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

5504^ Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Safety and efficacy of panitumumab (pmab) in HPV-positive (�) and HPVnegative
(-) recurrent/metastatic squamous cell carcinoma of the head and neck
(R/M SCCHN): Analysis of the global phase III SPECTRUM trial. Presenting
Author: Jan Stoehlmacher-Williams, University Hospital Carl Gustav Carus,
Dresden, Germany
Background: SPECTRUM evaluated the safety and efficacy of pmab, a fully human
monoclonal antibody against the epidermal growth factor receptor, with platinumbased
chemotherapy (CT) vs CT alone in patients (pts) with R/M SCCHN. This
predefined analysis presents outcomes by tumor HPV status. Methods: All tumor
samples were centrally reviewed. HPV status was determined using a validated
immunohistochemistry assay to p16INK4A by an independent lab blinded to
treatment assignments. Tumor samples were scored positive or negative according
to prespecified criteria. Results: Of 657 enrolled pts (ITT), 443 (67%) had samples
evaluable for HPV testing. Ninety-nine (22%) tumors were HPV� and 344 (78%)
were HPV- . HPV� rates varied by site (37% oropharynx, 19% larynx, 15% oral
cavity, and 13% hypopharynx) and geographic region (44% N America, 22% W
Europe, 21% Asia Pacific, 19% S America, and 18% E Europe). Demographics
were generally balanced except pts with HPV� vs HPV- tumors were more often
non-smokers (31% vs 14%), had oropharyngeal tumors (47% vs 23%), and had
poorly differentiated tumors (30% vs 13%). Efficacy results are shown (Table).
Adverse events were generally balanced between HPV� and HPV- pts. Conclusions:
Pts with HPV- R/M SCCHN administered pmab � CT had improved overall survival
(OS) and progression-free survival (PFS), whereas no improvement in OS or PFS was
observed in pts with HPV� tumors.
ITT
(n�657)
HPV �
(n�99)
HPV -
(n�344)
OS
Events - %
HR
74 73 77
a (95% CI)
P value
0.87 (0.73-1.05) 1.00 (0.61-1.64) 0.76 (0.59-0.97)
b
0.14 0.98 0.02
Median OS (pmab �
CT vs CT) - mos
11.1 vs 9.0 11.0 vs 12.6 11.7 vs 8.6
QITP
PFS
0.253
Events - %
HR
86 91 90
a (95% CI)
p-value
0.78 (0.66-0.92) 1.21 (0.76-1.92) 0.67 (0.53-0.84)
b
0.004 0.43 0.001
Median PFS (pmab �
CT vs CT) - mos
5.8 vs 4.6 5.6 vs 5.5 6.0 vs 5.1
QITP
ORR ITT
(n�566)
0.068
c
HPV �
(n�88) c
HPV -
(n�297) c
ORR (pmab �
CT vs CT) - %
36 vs 25 44 vs 32 35 vs 27
P value odds ratio 0.007 0.27 0.13
Abbreviations: QITP, quantitative interaction test p-value; ORR, objective response rate.
a b c
Stratified hazard ratio. Stratified log-rank test p-value. Pts with baseline measurable
disease per modified RECIST 1.0.
5506 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
PD-1:PD-L1(B7-H1) pathway in adaptive resistance: A novel mechanism
for tumor immune escape in human papillomavirus-related head and neck
cancers. Presenting Author: Sofia Lyford-Pike, Johns Hopkins Medical
Institutions, Baltimore, MD
Background: Human papillomavirus-associated head and neck squamous
cell carcinomas (HPV-HNSCC) are associated with a strong host immune
response. Despite ample tumor infiltrating lymphocytes (TILs), the cancer
is able to persist and grow. Here, we provide evidence for an adaptive
immune resistance mechanism mediated through the PD-1:PD-L1 pathway.
Methods: We evaluated the peripheral blood and tumor infiltrating
lymphocytes for PD-1 expression using flow cytometry in HPV-HNSCC
patients. We evaluted PD-L1 expression within the tumors using immunohistochemistry.
We performed functional assays evaluating IFN-gamma
secretion of PD-1� and PD-1(-) CD8� T cells isolated from the tumor
microenvironment of PD-L1� and PD-L1(-) HPV-related head and neck
cancers. Results: We found the majority of CD8� TILs in HPV-HNSCC
express the PD-1 co-inhibitory receptor. We report a striking association
between expression of its ligand PD-L1 on tumor cells and tumor associated
macrophages, and the presence of TILs. Interestingly, membranous
PD-L1 staining on tumor cells and CD68� antigen presenting cells was
geographically localized to the periphery of tumor nests and juxtaposed to
fronts of infiltrating T cells. Functional assays demonstrated that PD-1dependent
T cell inhibition required expression of PD-L1 in the tumor
microenvironment. Finally, we report localized expression of PD-L1 in the
deep crypts of normal tonsils, the site of HPV infection and origin of
HPV-HNSCC. Conclusions: Our findings support the role of the PD-1:PD-L1
interaction in creating an immune-privileged site for initial viral infection
and subsequently adaptive immune resistance once tumors are established
and suggest a rationale for therapeutic blockade of this pathway in patients
with HPV-HNSCC.
Head and Neck Cancer
357s
5505 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in
patients with recurrent or metastatic (R/M) squamous cell carcinoma of the
head and neck (SCCHN): Final results of phase II trial GORTEC 2008-03.
Presenting Author: Joel Guigay, Department of Medical Oncology, Institut
Gustave Roussy, Villejuif, France
Background: Cetuximab in combination with platinum and 5FU (PFEx) has
become a standard in first-line treatment of patients (pts) with R/M
SCCHN. Cetuximab and taxane combinations have shown promising
activity. This multicenter phase II study evaluates the efficacy and safety of
cetuximab, docetaxel and cisplatin combination (TPEx) as first-line treatment
in pts with R/M SCCHN. Methods: Pts were required to have WHO PS
0-1, no prior systemic therapy for R/M SCCHN, cumulative dose of cisplatin
less than 300 mg/m² and no prior anti-EGFR therapy. Pts received
docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and cetuximab (400
mg/m² on day 1 of cycle 1 then 250 mg/m² weekly), repeated every 21 days
x 4 cycles then followed by cetuximab 500 mg/m² every 2 weeks (wks) as
maintenance therapy until disease progression or unacceptable toxicity.
G-CSF support with lenograstim 150 �g/m²/day was delivered after each
cycle of chemotherapy. Response was assessed every 6 wks, according to
RECIST. The primary endpoint was objective response rate (ORR) at 12
wks. Secondary endpoints were safety, best overall response, progressionfree
survival (PFS), overall survival (OS) and biomarkers. Results: 54 pts
have been enrolled: 52 males, median age 57.8years (28-69), 12 (22.2%)
oropharynx, 55% metastatic.48 pts could be evaluated for ORR at 12 wks:
partial response, stable disease and progression were respectively found in
23 pts (PR 47.9%), 21 pts (SD 43.7%) and 4 pts (PD 8.3%). Best overall
ORR was 54% (1 CR, 27 PR). The median PFS and OS were 7.1 and 15.3
months, respectively. The 1-year OS was 58.6%. Median PFS after start of
maintenance therapy was 4.2 months. Toxicity was manageable with
G-CSF support. Treatment related toxicities included G4 neutropenia
(n�3). Grade 3 events were skin rash (n�5), hypersensitivity reaction
(n�3), mucositis (n�1), fatigue (n�1) and febrile neutropenia (n�1).
Alopecia was common. 1 toxic death was related to sepsis on feeding tube.
Conclusions: Efficacy analysis demonstrates that TPEx regimen is effective
and might be a relevant substitute for PFEx as first-line treatment in fit pts
with R/M SCCHN.
5507 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Intra-arterial infusion of recombinant adenoviral human p53 gene combined
chemotherapy for advanced oral cancer: A phase II double-blind
randomized clinical trial. Presenting Author: Yi Li, Department of Head and
Neck Oncology, West China Hospital of Stomatology, Sichuan University,
Chengdu, China
Background: The p53 tumor suppressor gene has been shown as having
multiple anti-tumor functions and being capable of enhancing the efficacy
of chemo-therapy. This study is to investigates clinical outcomes of
intra-arterial infusion ofrecombinant adenoviral human p53 gene (rAdp53)
combined with chemotherapy in treatment of advanced oral cancer.
Methods: Ninety-nine patients with stage III or IV oral carcinoma, satisfying
with the inclusion criteria, were randomly allocated to Group I (G1: n�35;
rAd-p53 plus chemotherapy), Group II (G2: n�33; rAd-p53), or Group III
(G3: n�31; chemotherapy). Intra-artery infusion of rAd-p53 were given
through superficial temporal artery reverse intubation at a dose 1-4 �1012 viral particles (VP) , once every 3 days for 6 times. Chemotherapy regimen
consisted of oxaplatin 200 mg/m2 on day1, bleomycin 8 mg/m2 on day 2,
6, 8 and Methotrexate 30 mg/m2 on day1, 8, for squamous cell carcinoma
(SCC), and oxaplatin 200 mg/m2 on day1, 5-Fu 200 mg/m2 on day1,3 and
cyclophosphamide 400 mg/m2 on day2, 8 for adenoid cystic carcinoma
(ACC). Results: The complete response rate (CR) in G1 (48.5%) was
significantly higher than in G2 (16.7%) and G3 (17.2%). The overall
response rates (RR) were 88.6%, 54.5%, and 51.6% for G1, G2 and G3,
respectively. The 3-year overall survival (OS) of G1 (82.9%) was significantly
higher than the patients in G2 (60.6%) and G3 (58.1%). All those
patients receiving rAd-p53 had a self-limited fever. Positive Bax immunostaining
was detected in all the patients receiving rAd-p53. Conclusions:
Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent
an alternative to the current standard treatment for the late stage oral
carcinoma.
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