Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial.
BACKGROUND
Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC.


METHODS
This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954.


RESULTS
Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n=38], cabozantinib [n=38], erlotinib plus cabozantinib [n=35]). Compared with erlotinib alone (median 1·8 months [95% CI 1·7-2·2]), progression-free survival was significantly improved in the cabozantinib group (4·3 months [3·6-7·4]; hazard ratio [HR] 0·39, 80% CI 0·27-0·55; one-sided p=0·0003) and in the erlotinib plus cabozantinib group (4·7 months [2·4-7·4]; HR 0·37, 0·25-0·53; one-sided p=0·0003). Among participants included in the safety analysis of the erlotinib (n=40), cabozantinib (n=40), and erlotinib plus cabozantinib (n=39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination.


CONCLUSIONS
Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population.


BACKGROUND
ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health.
Stanford Cancer Institute, Stanford, CA, USA. Electronic address: jwneal@stanford.edu.
Joel W
JW
Neal
Dana Farber Cancer Institute, Boston, MA, USA.
Suzanne E
SE
Dahlberg
Stanford Cancer Institute, Stanford, CA, USA.
Heather A
HA
Wakelee
Rutgers Cancer Institute of New Jersey, Newark, NJ, USA.
Seena C
SC
Aisner
Dana Farber Cancer Institute, Boston, MA, USA.
Michaela
M
Bowden
Dana Farber Cancer Institute, Boston, MA, USA.
Ying
Y
Huang
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
David P
DP
Carbone
Illinois CancerCare-Peoria, Peoria, IL, USA.
Gregory J
GJ
Gerstner
Park Nicollet Clinic, Saint Louis Park, MN, USA.
Rachel E
RE
Lerner
Community Hospital of the Monterey Peninsula, Monterey, CA, USA.
Jerome L
JL
Rubin
The Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Taofeek K
TK
Owonikoko
Saint Joseph Mercy Hospital, Ann Arbor, MI, USA.
Philip J
PJ
Stella
Roger Maris Cancer Center, Fargo, ND, USA.
Preston D
PD
Steen
Charleston Area Medical Center, Charleston, WV, USA.
Ahmed Ali
AA
Khalid
The Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Suresh S
SS
Ramalingam
D000368:Aged; D000813:Anilides / Q000008:administration & dosage / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*
D000813:Anilides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met