Practice Update: Oncology

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Neratinib Efficacy and ctDNA
Detection of HER2 Mutations
in HER2 Non-Amplified
Metastatic Breast Cancer
Clinical Cancer Research
Take-home message
• Patients with confirmed HER2-mutated non-amplified metastatic breast cancer
were treated with neratinib to evaluate outcomes in this single-arm phase II trial.
Of 381 tumors sequenced centrally, 9 demonstrated HER2 mutation. A further
13 cases were identified locally. Neratinib was administered to 16 patients. The
clinical benefit rate was 31%, with 1 complete response, 1 partial response, and 3
patients with stable disease ≥24 weeks. The median progression-free survival was
16 weeks. Despite prophylactic administration of loperamide, the most prevalent
grades 2 and 3 side effect was diarrhea, which affected 69% of patients. Baseline
ctDNA sequencing had a sensitivity of 79% and a specificity of 100% for identifying
the HER2 mutation.
• Neratinib demonstrates activity in patients with HER2-mutated nonamplified
metastatic breast cancer, and ctDNA sequencing is a noninvasive technique to
effectively identify patients with HER2-mutated cancers who may be eligible to
participate in clinical trials.
Abstract
PURPOSE Markers of chemotherapy efficacy in
metastatic colorectal cancer (mCRC) are essen-
tial for optimization of treatment strategies. We
evaluated the applicability of early changes in
circulating tumor DNA (ctDNA) as a marker of
therapeutic efficacy.
EXPERIMENTAL DESIGN This prospective study
enrolled consecutive patients with mCRC
receiving a first- or second-line chemother-
apy. CtDNA was assessed in plasma collected
before the first (C0), second (C1) and/or third
(C2) chemotherapy cycle, using picodroplet-dig-
ital PCR assays based either on detection of
gene mutation (KRAS, BRAF, TP53) or hyper-
methylation (WIF1, NPY). CT scans were centrally
assessed using RECIST v1.1 criteria. Multivariate
analyses were adjusted on age, gender, ECOG
performance status (PS), metastatic synchronic-
ity, and treatment line.
RESULTS Eighty-two patients with mCRC treated
in first- (82.9%) or second- (17.1%) line chemo-
therapy were included. Patients with a high (>10
ng/mL) versus low (≤0.1 ng/mL) ctDNA concen-
tration at C0 had a shorter overall survival (OS;
6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI,
2.5-12.6; P < 0.0001). By analyzing the evolution
of the ctDNA concentration between C0 and C2
or C1 (C2or1), we classified the patients in two
groups (named “good” or “bad ctDNA respond-
ers”). In multivariate analysis, patients belonging
to the group called “good ctDNA responder” (n
= 58) versus “bad ctDNA responder” (n = 15) had
a better objective response rate (P < 0.001), and
a longer median progression-free survival (8.5
vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P <
0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25;
95% CI, 0.11-0.57; P < 0.001).
CONCLUSION This study suggests that early
change in ctDNA concentration is a marker of
therapeutic efficacy in patients with mCRC.
Neratinib efficacy and circulating tumor DNA
detection of HER2 mutations in HER2 nonam-
plified metastatic breast cancer, Clin Cancer
Res 2017 Aug 15;[EPub Ahead of Print], CX Ma,
R Bose, F Gao, et al.
COMMENT
By Reshma L. Mahtani DO
The availability of HER2-targeted therapies has dramatically improved outcomes
for patients with HER2-positive breast cancer. Although ongoing studies such
as NSABP B47 are addressing the role of trastuzumab in HER2-negative breast
cancer, generally HER2-directed therapies are only administered to the roughly 20%
of breast cancer patients who have HER2 amplification. However, in patients who are
HER2-negative by immunohistochemistry (IHC) and fluorescence-in-situ-hybridization
(FISH), breast cancer genome sequencing has identified HER2-activating mutations.
Preclinical work has documented that the majority of these HER2 somatic mutations
are activating mutations, which are likely driving tumorigenesis in a small percent-
age of breast cancer patients overall (2%–4%). Furthermore, the presence of these
mutations confers resistance to the reversible HER2 inhibitor lapatinib, but not to the
irreversible HER2 inhibitor neratinib.
In the current study, 22 patients of 381 were found to harbor HER2 mutations, and the
authors report a CBR of 31% and PFS of 16 weeks when neratinib was administered as
a single agent. Circulating tumor DNA (ctDNA) sequencing was found to be accurate in
identifying the cases. These data add to data from other studies which have indicated
that the identification of HER2 mutations may offer additional targeted approaches for
a small subset of breast cancer patients. Ongoing basket-trial designs, such as the
design of the SUMMIT trial, are investigating the clinical potential of neratinib in a broad
spectrum of tumor types that harbor HER2 mutations. Data from these types of trials will
hopefully lead to a more personalized approach to treatment in oncology.
Dr. Mahtani is Assistant Professor, Division of Hematology/Oncology,
Sylvester Comprehensive Cancer Center, University of Miami Health
System.
EDITOR’S PICKS 9
VOL. 1 • NO. 3 • 2017