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

Primo N Lara, Jeff Longmate, Philip Mack, Karen Kelly, Mark A. Socinski, Ravi Salgia, Barbara Gitlitz, Tianhong Li, Mariana Koczywas, Karen L. Reckamp, David R Gandara

Research output: Contribution to journalArticle

35 Scopus citations

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 languageEnglish (US)
Pages (from-to)4321-4326
Number of pages6
JournalClinical Cancer Research
Volume21
Issue number19
DOIs
StatePublished - Oct 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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