Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study

Abstract

Background: This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose.

Methods: After a 4-week run-in period (gemcitabine 1000 mg m(-2) once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 weeks (maximum 250 mg); n=71) or gemcitabine plus standard-dose erlotinib (100 mg per day; n=75). The primary end point was to determine whether overall survival (OS) was improved by increasing the erlotinib dose. Secondary end points included progression-free survival (PFS), incidence of grade ⩾2 rash, and safety.

Results: Erlotinib dose escalation induced grade ⩾2 rash in 29 out of 71 (41.4%) patients compared with 7 out of 75 (9.3%) patients on standard dose. Efficacy was not significantly different in the dose-escalation arm compared with the standard-dose arm (OS: median 7.0 vs 8.4 months, respectively, hazard ratio (HR), 1.26, 95% confidence interval (CI): 0.88-1.80; P=0.2026; PFS: median 3.5 vs 4.5 months, respectively, HR, 1.09, 95% CI: 0.77-1.54; P=0.6298). Incidence of adverse events was comparable between randomised arms.

Conclusion: The erlotinib dose-escalation strategy induced rash in some patients; there was no evidence that the higher dose translated into increased benefit.

Figure 1

Study design of the phase II RACHEL (BO21128) study. The 4-week run-in period was based on a median onset for rash development in patients treated with erlotinib plus gemcitabine for 10 days (with 90% of patients experiencing rash within 44 days) seen in the PA.3 study (Wacker et al, 2007). Erlotinib dose escalation—starting at 150 mg per day increasing at 50 mg every 2 weeks until a maximum of 250 mg per day or grade ⩾2 rash developed (patients were held at the lowest dose that induced grade ⩾2 rash). A 50-mg increment allowed monitoring of rash development/other toxicities and ensured patients were not exposed to unnecessarily high doses of erlotinib. Abbreviations: ECOG PS=Eastern Cooperative Oncology Group performance status; OS=overall survival; PD=disease progression; PFS=progression-free survival.

Figure 2

CONSORT diagram of patient disposition through the study. Standard dose: patients with grade 0 or 1 rash after the run-in period and eligible for randomisation (no PD and no dose adjustments to <75% of the full dose of chemotherapy). Dose escalation: patients with grade 0 or 1 rash after the run-in period and eligible for randomisation (no PD and no dose adjustments to <75% of the full dose of chemotherapy). Non-randomised, non-eligible: patients with grade 0 or 1 rash after the run-in period, but non-eligible for randomisation (having PD or dose adjustments to <75% of the full dose of chemotherapy). Non-randomised, grade ⩾2 rash: patients with grade ⩾2 rash after the run-in period. Early dropouts: patients with ECOG PS 2, PD, or serious adverse event leading to treatment discontinuation or death before randomisation. Abbreviations: ECOG PS=Eastern Cooperative Oncology Group performance status; ITT=intent-to-treat; PD=disease progression. ^aOne patient excluded due to dose escalation before randomisation. ^bTwo patients randomised to the dose-escalation arm, but who did not receive dose escalation were added. ^cTwo patients randomised to the dose-escalation arm, but who did not receive dose escalation were removed and two patients with dose escalation from the non-randomised arm were added.

Figure 3

OS (from randomisation) for patients who were randomised to the standard therapy arm (gemcitabine plus erlotinib 100 mg per day) or the dose-escalation arm (gemcitabine plus escalating doses of erlotinib). Abbreviations: HR=hazard ratio; OS=overall survival.

Figure 4

OS (from the start of the run-in period) for patients who did not develop grade ⩾2 rash during the 4-week run-in period who were randomised to receive standard therapy (gemcitabine plus erlotinib 100 mg per day) or dose escalation (gemcitabine plus escalating doses of erlotinib), compared with non-randomised patients who developed grade ⩾2 rash during the run-in period. Abbreviation: OS=overall survival.