Phase II trial of trastuzumab (T), paclitaxel (P) and cisplatin (C) in metastatic (M) or recurrent (R) head and neck squamous cell carcinoma (HNSCC): Response by tumor EGFR and HER2/neu status

Abstract

5511 Background: EGFR expression is associated with poor prognosis and resistance of HNSCC to therapy. EGFR/Her2/neu heterodimers may potentiate receptor signaling and therapy resistance. T enhances cytotoxic effects of C and P in Her2/neu+ cell lines. Methods: A phase II trial evaluated the response rate (RR) of HNSCC pts to TPC as a function of Her2/neu and EGFR expression by immunohistochemistry (IHC). Secondary outcomes included toxicity, one-year progression-free (PFS) and overall (OS) survival. Eligible pts had M or R HNSCC, ECOG PS 0–1, CrCl >50 ml/min, and ANC >1500. Chemotherapy regimen consisted of P (175 mg/m2) and C (75 mg/m2) IV on day 1 and T (4 mg/kg day 1, cycle 1, 2 mg/kg subsequent) IV on day 1, 8 and 15 of 21. Paraffin embedded tumor was analyzed for Her2/neu (HercepTest) and EGFR (Zymed Lab) expression by IHC and for Her2/neu amplification by FISH (−/+) at LabCorp. Two-stage Simon design had 80% power for a 15% improvement in RR over 35% and required response in ≥ 14/42 pts by ECOG response criteria. Results: 61 pts (55 R HNSCC) received a median of 4 cycles (range 1–14) of TPC. Membrane staining of ≥ 10% of cells was observed for Her2/neu in 4/58 (6.9%, 95% CI 2–17) and for EGFR in 41/57 (72%, 95% CI 58–83). Her2/neu amplification was absent in 55/55 (0%, one-sided 97.5% CI 0–6.7) tumors. A RR of 36% (95% CI 24–50) was observed in 58 evaluable pts. RR was lower in pts with ≥ 10% staining by EGFR (25% versus 62.5%, p = 0.01). Her2/neu expression had no effect on RR (p = 0.75). Toxicities included two grade 5 dehydration/hypokalemia, and grade 3–4 neutropenia, fatigue, infection, nausea, vomiting, and neuropathy were common. Median follow-up was 4.2 yrs. For all 61 pts: median TTP was 4.3 mos, PFS 19.8% (95% CI 10.6–30.9) and OS 44% (95% CI 31.6–56.2) at 1 yr. Pts with <10% EGFR membrane staining had improved median PFS (6.7 vs 3.1 mos, p = 0.003) and OS (16.1 vs 7.4 mos, p = 0.005) when compared to patients with tumors with ≥ 10% EGFR. Conclusions: T did not improve RR to PC, likely because Her2/neu gene amplification and expression was rare. Tumor EGFR status significantly affected RR, PFS, and OS to the underlying regimen of PC. Sponsored by Bristol-Myers Squibb, Genentech, and Damon Runyon Cancer Research Foundation (MG). [Table: see text]

Activation of MET pathway predicts poor outcome to cetuximab in patients with recurrent or metastatic head and neck cancer

“…Cetuximab is a chimeric IgG1 monoclonal antibody that inhibits ligand binding to the EGFR extracellular domain [ 9 ] (hence interfering with receptor activation) and enhances the activity of chemotherapeutic agents [ 10 ]. Numerous clinical trials with cetuximab have improved the treatment of recurrent/metastatic HNSCC both as first-line therapy and following failure of platinum-based chemotherapy [ 11 , 12 ]. Since its approval for HNSCC in 2006, the clinical data produced suggest that cetuximab plays an important role in the locoregional treatment of these pathologies [ 13 ].…”

Targeting the ErbB Family in Head and Neck Cancer

“…93 The ErbB2-directed antibody trastuzumab was added to paclitaxel and carboplatin in a phase II study that included patients with metastatic or recurrent SCCHN. 94 The response rate (36%) was not higher than expected with this chemotherapy regimen alone. Lapatinib is a selective and potent dual competitive reversible inhibitor of the EGFR and ErbB2 TK.…”

Genomic alterations in human epidermal growth factor receptor 2 (HER2/ERBB2) in head and neck squamous cell carcinoma

“…Some have postulated that HER2 may be a potential target in HNSCC in general due to its frequent overexpression, but an early study that treated patients with a combination of trastuzumab, platinum, and paclitaxel showed no increase in response rate with the addition of trastuzumab to a platinum‐based chemotherapy regimen. None of the patients involved in this trial had alteration or amplification of HER2 , and so the lack of response is not surprising . HER2 amplification has been shown to be the most reliable predictor of response to trastuzumab …”