Two landmark randomized studies demonstrated improved survival of patients with head and neck cancer receiving the epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux) concurrent with radiotherapy compared with radiotherapy alone,1 and similar improvement in patients with recurrent/metastatic disease receiving cetuximab and chemotherapy compared with chemotherapy alone.2
These results prompted the hypothesis that a combination of radiotherapy and concurrent chemotherapy and cetuximab may improve the outcome of head and neck cancer patients compared with radiotherapy and chemotherapy, regarded as today’s standard of care for advanced disease. This hypothesis was supported by preclinical findings that cetuximab sensitizes tumor cells to cisplatin3 and radiotherapy4 as well as data on its activity in recurrent/metastatic head and neck cancer refractory to platinum-based chemotherapy.5
Failure to Improve Outcome
However, a randomized Radiation Therapy Oncology Group (RTOG) study testing this hypothesis has failed to confirm the presumed superiority of the combined therapy. As reviewed in this issue of The ASCO Post, Ang et al6 reported the results of a large study (N = 891) in patients with stage III/IV head and neck cancer randomly assigned to radiotherapy plus concurrent cisplatin, with and without concurrent cetuximab. They noted higher rates of acute toxicity, notably mucositis, and higher rates of treatment interruptions in the cetuximab-containing arm, but no significant differences in disease-free or overall survival.
What were the possible reasons for the failure to improve outcome by adding cetuximab? The authors raised a number of possibilities, one being that the higher toxicity observed in the cetuximab-containing arm may have increased interruptions in radiotherapy, neutralizing any potential tumor control benefit from the drug.
Another potential explanation is the similar mechanism of radiation sensitization by cisplatin and cetuximab (inhibition of repair of radiation-induced DNA damage) that may have prevented an additive or synergistic effect. If this explanation is valid, then the combination of cetuximab and a drug with a different sensitization mechanism, such as docetaxel, would be expected to be more effective, as has recently been suggested in a randomized study of postoperative radiotherapy with cisplatin and cetuximab or with docetaxel and cetuximab.7
Tumor p16 Status
The results of this study confirmed that patients with human papillomavirus (HPV)-related oropharyngeal cancer had significantly better outcomes compared with patients with non-HPV related cancers. No significant relationship was found between the effect of adding cetuximab and tumor HPV status.
This contrasts with the effect of another fully humanized IgG2 EGFR-specific monoclonal antibody, panitumumab (Vectibix), which did not show a survival benefit when added to cisplatin and fluorouracil in a randomized study in metastatic head and neck cancer. However, disease-free survival was improved by adding panitumumab, and most of the improvement was demonstrated in patients with p16-negative tumors.8
Taking into account the fact that EGFR overexpression is a characteristic of p16-negative tumors,9 this finding suggests that EGFR inhibition may be more effective in tumors that overexpress EGFR. However, in the Ang et al study, no such interaction between adding cetuximab and HPV tumor status was noted. Neither was such an interaction observed in a randomized study of chemotherapy with or without cetuximab for metastatic head and neck cancer, in which a survival benefit was observed in the chemotherapy-cetuximab arm compared with chemotherapy alone across both HPV-related and -unrelated cancers.10
While other studies found that patients with p16-positive oropharyngeal cancers may benefit more from the cetuximab-radiotherapy combination compared with chemoradiation,11 the evidence for no such interaction is much stronger.
Acute Mucositis
The main added toxicity observed with the cetuximab-chemoradiotherapy combination compared with chemoradiotherapy alone in RTOG 0522 was acute mucositis. The lack of excess mucositis in the radiation-concurrent-with-cetuximab arm compared with radiotherapy alone reported in the randomized study by Bonner et al1 raised the expectation that the main toxicity of aggressive chemoradiation for head and neck cancer can be prevented by substituting cetuximab for chemotherapy and that adding cetuximab to chemoradiation would not worsen this toxicity.
However, emerging data suggest that acute mucositis is quite prevalent in cetuximab-radiotherapy regimens, based on anecdotal data.12,13 Tsien et al treated patients planned for surgical resection with the EGFR tyrosine kinase inhibitor erlotinib and examined EGFR levels before and at post-erlotinib surgery in both cancer and mucosa samples.14 They found heterogeneity in mucosal EGFR expression both pretherapy and after erlotinib therapy, with similar heterogeneity found in the tumor specimens.
Substantial suppression of mucosal EGFR activity may explain higher mucositis rates, since the normal mucosa depends on EGFR activity for its proliferation. Moreover, the substantial heterogeneity in EGFR levels and response to EGFR inhibition suggest that some patients may be more prone to mucositis during cetuximab-radiotherapy than other patients. This issue needs to be investigated further.
Overcoming Cetuximab Resistance
What should be the next step? The combination of radiotherapy, cetuximab, and docetaxel may be more active than radiotherapy, cetuximab, and cisplatin, as detailed above, and RTOG plans a phase III study to assess this. In addition, recent studies have examined possible ways to enhance cetuximab activity.
The presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in head and neck cancer may serve to select the patients that may benefit most from concomitant administration of cetuximab and PI3K or mTOR inhibitors.15 Another strategy to overcome cetuximab resistance may be interrupting the RAS-MAPK pathway, which is activated in resistant cells, using an ERK1/2 inhibitor.16 Such strategies, if successful, will renew future interest in combining chemotherapy and EGFR inhibitors in advanced head and neck cancer. ■
Disclosure: Dr. Eisbruch reported no potential conflicts of interest.
References
1. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.
2. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116-1127, 2008.
3. Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637-4642, 1993.
4. Huang SM, Bock JM, Harari PM, et al: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935-1940, 1999.
5. Baselga J, Trigo JM, Bourhis J, et al: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23:5568-5577, 2005.
6. Ang KK, Zhang Q, Rosenthal DI, et al: Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:2940-2950, 2014.
7. Harari PM, Harris J, Kies MS, et al: Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol 32:2486-2495, 2014.
8. Vermorken JB, Stöhlmacher-Williams J, Davidenko I, et al: Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): An open-label phase 3 randomised trial. Lancet Oncol 14:697-710, 2013.
9. Vainshtein JM, Spector ME, McHugh JB, et al: Refining risk stratification for locoregional failure after chemoradiotherapy in human papillomavirus-associated oropharyngeal cancer. Oral Oncol 50:513-519, 2014.
10. Vermorken JB, Psyrri A, Mesía R, et al: Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: Retrospective analysis of the phase III EXTREME trial. Ann Oncol 25:801-807, 2014.
11. Pajares B, Trigo JM, Toledo MD, et al: Differential outcome of concurrent radiotherapy plus epidermal growth factor receptor inhibitors versus radiotherapy plus cisplatin in patients with human papillomavirus-related head and neck cancer. BMC Cancer 13:26, 2013.
12. Pryor DI, Burmeister E, Burmeister BH, et al: Distinct patterns of stomatitis with concurrent cetuximab and radiotherapy for head and neck squamous cell carcinoma. Oral Oncol 47:984-987, 2011.
13. Walsh L, Gillham C, Dunne M, et al: Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC). Radiother Oncol 98:38-41, 2011.
14. Tsien CI, Nyati MK, Ahsan A, et al: Effect of erlotinib on epidermal growth factor receptor and downstream signaling in oral cavity squamous cell carcinoma. Head Neck 35:1323-1330, 2013.
15. Wang Z, Martin D, Molinolo AA, et al: mTOR co-targeting in cetuximab resistance in head and neck cancers harboring PIK3CA and RAS mutations. J Natl Cancer Inst 106(9):dju215, 2014.
16. Boeckx C, Op de Beeck K, Wouters A, et al: Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins. Cancer Lett 354:365-377, 2014.
Dr. Eisbruch is Professor of Radiation Oncology at the University of Michigan Health System, Ann Arbor.
