Online Resource 1 Baseline patient demographics and disease characteristics

Parameter / All (n = 165) / Onartuzumab
+ bevacizumab
+ paclitaxel (n = 59) / Onartuzumab
+ placebo
+ paclitaxel (n = 49) / Placebo + bevacizumab
+ paclitaxel (n = 57)
Median age, years (range) / 52 (30–79) / 52 (35–79) / 54 (30–77) / 51 (37–69)
ECOG PS, n (%)
0
1
Missing / 96 (58.2)
67 (40.6)
2 (1.2) / 33 (55.9)
26 (44.1)
0 / 29 (59.2)
18 (36.7)
2 (4.1) / 34 (59.6)
23 (40.4)
0
Line of therapy, n (%)
First / 127 (77.0) / 46 (78.0) / 38 (77.6) / 43 (75.4)
Second / 38 (23.0) / 13 (22.0) / 11 (22.4) / 14 (24.6)
Number of metastatic sites, n (%)
0
1
2
3+ / 2 (1.2)
34 (20.6)
60 (36.4)
69 (41.8) / 0
11 (18.6)
24 (40.7)
24 (40.7) / 1 (2.0)
10 (20.4)
17 (34.7)
21 (42.9) / 1 (1.8)
13 (22.8)
19 (33.3)
24 (42.1)

ECOG PS Eastern Cooperative Oncology Group performance status

Online Resource 2 Summary of QTcF values (ms) at each time point, by treatment arm

Treatment arm / Summary statistics / Screening / Pre-dose / 0–15 min
post-dose / 60–75 min
post-dose / SDDV
Cycle 1, Day 1
Placebo + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / 57
413.2 (17.6)
412.5 (362 to 447) / 57
415.6 (17.1)
416.8 (359 to 454) / 56
423.6 (19.6)
423.9 (387 to 471) / 53
423.0 (19.0)
420.9 (376 to 486) / –
Onartuzumab + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / 59
408.8 (18.9)
408.3 (358 to 458) / 56
412.4 (19.0)
409.6 (364 to 459) / 53
421.9 (21.4)
420.2 (374 to 475) / 54
421.0 (19.2)
419.7 (378 to 467) / –
Onartuzumab + placebo + paclitaxel / n / 48 / 46 / 43 / 43 / –
Mean (SD) / 411.4 (21.4) / 413.8 (20.1) / 422.0 (21.3) / 421.9 (20.1)
Median (range) / 407.0 (380 to 470) / 413.1 (374 to 460) / 416.6 (379 to 478) / 417.5 (389 to 494)
Cycle 2, Day 1
Placebo + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / – / 53
418.9 (16.6)
419.0 (389 to 450) / 52
421.4 (15.7)
420.3 (396 to 459) / 51
421.6 (15.1)
421.7 (395 to 467) / –
Onartuzumab + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / – / 54
413.2 (22.4)
408.2 (359 to 453) / 52
419.0 (19.9)
416.7 (372 to 469) / 48
420.5 (19.4)
417.9 (361 to 469) / –
Onartuzumab + placebo + paclitaxel / n / – / 43 / 43 / 39 / –
Mean (SD)
Median (range) / 412.5 (21.8)
408.2 (365 to 478) / 415.8 (20.6)
414.3 (373 to 481) / 416.6 (21.0)
413.4 (374 to 481)
Cycle 4, Day 1
Placebo + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / – / 39
415.2 (17.1)
418.9 (384 to 452) / 38
416.9 (14.1)
416.4 (374 to 447) / 37
418.9 (13.0)
421.0 (398 to 452) / 26
410.1 (17.4)
408.2 (388 to 451)
Onartuzumab + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / – / 41
413.3 (17.3)
412.9 (381 to 459) / 37
416.8 (14.7)
415.5 (391 to 450) / 38
417.4 (15.2)
419.3 (376 to 446) / 26
407.8 (14.7)
407.6 (379 to 439)
Onartuzumab + placebo + paclitaxel / n / – / 31 / 28 / 29 / 25
Mean (SD)
Median (range) / 419.7 (17.1)
420.1 (382 to 451) / 424.4 (16.5)
420.6 (385 to 464) / 422.5 (17.5)
422.8 (381 to 463) / 411.2 (21.7)
413.9 (368 to 465)

SD standard deviation; SDDV study drug discontinuation visit

Online Resource 3 Summary of ΔQTcF values (ms) at each time point, by treatment arm

Change from baseline / Summary statistics / Pre-dose / 0–15 min
post-dose / 60–75 min
post-dose / SDDV
Cycle 1, Day 1
Placebo + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / – / 56
8.1 (16.1)
10.0 (–40 to 51) / 53
6.7 (15.4)
5.6 (–49 to 38) / –
Onartuzumab + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / – / 53
9.5 (12.7)
9.7 (–19 to 42) / 54
9.6 (12.1)
9.1 (–20 to 35) / –
Onartuzumab + placebo + paclitaxel / n / – / 43 / 43 / –
Mean (SD) / 8.6 (11.8) / 8.3 (13.7)
Median (range) / 9.6 (–17 to 33) / 8.5 (–25 to 34)
Cycle 2, Day 1
Placebo + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / 53
3.4 (13.3)
1.1 (–25 to 42) / 52
5.7 (16.0)
5.0 (–43 to 54) / 51
5.9 (14.8)
4.7 (–25 to 49) / –
Onartuzumab + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / 54
0.7 (14.9)
–0.9 (–39 to 38) / 52
6.9 (15.7)
7.2 (–26 to 36) / 48
8.8 (14.7)
7.2 (–22 to 37)
Onartuzumab + placebo + paclitaxel / n / 43 / 43 / 39
Mean (SD)
Median (range) / –1.5 (15.2)
–3.0 (–31 to 42) / 1.8 (14.1)
0.4 (–25 to 45) / 2.0 (14.4)
2.6 (–33 to35)
Cycle 4, Day 1
Placebo + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / 39
0.4 (16.3)
–3.7 (–33 to 31) / 38
1.9 (16.6)
4.2 (–34 to 43) / 37
4.0 (14.1)
0.8 (–30 to 33) / 26
–6.3 (16.3)
–4.4 (–36 to 36)
Onartuzumab + bevacizumab + paclitaxel / n
Mean (SD)
Median (range) / 41
0.8 (15.5)
2.3 (–38 to 36) / 37
5.2 (15.5)
5.3 (–43 to 34) / 38
5.0 (14.9)
4.2 (–42 to 31) / 26
–3.4 (13.6)
–3.8 (–24 to 23)
Onartuzumab + placebo + paclitaxel / n / 31 / 28 / 29 / 25
Mean (SD)
Median (range) / 2.8 (14.7)
3.5 (–27 to 39) / 7.2 (12.6)
5.9 (–20 to 31) / 5.2 (12.7)
5.0 (–19 to 30) / 1.1 (18.1)
1.9 (–31 to 50)

SD standard deviation; SDDV study drug discontinuation visit

Online Resource 4 Summary of ΔΔQTcF values (ms) at each time point, by treatment arm

Difference in mean change from
baseline*, mean (90% CI) / Pre-dose / 0–15 min
post-dose / 60–75 min
post-dose / SDDV
Cycle 1, Day 1
O+B+P arm – B+P arm / – / 0.9 (–4.1, 5.9) / 1.8 (–3.2, 6.7) / –
O+P arm – B+P arm / – / 0.2 (–5.1, 5.5) / 1.0 (–4.2, 6.2) / –
Cycle 2, Day 1
O+B+P arm – B+P arm / –3.3 (–8.6, 1.9) / 0.0 (–5.4, 5.4) / 1.7 (–3.6, 6.9) / –
O+P arm – B+P arm / –5.2 (–10.8, 0.3) / –4.5 (–10.1, 1.2) / –4.2 (–9.8, 1.4) / –
Cycle 4, Day 1
O+B+P arm – B+P arm / –0.5 (–6.5, 5.5) / 1.6 (–4.0, 7.2) / –0.2 (–5.4, 5.1) / 0.9 (–7.1, 9.0)
O+P arm – B+P arm / 3.3 (–3.2, 9.8) / 6.4 (0.4, 12.5) / 2.3 (–3.3, 7.9) / 5.0 (–3.1, 13.2)

*Results from ANOVA
B bevacizumab; O onartuzumab; P paclitaxel;SD standard deviation; SDDV study drug discontinuation visit

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Online Resource 5Goodness of fit plots for the final model

Online Resource 6Standardized residuals versus onartuzumab concentration in the final model. The line is generated by a LOESS (moving average) smoothing procedure with 75 % span and the shaded area is the 95 %CI of the smoothed mean

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