Phase II study of oral lapatinib, a dual-tyrosine kinase inhibitor, combined with chemoradiotherapy (CRT) in patients (pts) with locally advanced, unresected squamous cell carcinoma of the head and neck (SCCHN)

Reporter: Arpi Thukral, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 7, 2010

Presenter: K. J. Harrington, Royal Marsden Hospital, UK


  • Lapatinib is an oral small-molecule dual tyrosine kinase (TK) inhibitor of EGFR (epidermal growth factor receptor), which targets Her2 receptors.
    • This drug has been approved for use in treatment of locally advanced metastatic Her 2+ breast cancer.
  • In SCC of the head and neck (SCCHN), previous data has shown that EGFR overexpression is common and is a negative prognostic factor. (Caponigo, 2004)
  • In-vitro and in-vivo data have shown appreciable activity of lapatinib in SCCHN. (Rusnak, 2001)
  • This phase II randomized trial was undertaken to evaluate efficacy and tolerability of oral lapatinib, combined with chemoradiotherapy (CRT) in patients (pts) with locally advanced, unresected squamous cell carcinoma of the head and neck (SCCHN).


  • Eligibility criteria:
    • locally advanced unresected stage III/IVA/IVB SCCHN (oral cavity, oropharynx, hypopharynx, larynx)
    • ECOG performance status (PS) 0-2
  • Exclusion criteria:
    • StageT1N1 or T2N1
    • Stage IVC
    • Sites of nasopharynx, nasal sinuses, paranasal sinuses
  • All patients were treated with 3 cycles of cisplatin 100 mg/m2 (days 1, 22, 43) and radiotherapy (70 Gy/35 fractions/7 weeks). They were randomized to receive concurrent lapatinib 1500 mg versus placebo daily, followed by maintenance lapatinib or placebo until disease progression.
  • Lapatinib/placebo was started on week 1 prior to chemoRT to give a loading dose and achieve steady-state by the start of chemoRT.
  • Patients were stratified by tumor site (oral cavity, oropharynx, hypopharynx, larynx) and nodal status (N0,N1 vs. N2,N3).
  • The primary endpoint was complete response rate (CRR) by independent review 6 months post-CRT.
  • Secondary endpoints were progression free survival (PFS), overall survival (OS), local control, and safety.


  • 67 patients were prospectively enrolled on this trial from November 2006 to January 2009 in 9 countries globally (33 pts in placebo arm, 34 pts in lapatinib arm).
  • Median follow up: 12.8 months
  • Patient demographics were well-balanced for age, sex, performance status, and smoking history.
    • Median age: 56 years
    • 52%, 45%, and 3% had ECOG PS of 0, 1, and 2, respectively
    • 18% had stage III and 82% stage IV disease
      • Disease subsites: oropharynx 64%, hypopharynx 16%, larynx 12%, and oral cavity 7%.
    • 28% of patients had HPV, but rates were equal between both arms
    • Median XRT dose in both arms was 70 Gy, and both groups had similar doses and duration of Cisplatin.
  • Lapatinib combined with chemoRT was well-tolerated. The median duration of treatment in the Lapatinib arm was 151 days, which was longer than that of the placebo group.
    • The lapatinib group experienced a relative excess of diarrhea, rash, and skin reaction compared to the placebo group; however, there was no evidence of increased mucositis, nausea, or vomiting associated with lapatanib.
    • 2 patients had grade 4 cardiac events (MI and pericardial effusion) on maintenance lapatinib.
    • No grade 3/4 toxicities were observed during maintenance therapy except grade 3 localized edema in 3% of lapatinib patients and grade 3 weight loss in 3% of placebo patients.
  • There was a 17% difference between the 2 groups (36% with placebo vs. 53% with lapatinib) of complete response at 6 months, favoring the lapatinib group.
  • PFS: 12.1 mos vs. 20.4 mos for placebo and lapatinib groups, respectively.
  • OS: 23 mos vs. 30.9 mos for placebo and lapatinib groups, respectively.
  • Hazard ratios for progression-free and overall survival by independent review were 0.71 (95% CI 0.34-1.52) and 0.70 (95% CI 0.31-1.63), respectively. Confidence intervals crossed over 1.0 and these results were not significant.

Authors' Conclusions

  • The authors concluded that this trial met its primary endpoint of complete response at 6 months, and the results suggest that lapatinib has efficacy with chemoRT in this population of patients.
  • They also note that lapatinib was well tolerated when combined with CRT.

Clinical Implications

  • Previous clinical data supporting the role of EGFR inhibitors in SCCHN has been published by Bonner et. al. (NEJM, 2006). This trial demonstrated that treatment of locoregionally, advanced head and neck cancer with concomitant high-dose radiotherapy plus Cetuximab (a monoclonal antibody directed against EGFR) improves locoregional control and reduces mortality compared to radiation alone, without increased mucositis. Patients enrolled in this trial did not receive traditional chemotherapy.
    • This trial sets the standard of care for studies examining EGFR inhibitors in head and neck cancer.
  • This phase II trial provides interesting preliminary information about the combination of lapatinib, an oral TKI, with standard chemoRT. TKIs have a different mechanism of action than EGFR monoclonal antibodies, and therefore may show different results.
  • It is unclear why the authors chose 6 month CR rate as their primary endpoint. This is not a traditional endpoint in most phase II studies, and therefore the clinical relevance of these results is questionable. Traditional endpoints such as PFS, DFS, and OS were not significant in this study.
  • Lapatinib was also given as maintenance therapy after chemoRT and is unclear if responses were due to concurrent treatment, maintenance therapy, or both.
  • This is a very small study and one cannot draw definitive conclusions from these results; however, they may be hypothesis generating. Also, one must be aware that the data has been collected in a phase II trial and the study was underpowered. To determine its clinical relevance, this hypothesis should be ideally tested in a Phase III randomized trial.
  • Questions regarding design of a larger such trial abound. Is it redundant to repeat a large clinical trial of an EGFR inhibitor when we have great data supporting the use of Cetuximab? Is the mechanism of action different enough to cause large changes in results for patients? Larger trials to confirm small differences may not be warranted.
  • At the current time, justification of pursuit of a large Phase III trial examining the role of lapatinib in treatment of SCCHN seems somewhat questionable, since Cetuximab, has been demonstrated to have efficacy. Furthermore, the cost of lapatinib with CRT is approximately $81,200, which translates to $121,800 per life year gained.
  • It may be more beneficial and cost-effective to await results on current ongoing trials such as RTOG 0522 in which pts are randomized to receive chemoRT with or without Cetuximab. Others include EXTREME, NCIC, and DAHANCA 19 trials.