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

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. Isolated 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's activity in myeloid malignancies are not clear, but may involve aberrant Lyn, Syk and mTOR-mediated signaling. We report interim analysis results of a phase II trial examining the activity of erlotinib in the treatment of myelodysplastic syndromes.

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 eligible. 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 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. Responding patients (at least hematological response) 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. ORR in at least two of the first 20 patients (stage 1) was necessary to proceed with expanded accrual of 15 additional patients. The study was approved by scientific review committee and IRB, and monitored by independent internal montioring committee.

Between September 2009 and March 2010, 25 patients were enrolled at Moffitt Cancer Center (two patients were found to be ineligible after signing informed consent, the first had myeloblasts >30% and the second patient had low grade MDS progressed to CML, but treated). For the 24 patients treated on protocol, the median age was 71 (range: 64–80) years, 18 patients (75%) were male. Majority were Caucasians (n=23) (96%). According to the WHO classification cases included RCMD 1 (4.2%), RAEB-I 8 (33.3%), RAEB-II 8 (33.3%), CMML 2 (8.3%), AML 4 (16.7%), and MDSU 1 (4.2%). The IPSS risk group was low in 2 (8.3%) patients, int-1 in 7 (29.2%), int-2 in 8 (33.3%) and high risk in 7 (29.2%). The median number of prior treatments was 2 (range: 1–4); all patients (100%) had received a hypomethylating agent (azacitidine or decitabine).

The best responses for all 23 eligible subjects treated on study by IWG 2006 criteria were 3 marrow CR (13.0%), one HI (4.4%), and 6 (26.1%) stable disease, for a combined ORR of 4/23 (17.4%, 95% CI: 5%-39%). Four deaths occurred on study (sepsis=1, intracranial hemorrhage=1, sudden death=1, AML=1). The most common observed grade 3/4 toxicity according to CTCAE v3 in 24 treated patients were diarrhea (5, 20.8%), platelets (4, 16.7%), and rash: acne/acneiform (4, 16.7%).

Erlotinib has acceptable toxicity profile in MDS patients and anti-leukemia activity in higher risk MDS patients after hypomethylating agents’ failure. The study has proceeded to the stage 2 expansion.

Komrokji:Genentech: Research Funding. Off Label Use: Erlotinib use for MDS is investigational.