A Phase II Clinical Study of Erlotinib for Treatment of Myelodysplastic Syndromes

Erlotinib is an oral small molecule tyrosine kinase inhibitor that inhibits intracellular EGFR tyrosine kinase. Preclinical data suggest that erlotinib has in vivo and in vitro efficacy in MDS and AML (Boehrer et al., Blood, 2008), inducing apoptosis in MDS and AML cell lines and primary myeoblasts, and promoting myeloid differentiation. The antitumor effect of erlotinib was demonstrated in AML xenograft mouse model. Anecdotal case reports documented the haematological activity of erlotinib in patients who had lung cancer and concomitant MDS or AML. The precise non-EGFR kinase targets responsible for erlotinib activity in myeloid malignancies are not clear, but may involve aberrant Lyn, Syk and mTOR-mediated signaling. We report results of a phase II trial examining the activity of erlotinib in the treatment of poor prognostic group of myelodysplastic syndromes patients.

This is a single-institution two-stage phase 2 study. Eligibility includes confirmed int-2 or high risk MDS, low or int-1 risk patients with symptomatic anemia/ transfusion dependent anemia or patients with platelet counts < 50 × 10⁹/L or a significant clinical hemorrhage requiring platelet transfusions, ANC < 1 × 10⁹/L, and RAEB-t by FAB classification are also. All patients signed written infomred consent. Prior intensive induction chemotherapy, malignancy in the past 2 years, known history of HIV infection, ECOG PS 3–4 were key exclusions. Erlotinib was given as an oral 150 mg daily dose for 16 weeks. The dose was adjusted for diarrhea, rash and pulmonary toxicty. Study assessments included baseline and weekly complete blood counts and repeat bone marrow aspirate and biopsy at weeks 8 and 16; non-responders were removed from study after 16 weeks. Stable or responding patients continued study treatment until evidence of disease progression or relapse. The primary endpoint was the overall response rate ORR (CR, PR, marrow CR, or HI) as defined by the IWG 2006 criteria. Secondary endpoints inluced overall survival (OS), prgoression free survival (PFS), and leukemia free survival (LFS). The study was approved by scientific review committee and IRB.

Between September 2009 and January 2011, 39 patients signed consent at Moffitt Cancer Center (4 patients were found to be ineligible after signing informed consent, one patient had CML blast crisis transformation upon review but received < 1 week erlotinib). For the 35 patients treated on protocol, the mean age was 73 years, 80% were male, and majority 92% were Caucasian. According to the WHO classification cases included RCMD 2, RAEB-I 8, RAEB-II 9, CMML 6, AML 8 (RAEB-t by FAB), MDS/MPN-U 1. The IPSS risk group was low in 2 patients (4.2%), int-1 in 6 (17.14%), int-2 in 13 (37.14%) and high risk in 13 (37.14%) when applicable. The median number of prior treatments was 2, All patients had received a hypomethylating agent (azacitidine or decitabine). The median duration of follow up was 17 month.

The best responses for all eligible subjects on study by IWG criteria were 3 marrow CR, 2 HI, and 11 stable disease, for a combined ORR of 5/34 (14.7%). 4 death occurred on study (sepsis, intracranial hemorrhage, sudden death, AML). Nine patients were not evaluable for response (withdrew consent or off study due to adverse event before first evaluation). The overall best response for evaluable patients (n=26) was 5/26 (19%) (3 marrow CR and 2 HI). The most common observed grade 3/4 toxicity according to CTCAE v3 were diarrhea (17.1%), rash (17.1) %, fatigue, thrombocytopenia, and anorexia (5.7%) for each.

The median OS survival was 6.8 month (95%CI 4.9–13.2), the median PFS was 3.6 mo (95%CI 2–4.8), and LFS was 5 mo (95%CI 3.4–7.3). The median OS was 16.5 mo (95%CI 2.9–30) for patients who had HI or mCR, 7.1 mo (95% CI 0–12.5) for patients who had stable disease, and 5 month (95%CI 1–9) for patients who had progressive disease or were not evaluable. (p=0.06).

Erlotinib has acceptable toxicity profile in MDS patients and anti-leukemia activity in poor risk MDS patients after azanucleosides failure. Preclinical data suggest potential synergism in combination with azanucleosides and our future direction is to test erlotinib in combination with azacitidine for higher risk MDS patients.

Komrokji:Genentech: Research Funding. Off Label Use: erlotinib for treatment of MDS.