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

358s Head and Neck Cancer
5508 Clinical Science Symposium, Mon, 11:30 AM-1:00 PM
An international, double-blind, randomized, placebo-controlled phase III
trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma
(MTC) patients (pts) with documented RECIST progression at baseline.
Presenting Author: Patrick Schoffski, Department of General Medical
Oncology, University Hospitals Leuven, Leuven, Belgium
Background: MTC arises from parafollicular cells of the thyroid gland,
accounts for 5-8% of thyroid cancers and represents an unmet medical
need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET.
We conducted a phase III study of cabo vs placebo (P) in pts with
progressive, unresectable, locally advanced or metastatic MTC. Methods:
Eligible pts were required to have documented RECIST progression within
14 months of screening. The primary efficacy measure was progression-free
survival (PFS) as assessed by an independent review facility (IRF) using
RECIST. Secondary efficacy measures included objective response rate
(ORR) and overall survival (OS). The study has 90% power to detect a 75%
increase in PFS and 80% power to detect a 50% increase in OS. Tumor
assessments occurred every 12 weeks. Crossover between treatment arms
was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts
(median age 55 yrs; 67% male; 96% measureable disease; RET mutation
status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%,
no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base
[175 mg salt form] qd; n�219) or P (n�111). The planned primary PFS
analysis included events through the date of the 138th event. As of
15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving
study treatment. Statistically significant PFS prolongation of 7.2 mo was
observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28,
95% CI 0.19-0.40, p�0.0001). PFS results favored the cabo group across
subset analyses including RET status and prior TKI use. ORR was 28% for
cabo vs 0% for P (p�0.0001). An interim analysis of OS (44% of the 217
required events) did not show a difference between cabo and P. The most
frequent grade �3 adverse events (cabo vs P) were diarrhea (15.9 vs
1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs
2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%).
Conclusions: This phase III study met its primary objective of demonstrating
substantial PFS prolongation with cabo vs. P in a patient population with
MTC and documented progressive disease in need of therapeutic intervention.
5510 Clinical Science Symposium, Mon, 11:30 AM-1:00 PM
A molecular diagnostic panel for thyroid cancer disease management.
Presenting Author: Shih-min Cheng, Quest Diagnostics Nichols Institute,
San Juan Capistrano, CA
Background: In 2009, the American Thyroid Association revised its guidelines
for patients with thyroid nodules and differentiated thyroid cancers,
recommending BRAF, RAS, RET/PTC, and PAX8-PPAR� molecular testing
in patients with indeterminate fine-needle aspirate (FNA) cytology. Alterations
in any of these markers in thyroid nodules are strongly associated with
malignancy. We studied the prevalence of these alterations in thyroid FNA
specimens in order to establish a strategy to improve disease management.
Methods: DNA and RNA were extracted from thyroid FNA specimens
(N�149) and tested for BRAF mutations using allele-specific PCR (V600E
and K601E); for RAS (H-, K-, N-) mutations using pyrosequencing (codons
12, 13, and 61); and for RET/PTC1 and RET/PTC3 rearrangements and
PAX8-PPAR� translocations using RT-PCR. Results: Overall, 90 (60.4%) of
the specimens had alterations in �1 of the 4 molecular markers (Table).
BRAF V600E mutations (54.4%) were the most prevalent mutations in
papillary thyroid cancer (PTC); no K601E mutations were found. RAS
mutations were found in PTC, follicular adenoma (FA), and follicular
thyroid cancer (FTC) specimens; half of these mutations involved N-RAS
Q61. RET/PTC rearrangements were detected in 3.5% of PTC specimens
and were evenly distributed between the 2 major subtypes, RET/PTC1 and
RET/PTC3. PAX8/PPAR� translocations were detected in 18.8% of FTC
but not in FA, probably due to small sample size. Out of 7 indeterminate
thyroid nodules, 2 had BRAF mutations and 2 had RAS mutations. The
presence of the 4 markers was generally mutually exclusive; only 1 PTC
specimen had concurrent RAS and RET/PTC1 alterations. Conclusions: The
prevalence of BRAF, RAS, RET/PTC, and PAX8/PPAR� alterations in
thyroid cancer specimens highlights the potential for targeted therapeutic
strategies. The mutually exclusive pattern of alterations also suggests a
hierarchical screening strategy for samples with limited availability.
Prevalence of marker alterations in thyroid FNA specimens (NT � not
tested).
Diagnosis #
BRAF
(%)
RAS
(%)
RET/PTC
(%)
PAX8/PPAR�
(%)
Total
(%)
PTC 114 62 (54.4) 11 (9.6) 4 (3.5) NT 77 (67.5)
FA 12 NT 2 (16.7) NT 0 2 (16.7)
FTC 16 NT 5 (31.3) NT 3 (18.8) 8 (50%)
Indeterminate 7 2 (28.6) 2 (28.6) 0 0 4 (57.1)
5509^ Clinical Science Symposium, Mon, 11:30 AM-1:00 PM
Reacquisition of RAI uptake in RAI-refractory metastatic thyroid cancers by
pretreatment with the MEK inhibitor selumetinib. Presenting Author: Alan
Loh Ho, Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Therapies for radioactive iodine (RAI)-refractory thyroid cancers
of follicular origin (TC-FCO) are desperately needed. TC-FCO mouse
models show that blocking mitogen-activated protein kinase (MAPK)
signaling with a MAP kinase kinase 1/2 (MEK1/2) inhibitor increases
sodium iodide symporter expression and iodine incorporation. This 20
patient (pt) pilot study aimed to evaluate if the MEK1/2 inhibitor selumetinib
(AZD6244, ARRY-142866) can reverse RAI-refractoriness in
TC-FCO pts (NCT00970359). Methods: RAI-refractory TC-FCO disease was
defined as: 1) non-RAI-avid lesion/s on a diagnostic or post-therapy RAI
scan, 2) RAI-avid lesion/s that was stable or increased in size after RAI
therapy, or 3) fluorodeoxyglucose (FDG)-avid lesion/s by positron emission
tomography (PET) scan. rhTSH-stimulated lesional dosimetry with 124I PET
was performed prior to and after 4 weeks of treatment with selumetinib (75
mg orally bid). If the second 124I PET scan predicted a lesional RAI dose of
� 2000 cGy, therapeutic RAI was administered while on the drug. Primary
endpoints were to evaluate changes in tumor iodine uptake and RECIST
response after RAI therapy; changes in serum thyroglobulin (TG) after RAI
was a secondary endpoint. Results: 24 pts were enrolled, 22 eligible, and
20 evaluable. For the 20 evaluable pts, median age was 61 (range 44-77
yrs), 11 were men. 19 pts had tumors analyzed for BRAF and N-,K- RAS
mutations. 8 pts had BRAF mutant (MUT), 11 BRAF wild-type (WT)
tumors; 1 pt to be analyzed. Selumetinib increased 124I uptake in 12 of the
20 pts (4 of 8 BRAF MUT; 8 of the 12 other pts). The 8 of those 12 pts
achieving sufficient iodine avidity to warrant RAI therapy included all 5 pts
known to be NRAS MUT to date and 1 BRAF MUT pt. Of the 7 pts who have
received RAI, 5 had partial responses (PRs); 2 stable disease (SD). Mean
percent reduction in TG in this group (pre- vs 2 months post- RAI) was
91%. No � grade 2 CTCAE toxicities attributable to selumetinib were
observed. 1 pt was diagnosed with myelodysplastic syndrome � 51 weeks
after RAI (unrelated to selumetinib). Conclusions: Selumetinib can enhance
iodine uptake in a subset of RAI-refractory TC-FCO and may be
particularly effective for RAS MUT tumors.
5511 Poster Discussion Session (Board #1), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
A multicenter randomized controlled trial (RCT) of adjuvant chemotherapy (CT)
in nasopharyngeal carcinoma (NPC) with residual plasma EBV DNA (EBV DNA)
following primary radiotherapy (RT) or chemoradiotherapy (CRT). Presenting
Author: Anthony T. C. Chan, Department of Clinical Oncology, Prince of Wales
Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
Background: The benefit of adjuvant CT in NPC is unclear. Administering CT after
full-dose CRT presents challenges in treatment compliance and toxicity. Post-RT
EBV DNA predicts poor survival and may be a biomarker of subclinical residual
disease. We conducted a biomarker driven RCT using EBV DNA to select high
risk NPC patients (pts) for adjuvant CT while sparing low risk pts from
unnecessary toxicity. Methods: Biopsy proven NPC, AJCC stage IIB-IVB, detectable
EBV DNA at 6-8 wks post-RT, no persistent locoregional disease or distant
metastasis, ECOG 0 or 1, adequate organ function. Randomised with stratification
for primary therapy (RT Vs CRT) and tumor stage (II/III Vs IV) to arm A
(adjuvant cisplatin 40 mg/m2 and gemcitabine 1000mg/m2, both given on
D1�8 q3w x 6 cycles) or arm B (clinical follow-up). EBV DNA and PET scan were
performed before and 6 months after randomization. Primary endpoint was
relapse free survival and secondary endpoints included toxicity of adjuvant CT.
With a hazard ratio of 2, 100 pts were required with a power of 0.8 and an alpha
at 0.05. This safety analysis was approved by DMSC. Results: From 9/2006 to
12/2011, 514 pts consented for EBV DNA screening, 95 with detectable EBV
DNA consented for adjuvant study. After work-up, 74 were eligible for randomization
(37 to arm A; 37 to arm B). The two arms were well balanced in baseline
characteristics. 80% received prior neoadjuvant and/or concurrent CT. Staging:
IIB (36.5%), III (29.7%), IVA (18.9%), IVB (14.8%). Five pts refused adjuvant
CT after randomization. Overall 65% and 57% completed 5 and 6 cycles
respectively. Mean dose intensity (DI): 84% for cisplatin (22.5 mg/m2/wk, range
0.0-26.7), 92% for gemcitabine (612.8 mg/m2/wk, range 333.3-777.8).
Treatment related adverse events above CTC G2 were summarized in Table.
Conclusions: Delivery of 6 cycles of adjuvant CT is feasible with acceptable
toxicity after full dose RT or CRT.
Events (No) G3 G4 G5
Non-hematological
Bleeding 1 1
Electrolytes 2 1
Fatigue 1
Hearing 3
Infection 1
Mucositis 1
syncope 2
Weight loss 1
Hematological
Febrile neutropenia 1
Hemoglobin 10
Neutrophils 14 10
Platelets 2
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