Cetuximab plus Radiotherapy for Head and Neck Cancer Rena Callahan Journal Club UCLA Internal Medicine Faculty Discussant: Steven Wong

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck Bonner JA; Harari PM; Giralt J; Azarnia N; Shin DM; Cohen RB; Jones CU; Sur R; Raben D; Jassem J; Ove R; Kies MS; Baselga J; Youssoufian H; Amellal N; Rowinsky EK; Ang KK N Engl J Med. 2006 Feb 9 Volume 354(6):567-78.

Objectives Head and Neck Cancer The role of EGFR Cetuximab overview Trial overview Trial Discussion Future prospects

Head and Neck Cancer

The role of EGFR

Cetuximab overview

Trial overview

Trial Discussion

Future prospects

Head and Neck Cancer (HNC) 40,000 cases annually in U.S. >60% locoregionally advanced Males>Females African American>Whites Increased Risk: Tobacco and ETOH

40,000 cases annually in U.S.

>60% locoregionally advanced

Males>Females

African American>Whites

Increased Risk: Tobacco and ETOH

Head and Neck Anatomy

EGFR Cell surface growth regulator expressed by two-thirds of all human cancer cells Upregulated in 98% of HNC EGFR expression has prognostic significance (Ang 2002)

Cell surface growth regulator expressed by two-thirds of all human cancer cells

Upregulated in 98% of HNC

EGFR expression has prognostic significance

(Ang 2002)

EGFR

Cetuximab Recombinant human/mouse chimeric Monoclonal antibody vs EGFR Binds EGFR, HER1, c-ErbB-1 on both normal and tumor cells Blocks EGF and other ligand binding Binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases Inhibits cell growth, induction of apoptosis, and decreases matrix metalloproteinase and vascular endothelial growth factor production.

Recombinant human/mouse chimeric Monoclonal antibody vs EGFR

Binds EGFR, HER1, c-ErbB-1 on both normal and tumor cells

Blocks EGF and other ligand binding

Binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases

Inhibits cell growth, induction of apoptosis, and decreases matrix metalloproteinase and vascular endothelial growth factor production.

Cetuximab Adverse Events Infusion reactions acneform skin rash nail disorder

Infusion reactions

acneform skin rash

nail disorder

Cetuximab Rash

The Approval of Cetuximab

Treatment – Locally Advanced HNC Organ preservation Radiation vs. 5-yr survival 10-30% Chemo and Radiation vs. Chemoradiation Increased Survival (Brizel 1998, Wendt 1998, Calais 1999, Budach 2006) Increased Toxicity Severe mucositis 71% vs 39% (Calais 1999)

Organ preservation

Radiation vs.

5-yr survival 10-30%

Chemo and Radiation vs.

Chemoradiation

Increased Survival (Brizel 1998, Wendt 1998, Calais 1999, Budach 2006)

Increased Toxicity

Severe mucositis 71% vs 39% (Calais 1999)

Radiation Short doubling times in HNC Accelerated fractionation Same dose over shorter time Goal=prevent tumor repopulation Hyperfractionation Multiple, smaller doses, daily Increased total dose Goal=reduced toxicity

Short doubling times in HNC

Accelerated fractionation

Same dose over shorter time

Goal=prevent tumor repopulation

Hyperfractionation

Multiple, smaller doses, daily

Increased total dose

Goal=reduced toxicity

Radiation toxicity Acute mucositis, odynophagia, dysphagia, hoarseness, xerostomia, dermatitis, and weight loss Late Xerostomia, osteoradionecrosis, fibrosis, stricture, thyroid dysfunction, carotid stenosis/rupture

Acute

mucositis, odynophagia, dysphagia, hoarseness, xerostomia, dermatitis, and weight loss

Late

Xerostomia, osteoradionecrosis, fibrosis, stricture, thyroid dysfunction, carotid stenosis/rupture

Chemoradiation Rationale Radiosensitizers Targeting micrometastases Overcoming radioresistance 5-FU, cisplatin, carboplatin , taxane, MTX, mitomycin cetuximab

Rationale

Radiosensitizers

Targeting micrometastases

Overcoming radioresistance

5-FU, cisplatin, carboplatin , taxane, MTX, mitomycin

cetuximab

Chemoradiation-Toxicity Cisplatin Nausea/vomiting Nephrotoxicity Neuropathy Pulmonary fibrosis Myelosuppression

Cisplatin

Nausea/vomiting

Nephrotoxicity

Neuropathy

Pulmonary fibrosis

Myelosuppression

Staging TNM Any metastases=Stage IV Mets to lungs>liver>bone AJCC 2002

TNM

Any metastases=Stage IV

Mets to lungs>liver>bone

Karnofsky Score 100% - normal, no complaints, no signs of disease 90% - capable of normal activity, few symptoms or signs of disease 80% - normal activity with some difficulty, some symptoms or signs 70% - caring for self, not capable of normal activity or work 60% - requiring some help, can take care of most personal requirements 50% - requires help often, requires frequent medical care 40% - disabled, requires special care and help 30% - severely disabled, hospital admission indicated but no risk of death 20% - very ill, urgently requiring admission, requires supportive measures or treatment 10% - moribund, rapidly progressive fatal disease processes 0% - death.

100% - normal, no complaints, no signs of disease

90% - capable of normal activity, few symptoms or signs of disease

80% - normal activity with some difficulty, some symptoms or signs

70% - caring for self, not capable of normal activity or work

60% - requiring some help, can take care of most personal requirements

50% - requires help often, requires frequent medical care

40% - disabled, requires special care and help

30% - severely disabled, hospital admission indicated but no risk of death

20% - very ill, urgently requiring admission, requires supportive measures or treatment

10% - moribund, rapidly progressive fatal disease processes

0% - death.

Patients Stage III or IV, nonmetastatic Measurable disease Squamous Cell CA Oropharynx, hypopharynx, or larynx Karnofsky score >60% Normal hematopoetic, hepatic, renal function Life expectancy >1 year

Stage III or IV, nonmetastatic

Measurable disease

Squamous Cell CA

Oropharynx, hypopharynx, or larynx

Karnofsky score >60%

Normal hematopoetic, hepatic, renal function

Life expectancy >1 year

424 Patients High dose radiotherapy High dose Radiotherapy + Cetuximab randomized N=213 N=211 Phase III, Randomized, Multicenter Study Design

Exclusion Criteria Previous Cancer Chemo within last 3 years Previous surgery Previous radiation

Previous Cancer

Chemo within last 3 years

Previous surgery

Previous radiation

Treatment Radiation One of 3 regimens, chosen by investigator Concomitant boost, once-daily, or twice-daily Maximum of two 5-day treatment breaks +/- Cetuximab Started 1 wk prior to RT and continued through end Loading 400 mg/m2, then weekly 250 mg/m2

Radiation

One of 3 regimens, chosen by investigator

Concomitant boost, once-daily, or twice-daily

Maximum of two 5-day treatment breaks

+/- Cetuximab

Started 1 wk prior to RT and continued through end

Loading 400 mg/m2, then weekly 250 mg/m2

End Points Primary Duration of locoregional control Blinded review by independent committee Secondary Overall survival Progression-free survival Overall response rate Safety

Primary

Duration of locoregional control

Blinded review by independent committee

Secondary

Overall survival

Progression-free survival

Overall response rate

Safety

Statistical Analyses Required 208 pts per group for 90% power for primary end point Intention to treat Kaplan-Meier for time-to-event Cox regression methods for hazard ratios

Required 208 pts per group for 90% power for primary end point

Intention to treat

Kaplan-Meier for time-to-event

Cox regression methods for hazard ratios

Patient Characteristics

Results- Patients Balanced between both treatment groups with respect to- Compliance Type of RT chosen Subsequent neck dissections Subsequent salvage surgery Subsequent chemotherapy

Balanced between both treatment groups with respect to-

Compliance

Type of RT chosen

Subsequent neck dissections

Subsequent salvage surgery

Subsequent chemotherapy

Results-efficacy

Locoregional Control HR=.68; (95% CI .52 to .89)

Overall Survival HR=.74; (95% CI .57 to .97)

Results- Risk reduction Locoregional control at 3 years 47% in combination arm vs 34% Absolute Risk Reduction 13% NNT = 8 Overall survival at 3 years 55% in combination arm vs 45% Absolute Risk Reduction 11% NNT = 9

Locoregional control at 3 years 47% in combination arm vs 34%

Absolute Risk Reduction 13%

NNT = 8

Overall survival at 3 years 55% in combination arm vs 45%

Absolute Risk Reduction 11%

NNT = 9

Results-safety 13 patients discontinued cetuximab 4 due to hypersensitivity post 1 st dose 8 due to grade 3 rash Cetuximab did NOT add to radiation toxicities including mucositis, xerostomia, dyphagia, pain, (weight loss), decreased performance status

13 patients discontinued cetuximab

4 due to hypersensitivity post 1 st dose

8 due to grade 3 rash

Cetuximab did NOT add to radiation toxicities including mucositis, xerostomia, dyphagia, pain, (weight loss), decreased performance status

Results-safety

Study Limitations Lacked “standard of care” arm Different RT regimens Not site specific Results for hypopharyngeal subgroup Longer term data Quality of Life Data Need for PEG? Concomitant boost vs other RT Late complications

Lacked “standard of care” arm

Different RT regimens

Not site specific

Results for hypopharyngeal subgroup

Longer term data

Quality of Life Data

Need for PEG?

Concomitant boost vs other RT

Late complications

So, will this study change practice? Better survival with other chemoradiation regimens (Vokes 2003, Brizel 1998) But, better safety profile with cetuximab+XRT Consider for those with low performance status

Better survival with other chemoradiation regimens (Vokes 2003, Brizel 1998)

But, better safety profile with cetuximab+XRT

Consider for those with low performance status

Chemoradiation Studies Argiris A. Update on chemo radiotherapy for head and neck cancer . Curr Opin Oncol 2002;14:323-329.

Future Studies RT+cetuximab vs RT+platinum RT+cetuximab+chemotherapy+neoadjuvant chemotherapy Patterns of failure changing; distant vs local RT + Cetuximab + Chemotherapy Pfister 2006 Phase II trial, n=22 XRT + Cetuximab + Cisplatin 3 year OS 76%, PFS 56%, LRC 71% But, closed due to adverse events

RT+cetuximab vs RT+platinum

RT+cetuximab+chemotherapy+neoadjuvant chemotherapy

Patterns of failure changing; distant vs local

RT + Cetuximab + Chemotherapy

Pfister 2006

Phase II trial, n=22

XRT + Cetuximab + Cisplatin

3 year OS 76%, PFS 56%, LRC 71%

But, closed due to adverse events

Future studies Which agents are the best to combine with radiation? What is the role of adding targeted therapies? Is combination chemotherapy better than single-agent chemotherapy? Is altered fractionation better than conventional fractionation with CRT? Does induction chemotherapy provide additional benefit?

Which agents are the best to combine with radiation?

What is the role of adding targeted therapies?

Is combination chemotherapy better than single-agent chemotherapy?

Is altered fractionation better than conventional fractionation with CRT?

Does induction chemotherapy provide additional benefit?

Discussion- Cancer therapy trials Difficulty with true control arms Difficulty with blinding When the “gold standard” keeps changing

Difficulty with true control arms

Difficulty with blinding

When the “gold standard” keeps changing

References Adelstein DJ; Li Y; et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003 Jan 1;21(1):92-8. Al-Sarraf M; LeBlanc M; et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998 Apr;16(4):1310-7. Ang, KK et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62:7350. Brizel DM; Albers ME et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998 Jun 18;338(25):1798-804. Budach W et al. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer. 2006 Jan 31;6:28. Calais G; Alfonsi M et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999 Dec 15;91(24):2081-6. Cohen, EE, Lingen, MW, Vokes, EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 2004; 22:1743. Dassonville, O, Formento, JL, Francoual, M, et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993; 11:1873. Denis, F et al Final Results of the 94-01 French Head and Neck Oncology and Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma J Clin Oncol 2004 22: 69-76 El-Sayed, S, Nelson, N. Adjuvant and adjuvantive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14:838. Forastiere, AA et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349:2091. Jeremic, B, Shibamoto, Y, Milicic, B, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prosepective randomized trial. J Clin Oncol 2000; 18:1458. Kies MS; et al. Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival. J Clin Oncol 1998 Aug;16(8):2715-21. Pfister, DG, Su, YB, Kraus, DH, et al. concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006; 24:1072. Pignon JP et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000 Mar 18;355(9208):949-55. Posner, M et al Cetuximab and Radiotherapy for Head and Neck Cancer N Engl J Med 2006 354: 634-636 Wendt TG et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998 Apr;16(4):1318-24.

Adelstein DJ; Li Y; et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003 Jan 1;21(1):92-8.

Al-Sarraf M; LeBlanc M; et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998 Apr;16(4):1310-7.

Ang, KK et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62:7350.

Brizel DM; Albers ME et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998 Jun 18;338(25):1798-804.

Budach W et al. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer. 2006 Jan 31;6:28.

Calais G; Alfonsi M et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999 Dec 15;91(24):2081-6.

Cohen, EE, Lingen, MW, Vokes, EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 2004; 22:1743.

Dassonville, O, Formento, JL, Francoual, M, et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993; 11:1873.

Denis, F et al Final Results of the 94-01 French Head and Neck Oncology and Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma J Clin Oncol 2004 22: 69-76

El-Sayed, S, Nelson, N. Adjuvant and adjuvantive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14:838.

Forastiere, AA et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349:2091.

Jeremic, B, Shibamoto, Y, Milicic, B, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prosepective randomized trial. J Clin Oncol 2000; 18:1458.

Kies MS; et al. Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival. J Clin Oncol 1998 Aug;16(8):2715-21.

Pfister, DG, Su, YB, Kraus, DH, et al. concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006; 24:1072.

Pignon JP et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000 Mar 18;355(9208):949-55.

Posner, M et al Cetuximab and Radiotherapy for Head and Neck Cancer N Engl J Med 2006 354: 634-636

Wendt TG et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998 Apr;16(4):1318-24.