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