Abstract
Purpose: Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the EGFR inhibitor erlotinib in erlotinibsensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK-2206, a highly selective inhibitor of AKT, in NSCLC patients. Experimental Design: Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg orally every day + MK-2206 45 mg orally every alternate day on a 28-day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20%at 12 weeks (stratum2: EGFR wild-type). Results: Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were, respectively,9%and 40% in stratum 1;3%and 47% in stratum 2. Median progression-free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2. Conclusions: Combination MK-2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild-type NSCLC. Although activity was seen in EGFR-mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild-type NSCLC.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4321-4326 |
| Number of pages | 6 |
| Journal | Clinical Cancer Research |
| Volume | 21 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 2015 |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Phase II study of the AKT inhibitor MK-2206 plus erlotinib in patients with advanced non-small cell lung cancer who previously progressed on erlotinib. / Lara, Primo N; Longmate, Jeff; Mack, Philip; Kelly, Karen; Socinski, Mark A.; Salgia, Ravi; Gitlitz, Barbara; Li, Tianhong; Koczywas, Mariana; Reckamp, Karen L.; Gandara, David R.
In: Clinical Cancer Research, Vol. 21, No. 19, 01.10.2015, p. 4321-4326.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase II study of the AKT inhibitor MK-2206 plus erlotinib in patients with advanced non-small cell lung cancer who previously progressed on erlotinib
AU - Lara, Primo N
AU - Longmate, Jeff
AU - Mack, Philip
AU - Kelly, Karen
AU - Socinski, Mark A.
AU - Salgia, Ravi
AU - Gitlitz, Barbara
AU - Li, Tianhong
AU - Koczywas, Mariana
AU - Reckamp, Karen L.
AU - Gandara, David R
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Purpose: Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the EGFR inhibitor erlotinib in erlotinibsensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK-2206, a highly selective inhibitor of AKT, in NSCLC patients. Experimental Design: Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg orally every day + MK-2206 45 mg orally every alternate day on a 28-day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20%at 12 weeks (stratum2: EGFR wild-type). Results: Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were, respectively,9%and 40% in stratum 1;3%and 47% in stratum 2. Median progression-free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2. Conclusions: Combination MK-2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild-type NSCLC. Although activity was seen in EGFR-mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild-type NSCLC.
AB - Purpose: Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the EGFR inhibitor erlotinib in erlotinibsensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK-2206, a highly selective inhibitor of AKT, in NSCLC patients. Experimental Design: Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg orally every day + MK-2206 45 mg orally every alternate day on a 28-day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20%at 12 weeks (stratum2: EGFR wild-type). Results: Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were, respectively,9%and 40% in stratum 1;3%and 47% in stratum 2. Median progression-free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2. Conclusions: Combination MK-2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild-type NSCLC. Although activity was seen in EGFR-mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild-type NSCLC.
UR - http://www.scopus.com/inward/record.url?scp=84945578894&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84945578894&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-3281
DO - 10.1158/1078-0432.CCR-14-3281
M3 - Article
C2 - 26106072
AN - SCOPUS:84945578894
VL - 21
SP - 4321
EP - 4326
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 19
ER -