SAN DIEGO, CA—Erlotinib was found to have an acceptable toxicity profile in patients with myelodysplastic syndromes (MDS) and antileukemic activity in those with poor risk MDS in whom treatment with azanucleoside agents has failed, according to results of a Phase 2 study presented during the 53rd American Society of Hematology Annual Meeting and Exposition.

Erlotinib, a small molecule tyrosine kinase inhibitor that inhibits intracellular EGFR tyrosine kinase, has shown preclinical efficacy in MDS and acute myeloid leukemia (AML). The agent induces apoptosis in MDS and AML cell lines and primary myeloblasts, promoting myeloid differentiation, and has an antitumor effect in AML xenograft mouse models. In patients with lung cancer and concomitant MDS or AML, anecdotal case reports have documented the hematological activity of erlotinib. However, the precise non-EGFR kinase targets responsible for this activity have yet to be identified; they may involve aberrant Lyn, Syk and mTOR-mediated signaling.

Rami S. Komrokji, MD, and colleagues at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, conducted a two-stage Phase 2 trial to examine the activity of erlotinib in the treatment of a poor prognostic group of patients with MDS. Patients were eligible if they had confirmed int-2 or high-risk MDS; low or int-1 risk with symptomatic anemia or transfusion-dependent anemia; platelet counts <50×109/L; a significant clinical hemorrhage requiring platelet transfusions; ANC <1×109/L; or refractory anemia with excess blasts in transformation (RAEB-t) by French-American-British (FAB) classification.

Key exclusion criteria were prior intensive induction chemotherapy, malignancy in the past two years, known history of HIV infection, and ECOG performance status 3–4. Oral erlotinib 150mg/day was administered for 16 weeks; dose adjustments were indicated for diarrhea, rash, and pulmonary toxicity. Baseline and weekly complete blood counts and repeat bone marrow aspirate and biopsy at Weeks 8 and 16 were assessed; nonresponders were removed from the study after 16 weeks. Patients who responded or had stable disease (SD) continued treatment with erlotinib until evidence of disease progression or relapse.

Primary endpoint was overall response rate (ORR), defined as complete response (CR), partial response (PR), marrow CR or hematologic improvement (HI) by International Working Group (IWG) 2006 criteria. Secondary endpoints were overall survival (OS), progression-free survival (PFS), and leukemia-free survival (LFS).

Between September 2009 and January 2011, 39 patients signed consent forms; however, four patients subsequently were found to be ineligible. The 35 patients treated (including one who had a CML blast crisis transformation and received less than one week of treatment with erlotinib) had a mean age of 73 years, 80% were male, and the majority (92%) were Caucasian.

By World Health Organization (WHO) classification, the 34 remaining patients were classified with refractory cytopenia with multilineage dysplasia (RCMD, n=2), refractory anemia with excess of blasts (RAEB-I; n=8), RAEB-II; n=9), chronic myelomonocytic leukemia (CMML; n=6), AML (n=8; RAEB-t by FAB), and myelodysplastic syndrome/myeloproliferative overlap neoplasms-unclassifiable (MDS/MPN-U, n=1). When applicable, the International Prognostic Scoring System (IPSS) risk group was low in two patients (4.2%), int-1 in six (17.14%), int-2 in 13 (37.14%), and high risk in 13 (37.14%). Median number of prior treatments was two, and all patients had been receiving the hypomethylating agent azacitidine or decitabine. Median duration of follow-up was 17 months.

By IWG criteria, ORR was 14.7% (5 of 34 patients), representing best responses for all eligible patients of marrow CR (n=3) and HI (n=2); 11 patients had stable disease (SD). 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%) (three marrow CR and two HI). Median OS was 6.8 months (95% CI: 4.9–13.2) and median PFS, 3.6 months (95% CI 2–4.8); LFS was 5 months (95% CI: 3.4–7.3). For the five patients with marrow CR and HI, median OS was 16.5 months (95% CI: 2.9–30) and, for those with SD, 7.1 months (95% CI: 0–12.5). Among patients who had disease progression or were not evaluable, median OS was 5 months (95% CI 1–9; P=0.06)

Grade 3/4 toxicities occurring most commonly were diarrhea (17.1%), rash (17.1%), fatigue (5.7%), thrombocytopenia (5.7%), and anorexia (5.7%). Four deaths occurred in the study that were attributed to sepsis, intracranial hemorrhage, AML, and sudden death.

Dr. Komrokji and colleagues concluded that preclinical data suggest potential synergism for erlotinib in combination with azanucleosides; therefore, future studies that test erlotinib in combination with azacitidine in patients with higher risk MDS are warranted.