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. Author manuscript; available in PMC: 2015 Aug 1.
Published in final edited form as: Cancer. 2014 Apr 17;120(15):2289–2298. doi: 10.1002/cncr.28723

Table.

Tier 1: Clinically actionable resistance mechanisms
Mechanism Prevalence Potential Therapy Efficacy data
EGFR T790M24 49–63%20,21,22 CO-168628 66% RR in 9 T790M+ patients at highest dose level†
AZD929127 43% RR in 35 patients from all dose levels

  • 50% RR in 18 T790M+ patients

  • 20% RR in 5 T790M+ patients
afatinib + cetuximab65 30% RR and median 4.7 month PFS in 96 patients at maximum tolerated dose

  • 32% RR in 53 T790M+ patients

  • 28% RR in 39 T790M- patients
Small Cell Transformation29 3–14%21,22 platinum–etoposide21 60% RR in 5 patients
Tier 2: Clinical trials ongoing
Mechanism Prevalence Potential Therapy Ongoing Clinical Trials
MET amplification30,31 5–11%20,21,22 cabozantinib + erlotinib
LY2875358 +/− erlotinib
INC280 + gefitinib		 Phase II (NCT01866410)
Phase II (NCT01900652)
Phase IB/II (NCT01610336)
HER2 amplification32 12–13%22,32 High-dose intermittent
afatinib dacomitinib

intermittent dacomitinib		 Phase Ib (NCT01647711)
Phase III versus placebo (NCT1000025), with a pre-planned subgroup analysis in EGFR-mutant cancers

Phase II (NCT01858389)
PIK3CA mutation35 0–5%21,22 BKM120 + gefitinib
BKM120 + erlotinib		 Phase I (NCT01570296)
Phase II (NCT01487265)
ERK amplification37 N/a selumetinib + gefitinib PhaseIb/II (NCT02025114)
BRAF V600E33 1%33 Combinations of BRAF and EGFR inhibitors are in development in colorectal cancer34
Tier 3: Pre-clinical (CRKL amplification, AXL overexpression, elevated HGF) 38–42
†

Response data presented only for T790M positive patients.