Rociletinib in EGFR-mutated non-small-cell lung cancer.
BACKGROUND
Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.


METHODS
In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.


RESULTS
A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).


CONCLUSIONS
Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).
From Massachusetts General Hospital (L.V.S., R.S.H., J.L., Z.P.), Harvard Medical School (L.V.S., G.R.O., R.S.H., Z.P.), and Dana-Farber Cancer Institute (G.R.O.) - all in Boston; the Drug Development Department, Université Paris-Sud, Gustave Roussy Cancer Campus (J.-C.S.), and Institut Gustave Roussy (A.V.), Villejuif - both in France; the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (J.W.G., E.B.G., M.A.M., S.N.), and Stanford Cancer Institute, Stanford University, Stanford (H.A.W., J.W.N.) - both in California; the Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit (S.M.G., C.G., A.J.W.); University of Texas M.D. Anderson Cancer Center, Houston (V.P.); the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.); the Medical University of Gdansk, Gdansk, Poland (R.D.); the University of Colorado (D.L.A., D.R.C.) and University of Colorado Cancer Center (R.C.D.) - both in Aurora; and Clovis Oncology, San Francisco (M.R., C.A.K., S.J.-T., S.L.M., A.R.A.), Boulder, CO (J.I., D.D.), and Cambridge, United Kingdom (L.R.).
Lecia V
LV
Sequist
Jean-Charles
JC
Soria
Jonathan W
JW
Goldman
Heather A
HA
Wakelee
Shirish M
SM
Gadgeel
Andrea
A
Varga
Vassiliki
V
Papadimitrakopoulou
Benjamin J
BJ
Solomon
Geoffrey R
GR
Oxnard
Rafal
R
Dziadziuszko
Dara L
DL
Aisner
Robert C
RC
Doebele
Cathy
C
Galasso
Edward B
EB
Garon
Rebecca S
RS
Heist
Jennifer
J
Logan
Joel W
JW
Neal
Melody A
MA
Mendenhall
Suzanne
S
Nichols
Zofia
Z
Piotrowska
Antoinette J
AJ
Wozniak
Mitch
M
Raponi
Chris A
CA
Karlovich
Sarah
S
Jaw-Tsai
Jeffrey
J
Isaacson
Darrin
D
Despain
Shannon L
SL
Matheny
Lindsey
L
Rolfe
Andrew R
AR
Allen
D Ross
DR
Camidge
D000178:Acrylamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000178:Acrylamides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000589977:rociletinib; D066246:ErbB Receptors