Enzastaurin, an oral serine/threonine kinase inhibitor, as second- or third-line therapy of non-small-cell lung cancer.
OBJECTIVE
Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non-small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.


METHODS
Patients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status <or= 2, and <or= two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.


RESULTS
Fifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS >or= 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade <or= 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).


CONCLUSIONS
Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for >or= 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.
Oh
Yun
Y
Anderson Cancer Center, Houston, TX, USA.
Herbst
Roy S
RS
Burris
Howard
H
Cleverly
Ann
A
Musib
Luna
L
Lahn
Michael
M
Bepler
Gerold
G
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016879:Salvage Therapy; D015996:Survival Rate
D007211:Indoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C504878:enzastaurin