Annual Meeting Proceedings Part 1 - American Society of Clinical ...

7520 Poster Discussion Session (Board #10), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial
of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line
treatment for Chinese patients with EGFR mutation-positive advanced
non-small cell lung cancer (NSCLC). Presenting Author: Caicun Zhou,
Shanghai Pulmonary Hospital, Tongji University School of Medicine,
Shanghai, China
Background: The OPTIMAL study demonstrated significant superiority for E
versus GC in terms of progression-free survival (PFS), objective response
rate, tolerability and quality of life (QoL) in first-line advanced NSCLC
patients with EGFR activating mutations (Act Mut�). Here we report OS
data from OPTIMAL (ClinicalTrials.gov NCT00874419). Methods: Chemotherapy-naive
Chinese patients with advanced NSCLC and EGFR Act
Mut�, ECOG performance status (PS) 0–2 and measurable disease were
randomized to E (150 mg/day), or GC, and stratified by histology, smoking
status and mutation type. OS at final data cut-off (15 Nov 2011) was
evaluated for the entire intent-to-treat (ITT) population. Subgroup analysis
of OS by gender, histology, smoking status, PS, presence of skin rash and
type of mutation was performed. Details of second- or later-line therapy
were also documented for each patient. Results: A total of 165 patients
were randomized to treatment and 154 patients received at least one dose
of study drug (ITT population; E, n�82; GC, n�72). A total of 7 patients
are still responding to erlotinib in the E arm. Post-study therapy included
chemotherapy (doublet, n�38, or mono, n�8), or experimental drugs in
clinical trials (n�10) in the E arm, and EGFR tyrosine kinase inhibitor (TKI)
therapy (n�49) or chemotherapy (n�7) in the GC arm. Post-study
treatment was not received by 26 and 16 patients in the E and GC arms,
respectively. A total of 84 deaths were reported (E, n�47; GC, n�37). OS
did not differ significantly between the two treatment arms (HR�1.065,
p�0.6849), and no significant difference in OS was observed in the
different subgroups. Conclusions: The lack of a statistically significant
difference in OS in the OPTIMAL study was possibly due to a high level of
cross-over to EGFR TKI therapy in the GC arm. However, the significant
benefits reported with E in terms of PFS, QoL and tolerability in this study
suggest that E should be considered as one of the standard first-line
treatments for patients with advanced EGFR Act Mut� NSCLC.
7522 Poster Discussion Session (Board #12), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
EGFR compound mutants and survival on erlotinib in non-small cell lung
cancer (NSCLC) patients (p) in the EURTAC study. Presenting Author:
Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain; Pangaea
Biotech, USP Institut Universitari Dexeus, Barcelona, Spain
Background: When EGFR compound mutants (exon 19 deletions or L858R
plusT790M) are present at the time of clinical resistance to erlotinib,
patients attain longer overall survival (OS) (Oxnard et al. CCR 2011). The
H1975 cell line, harboring L858R plus T790M prior to treatment, is
sensitive to gefitinib (Sordella et al. Science 2004; Faber et al. Cancer
Discovery 2011), though the compound mutant may become dominant
after multiple passages in vitro, leading to resistance (Pao et al. PLoS Med
2005). Methods: The EURTAC trial (clinicaltrials.gov NCT00446225)
randomized 174 p with EGFR exon 19 deletions or L858R mutations to
receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7
months (m) vs 5.2 m, respectively (P�0.0001). No differences in OS were
observed.123 p with remaining available pre-treatment tumor tissue were
re-analyzed for the concomitant presence of the T790M mutation with an
allelic discrimination Taqman assay in the presence of a PNA clamp
designed to inhibit the amplification of the exon 20 wild-type (wt) allele.
This assay is capable of detecting the T790M allele at a ratio of 1:5000 wt
alleles. Results: The T790M mutation was detected in 21/64 (32.8%) p in
the erlotinib arm and 26/59 (44.1%) in the chemotherapy arm. PFS was
12.1 m for p with mutant T790M in the erlotinib arm, 8.8 m for p with wt
T790M in the erlotinib arm, 6.3 m for p with mutant T790M in the
chemotherapy arm, and 4.5 m for p with wt T790M in the chemotherapy
arm (P�0.0001). OS was not reached for p with mutant T790M in the
erlotinib arm, 16.1 m for p with wt T790M in the erlotinib arm, 22.6 m for
p with mutant T790M in the chemotherapy arm, and 18.4 m for p with wt
T790M in the chemotherapy arm (P�0.04). Conclusions: Our unexpected
finding that p with EGFR compound mutants attain the maximum benefit
from erlotinib suggests a need for more sensitive assays to detect EGFR
compound mutants and for studies of inhibitors targeting the EGFR T790M
mutation. Whole genome sequencing may provide greater understanding of
the genetic factors involved in the differences in OS.
Lung Cancer—Non-small Cell Metastatic
485s
7521 Poster Discussion Session (Board #11), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Updated overall survival results of WJTOG 3405, a randomized phase III
trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the
first-line treatment for patients with non-small cell lung cancer harboring
mutations of the epidermal growth factor receptor (EGFR). Presenting
Author: Tetsuya Mitsudomi, Department of Thoracic Surgery, Aichi Cancer
Center Hospital, Nagoya, Japan
Background: WJTOG3405 met its primary endpoint of progression free
survival (PFS) (9.2 months (mo.) for G vs. 6.3 mo. for CD, hazard ratio (HR)
0.489, 95% confidence interval (CI): 0.336-0.710). (Mitsudomi et al.,
Lancet Oncol., 2010). However, the impact on overall survival (OS) was not
clear then because of relatively short follow-up period. Methods: Overall
survival (OS) was re-evaluated using updated data (data cutoff, 31 July,
2011, median follow-up, 34 months) for 172 patients. Results: Eighty-two
events had occurred (48%). Median survival time (MST) for G arm was 36
mo. (95% CI: 26.3 -) which was not significantly different from 39 mo.
(95% CI: 31.2 -) for CD arm (HR 1.185, 95% CI 0.767-1.829).
Multivariate analysis using Cox proportional hazards model revealed that
none of covariates (treatment arm, smoking status, sex, age, postoperative
recurrence or IIIB/IV, and mutation type) significantly affected OS. In the G
arm, MST of patients with exon 19 deletion (36 mo.) was comparable to
that of patients with L858R (35 mo.). In the CD arm, 78 patients (91%)
received EGFR-TKI as the 2nd or later line treatment, whereas in the G arm,
52 patients (61%) received platinum doublet. Accordingly, 130 patients
received both platinum doublet and EGFR-tyrosine kinase inhibitor (TKI)
and 34 patients received EGFR-TKI without platinum doublet in their
whole courses of therapy. MST for the former and the latter group were 36
months (95% CI: 31.2-45.7) and 45 months (95% CI: 25.6-), without
significant difference. Conclusions: This update OS analysis revealed that G
for advanced NSCLC with EGFR mutation offers distinct survival benefit of
3 years. There was no difference in OS whether the first-line treatment was
G or CD, in accordance with the precedent studies. The reason why PFS
difference was not translated into OS difference is probably due to high
cross over rate to EGFR-TKI. However, it was noteworthy that 40% of
patients in the G arm could be managed without platinum doublet and yet
had similar outcome.
7523 Poster Discussion Session (Board #13), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion
mutations within the tyrosine kinase domain of EGFR. Presenting Author:
Daniel Botelho Costa, Beth Israel Deaconess Medical Center/Harvard
Medical School, Boston, MA
Background: Epidermal growth factor receptor (EGFR) mutations (M) define
an important subgroup of non-small-cell lung cancer (NSCLC). Most
patients whose tumors harbor exon 19 deletions or L858R EGFR M have
responses to reversible ATP-mimetic EGFR tyrosine kinase inhibitors
(TKIs), gefitinib and erlotinib. Exon 20 insertion M comprise ~5% of EGFR
M, occur at the N-lobe of EGFR after its C-helix (AA M766), and nearly all
NSCLCs with EGFR exon 20 insertion M display lack of responses to EGFR
TKIs (Yasuda H. Lancet Oncol 2011). Methods: We have 1) compiled
genotype-clinical outcomes of EGFR exon 20 insertion M NSCLCs to EGFR
TKIs, 2) generated a comprehensive panel of exon 20 EGFR M constructs
using site-directed mutagenesis and introduced them into Ba/F3 cells for in
vitro analysis, and 3) compared NSCLC cell lines with EGFR M to a novel
malignant pleural effusion-derived cell line. Results: The disease control
rate of gefitinib or erlotinib was significantly higher in EGFR exon 20
insertion M located within the C-helix (3/3,100%) when compared to M
following the C-helix (1/14, 7%; p�0.00059). The NSCLC with EGFR-
A763_Y764insFQEA (located within the C-helix of EGFR) achieved a
partial response to erlotinib that lasted 18 months. Most other exon 20
insertion M-positive NSCLCs did not respond (p�0.07). Eight representative
exon 20 insertion M were studied (including EGFR-
A763_Y764insFQEA, Y764_S765insHH, A767_V769dupASV,
D770_N771insNPG, H773_V774insH). All, but A763_Y764insFQEA,
were resistant to micromolar concentrations (C) of EGFR TKIs. Ba/F3 cells
with EGFR-A763_Y764insFQEA underwent apoptosis upon exposure to
nanomolar C of erlotinib. A patient-derived cell line with EGFR-
A763_Y764insFQEA had phosphorylated EGFR, ERK and AKT inhibited by
nanomolar C of erlotinib. Conclusions: Not all EGFR exon 20 insertion
mutations are resistant to EGFR TKIs, and in specific EGFR-
A763_Y764insFQEA is an EGFR TKI-sensitive M. This finding has clinical
implications for the care of the 10,000 cases of EGFR exon 20 insertion M
NSCLC diagnosed yearly and points towards the need to define the
molecular mechanisms that underlie differential responses to EGFR TKIs.
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