Defining the Role of Cetuximab in Treatment of Head and Neck Squamous Cell Carcinoma

1
Defining the Role of Cetuximab in Treatment of
Head and Neck Squamous Cell Carcinoma

• James C. Mosley, III, M.D.

2
Introduction

• Squamous Cell Carcinoma of the head and neck
  (HNSCC) accounts for 45,000 cancer diagnoses in
  the US each year, with 11,000 deaths
• Disease is potentially curable at an early stage
• However, many patients (60) present with
  advanced disease
• Of patients with locally advanced disease
  (LA-HNSCC), less than 50 live for 3 years with
  standard therapies (surgery and XRT)
• Also, locoregional recurrences and distant
  metastases (R/M HNSCC) occur in 40-60

3
Introduction

• Over the last 30 years, treatment paradigms for
  HNSCC have changed from surgery and irradiation,
  to include medical oncology
• The exact timing and role of chemotherapy remains
  to be determined
• These combinations have been met with varying
  degrees of success, but are sometimes complicated
  by dose-limiting toxicities
• Recently, great interest has arisen for the use
  of targeted agents in many solid tumors

4
Introduction

• Based on a large body of preclinical
  investigations, use of the EGFR-inhibitor
  cetuximab has become more widespread in HNSCC
• However, questions about who, when, and how to
  administer remain

5
Epidermal Growth Factor Receptor (EGFR)

• Transmembrane growth factor receptor with
  Tyrosine Kinase (TK) activity, belonging to
  erbB/Her family (erbB1/Her1)
• In response to ligand binding, EGFR dimerizes
  stimulating TK activity in the intracellular
  domain
• Phosphorylation of the tyrosine residues results
  in downstream signaling through various pathways,
  resulting in control of cellular proliferation
  and survival

Harari, J Clin Oncol 2007, 25 4057-4065
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Fig 1. Network of epidermal growth factor
receptor (EGFR) interactions with downstream
signaling pathways
Harari, P. M. et al. J Clin Oncol 254057-4065
2007
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EGFR Role in HNSCC

• EGFR frequently overexpressed in HNSCC
• 80-90 of HNSCC tumors display aberrant
  expression
• Several groups have evaluated relationship to
  EGFR expression and surivival
• Correlated with poor prognosis
• Level of expression not correlated with response
  to cetuximab

Panikkar, Cancer Invest 2008, 26 96-103
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ASCO Virtual Meeting 2005
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Cetuximab

• Chimeric monoclonal IgG1 antibody to the
  extracellular binding domain of EGFR
• Stimulates receptor internalization and
  down-regulation from the cell surface
• Also induces ADCC
• No clear molecular markers to predict response in
  HNSCC have been identified
• EGFR mutational status does not appear to be
  significant factor in HNSCC

Gebia, Annals of Oncology 2007, 18 s6,
vi5-vi7 Panikkar, Cancer Invest 2008, 26 96-103
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LA-HNSCC

• Therapy has evolved over many years from
  primarily surgery to XRT to now the inclusion of
  chemotherapy
• Combination of chemotherapy with XRT (CRT) has
  demonstrated increased benefit at a cost of
  potentially prohibitive toxicities
• In some patients with unresectable disease,
  resection can be accomplished after induction
  therapy
• Others may be spared from potentially disfiguring
  procedures with current therapies
• Cetuximab has been evaluated in combination with
  XRT, CRT, and Induction therapies

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Cetuximab XRT

• Early pre-clinical studies demonstrated that
  cetuximab had radio-sensitizing properties in
  cell culture and xenograft assays
• A phase I study of cetuximab and XRT demonstrated
  objective responses in all patients treated, as
  well as very manageable side effect profile
• In 2006, Bonner et al. reported a randomized
  phase III multinational study of patients with
  LA-HNSCC receiving RT alone versus RT cetuximab.

Bonner, NEJM 2005, 354 567-78
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UAB-9901

• 424 patients randomized to receive XRT alone
  (213) versus XRT with cetuximab (211)
• Cetuximab given as 400 mg/m2 loading dose one
  week prior to XRT, followed by 250 mg/m2 weekly
  for duration of XRT (400/250)
• Primary endpoint was duration of LRC
• Secondary endpoints were OS, PFS, ORR and safety

Bonner, NEJM 2005, 354 567-78
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UAB-9901 Study Design
HNC Update, Vol 1 Issue 1 2007
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Bonner, NEJM 2005, 354 567-78
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Bonner, NEJM 2005, 354 567-78
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Bonner, NEJM 2005, 354 567-78
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UAB-9901 Results

• Median duration of LRC was 24.4 months for
  combined therapy versus 14.9 months for XRT alone
  (p0.005) a 32 reduction in risk for
  locoregional progression
• Median OS was 49 months for combined therapy
  versus 29.3 months for XRT alone (p0.05)
• Only difference in toxicity was rash and infusion
  reactions
• There was significant benefit with addition of
  cetuximab to radiation, with minimal increase in
  adverse events

Bonner, NEJM 2005, 354 567-78
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UAB-9901 Results

• Post hoc analysis demonstrated greatest benefit
  in OP tumors
• Median LRC was 49 months with combined therapy
  compared to 23 months with XRT alone
• Hypopharyngeal tumors demonstrated a median LRC
  of only 12.5 months with combined therapy versus
  10.3 months with XRT alone
• Laryngeal cancers demonstrated median LRC of 12.9
  months with combined therapy versus 11.9 months
  with XRT alone
• There was also a difference seen with XRT used
• Since the inception of this trial, phase III data
  has emerged demonstrating superiority of
  cisplatin XRT versus XRT alone which is now
  the standard of care

Panikkar, Cancer Invest 2008, 26 96-103
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UAB-9901 Results

• These findings pose interesting questions
• Should we stratify our use of cetuximab in
  combination with XRT based on tumor location?
• What is the optimal radiation schedule for use in
  this setting?
• What about the combination of cetuximab with
  chemoradiotherapy (CRT)?

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Cetuximab CRT

• Pfister et al. evaluted a phase II study of
  cetuximab in combination with cisplatin XRT for
  LA, non-metastatic HNSCC
• Patients received concomitant boost XRT, with
  cisplatin on weeks 1 and 4 and weekly cetuximab
  for 10 weeks
• 22 patients were enrolled in 2000, 21 received
  treatment
• Accrural was halted early due to 2 deaths and 3
  significant AEs in short succession

Pfister, J Clin Oncol 2006, 24 1072-8
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Cetuximab CRT

• Despite halted accrual and 2 grade 5 events,
  3-year OS was 76 with median follow-up of 52
  months
• median OS not yet reached
• 3-year PFS was 56
• 3-year LRC was 71
• AEs leading to halting of accrual are unlikely a
  result of the therapies given

Pfister, J Clin Oncol 2006, 24 1072-8
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(No Transcript)
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Cetuximab CRT

• Despite halted accrual and 2 grade 5 events,
  3-year OS was 76 with median follow-up of 52
  months
• median OS not yet reached
• 3-year PFS was 56
• 3-year LRC was 71
• AEs leading to halting of accrual are unlikely a
  result of the therapies given
• Would these findings hold true in a larger series?

Pfister, J Clin Oncol 2006, 24 1072-8
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Cetuximab CRT

• RTOG-0522 should address these issues
• Phase III trial of concomitant boost XRT with
  cisplatin alone versus cisplatin with cetuximab
• Target accrual of 720 patients

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RTOG-0522
HNC Update, Vol 1 Issue 1 2007
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Cetuximab Induction CT

• Controversy over role of induction chemotherapy
  in LA-HNSCC
• Recently, 3 randomized trials have demonstrated
  superior response rates of docetaxel when added
  to cisplatin and 5-fluorouracil for induction
  chemotherapy
• TAX 323, TAX 324, GORTEC
• Can cetuximab improve our current induction
  therapy strategies?

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Cetuximab Induction CT

• Kies et al. reported a phase II feasibility study
  of cetuximab with paclitaxel and carboplatin in
  neoadjuvant setting
• 47 patients were enrolled
• 89 had OP primaries
• Demonstrated a 98 ORR with a 26 CR rate
• What about cetuximab with more common induction
  regimen of TPF?

Kies, ASCO Proceedings 2006, 24 s18 5520
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TPF-C for LA-HNSCC

• Retrospective analysis of 23 patients with
  LA-HNSCC treated with TPF-C at BJC
• Designed to assess efficacy and feasibility

Kuperman, ASCO Poster Session 2007 6072
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TPF-C for LA-HNSCC
Medications
Day 1 Day 8
Day 15 Day 22
T
P
F
C
? The cisplatin and docetaxel were dosed at 75
mg/m2 on day 1 and 5-fluorouracil was 750
mg/m2/day for 3 days. ? The cetuximab was given
as a 400 mg/m2 loading dose on the first day of
therapy and then 250 mg/m2 weekly. ?Some
Patients received GCSF and ciprofloxacin
prophylaxis.
Kuperman, ASCO Poster Session 2007 6072
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TPF-C Induction Demographics
Kuperman, ASCO Poster Session 2007 6072
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TPF-C Induction Results
Kuperman, ASCO Poster Session 2007 6072
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TPF-C Induction Results
Kuperman, ASCO Poster Session 2007 6072
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TPF-C Induction

• TPF-C induction was feasible and well-tolerated
• Cetuximab with induction therapy resulted in
  impressive response rates
• In larger, prospective series, will addition of
  cetuximab improve on the 3-yr OS of 62 seen in
  TAX 324, or the 11 month PFS seen in TAX 323?
• German study of TPF-C with XRT ongoing

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R/M HNSCC

• Median survival of patients with R/M HNSCC is 6-8
  months in most series, with a PFS of 2-3 months
• Chemotherapeutic regimens have demonstrated
  30-35 ORR
• Several standard chemotherapeutic regimens have
  significant activity in this setting and can
  provide palliation of symptoms
• These include platinums, 5-FU, docetaxel,
  paclitaxel, MTX, ifosfamide, gemcitabine, and
  bleomycin
• However, no regimen has conferred a survival
  advantage in this setting

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R/M HNSCC

• One of the earliest studies investigating the use
  of cetuximab in the R/M setting was by Burtness
  et al.
• Phase III study of 117 eligable patients
  randomized to cisplatin palcebo versus
  cisplatin cetuximab as first-line therapy
• 4 weekly cycles were given
• No significant difference in PFS or OS
• Significant difference in ORR
• 26.3 in combination group versus 9.8 in the
  cisplatin/placebo group (p0.03)

Burtness, J Clin Oncol 2005, 23 8646-54
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R/M HNSCC

• Cetuximab was well tolerated with no significant
  increase in overall toxicities
• Burtness study concluded that cetuximab was
  active in R/M HNSCC

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LBA 6091
Vermorken, ASCO Virtual Meeting 2007 LBA 6091
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EXTREME, Vermorken et al.

• Inclusion Criteria included R/M HNSCC, measurable
  disease by CT,KPS 70
• Primary endpoint was overall survival
• 442 patients randomized to PF versus PF-C

Vermorken, ASCO Virtual Meeting 2007 LBA 6091
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Vermorken, ASCO Virtual Meeting 2007 LBA 6091
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Vermorken, ASCO Virtual Meeting 2007 LBA 6091
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Vermorken, ASCO Virtual Meeting 2007 LBA 6091
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EXTREME Conclusions

• Addition of Cetuximab to first-line therapy
  therapy resulted in significantly prolonged OS
  with a median of 2.7 months compared to
  chemotherapy alone
• An increase of 35 in survival
• Randomized trials of PF alone demonstrated
  response rates of 30-35 with median OS of 8-9
  months
• First randomized phase III trial to demonstrate a
  survival benefit over platinum-based therapy in
  this setting!

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EXTREME Questions

• Does cetuximab need to be given with PF to see
  the benefit?
• What would cross-over demonstrate?

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Vermorken, ASCO Virtual Meeting 2007 LBA 6091
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EXTREME Questions

• Does cetuximab need to be given with PF to see
  the benefit?
• What would cross-over demonstrate?
• Should all patients in the R/M setting receive
  cetuximab?
• What about taxanes in combination with cetuximab?

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Hitt, ASCO Virtual Meeting 2007 6012
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Hitt, ASCO Virtual Meeting 2007 6012
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Paclitaxel/Cetuximab in R/M HNSCC

• Phase II trial of first-line cetuximab and weekly
  paclitaxel in R/M HNSCC
• Primary endpoint ORR
• 46 patients enrolled
• 42 evaluable for response
• Patients given paclitaxel 80 mg/m2 qwk and
  cetuximab 400/250
• Results
• ORR 60 with CR of 24, DCR 88
• Median PFS 5 months (median F/U 5.6 months)
• Median OS not yet reached

Hitt, ASCO Virtual Meeting 2007 6012
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Hitt, ASCO Virtual Meeting 2007 6012
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Paclitaxel/Cetuximab in R/M HNSCC

• Phase II trial of first-line cetuximab and weekly
  paclitaxel in R/M HNSCC
• Primary endpoint ORR
• 46 patients enrolled
• 42 evaluable for response
• Patients given paclitaxel 80 mg/m2 qwk and
  cetuximab 400/250
• Results
• ORR 60 with CR of 24, DCR 88
• Median PFS 5 months (median F/U 5.6 months)
• Median OS not yet reached
• Toxicity was modest
• Grade 3/4 rash in 27, neutropenia in 13

Hitt, ASCO Virtual Meeting 2007 6012
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Hitt, ASCO Virtual Meeting 2007 6012
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ASCO Virtual Meeting 2007
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Platinum-Refractory Disease

• Patients with R/M disease who progress on
  platinum have dismal prognosis with median OS of
  100 days
• Early work by Baselga et al. demonstrated that
  cetuximab cis/carboplatin resulted in ORR of
  10 with DCR of 53 in patients who had
  progressed on platinum in the R/M setting
• Trigo et al. reported at ASCO 2004 an ORR of 13
  with cetuximab in patients previously treated
  with platinum in a phase II, open-label study
• Vermorken et al. reported final results of the
  open-label study in JCO last year

Baselga, J Clin Oncol 2005, 235568-77 Vermorken,
J Clin Oncol 2007, 252171-77
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Platinum-Refractory Disease

• Patients had R/M disease not suitable for local
  therapy with documented PD on cisplatin
• Patients were given cetuximab 400/250 weekly for
  6 wks
• Pts with SD or better continued until PD
• Pts with PD were given salvage with cetuximab
  platinum
• Primary endpoint was ORR

Vermorken, J Clin Oncol 2007, 252171-77
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Trigo, ASCO Virtual Meeting 2004 5502
ASCO Virtual Meeting 2004
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Platinum-Refractory Disease

• Patients had R/M disease not suitable for local
  therapy with documented PD on cisplatin
• Patients were given cetuximab 400/250 weekly for
  6 wks
• Pts with SD or better continued until PD
• Pts with PD were given salvage with cetuximab
  platinum
• Primary endpoint was ORR
• 103 patients were enrolled and 51 had PD after
  initial 6 cycles
• ORR was 13 with DCR of 46 in single-agent phase
• ORR was 0 with DCR of 26 in the salvage phase
• Median OS was 178 days

Vermorken, J Clin Oncol 2007, 252171-77
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Future for Cetuximab

• Clearly active in LA and R/M disease states
• Well tolerated, adding little toxicity to current
  regimens
• Optimal timing and scenario are yet to be
  elucidated
• Trials of cetuximab with concurrent CRT
• Trials of induction CT
• Trials of combination therapies in the R/M
  setting
• Taxanes
• With other targeted therapies
• Difficult to perform large studies due to
  incidence
• Will we be able to predict who will respond?