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    Targeted Drugs No Help in Head and Neck Cancer

    Thu, Mar 7, 2013

    Oral Cancer News

    Source: medpagetoday.com
    Author: Charles Bankhead, Staff Writer, MedPage Today
    Date: March 05, 2013
     

    The addition of targeted agents to standard chemotherapy failed to improve efficacy in two different trials of advanced head and neck cancer.

    In one trial, patients given gefitinib (Iressa) in addition to docetaxel lived about a month longer than those who received docetaxel plus placebo. In the other trial, adding erlotinib (Tarceva) to cisplatin-based chemoradiation did not improve response rate or progression-free survival.

    However, neither regimen was associated with increased toxicity compared with standard chemotherapy, investigators reported online in the Journal of Clinical Oncology.

    Noting the lack of useful biomarkers to guide the use of targeted agents, the authors of an accompanying editorial said that experience to date suggests current strategies amount to “skimming the surface of a problem that is exceedingly complex.”

    “It is unlikely that genomic sequencing alone will represent a panacea to the therapeutic challenges in squamous cell carcinoma of the head and neck,” said Aaron R. Hansen, MBBS, and Lillian L. Siu, MD, of Princess Margaret Cancer Center in Toronto. “Comprehensive characterization that encompasses a broader omics-based molecular evaluation, as well as immune function assessments, is urgently needed.”

    The rationale for the gefitinib and erlotinib trials came from evidence that the drugs targeting epidermal growth factor receptors (EGFR) have synergism with conventional chemotherapeutic agents, have radiosensitizing properties, and have demonstrated modest activity as monotherapy in some clinical studies.

    Cetuximab (Erbitux), another EGFR inhibitor, has been approved for use with radiation therapy or as monotherapy in selected patients with head and neck cancer.

    Gefitinib-Docetaxel

    Preliminary studies of the docetaxel-erlotinib combination showed considerable toxicity that required dose reductions. As a result, the investigators chose to evaluate gefitinib in combination with docetaxel.

    “Our hypothesis was that the addition of gefitinib to docetaxel will be synergistic and improve outcomes of previously treated and/or compromised performance status patients with recurrent or metastatic squamous cell carcinoma of the head and neck,” Athanassios Argiris, MD, of the University of Texas Health Science Center at San Antonio, and co-authors wrote.

    Eligible patients had recurrent or metastatic disease and Eastern Cooperative Oncology Group (ECOG) performance status 2 or ECOG 0 to 2 and previous exposure to chemotherapy. All patients received weekly docetaxel and were randomized to gefitinib or placebo.

    Treatment continued until disease progression, and the primary endpoint was overall survival.

    The phase III trial had a patient-accrual goal of 330, but enrollment ended after 270 patients when an interim analysis suggested efforts to demonstrate improvement in the primary endpoint would prove futile.

    The results showed a median overall survival of 6 months in the docetaxel-placebo arm and 7.3 months with the docetaxel-gefitinib regimen. An unplanned analysis suggested that patients younger than 65 benefited from gefitinib (7.6 versus 5.2 months median overall survival, P=0.04).

    Grade 3/4 toxicity occurred in a similar proportion of patients in both treatment arms, with the exception of diarrhea, which was more common with gefitinib.

    Erlotinib-Cisplatin

    The erlotinib trial involved 204 patients with locally advanced squamous cell carcinoma of the head and neck. All patients received cisplatin-based chemoradiation and were randomized to the EGFR inhibitor or no further therapy.

    The primary endpoint was complete response rate, and progression-free survival (PFS) was the secondary endpoint, as reported by Renato G. Martins, MD, of the University of Washington in Seattle, and colleagues.

    The results showed a complete response rate of 40% without chemoradiation and 52% with chemoradiation plus erlotinib, a difference that did not achieve statistical significance (P=0.08). After a median follow-up of 26 months, PFS also did not differ significantly between the two treatment arms (HR 0.9, P=0.71).

    Investigators prospectively evaluated p16 status in 90 patients. A positive result was defined as “strong, diffuse nuclear and cytoplasmic staining in ≥70% of tumor cells.” Patients with p16-positive tumors had significant improvement in the hazard for progression when they received erlotinib (HR 0.39, P=0.04).

    Martins and colleagues also evaluated the relationship between development of rash and PFS in patients who received erlotinib. The analysis revealed rash as a significant predictor of improved PFS (HR 0.41 versus erlotinib-treated patients without rash, P=0.03).

    “Despite preclinical data suggesting that erlotinib could be synergistic with both chemotherapy and radiotherapy, erlotinib previously failed to improve outcome in metastatic non-small cell lung cancer,” Martins and colleagues noted in their discussion. “Here, erlotinib failed to improve the outcome of locally advanced squamous cell carcinoma of the head and neck when combined with cisplatin-radiotherapy.”

    Although disappointing, the results do not represent the end of the line for investigation of targeted agents in head and neck cancer, Ellie Maghami, MD, of City of Hope in Duarte, Calif., told MedPage Today. Echoing the sentiments of Hansen and Liu, Maghami said the true potential of targeted agents in head and neck cancer will not be determined in the absence of accurate biomarkers to guide patient selection.

    The gefitinib study was supported by AstraZeneca. The erlotinib study was supported by Genentech.

    Argiris disclosed a relationship with AstraZeneca. Co-authors disclosed relationships with AstraZeneca, Boehringer Ingelheim, Genentech, and sanofi-aventis.

    Martins disclosed relationships with Genentech and OSI Pharmaceuticals. Co-authors disclosed relationships with XCENDA Amerisource Bergen Consulting Services, Genentech, Intuitive Surgical, and OSI Pharmaceuticals.

    Siu disclosed relatinships with Roche, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim.

    Primary source: Journal of Clinical Oncology
    Source reference:
    Argiris A, et al “Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: An Eastern Cooperative Oncology Group trial” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.45.4272.

    Additional source: Journal of Clinical Oncology
    Source reference:
    Martins RG, et al “Cisplatin and radiotherapy with or withoout erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.46.3299.

    Additional source: Journal of Clinical Oncology
    Source reference:
    Hansen AR, Siu LL “Epidermal growth factor receptor targeting in head and neck cancer: Have we been just skimming the surface?” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.47.9220.

     

     * This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

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