THERAPIES FOR HEAD AND NECK CANCERS

KAREN A. VILLANUEVA M.D. FPCP, FPSMO CONSULTANT MANILA DOCTORS HOSPITAL ASIAN HOSPITAL AND MEDICAL CENTER

ONCOLOGY Drug Development

Steps in cancer drug development
Identify Candidate Compounds Screening Preclinical Evaluation Production and Formulation Toxicology Pharmacology Biochemistry

Phase I, II, III, IV Clinical Trials General Medical Practice

Cytotoxics Molecular

targeted

treatment

CYTOTOXICS

Phase nonspecific
1. Cycle-nonspecific- kill non dividing cells 2. Cycle specific, phase nonspecific- are effective only if the cells proceed through the generation cycle, but they can inflict injury at any point in the cycle

Phase specific - are effective only if present during a particular phase of the cycle

ONCOLOGY Principles of Chemotherapy

Antibiotics Antimetabolites
S (2-6h) G2 (2-32h) M (0.5-2h) Vinca alkaloids

Action sites of cytotoxic agents

Mitotic inhibitors Taxoids

Alkylating agents

Cell cycle level

G1 (2-h)

G0

Classification of cytotoxic agents

Alkylating Agents AntiMetabolites Mitotic Inhibitors Antibiotics Others

ONCOLOGY Principles of Chemotherapy

Busulfan Carmustine Chlorambucil Cisplatin Cyclophosphamide Ifosfamide Melphalan

Cytosine Arabinoside Floxuridine Fluorouracil Mercaptopurine Methotrexate

Etoposide Teniposide Vinblastine Vincristine Vindesine Taxoids

Bleomycin Dactinomycin Daunorubicin Doxorubicin Mitomycin-c Mitoxantrone Plicamycin

L-asparaginase Hydroxyurea Procarbazine

ONCOLOGY Principles of Chemotherapy

Aim of combination therapy

INCREASED EFFICACY

ACTIVITY
Different mechanisms of action Different mechanisms of resistance

SAFETY
Compatible side effects

Medical therapies in head

and neck cancers

MTX

5FU

Cisplatin

Taxanes Anthracycline

Biotherapies targeted therap.

Bleomycin Mitomycin Vinblastin Oncovin

1960

1980

2000

Alkylating Agents
Target DNA Causes cross-linking of DNA strands Cytotoxicity is probably a result of damage to DNA templates Cell cycle specific but not phase specific

CISPLATIN

Platinum agent MOA:Binds and crosslinks DNA strands Toxicity: - cumulative renal insufficiency - peripheral sensory neuropathy - ototoxicity

Cont. - severe nausea and vomiting - hypokalemia, hypomagnesemia Administered through IV infusion Antiemetics and hydration are very important Metabolites are excreted in the urine

CARBOPLATIN
Platinum agent MOA: covalent binding to DNA Toxicity: - myelosuppression - nausea and vomiting - less nephrotoxic than cisplatin IV infusion Metabolized in the urine

Antimetabolites
Fluorouracil

MOA: Interferes with DNA synthesis by blocking thymidylate synthethase. Interferes with RNA function and protein synthesis. Cell cycle S phase specific

Toxicity: myelosuppression mucositis diarrhoea vein pigmentation hand foot syndrome

Administered as IV push or IV infusion Usually given in combination with leucovorin in other regimens Drug degradation occurs in the liver

GEMCITABINE

Gemzar MOA: cytidine analog that inhibits ribonucleotide reductase IV infusion Myelosuppression, nausea, vomiting Nearly entirely excreted in the urine

Mitotic Spindle Agents

These drugs bind to microtubular proteins, thus inhibiting microtubule assembly and resulting in dissolution of the mitotic spindle structure. Promote microtubular resistance to depolymerization, resulting in the production of non functional microtubules. Cell cycle M phase specific

PACLITAXEL

Taxoids Taxol MOA: Anti-microtubules resulting to mitotic arrest Toxicity: neutropenia anaphylactic shock myelosuppression nausea and vomiting

neuropathy alopecia arthralgias and myalgias Administered as IV infusion over 3-24 hours Premedicate with steroids, H2 receptor antagonist, anti histamine Special filtered tubing is required

DOCETAXEL Taxoids Taxotere MOA: Anti-microtubules resulting to mitotic arrest Toxicity: Anaphylaxis fluid retention

myelosuppression nausea and vomiting stomatitis Administered as IV infusion over 1 hour Premedicate with dexamethasone one day before until one day after Majority are excreted in the feces

A phase III trial of docetaxel, cisplatin and 5fluorouracil (TPF) vs. cisplatin and 5-fluorouracil (PF) induction chemotherapy followed by chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) TAX 324 Posner MR et al. Special Session (Oral)

TAX 324: study design

3 x TPF q3w
Locally advanced SCCHN: organ preservation, resectable with low curability, unresectable Carboplatinum

T Taxotere P Cisplatin F 5-FU

75 mg/m2 100 mg/m2 1000 mg/m2

D1 D1 D15

AUC 1.5 weekly

3 x PF q3w D1 P Cisplatin 100 1000 mg/m2 D15 F 5-FU mg/m2

Daily radiotherapy

TAX 324: overall survival

100 90 80 Survival probability (%) 70 60

Log-rank p=0.0058 Hazard ratio=0.70

50
40 30 20 10 0 0 TPF: PF:
255 246

TPF (n=255) PF (n=246)

6
234 223

12
196 169

18
176 146

24
163 130

Number of patients at risk

30 36 42 Survival time (months)

136 107 105 85 72 57

48
52 36

54
45 32

60
37 28

66
20 10

72
11 7

TAX 324: authors conclusions

TPF is the most effective combination regimen for induction chemotherapy

TPF regimens improve survival and engender less toxicity in locally advanced SCCHN, compared with PF

TPF is now the standard of care for induction chemotherapy TPF is the appropriate platform for curative therapy, to which new molecularly targeted therapies should be added

Targeted treatment for head and neck cancers

EGFR expression in selected human tumors

Tumor type Head and neck Colon Prostate Pancreatic Breast Renal Cervix % of tumors expressing EGFR (range) 90 100% 75 89% up to 100% up to 95% up to 91% up to 90% up to 82%

Non-small cell lung cancer Ovarian

Bladder Primary glioblastoma

up to 80% up to 77%
up to72% up to 63%

EGFR expression is associated with poor prognosis

The EGFR is expressed in 90-100% of head

and neck cancers

EGFR expression is associated with:

Reduced disease-free survival Reduced overall survival An increased risk of metastasis/invasion

in a number of different solid tumor types, including head and neck cancer

EGFR inhibition via Monoclonal Antibodies

EGFR signaling

Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.

Cetuximab (ERBITUX)
Mode of action

ERBITUX

ERBITUX Characteristics
ERBITUX is an IgG1 monoclonal antibody (MAb)

ERBITUX comprises four polypeptide chains: two identical heavy and two identical light chains

ERBITUX targets the human EGFR with a higher affinity than its natural ligands (TGF-, EGF), thus competitively inhibiting their binding

ERBITUX promotes the internalization and degradation of EGFR, leading to down regulation of cell surface receptors and reduced receptor signaling

Toxicity: myelosuppression nausea and vomiting acne like rash Administered as IV infusion over 2 hours

ERBITUX Summary of clinical studies in head and neck cancer

Phase Locally advanced SCCHN Recurrent and/or metastatic SCCHN (first-line) I / III III Treatment - ERBITUX + radiotherapy + chemotherapy Studies Robert 2001; Bonner 2006 Burtness 2005

Recurrent and/or metastatic SCCHN progressing on platinum

Recurrent and/or metastatic nasopharyngeal carcinoma

II

+ chemotherapy

Trigo 2004; Baselga 2005; Herbst 2005

Chan 2005

II

+ chemotherapy

Current treatment standards in locally advanced SCCHN

Radiotherapy only

Erbitux + Radiotherapy

Chemotherapy + Radiotherapy

RT + Erbitux in locally advanced SCCHN

Erbitux in locally advanced SCCHN: Bonner Phase III study

RT + Erbitux (n=211)

Stage III and IV non-metastatic SCCHN

N=424

Erbitux initial dose (400 mg/m2) Erbitux (250 mg/m2) + RT (wks 28)

RT (n=213)

Primary endpoint: duration of locoregional control

Secondary endpoints: OS, PFS, RR, QoL, and safety

Bonner et al. NEJM 2006

Erbitux in locally advanced SCCHN: Significant benefit in locoregional control

100

RT + Erbitux RT
HR=0.68 [95% CI: 0.520.89] p=0.005

80

3-year control rate

Locoregional control (%)

60

24.4 months
14.9 months

47%

40

20

34%
0 10 20 30 40 50 60

Months
Bonner et al. NEJM 2006

Erbitux in locally advanced SCCHN:

5-year survival update

100 90 80 70 60

RT + Erbitux RT
HR=0.73 [95% CI: 0.560.95] p=0.018

5-year survival rate 46%

49.0 months

Overall survival (%)

50 40

30
20 10 0 0 10

29.3 months 36%

20

30

40

50

60

70

Months
Bonner et al. Lancet Oncol 2010

Erbitux in locally advanced SCCHN: Skin rash correlates with survival

100 90 80 70 Grade 24 rash group (n=127)

Grade 0/1 rash group (n=81)

HR=0.49 (95% CI: 0.340.72) p=0.002

Probability of survival (%)

60 50 40

30
20 10 0 0 10

25.6 months

> 68.8 months

20

30

40

50

60

70

Months
Bonner et al. Lancet Oncol 2010

Erbitux in locally advanced SCCHN

Adding Erbitux to RT has proven to significantly

Prolong survival Control disease longer Increase response rate

Erbitux in metastatic or recurrent SCCHN

CT plus Erbitux in 1st-line SCCHN:

Consistent efficacy regardless of CT type
ORR (%)
20 36* 10 26* 36 Author Vermorken 2008 Burtness 2005 Bourhis 2006 Phase III N 442 Regimen PF PF + Erbitux Cis + Placebo Cis + Erbitux PF + Erbitux

Median PFS (months)

3.3 5.6* 2.7 4.2 5.1a

Median OS (months)
7.4 10.1* 8.0 9.2 9.8

III
I/II

117
53

Hitt 2007
Buentzel 2007

II
II

42
23

Pacli + Erbitux
Pacli/Carbo + Erbitux

60
56

5.0
5.0a

NRb
8.0

*Statistically significant aTTP: bMedian OS not reached after a median follow-up of 5.6 months
Vermorken et al. NEJM 2008; Burtness et al. JCO 2005; Bourhis et al. JCO 2006; Hitt et al. ASCO 2007; Buentzel et al. ASCO 2007

st-line 1

SCCHN: EXTREME trial

Erbitux in 1st-line SCCHN EXTREME: Phase III study design

N=442

r/m SCCHN
Prior CT KPS (<80 vs 80)

CT + Erbitux

Erbitux until PD

CT
Erbitux Initial dose 400 mg/m2 then 250 mg/m2 weekly until progressive disease (PD)

CT Cisplatin (100 mg/m2 IV, day 1) or Carboplatin (AUC 5, day 1) + 5-FU (1000 mg/m2 IV, days 14) Every 3 weeks, up to 6 cycles

Primary endpoint: OS Secondary endpoints include: PFS, RR, safety

Vermorken et al. NEJM 2008

Erbitux in 1st-line SCCHN EXTREME: Significant RR benefit

Adding Erbitux almost doubles RR
40

36
OR=2.33 (95% CI: 1.503.60) p<0.001

Response rate (%)

30

20
20 10 0 CT (n=220)
CR: complete response

CR=0.9

CR=6.8
CT + Erbitux (n=222)
Updated from Vermorken et al. NEJM 2008

Erbitux in 1st-line SCCHN EXTREME: significant PFS benefit

100 90 80

CT (n=220) CT + Erbitux (n=222) HR=0.54 (95% CI: 0.430.67) p<0.001

Progression-free survival (%)

70 60 50 40 30 20 10

5.6 months 3.3 months

+ 2.3 months

0 0 3 6 9 12
15
Vermorken et al. NEJM 2008

Months

CT + Erbitux in
Significantly improves OS
Significantly increases PFS Almost doubles RR

st-line 1

SCCHN

Adding Erbitux to platinum-based CT

CT + Erbitux is feasible in SCCHN patients

Benefit of Erbitux regardless of known biomarkers CT + Erbitux is the standard in 1st-line SCCHN

Cetuximab Plus Platinum-Based Chemotherapy

Progress under platinum 15 October 1998

One cycle cetuximab + platinum 9 November 1998

Summary of Treatments
Squamous Cell Carcinoma ( Maxillary, Ethmoid, Lip, Oral, Oropharynx, Hypopharynx, Glottic, Larynx, Supraglottic, Occult Primary ) 1. Primary Systemic with concurrent RT - Cisplatin alone - Cis-infusional 5FU

- 5FU - Cis-Pacli

- Carbo-infusional 5FU - Cetuximab -Nimotuzumab

2. Post op chemo-RT - Cisplatin alone 3.Induction followed by chemo-RT - Docetaxel -Cisplatin -5FU

Nasopharyngeal CA - Cisplatin with RT followed by Cisplatin and 5FU

THANK YOU