SUPPLEMENTARY FIGURES AND TABLES
Supplementary Figure S1. OS by stratification factor for
patients in the randomised study arms.
Abbreviations: CI = confidence interval; HR = hazard ratio; OS
= overall survival.
1
Supplementary Figure S2. Presence of biomarkers at initial
diagnosis for the randomised study arms (patients in the
standard-dose arm and patients in the dose-escalation arm)
and OS stratified by biomarker status.
Abbreviations: CI = confidence interval; EGFR = epidermal
growth factor receptor; FISH = fluorescence in-situ
hybridization; HR = hazard ratio; IHC = immunohistochemistry;
OS = overall survival.
a
HR corresponding to the randomised standard-dose and
dose-escalation arm.
2
3
Supplementary Table S1. Strategies for rash management in the
RACHEL study
Erlotinib dose
Rash
modification
Treatment
Grade 1
No erlotinib dose
No intervention or treated with
modifications
topical hydrocortisone (1% or 2.5%
cream) or clindamycin (1% gel) at
the investigators’ discretion
Grade 2
No erlotinib dose
Hydrocortisone (2.5% cream), or
modifications
clindamycin (1% gel), or
pimecrolimus (1% cream), with the
addition of either doxycycline
(100mg, po bid) or minocycline
(100mg, po bid)
Grade 3
Erlotinib dose
As for grade 2 rash, but with the
reductions until
addition of methylprednisolone
grade ≤2 rash
4mg
achieved, at which
point the dose
could be reescalated
Grade 4
Discontinue
As for grade 3 rash
erlotinib
Abbreviation: bid = twice daily; po = oral.
4
Supplementary Table S2. Incidence of grade ≥2 rash in the
randomised population who had grade ≤1 rash after the 4-week runin period
Standard dose
Dose escalation
(n=75)
(n=70)
7 (9.3)
29 (41.4)
3.8–18.3
29.8–53.8
Patients with grade ≥2
rash, n (%)
95% CI for grade ≥2
rash
Difference in rates
32.10
95% CI for difference in
18.0–46.2
rates
P value (χ2 test)
<0.0001
Median time from
randomisation to onset
71 (6–347)
28 (2–537)
of grade ≥2 rash, days
(range)
Abbreviation: CI = confidence interval.
5
Supplementary Table S3. Summary of exposure to erlotinib and
gemcitabine for the randomised arms
Randomised
Non-randomised
Standard dose
Dose escalationa
Grade ≥2 rash
(n=77)
(n=71)
(n=105)
Total cumulative erlotinib dose (mg)
Mean
17 025
26 823
13 749
SD
12 808
26 713
9067
1460
3170
885
Median
15 900
15 450
11 300
Range
2800–70 100
3200–152 350
1800–50 300
SEM
Total cumulative gemcitabine dose (mg)
Mean
29 097
24 654
24 994
SD
19 335
16 279
15 519
2203
1932
1514
Median
25 200
18 700
21 600
Range
7000–10 5200
6583–83 220
5500–76 000
SEM
Abbreviations: SD = standard deviation; SEM = standard error of
the mean.
aIn
the dose-escalation arm, 70 patients received 150mg/day,
49 patients then escalated to 200mg/day, 28 patients then
escalated to 250mg/day, and one patient was escalated to
300mg/day (in error).
6
Supplementary Table S4. Reasons for withdrawal from trial
treatment
NonRandomised
randomised
Standard
Dose
Grade ≥2
dose
escalation
rash
(n=75)
(n=71)
(n=105)
4 (5.3)
7 (9.9)
8 (7.6)
4 (5.3)
1 (1.4)
5 (4.8)
57 (76)
52 (73.2)
84 (80)
0 (0)
1 (1.4)
0 (0)
0 (0)
0 (0)
1 (1.0)
Refused treatment
7 (9.3)
6 (8.5)
3 (2.9)
Other (including ‘did not
1 (1.3)
3 (4.2)
5 (4.8)
73 (97)
70 (99)
106 (100)
Reason for withdrawal, n
(%)
Safety
Adverse event (including
intercurrent illness)
Death
Non-safety
Insufficient therapeutic
response
Violation of selection
criteria at entry
Other protocol violation
cooperate’ and ‘withdrew
consent’)
Total
7
Supplementary Table S5. Dose reductions/interruptions
NonRandomised
Dose reductions/
interruptions, n (%)
Erlotinib
Gemcitabine
randomised
Standard
Dose
Grade ≥2
dose
escalation
rash
14/77 (18)
31/71 (44)
33/105 (31)
54/77 (70.1)
51/71 (71.8)
93/105 (88.6)
8