Table.
Tier 1: Clinically actionable resistance mechanisms
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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
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afatinib + cetuximab65 | 30% RR and median 4.7 month PFS in 96 patients at maximum tolerated dose
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Small Cell Transformation29 | 3–14%21,22 | platinum–etoposide21 | 60% RR in 5 patients |
Tier 2: Clinical trials ongoing
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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) |
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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) |
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PIK3CA mutation35 | 0–5%21,22 | BKM120 + gefitinib BKM120 + erlotinib |
Phase I (NCT01570296) Phase II (NCT01487265) |
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ERK amplification37 | N/a | selumetinib + gefitinib | PhaseIb/II (NCT02025114) |
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BRAF V600E33 | 1%33 | Combinations of BRAF and EGFR inhibitors are in development in colorectal cancer34 | |
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Tier 3: Pre-clinical (CRKL amplification, AXL overexpression, elevated HGF) 38–42 |
Response data presented only for T790M positive patients.