1. 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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3. 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

4. R Study Design Treatment A: concurrent delivery of:
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
Treatment B: concurrent delivery of:
70-72 Gy/ 42 fractions over 6 weeks
Cisplatin 100 mg/m2 q3weekly x 2
Stage III-IV
(non-metastatic)
carcinoma of
the oropharynx,
larynx, or
hypophyarynx
PS 0-1

5. RESULTS 63 64 NS 83 80 2 year PFS (%) OS (%) Treatment A B p-value
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 (78%) of events had occurred.

6. RESULTS
NB: p16 is a marker for HPV infection in HNC

7. Skin Reactions – In Field Skin Reactions – Out of Field
TOXICITY
Treatment A
All
Gr 3/4 B
Mucositis
81%
43%
72%
33%
Skin Reactions – In Field
77%
25%
79%
15%
Skin Reactions – Out of Field
80%
19%
14% 1%

8. STUDY COMMENTARY
The addition of cetuximab to the radiation-cisplatin 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!!

9. 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

10. CANADIAN MEDICAL ONCOLOGISTS
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