A randomized phase III trial (RTOG 0522) of concurrent
accelerated radiation plus cisplatin with or without
cetuximab for stage III-IV head and neck squamous cell
carcinomas (HNC).
Authors: Ang KK, Zhang QE, Rosenthal DI, Nguyen-Tan P, Sherman EJ, Weber RS, Galvin
JM, Schwartz DL, El-Naggar AK, Gillison ML, Jordan R, List MA, Konski AA, Thorstad WL,
Trotti A, BeitlerJJ, Garden AS, Spanos WJ, Yom SS and RS Alelrod
Reviewed by Dr. Stephanie Snow
ASCO 2011 abstract 5500 Oral Session June 6, 2011
Date posted: June 2011
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STUDY BACKGROUND
• Cisplatin based chemotherapy delivered concurrently
with radiotherapy is a standard of care for locally
advanced HNC of the oropharynx, hypopharynx and
larynx
• The EGFR monoclonal antibody, cetuximab, has also
been shown to improve OS when combined with
standard radiotherapy compared to standard
radiotherapy alone in this disease group
• Adding cetuximab to cisplatin chemotherapy has been
shown to improve outcomes in randomized trials the
recurrent/metastatic HNC setting:
– Cetuximab + Cisplatin = improved RR
– Cetuximab + 5FU/Platin = improved RR, PFS and OS
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Study Design
n = 895
Primary
Outcome:
Progression
Free Survival
Treatment A: concurrent delivery of:
Cetuximab 400 mg/m2 x1, then 250 mg/m2 /week
70-72 Gy/ 42 fractions over 6 weeks
Cisplatin 100 mg/m2 q3weekly x 2
R
Stage III-IV
(non-metastatic)
carcinoma of
the oropharynx,
larynx, or
hypophyarynx
PS 0-1
Treatment B: concurrent delivery of:
70-72 Gy/ 42 fractions over 6 weeks
Cisplatin 100 mg/m2 q3weekly x 2
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RESULTS
Treatment
A
Treatment
B
p-value
2 year
PFS (%)
63
64
NS
2 year
OS (%)
83
80
NS
Based on median follow up time of 2.4 years – early closure at 3rd interim
analysis because <10% chance study would be positive for the primary
endpoint . 337 (78%) of events had occurred.
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RESULTS
NB: p16 is a marker for HPV infection in HNC
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TOXICITY
Treatment
A
All
Treatment
A
Gr 3/4
Treatment
B
All
Treatment
B
Gr 3/4
Mucositis
81%
43%
72%
33%
Skin
Reactions –
In Field
77%
25%
79%
15%
Skin
Reactions –
Out of Field
80%
19%
14%
1%
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STUDY COMMENTARY
• The addition of cetuximab to the radiationcisplatin standard of care did not improve
progression free or overall survival
• The triplet regimen was associated with
higher rates of mucositis and skin
reactions
• This was a surprising result!!
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STUDY COMMENTARY
• Reasons why trial may not have been positive:
– Early reporting at 2.4 years:
• But only ~20% of events left to occur
– Drug under-delivery
• In treatment arm A, 26% subjects did not receive more than
five weeks of cetuximab
– Redundancy of MOA of radio-sensitization
– Study population: ~70% oropharyngeal primaries
• HPV status of oropharyngeal subjects – may have made up
as much as 50% of the study population if extrapolate from
the p16 data on those subjects with tissue available
• ? Cetuximab not effective in the p16 +ve population
• If so, there may still be a role for the combination in the p16
negative patient
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BOTTOM LINE FOR
CANADIAN MEDICAL ONCOLOGISTS
• Outside of the context of clinical trials, the
practice of using both cetuximab and
cisplatin concurrently with radiotherapy
has not been standard in Canada
• Thus these results will not change our
current standard of care
• Stay tuned for results from future trials that
will address the specific question of the
efficacy of EGFR inhibition in the HPV
positive HNC, e.g. RTOG 1016
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