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

7528 Poster Discussion Session (Board #18), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Rebiopsy of non-small cell lung cancer patients with acquired resistance to
EGFR-TKI: Comparison between T790M mutation-positive and -negative
populations. Presenting Author: Akito Hata, Division of Integrated Oncology,
Institute of Biomedical Research and Innovation, Kobe, Japan
Background: The secondary epidermal growth factor receptor (EGFR)
mutation T790M accounts for approximately half of acquired resistances to
EGFR-tyrosine kinase inhibitors (TKI). A recent report has demonstrated
the presence of T790M predicts a favorable prognosis and indolent
progression, compared to the absence of T790M after TKI failure. However,
rebiopsy to confirm T790M status can be challenging due to limited tissue
availability and procedural feasibility, and little is known regarding the
differences among patients with or without T790M. Methods: We investigated
73 patients harboring EGFR sensitive mutations who had undergone
rebiopsy to confirm the emergence of T790M after TKI failure. The peptide
nucleic acid-locked nucleic acid PCR clamp method was used in EGFR
mutational analyses. Patient characteristics (age, gender, smoking history,
performance status, EGFR mutation site, initial TKI, response to initial TKI,
line of initial TKI, progression-free survival with initial TKI, and biopsy site)
and postprogression survivals (PPS) after initial TKI failure, were retrospectively
compared in patients with and without T790M. Results: We identified
T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal
fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions
(25 lung tissue, 24 pleural effusion, and 3 lymph node) (p � 0.0225).
Other characteristics had no statistical association with the detection of
T790M. Median PPS in patients with T790M was 34.0 months, and in
those without T790M, 14.5 months (p � 0.0038). Although none of our
patients received TKIs continuously after initial failure, 56 (77%) patients
were re-administered TKIs. Regardless of T790M status, PPS in patients
with TKI re-administration (23.4 months) was significantly longer than
without re-administration (10.4 months) (p � 0.0085). Conclusions: The
emergence of T790M in CNS is rare compared with other lesions. Patients
with T790M after TKI failure have significantly better prognosis than those
without T790M. The effectiveness of TKI re-administration or continuous
administration beyond progression is suggested after initial TKI failure.
7530 Poster Discussion Session (Board #20), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine
kinase inhibitor, for patients with EGFR-mutant lung cancers. Presenting
Author: Mark G. Kris, Memorial Sloan-Kettering Cancer Center, New York,
NY
Background: Dacomitinib irreversibly inhibits EGFR, HER2 and HER4, and
showed superior activity vs. reversible EGFR tyrosine kinase inhibitors in
EGFR-mutant lung cancer models, including resistant forms. This openlabel
Phase II study evaluates dacomitinib as 1st-line treatment (tx) for
patients (pts) with lung cancers. Pts with sensitizing EGFR deletions/
mutations in exons 19 or 21 are reported here. Methods: Pts had stage
IIIB/IV adenocarcinoma, no prior systemic tx, had smoked �10 pack years
(none within 15 years of enrollment) or had known EGFR mutation. Pts
received dacomitinib orally once daily continuously at 45 mg, or 30 mg
with the option to escalate to 45 mg; evaluation was every 28 days.
Endpoints included progression-free survival rate at 4 months (PFS at 4M,
primary); PFS, and partial response (PR) rate. Results: 92 pts enrolled; 47
had EGFR mutation in exons 19 (n�25) or 21 (n�22), 33 were female and
27 Asian. 34/46 evaluable pts with EGFR exon 19 or 21 mutations had a
PR (PR rate � 74%; 95% CI: 59–86; exon 19 � 72%; exon 21 � 76%).
PR rates and preliminary PFS were not significantly different for exons 19
and 21. Preliminary PFS at 4M was 96% (95% CI: 84–99), preliminary
PFS rate at 1 year was 77% (95% CI: 61–87) and preliminary median PFS
was 17 months (95% CI: 13–24). Median tx duration was 13.1 months. For
pts with EGFR wild-type lung cancers, PR and PFS at 4M rates were 7%
(n�14; 95% CI: 0–34) and 33% (n�14; 95% CI: 11–58), respectively,
and for pts with EGFR unknown lung cancers, 46% (n�22; 95% CI:
24–68) and 68% (n�24; 95% CI: 45– 83), respectively. 7 pts had lung
cancers with non-sensitizing EGFR mutations; 2 had a PR and 3 SD. For all
92 pts, common side effects included dermatitis acneiform (grade 3/4 �
17%/0) and diarrhea (14%/0). 3/46 pts with EGFR exon 19 or 21
mutations discontinued tx due to drug-related toxicity. Conclusions: 74% of
pts in this cohort with EGFR exon 19 or 21 mutant lung cancers
experienced PRs with 1st-line dacomitinib; preliminary PFS rate was 77%
at 1 year; preliminary median PFS was 17 months; further research is
planned in this pt population. As dacomitinib is well tolerated, with
preclinical activity against HER2, a cohort of pts with HER2 mutant lung
cancers is recruiting.
Lung Cancer—Non-small Cell Metastatic
487s
7529 Poster Discussion Session (Board #19), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Concordance of driver mutations in primary and matched metastasis from
patients with non-small cell lung cancer (NSCLC) using next-generation
sequencing (NGS). Presenting Author: Stéphane Vignot, Institut Gustave
Roussy, INSERM U981, Villejuif, France
Background: Progress in treating NSCLC continues to be limited by high
recurrence rates after definitive treatment of localized disease and frequent
presentation with metastatic disease. In these pts, diagnostic samples are
often limited in size and may be inadequate for genotyping necessary in
this disease. In applying genomic profiling to aid treatment planning for
patients with metastatic NSCLC, it is critical to determine whether archived
primary tumor adequately reflects the genomic spectrum of the patient’s
metastatic disease or whether biopsy of a metastatic site is required. We
undertook this study using NGS technology to characterize paired primarymetastatic
biopsy genomic profiles. Methods: Primary and matched metastatic
tumor pairs plus adjacent normal tissue from 15 pts with NSCLC
(adenocarcinoma 9/squamous 4/large cell 2) and heavy smoking history
were analyzed using a targeted NGS assay in a CLIA laboratory (Foundation
Medicine). Genomic libraries were captured for 3230 exons in 182
cancer-related genes plus 37 introns from 14 genes often rearranged in
cancer and sequenced to average median depth of 778X with 99% of bases
covered �100X. Results: Among the 30 tumors, 373 somatic alterations
were identified; 96 were known NSCLC drivers including: TP53 (14 pts),
KRAS (4 pts), SOX2 (4 pts), STK11 (2 pts), CDKN2A (2 pts) and
SMARCA4 (2 pts) in full agreement with their respective histological type.
In all cases (15/15), primary and metastatic tumors from the same patient
demonstrated 90% driver mutation concordance (74/82, 95 % CI, 82-
95%). For other mutations, the majority of which are likely passengers, the
69% (201/291) concordance rate was significantly lower (p� .001).The
total number of alterations between primaries (190) and metastases (183)
was remarkably similar. Conclusions: These results suggest that genomic
profiles of primary tumor can identify the key somatic alterations present in
matched NSCLC metastases and therefore is a suitable specimen for
clinical decision making in the majority of cases. Our data does not support
the routine need for a new biopsy upon recurrence since variability in
mutational status is low.
7531 Poster Discussion Session (Board #21), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
A randomized discontinuation phase II trial of ridaforolimus in non-small
cell lung cancer (NSCLC) patients with KRAS mutations. Presenting
Author: Gregory J. Riely, Memorial Sloan-Kettering Cancer Center, New
York, NY
Background: Mutations in KRAS are present in ~25% of patients with
advanced NSCLC. Preclinical data support the role of mammalian target of
rapamycin (mTOR) in KRAS mediated oncogenesis. Ridaforolimus is an
inhibitor of mTOR which has been shown to have efficacy in advanced
endometrial cancer and soft tissue sarcoma. Everolimus, another mTOR
inhibitor was previously evaluated in unselected patients with advanced
NSCLC and found to have a response rate �5%. We hypothesized that by
enrichment for patients with NSCLC and KRAS mutations, treatment with
ridaforolimus would be associated with prolonged stable disease relative to
available standard treatments for NSCLC. Methods: Patients with stage
IIIB/IV non-small cell lung cancer with KRAS mutation who had received
prior chemotherapy for NSCLC began treatment with oral ridaforolimus 40
mg once daily on a 5 day/week schedule. After 8 weeks, patients with
�30% tumor shrinkage remained on ridaforolimus and patients with
�20% tumor growth discontinued treatment. Patients with stable disease
were randomized 1:1 to placebo or ridaforolimus. The primary endpoint of
the study was progression-free survival (PFS) after randomization. Results:
79 patients were enrolled (40 women, median age 58 [range 28-85]). The
overall response rate (CR�PR) at 8 weeks was 1/79 (1%, 95% CI 0-7%).
28 patients with stable disease at 8 weeks were randomized to ridaforolimus
or placebo. Median PFS based on investigator assessment from
randomization was significantly longer with ridaforolimus (4 months) than
placebo (2 months, p�0.013, HR 0.36). Median OS from randomization
was 18 months in the ridaforolimus treated arm and 5 months in the
placebo treated group, (HR 0.46, p�0.09). The most common grade �3
adverse events were fatigue (10%), mucositis/stomatitis (10%), pneumonia
(10%), dyspnea (9%), diarrhea (6%), and hyperglycemia (6%).
Conclusions: In patients with KRAS mutant NSCLC who had stable disease
after 8 weeks of ridaforolimus, ridaforolimus was associated with prolonged
progression-free survival. Further evaluation of ridaforolimus in this patient
population is warranted.
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