1. The document discusses several trials evaluating the addition of cetuximab, an EGFR inhibitor, to radiotherapy or chemoradiotherapy for squamous cell carcinoma of the head and neck. 2. The landmark Bonner trial showed improved locoregional control and overall survival when cetuximab was added to radiotherapy alone. 3. Subsequent trials like RTOG 0522 and TREMPLIN found no additional benefit when cetuximab was added to chemoradiotherapy, with increased toxicity. 4. For HPV-positive oropharyngeal cancer, trials like RTOG 1016, De-ESCALATE and TROG 12.01 found replacement

1. Radiotherapy and Cetuximab for Squamous
Cell Carcinoma of Head and Neck
Bonner trial and subsequent trials
Presenter: Dr. Namrata Das
Senior Resident, Radiation Oncology
Moderator: Dr. Ahitagni Biswas
Additional Professor, Radiation Oncology
13.08.2022

2. Outline
• Epidermal growth factor receptor (EGFR) inhibitors
• RT alone vs RT + Cetuximab: Bonner trial
• CRT vs CRT + Cetuximab: RTOG 0522
• Cetuximab in laryngeal preservation: TREMPLIN trial
• Cetuximab in HPV positive OPC: RTOG 1016, De-ESCALATE, TROG
• Other EGFR inhibitors: Panitimumab, Nimotuzumab
• Future directions

3. EGFR targeted therapy
• The family of ERBB or epidermal growth
factor (EGF) receptors includes four
members: EGFR/ERBB1, ERBB2, ERBB3
and ERBB4.
• EGFR and ERBB2: involved in
development of numerous types of human
cancer – pursued as targets for therapy
• Two types of EGFR inhibitors: (1)
antibodies directed against the
extracellular domain of EGFR (more
specific), (2) small-molecule tyrosine-
kinase inhibitors (TKIs) that compete with
ATP in the tyrosine-kinase domain of the
receptor Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005

4. EGFR Expression in Head and Neck cancer
• HNCs have high levels of
expression of EGFR and/or
other ERBB family proteins
• EGFR: biomarker of poor
prognosis
• EGFR: biomarker for resistance
to radiotherapy
Ang KK, Andratschke NH, Milas L. Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy. Int J Radiat Oncol Biol Phys. 2004

5. Cetuximab Nimotuzumab Panitimumab

6. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006 Feb 9;354(6):567-78.
• Multinational (USA, Europe), RCT
• Purpose: to compare radiotherapy alone with radiotherapy plus cetuximab in the
treatment of loco-regionally advanced (Stage III, IV) HNSCC (oropharynx, larynx,
hypopharynx)
• Recruitment: 1999-2002, published in 2006

7. Background
Surgery
Surgery +/-
Radiotherapy
Radiotherapy +/-
Surgery
+/- Chemotherapy
Radiotherapy +/-
+/- Chemotherapy
? Targeted Therapy
(EGFR inhibition)
• Loco-regionally advanced HNSCC: treatment paradigm has evolved over time
• Radiation increases EGFR expression + blockage of EGFR sensitizes cells to radiation: synergistic
effect
Pre-operative irradiation
in the treatment of
advanced laryngeal
carcinoma (1971)
Bryce DP, Rider WD et al, . Laryngoscope. 1971
Kramer S, Gelber RD, et al. Head Neck Surg. 1987
RTOG 73-03 (1987)
Altered fractionation
Concurrent
chemoradiation
Targeted therapy –
lesser toxicity that
chemotherapy with
similar efficacy?

8. Methods
Stage III, IV
HNSCC (oropharynx, hypopharynx, larynx)
n = 424
RT + cetuximab
RT only
• Median age: less than 60 years
• > 80 % were KPS 80 – 100 (ECOG 1)
• 60% were carcinoma oropharynx
• AJCC 5th edition staging
• EGFR staining not mandatory
• Both groups balanced

9. • Maximum of two five day treatment gaps allowed
• Quality assurance protocol for radiotherapy
defined
56%
18%
26%
Figure: Nguyen LN, Ang KK. Radiotherapy for cancer of the head and
neck: altered fractionation regimens. Lancet Oncol. 2002

10. Cetuximab Regimen:
• First dose: 1 week before RT initiation – 400 mg/m2
• Subsequent doses: weekly with radiotherapy – 250 mg/m2
• Premedication: H1 antagonist
• Discontinued if Grade 3, 4 hypersensitivity occurred

11. Statistical analysis
• Primary endpoint: locoregional control
• Locoregional progression: time from randomization to first documented progression,
recurrence of locoregional disease or death from any cause
• Sample size was calculated assuming addition of cetuximab increases locoregional control
from 44% to 57% at one year (90% power, 5% significance level, two sided log rank test,
sample size per group = 208)
• Assessment of response was done in the first year (after a minimum of 4 weeks): partial
response – at least 50% reduction in sum of bidimensional products of all measurable
lesions

12. Results
• Median duration of locoregional
control: 24 months in combined
therapy , 14.9 months in RT only
• 1yr LCR: 63% versus 55%
• 3 yr LCR: 47% versus 34%
• 32% reduction in risk of locoregional
progression

13. Results
• Median overall survival: 49 months in
combined therapy, 29 months in RT
only
• 2yr OS: 62% versus 55%
• 3 yr OS: 55% versus 45%
• 26% reduction in the risk of death in
the test arm

14. Best overall response
(complete and partial
response) favoured
cetuximab arm – 74% versus
64%, odds ratio:0.57 (CI:
0.35-0.90, p = 0.002)

15. • 4 patients discontinued
cetuximab after first dose, 9
others during the treatment
course (hypersensitivity)
• Acute adverse effects more
in the cetuximab group:
acneiform dermatitis, infusion
reactions
• Other acute reactions similar
• 20% late adverse effects in
each group

16. Discussion
• Addition of cetuximab to radiotherapy improves locoregional control, survival
• 10% absolute survival benefit at 3 years
• Not associated with excess of severe toxicity
• Potential to add it with altered fractionation schedules unlike chemotherapy
where there is a concern for added toxicity
• Potential for further gains when added to chemo-radiotherapy

17. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from
a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010
5 year survival update of the Bonner trial Lancet Oncol, 2010
Bonner et al.
• Median survival: 49
months in combined
therapy, 29 months in RT
only
• 5 yr OS: 45% versus 36%
• 27% reduction in the risk
of death in the test arm

18. Though not powered for
subgroup analysis:
oropharyngeal site, site of
study being the USA, KPS
90, younger age favoured
cetuximab arm more

19. Median survival: 69 months in patients with prominent rash (>= Grade 2) versus 25.6
months in patients with Grade 1 rash (HR: 0.49)
Onset of rash was within 35 days of treatment initiation in 95% patients

20. Since cetuximab does not cause additional
toxicity, can it be added to chemoradiation
regimes?

21. RTOG 0522
Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab
for Stage III to IV Head and Neck Carcinoma
JCO, 2014
Ang et al.
Locally advanced (Stage III, IV) HNSCC
N= 940
Arm A: Accelerated RT with
cisplatin
Arm B: Accelerated RT with
cisplatin, cetuximab
◊ RCT ◊ 940 patients ◊ Stage III, IV
HNSCC (oropharynx: 70% - 2/3rd HPV +ve,
larynx: 22%, hypopharynx: 7%)
◊Primary outcome: PFS
Treatment details:
1) RT: Accelerated – 72 Gy
over 42 fractions in 6 weeks
(C-boost) or 70 Gy over 35
fractions over 6 weeks (twice
a day, one day per week)
[86% IMRT, 13% 3D-CRT]
2) Cisplatin (100 mg/m2): D1,
D22
3) Cetuximab: Same as Bonner
trial

22. Results:
1) No difference in PFS, OS (3 years PFS: 61 v 59%; OS: 72% v 75%)
2) More frequent RT interruptions in Arm B (26% v 15%)
3) Increased G3, 4 acute toxicities (mucositis, rash, fatigue, anorexia, hypokalemia) in Arm B
4) 10 versus 3 treatment related deaths in Arm B
ADDITION OF CETUXIMAB TO RADIATION AND CISLATIN DOES NOT IMPROVE OUTCOME

23. TREMPLIN TRIAL
Induction Chemotherapy Followed by Either Chemoradiotherapy or
Bioradiotherapy for Larynx Preservation
JCO, 2013
Lefebvre et al.
◊ RCT ◊ Induction chemotherapy (IC)– Cisplatin, Docetaxel D1; 5-FU
D1-5
◊Primary outcome: 3 month Laryngeal Preservation (LP) rate ◊
Patients with < 50% response after IC: salvage surgery
Locoregionally advanced hypopharyngeal/laryngeal cancer
n = 153
Responders post induction chemotherapy (>50% response)
N = 116
Conventional RT + Cisplatin
(n=60)
Conventional RT +
cetuximab (n=56)
Result:
• Similar laryngeal
preservation rates between
both arms (95% v 93%)
• Laryngeal Function
Preservation: 87% versus
82%
• OS at 18 months: 92%
versus 89%
• Cumulative local failures:
(five [8.3%] v eight [14.3%],
respectively
• No difference in toxicity

24. Can Cetuximab replace chemotherapy in the
favourable HPV positive group?

25. RTOG 1016
Radiotherapy plus cetuximab or cisplatin for human papillomavirus (HPV)-
positive oropharyngeal cancer
Gillison et al.
Lancet 2019
◊ RCT ◊ 800 patients
◊HPV + OPC, T1-2, N2a-N3; T3-4, N0-3 (AJCC 7th)
◊End point: Overall survival, ◊2011-2014
HPV + OPC
N = 800
RT with three weekly
cisplatin
RT with cetuximab
Treatment details:
1) RT: Accelerated –70 Gy over
35 fractions over 6 weeks
(twice a day, one day per
week) by IMRT
2) Cisplatin (100 mg/m2): D1,
D22
3) Cetuximab: Same as Bonner
trial

26. Result:
• Non-inferiority of OS not
established
• 5 years OS: 77%
(cetuximab) v 84.6%
(cisplatin)
• No difference in acute, late
toxicity

27. RTOG 0129
Human Papillomavirus and Survival of Patients with
Oropharyngeal Cancer
Ang et al.
NEJM 2009

28. In view of excellent prognosis of low risk HPV positive OPC, will
replacing cisplatin with cetuximab lead to decreased symptom burden
and toxicity while maintaining equal efficacy?

29. De-ESCALATE
Radiotherapy plus cisplatin or cetuximab in low-risk human
papillomavirus-positive oropharyngeal cancer
Mehanna et al.
Lancet 2019
◊ RCT ◊ 334 patients
◊HPV + OPC, low risk: never smoker or pack years
<10 ◊ Overall grade 3-5 toxicity at 24 months
Low risk Oropharyngeal Cancer, n = 334
RT with three weekly
cisplatin
RT with cetuximab
Treatment details:
1) RT: 70 Gy over 35 fractions
over 5 weeks (twice a day,
one day per week) by IMRT
2) Cisplatin (100 mg/m2): D1,
D22, D43
3) Cetuximab: Same as Bonner
trial

30. Result:
• No difference in toxicity, QOL
• Reduced 2 yr OS: 97.5% (control) v 89.4 (cetuximab)
• Reduced 2 yr local control

31. TROG 12.01 IJORB, 2021
Rischin et al.
Low risk Oropharyngeal Cancer
RT with weekly cisplatin RT with cetuximab
◊ RCT ◊ 189 patients
◊Primary outcome: Symptom severity
assessed by M D Anderson Symptom
Inventory : baseline to 13 weeks post
treatment
Treatment details:
1) RT: 70 Gy over 35 fractions
over 7 weeks
2) Cisplatin (40 mg/m2): weekly
3) Cetuximab: Same as Bonner
trial

32. Result: No difference in symptom burden;
3 year freedom from progression: significantly reduced with cetuximab (80% versus 93%
with cisplatin)

33. Where do other EGFR inhibitors stand?

34. HN.6: Effect of Standard Radiotherapy With Cisplatin vs Accelerated
Radiotherapy With Panitumumab in Locoregionally Advanced Squamous Cell
Head and Neck Carcinoma
JAMA Oncol,
2017
Siu et al.
◊ RCT ◊ Preceded by Phase II CONCERT 1, 2
(negative trials)
◊ Stage III, IV HNSCC ◊ Primary outcome: PFS
Locally advanced HNSCC, n = 320
Conventional RT with 3 -
weekly cisplatin (3
cycles): Arm A
Accelerated RT +
Panitumumab (9 mg/kg
x 3): Arm B
Treatment details:
1) Arm A: Conventional
fractionation: 70 Gy over 35
fractions in 7 weeks
2) Arm B: Accelerated –70 Gy
over 35 fractions over 6
weeks (twice a day, one day
per week)
3) Cisplatin (100 mg/m2): D1,
D22
4) Panitumumab: 9mg/kg for 3
doses

35. Results:
1. 2 year PFS similar between
two groups (73 v 76%)
2. No difference in toxicity
3. Non-inferiority of Arm B
could not be established
PFS of panitumumab plus
accelerated-fractionation RT
was not superior to cisplatin
plus standard-fractionation
RT in LA-SCCHN and non-
inferiority was not proven

36. A Randomized Phase 3 Trial Comparing Nimotuzumab
plus Cisplatin Chemoradiotherapy Versus Cisplatin Chemoradiotherapy Alone
in Locally Advanced Head and Neck Cancer
Cancer, 2019
Patil et al.
◊ RCT ◊ Indian setting ◊ 2012-2018
◊ Stage III, IV HNSCC (50% OP, 17%
Hypo, 31% Larynx) ◊ Primary outcome:
PFS
Locally advanced HNSCC, n = 536
Conventional RT with
weekly cisplatin (30
mg/m2): CRT
Conventional RT with
weekly cisplatin (30 mg/m2)
+ Nimotuzumab (200 mg):
NCRT
Results:
1. 2 year PFS favoured NCRT
(61.8% v 50%, p = 0.004,
HR: 0.69)
2. 2 year OS improved but not
statistically significant –
longer FU required (63.8 v
57.7%)

37. Key points:
1. Reflects Indian population: low p16 positive
(15-22%), high tobacco smoking history
2. Trial had 50% OPC, 21% patients with
nodal ECE which in addition to point 1
might explain lower PFS rates as
compared to western data
3. Additional toxicity only increased G3
mucositis – did not lead to RT breaks
4. Option to add nimotzumab in centres giving
weekly cisplatin

38. Future directions

39. GORTEC 2015-01/ “PembroRad”:
Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in
locally advanced head and neck squamous cell carcinoma (LA-HNSCC)
Annals of
Oncology, 2020
Bourhis et al.
◊ Phase II ◊ Cisplatin ineligible ◊
◊ Stage III, IV HNSCC ◊ Primary outcome:
15 month locoregional control rate (LRC)
Locally advanced HNSCC, n = 131
RT + Cetuximab RT + Pembrolizumab
Treatment details:
1) RT: 69.96 Gy - IMRT
2) Pembrolizumab: 200 mg, 3 weekly with RT
3) Cetuximab: same as Bonner trial
Results:
1) LRC (15 month): 59% Cetux-RT arm, 60%
Pembo-RT arm (not significant)
2) Acute toxicity less in Pembro RT arm: 74% v
92% with at least one G3 toxicity
3) 2 yr PFS: 40% in Cetux-RT v 42% in Pembro RT
(no difference)
Compared to Cetuximab, concurrent Pembrolizumab
did not improve outcomes but appeared less toxic

40. Surgery
Surgery +/-
Radiotherapy
Radiotherapy +/-
Chemotherapy
Radiotherapy +/-
Chemotherapy
? Targeted Therapy
(EGFR inhibiton)
Radiotherapy +/-
Surgery
Chemotherapy +/-
EGFR inhibition
?Immunotherapy
Addition of concurrent immunotherapy to chemoradiation in locoregionally
advanced HNCC?
1. Avelumab: RCT where Avelumab was added to CRT – Javelin Head and Neck
100: negative trial with a paradoxical decrement in PFS (HR: 1.21) with
Avelumab
2. Pembrolizumab: Keynote 412 – preliminary analysis has shown no added
benefit

41. Conclusion
• Cetuximab based bioradiotherapy is not non-inferior to cisplatin based CRT (OS,
PFS, LRC) in HPV +ve low risk OPSCC
• Cetuximab based bioradiotherapy did not reduce the burden on acute, late severe
toxicities compared to cisplatin based CRT, particularly in HPV + low risk OPSCC
• Toxicity spectrum of cisplatin (nephrotoxicity, ototoxicity, CINV, dyselectrolytemia)
different from cetuximab (acneiform rash, infusion reaction, hypomagnesemia)
• Cisplatin ineligible patients (GFR < 50ml/min, allergy to platinum, mod-severe
SNHL): cetuximab is a valid alternative based on Bonner trial
• Substitution of Cetuximab with Pembrolizumab in cisplatin ineligible patients has
failed to augment PFS, LRC benefit

42. Thank you
Questions?