Phase II study of erlotinib given daily for patients with metastatic melanoma (MM)

Abstract

18002 Background: Erlotinib is a small molecule tyrosine kinase inhibitor (TKI) that targets epidermal growth factor receptor (EGFr). The EGFr is a potential therapeutic target because it is expressed by a number of malignancies, including melanocytic lesions, and in some plays an important role in the biology of the cancer. Our aim was to conduct a phase II study evaluating erlotinib in patients (pts) with measurable metastatic melanoma. Methods: Eligibility criteria included measurable disease, ECOG PS = 0–1, and adequate organ function. Pts were eligible if they received up to one prior therapy for metastatic disease. Pts received a daily dose of erlotinib 150 mg. The primary outcomes were overall response rate and response duration. The study had a two-stage design with closure at 14 pts if there were no objective RECIST responses. Secondary outcomes included overall safety and tolerability of erlotinib. Results: Between August 2003 and August 2004, a total of 14 pts with MM were accrued. The majority of pts were male 12:2 = M, median age = 57.5 yrs (range 38 to 80 yrs). Stage of disease included M1a (n = 7), M1b (n = 5), M1c (n = 2) and performance status was equally divided between 0 and 1 (7 pts each). Seven pts (50%) had prior adjuvant therapy and six pts (43%) had at least one prior therapy for metastatic disease. Four pts (29%) had no prior therapy. No objective responses were observed. Four pts (29%) had stable disease at their initial 8-week evaluation of which only 2 had SD>6 months (228 and 365 days). One pt with SD withdrew from the study on day 68 for grade II toxicities. There were no Grade III/IV hematological or biochemical toxicities. Grade III toxicities were diarrhea and anorexia, each in a single patient. Most pts (n = 12) experienced at least a grade I dermatological toxicity manifested as an acneiform rash and/or pruritis. The median progression free survival (PFS) of all 14 pts was approximately 60 days with a range of 35 to 365 days. The median PFS of those with SD was 192.5 days. Conclusions: Erlotinib given daily at 150 mg is well tolerated in pts with MM. However, it has minimal to no single agent activity. Any further investigation of this drug should be pursued in combination with other agents only if a strong scientific/clinical rationale exists. No significant financial relationships to disclose.

Receptor tyrosine kinases and their activation in melanoma

“…Initial clinical trials of imatinib for metastatic melanoma were disappointing. There was no objective response or disease progression at 6 months in groups of 16 and 26 patients (Ugurel et al, 2005;Wyman et al, 2006), despite positivity for KIT protein in most melanomas in the first group. However, an anecdotal report described a major response in one patient with a mucosal melanoma containing mutant KIT (Lutzky et al, 2008).…”

“…However, treatment with another EGFR inhibitor, erlotinib, did not affect melanoma cell proliferation although there was inhibition of MAPK and AKT signalling pathways (Schicher et al., 2009). Moreover, in a phase II clinical study, erlotinib (150 mg daily) was preliminarily reported to have minimal or no single‐agent activity against metastatic melanoma (Wyman et al., 2006). A recent study also found that increased ERBB3 expression is a marker of poor prognosis in melanoma, with frequent high expression in melanoma and no expression in normal melanocytes (consistent with the above phospho‐array findings).…”

Systemic therapy for metastatic malignant melanoma – from deeply disappointing to bright future?

“…The role of inhibitors of ckit in these subtypes is under evaluation (50). A phase II trial of erlotinib in 14 patients showed no responses (51).…”