Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer.
OBJECTIVE
Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy.


METHODS
Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients.


RESULTS
Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients.


CONCLUSIONS
Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.
Bissett
Donald
D
Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, United Kingdom. d.bissett@arh.grampian.scot.nhs.uk
O'Byrne
Ken J
KJ
von Pawel
J
J
Gatzemeier
Ulrich
U
Price
Allan
A
Nicolson
Marianne
M
Mercier
Richard
R
Mazabel
Elva
E
Penning
Carol
C
Zhang
Min H
MH
Collier
Mary A
MA
Shepherd
Frances A
FA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D009930:Organic Chemicals / Q000009:adverse effects / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*
D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D011480:Protease Inhibitors; C113282:prinomastat