Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.
Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required.


CONCLUSIONS
This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms.
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Zofia
Z
Piotrowska
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Matthew J
MJ
Niederst
Clovis Oncology, San Francisco, California.
Chris A
CA
Karlovich
Stanford Cancer Institute, Stanford University, Stanford, California.
Heather A
HA
Wakelee
Stanford Cancer Institute, Stanford University, Stanford, California.
Joel W
JW
Neal
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Mari
M
Mino-Kenudson
Massachusetts General Hospital, Boston, Massachusetts.
Linnea
L
Fulton
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Aaron N
AN
Hata
Massachusetts General Hospital, Boston, Massachusetts.
Elizabeth L
EL
Lockerman
Massachusetts General Hospital, Boston, Massachusetts.
Anuj
A
Kalsy
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Subba
S
Digumarthy
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Alona
A
Muzikansky
Clovis Oncology, San Francisco, California.
Mitch
M
Raponi
Massachusetts General Hospital, Boston, Massachusetts.
Angel R
AR
Garcia
Massachusetts General Hospital, Boston, Massachusetts.
Hillary E
HE
Mulvey
Massachusetts General Hospital, Boston, Massachusetts.
Melissa K
MK
Parks
Massachusetts General Hospital, Boston, Massachusetts.
Richard H
RH
DiCecca
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Dora
D
Dias-Santagata
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
A John
AJ
Iafrate
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Alice T
AT
Shaw
Clovis Oncology, San Francisco, California.
Andrew R
AR
Allen
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Jeffrey A
JA
Engelman
Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. lvsequist@partners.org.
Lecia V
LV
Sequist
D000178:Acrylamides / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000097:blood; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics
D000178:Acrylamides; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000589977:rociletinib; C512478:EGFR protein, human; D066246:ErbB Receptors