 1000, 1250 mg/m2 / 18 / 18 / 226 / Cycle 1: Day 1 (pre-dose, 0.25, 1.5, 4, and 8 h post-infusion), Days 2, 5, 8, 15
Cycle 2: Day 1(pre-dose, EOI), Days 8, 15, 22
BO17021 / Ib / Advanced solid tumors / Pertuzumab: 1050 mg q3w + docetaxel 60, 75 mg/m2
Pertuzumab 840/420mg q3w + docetaxel 75, 100 mg/m² / 19 / 19 / 221 / Cycle 1: Day 1 (pre-dose, 0.25, 1.5, 4, and 8 h post-infusion), Days 3, 6, 9, 16
Cycle 2: Day 1(pre-dose, EOI), Days 8, 15, 22
WO20024 / Ib / Advanced NSCLC / Pertuzumab 840/420mg q3w
Erlotinib: 100, 150mg/day / 15 / 10 / 91 / Cycle 1: Day 1 (pre-dose, 0.5, 1.5, 4, 8, and 24 h post-infusion), Days 8, 15, 22
TOC3258g / II / Platinum-resistant ovarian, peritoneal, or fallopian tube cancer / Gemcitabine 800mg/m2 + pertuzumab 840/420mg q3w
Gemcitabine 800mg/m2+placebo / 65
65 / 22 / 128 / Cycles 1 and 2: Day 1 (pre-dose, EOI), Day 8
Cycles 3: Day 1 (pre-dose, EOI)
CLEOPATRA / III / HER2-positive MBC (first-line treatment) / Pertuzumab 840/420mg + docetaxel + trastuzumab
Placebo + docetaxel + trastuzumab / 407
397
/ 20 / 181 / Cycles 1, 3, 6, 9, 12, 15, 18, and 28–42 days after discontinuation: Day 1 (pre-dose, EOI)

a840/420 mg: 840 mg loading dose in Cycle 1 followed by 420 mg maintenance dose in subsequent cycles

Online Resource 2Baselinepatientcharacteristics (ALBUalbumin,ALKalkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase,BSAbody surface area,BWTbaseline body weight,CRP C-reactive protein, ECOG PS Eastern Cooperative Oncology Group performance status, HER2human epidermal growth factor receptor 2,HER2ECD human epidermal growth factor receptor 2 extra-cellular domain,LBW lean body weight, NSCLC non-small cell lung cancer, SCr serum creatinine, TBIL total bilirubin)

Continuous covariates / N / Median (5th–95th percentile)
Age (years) / 481 / 60 (40–77)
LBW (kg) / 450 / 49.2 (38.9–69.6)
BWT (kg) / 477 / 72 (50.2–101.5)
BSA (m2) / 450 / 1.80 (1.49–2.19)
SCr (mg/dL) / 481 / 0.88 (0.6–1.3)
ALK (IU/L) / 481 / 105 (54–367)
ALBU (g/dL) / 477 / 3.9 (2.9–4.65)
TBIL (mg/dL) / 480 / 0.5 (0.2–1.0)
AST (IU/L) / 481 / 27 (15–63)
ALT (IU/L) / 481 / 21 (9–56)
CRP (mg/L) / 305 / 8.1 (0.8–115.6)
HER2ECD (ng/mL) / 352 / 11.0 (7.0–31.4)
Categorical covariates / Percentage (N = 481)
Sex
Male
Female /
37.6
62.4
Race
Non-Japanese
Japanese /
95.4
4.6
ECOG PS
0
≥1
Unknown /
56.1
43.5
0.4
Number of metastatic sites
1–2
≥3
Unknown /
65.1
33.7
1.2
Liver metastases
No
Yes
Unknown /
67.4
31.4
1.2
Primary tumor type
Breast
Ovarian
Prostate
NSCLC
Other /
20.4
25.6
22.7
11.0
20.4
Chemotherapy
No
Yes /
81.5
18.5
HER2 expression level
0
1
2
3
Unknown /
0.8
6.9
8.9
3.5
79.8

Online Resource 5Sensitivity of observedpertuzumab pharmacokinetic parameters to ALBU and LBW (ALBUalbumin, CL elimination clearance, LBW lean body weight, Vc volume of central compartment, Vp volume of peripheral compartment)

PK parameter, typical value / Covariate / Impact on PK parameters
Name / typical value / Percentile / Value / PK parameter, value at covariate percentile / Change from typical (%)
CL, 0.235 L/day / ALBU / 3.9 g/dL / 5th / 2.9 g/dL / 0.322 / 36.9
95th / 4.6 g/dL / 0.195 / –17.0
LBW / 48 kg / 5th / 39 kg / 0.212 / –10.3
95th / 69 kg / 0.284 / 20.3
Vc, 3.11 L / LBW / 48 kg / 5th / 39 kg / 2.67 / –14.5
95th / 69 kg / 4.09 / 30.7
Vp, 2.46 L / LBW / 48 kg / 5th / 39 kg / 2.08 / –16.0
95th / 69 kg / 3.34 / 34.7

Online Resource 7 Observed effect of baseline CRP on steady-state serum pertuzumab trough concentrations (trough concentrations normalized to typical LBW (48 kg) and ALBU (3.9 g/L); CRP C-reactive protein,Cmin,SS steady-state trough serum concentration)

Sensitivity result / Baseline CRP (mg/L)
≥0, <5 / ≥5, <8 / ≥8, <23 / ≥21, <239
Patients, N / 114 / 39 / 76 / 76
Median Cmin,SS(μg/mL) / 65.5 / 53.7 / 46.4 / 42.5
Patients with Cmin,SS <20 μg/mL, N (%) / 0 (0) / 1 (2.6) / 5 (6.6) / 6 (7.9)