July 10, 2013
2 min read

Novel TKI shows promise in ALK-positive patients

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PARIS — The novel tyrosine kinase inhibitor AP26113 shows promising anti-tumor activity in patients with anaplastic lymphoma kinase-positive malignancies, according to study results presented at the WIN Symposium.

AP26113 (Ariad Pharmaceuticals) — which appears to be well tolerated — also demonstrated initial evidence of activity in patients with epidermal growth factor receptor (EGFR) mutations.

Lyudmila Bazhenova, MD, associate clinical professor of medicine in the division of hematology-oncology and medical director of the UC San Diego Moores Cancer Center Infusion Center, and colleagues launched the open-label, multicenter phase 1/2 study to evaluate AP26113 in patients with advanced malignances, excluding leukemia, who were refractory to available therapies or for whom no standard treatments exist.

As of January, 44 patients (64% women) were enrolled in the dose-finding portion of the study; of them, 37 had non–small cell lung cancer (NSCLC). Median patient age was 60 years.

All patients received AP26113 orally once daily. Dosing regimens were 30 mg (n=3), 60 mg (n=3), 90 mg (n=8), 120 mg (n=8), 180 mg (n=11), 240 mg (n=9) and 300 mg (n=2).

Twenty-six patients discontinued treatment. Of them, 18 stopped due to disease progression, six stopped due to adverse events and two patients died. The deaths possibly were related to treatment, according to researchers.

The most common adverse events were nausea (45%), fatigue (39%) and diarrhea (27%). The most common grade 3/4 treatment-related adverse event was diarrhea (5%).

The researchers reported two dose-limiting toxicities. They were grade 3 alanine transaminase (ALT) level increase among patients assigned to the 240 mg dose and grade 4 dyspnea among patients assigned to the 300 mg dose.

Twenty-one of the 44 patients enrolled had ALK-positive disease (18 with NSCLC and three with other malignancies). Ten of the 18 evaluable ALK-positive patients demonstrated response, according to researchers. Responses were observed in two of three patients with no prior exposure to crizotinib (Xalkori, Pfizer), as well as eight of 12 patients who underwent one prior crizotinib treatment. The longest response was 40 weeks and was still ongoing at time of data collection.

Five ALK-positive patients had untreated or progressing CNS lesions at baseline. Four of them — including one patient resistant to crizotinib and LDK378 (Novartis), a novel anaplastic lymphoma kinase TKI — demonstrated evidence of radiographic improvement in CNS on follow-up scans.

Sixteen patients — 15 with NSCLC and one with small cell lung cancer — had EGFR mutations. Fourteen of those 16 patients had undergone one or more prior EGFR TKI regimens. Twelve EGFR-positive patients underwent a follow-up scan. One patient, who was assigned to the 120 mg dose, responded (21 weeks, ongoing). Six others had stable disease (range, 7 to 31 weeks; two ongoing).

The phase 2 portion of the study will begin after the recommended dose is determined, researchers wrote. Researchers will divide patients into four cohorts — crizotinib-naive NSCLC, crizotinib-resistant NSCLC, EGFR TKI-resistant NSCLC and those with other tumors.


For more information:

Bazenhova L. Abstract #P6.09. Presented at: WIN Symposium; July 10-12, 2013; Paris.


Disclosure: The researchers report no relevant financial disclosures.