In April 2011 (EJCMO 2011; 3, 25-31), we published the most relevant data at that time regarding the use of epidermal growth factor receptor (EGFR) inhibitors in head and neck squamous cell carcinoma (HNSCC). As we originally described, cetuximab (a monoclonal IgG1 chimeric [mouse/human] antibody against EGFR) is the most commonly used agent in combination with radiation therapy alone or in combination with chemotherapy (“chemoimmunotherapy”) plus radiation for locally advanced disease. Also, using cetuximab with a platinum- and 5-fluorouracil-based regimen, clinicians have been able to improve not only response rate and progression-free survival (PFS) but also overall survival (OS) in metastatic HNSCC. Several gaps need to be investigated with this agent and other novel therapies. In particular for cetuximab: first, its use in induction therapy followed by concurrent modality (+/- cetuximab use); second: its comparison head-to-head against cisplatin high-dose therapy (our current but “old” standard); third: its effect on HPV positive tumors must be studied.
Since our initial publication, new data have tried to answer some of these questions. The first question has two recent studies presented at the 2011 American Society of Clinical Oncology (ASCO) meeting. In the study “ERBITUX Added to Two Concurrent Chemoradiotherapy Platforms in Locally Advanced Head and Neck Cancer”(EPIC), induction therapy of paclitaxel/carboplatin/cetuximab (PCC) followed by concurrent chemoradiation with two different regimens was given. One of the regimens used FHX-based backbone plus cetuximab (CetuxFHX) and the other cisplatin plus cetuximab (“similar” to RTOG 0522; CetuxP). The objective response was 90% for PCC regimen and disease control rate was 98%; this regimen was well tolerated. In terms of the two combined modalities, there was no difference in terms of PFS (83 vs 83%) and OS (92 vs 94%) at two-years. When CetuxFHX was compared with TFHX historical control, no difference in PFS was seen. Toxicity was variable with more grade 3-4 neutropenia and dehydration for CetuxP and more dermatitis/rash for CetuxFHX. More comparing data in terms of efficacy between cetuximab and cisplatin as radiosensitizer was added by the TREMPLIN study. In the same ASCO meeting, Lefebvre et al presented the three- and 18-month follow up for the primary and secondary endpoints of the TREMPLIN study. Herein, after being treated with induction TPF regimen, patients who obtained more or equal than partial remission were randomized to receive either high-dose cisplatin (HD-P) for three cycles plus 70 Gy radiation (arm 1) or cetuximab plus 70 Gy (arm 2). At three- and 18-months follow up for primary and secondary endpoints, respectively, the authors found that larynx preservation was similar in both groups (95% vs 93%, P = 0.63) and no difference in larynx function preservation (87 vs 82%, P = 0.68) and OS (92 vs 89%, P = 0.44) were observed. In terms of toxicity such as renal, hematological, poor general condition, and infusion-related reaction, cetuximab arm required less protocol modifications due to these toxicities. For our second question, eagerly awaited to be answered, a landmark study (RTOG 0522) compared head-to-head HD-P (2 cycles) plus radiation +/- cetuximab. The goal here was to improve PFS with the addition of cetuximab to HD-P and radiation. The study did not show any difference in PFS and OS between the two groups. We should expect these two drugs to act synergistically in combination with radiation therapy as each of them blocks different phases of the cell-cycle, inducing apoptosis. Unfortunately, this large phase III failed to prove this concept. Finally, in terms of HPV status, our last question, most of the reports thus far are retrospective, and make difficult any final conclusion. Nonetheless, we must point out that all these analyses continue showing a good prognosis for those tumors being positive for the presence of HPV. A new study led by RTOG (RTOG 1016) will help us to answer our third question. This is a phase III trial comparing head-to-head cetuximab versus cisplatin in combination with radiation therapy only in patients with HPV-associated oropharynx cancer. This study will use the same chemotherapy-backbone than RTOG 0522 (only two cycles of HD-P) will be given in both arms. One hope in these HPV trials is that we not only can achieve better outcomes but also the fact that if that is true maybe the patients can get less aggressive interventions for the same benefit or better because they have a better prognosis.
Recently, a study published in the September 7, 2011 issue of Science Translational Medicine by Yonesaka et al. described an important issue in terms of how can we face in the near future cetuximab-resistant tumors. As this agent continues paving its roadmap in the treatment of not only HNSCC, but also colorectal and lung cancers, we also need to prepare ourselves to face cetuximab-resistant tumors soon. Yonesaka et al. have shown that ERBB2 is upregulated in these cetuximab-resistant tumor cells and consequently, it turns on extracellular signal-regulated kinase 1/2 (ERK 1/2)-mediated growth, differentiation, and survival. What makes this finding more interesting and promising is the fact that by interfering ERBB2 pathway, the researchers were able to restore cetuximab efficacy, controlling these cancer cells again.
In summary, in the last six months, we have been able to get some important questions about cetuximab regarding safety, combination options, and where to place cetuximab in the treatment algorithm of HNSCC. However, more research is needed and new questions were raised from the recent studies presented. The new and exciting data presented on cetuximab, basically starts to open other treatment opportunities beyond its only two clinical indications approved by the US FDA which are single agent in the metastatic setting or in combination with radiation therapy for locally advanced HNSCC. Obviously, these promising data will need validation in the context of well conducted and rigorously designed clinical trials. I leave this column with the “appetizer” brought by the Dana-Farber Cancer Institute colleagues, discovering mechanism of resistance to cetuximab. The implications of these findings are enormous and clinical trials combining ERBB2 inhibitors plus cetuximab seems to be very compelling.
About the Author & Co-authors
Edgardo S. Santos, M.D., FACP.
Associate Professor of Clinical Medicine
Associate Director, Hematology-Oncology Fellowship Program
Co-Leader, Head and Neck Cancer Program
Member, Thoracic Oncology Program
Division of Hematology and Medical Oncology
University of Miami/Sylvester Comprehensive Cancer Center
Miami, Florida
Dr. Edgardo S. Santos
Dr. Santos earned his M.D. in 1994 at the University of Panama, School of Medicine, Republic of Panama. Dr. Santos completed his internship and residency training in Internal Medicine at Jackson Memorial Medical Center, University of Miami School of Medicine, Miami, Florida. Then, he went on to complete his fellowship in Hematology/Oncology at Sylvester Comprehensive Cancer Center, Miami, Florida. Dr. Santos has authored or co-authored several manuscripts in peer-reviewed journals and also serves as reviewer for several scientific journals. Dr. Santos is a member of the Editorial Board of Expert Review series and Recent Patents on Biomarkers. He has lectured mostly on topics related to lung and head and neck cancers as well as lymphoproliferative disorders and multiple myeloma.
He is a former faculty member of Tulane University Health Sciences Center (2004-2008) where he was appointed as an Assistant Professor of Medicine and also occupied several administrative and educational positions including: Tulane Principal Investigator at Southwest Oncology Group (SWOG), Associate Scientific Director of Tulane Cancer Center’s Office of Clinical Research, Associate Director of the Fellowship Program (Tulane University School of Medicine), Chief of the Hematology/Oncology section at the Southeast Louisiana Veterans Healthcare System, Chair of the Committee Research Advisory Board, and Co-Leader of Clinical Research at Louisiana Cancer Research Consortium. He is an active member of several medical societies including the American Association for Cancer Research, the International Association for the Study of Lung Cancer, the American Society of Clinical Oncology, the European Society of Medical Oncology, the American Society of Hematology, and the American College of Physicians-American Society of Internal Medicine. To date, Dr. Santos is the Associate Director of the Hematology/Oncology Fellowship Program at the University of Miami Miller School of Medicine, the Co-Leader of the Head and Neck Cancer Program and a member of the Thoracic Oncology program. He also serves as the Co-Chair of the Hem/Onc International Fellowship Program. Dr. Santos’ main interests are clinical trials (phase I/II) in head and neck and lung cancers.
Dr. Cesar A. Perez
Cesar Perez, M.D.
Clinical Research Fellow
Division of Hematology/Oncology
University of Miami Miller School of Medicine
Sylvester Comprehensive Cancer Center
1475 NW 12th Avenue, D8-4
Miami, FL 33136
Phone: 305-585-5196
Facsimile: 305-545-8933
Email: CPerez5@med.miami.edu
Dr. Luis E. Raez
Luis E. Raez, MD, FACP, FCCP, MACSG
Co-Director Thoracic Oncology Program
Memorial Cancer Institute (MCI)
Memorial Health Care System
801 N Flamingo Road, Suite 11
Pembroke Pines Florida 33028
Phone: 954-8446868
Fax: 954-4434747
Email: lraez@mhs.net
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