Update on Targeted Therapies in Head and Neck Cancers

Everett E. Vokes, MD

Targeted therapies, including tyrosine kinase inhibitors (TKIs), are increasingly being investigated in head and neck cancers, including recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) and advanced thyroid cancers.

“I think targeted therapies in head and neck cancer have actually been more of a promise than a real achievement, with the exception of thyroid cancer, where they have made a lot of contribution,” noted Everett E. Vokes, MD, Giant of Cancer Care recipient for Head and Neck Cancer, John E. Ultmann Professor, chair, department of medicine, and Physician-in-Chief at the University of Chicago, citing the recent success of therapies like sorafenib in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).¹

“For squamous cell cancers of the head and neck, you had a lot of promise when cetuximab came around,” Vokes said, noting that this epidermal growth factor receptor (EGFR)-targeted treatment, added to chemotherapy or sometimes radiation, can be used for patients with SCCHN and recurrent disease.²“Beyond that, targeted therapies are really more of an investigational interest [for SCCHN] at this point,” he said. “We are still struggling to define the relevant driver mutations, and how to best target them.”

Ezra Cohen, MD, on Immunotherapy in Head and Neck Cancers

Cohen is a professor at UC San Diego Moores Cancer Center.

However, Vokes acknowledged the potential of major groundbreaking initiatives, such as The Cancer Genome Atlas. “The Cancer Genome Project has been very helpful” he said, noting the recent identification of several relevant mutations in SCCHN.³“We will see, in the next few years, whether that can hopefully be translated into clinical achievement.”

RM-SCCHN

This article highlights some recent, mostly phase II findings in SCCHN and thyroid cancer.In a review of 5 clinical trials of various EGFR-targeted TKIs, including erlotinib, lapatinib, or gefitinib, Cohen et al concluded that, in combined analysis, older age, better performance status, and the occurrence of adverse events (AEs), such as rash, diarrhea, and stomatitis, were predictors of better progression-free survival (PFS) and overall survival (OS).⁴

In a phase II trial, de Souza and colleagues assessed the use of lapatinib in 2 cohorts of patients with RM-SCCHN: those who had not received prior anti-EGFR therapy (arm A) and those who had received prior anti-EGFR therapy (arm B).⁵This trial showed lapatinib to be largely inactive in both sets of patients as monotherapy, with stable disease (SD) observed as the best response in 41% and 17% of subjects in arms A and B, respectively, and no observed partial response (PR) or complete response (CR).⁵

A small study of foretinib, a multikinase inhibitor that predominantly targets the mesenchymal epithelial transition (MET) receptor, also showed SD as the best response in RM-SCCHN patients, with minor tumor shrinkage observed in 7 of 14 patients (50%). Study authors left open the possibility for further study of foretinib as combination therapy.⁶

Figitumumab, an antibody inhibitor of the insulin-like growth factor receptor (IGF-1R), has also been evaluated as a monotherapy in RM-SCCHN patients.⁷This phase II study showed no significant activity of figitumumab in this population, and the trial was closed prematurely.

In a phase II study of cutaneous squamous cell carcinoma (CSCC) patients (N=23; n=22 evaluable for response and toxicity), induction therapy with gefitinib resulted in an overall response rate (ORR) of 45.5%, with 18.2% CR and 27.3% PR; the 2-year PFS, disease-specific survival, and OS rates were 63.6%, 72.1%, and 72.1%, respectively, and the treatment was well tolerated.⁸The authors concluded that EGFR TKIs should be further evaluated for the treatment of CSCC, and that, although none were identified in the study, biomarkers could help identify patients most likely to respond.⁸

Thyroid Cancer

Similarly, the pan-human EGF receptor TKI dacomitinib has also demonstrated activity as a first-line therapy for patients with RM-SCCHN in a single-arm phase II study of 69 patients.⁹Among 63 evaluable patients in the study, an ORR of 12.7% was observed (0 CR, 8 PR), and 57.1% of patients had SD, with 14.3% experiencing SD for 24 weeks or greater; high-grade treatment-related AEs were predominantly diarrhea, acneiform dermatitis, and fatigue.⁹The multikinase inhibitor vandetanib, which targets RET as well as the vascular endothelial growth factor receptor (VEGFR) and EGFR signaling pathways, has demonstrated activity in locally-advanced or metastatic hereditary medullary thyroid cancer (MTC), for which no therapy had previously been available.10 In this study, a disease control rate (PR or SD for >24 weeks) was observed in 22 of 30 patients (73%), with PR observed in 6 patients (20%), and median PFS was >27 months, indicative of clinically relevant tumor control. These rates were achieved with a largely manageable AE profile.¹⁰

Clinical Pearls

• Despite recent success of therapies like sorafenib in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) and cetuximab, an EGFR-targeted treatment added to chemotherapy or radiation in patients with SCCHN and recurrent disease, most targeted therapies for head and neck cancers require further investigation.
• Some agents in clinical trials for the treatment of RM-SCCHN include lapatinib, foretinib, gefitinib, and dacomitinib.
• Some targeted therapies under investigation for thyroid cancer include vandetanib and cabozantinib.

Similarly, cabozantinib is a TKI with activity at MET, VEGFR2, and RET that has also been shown to have activity in MTC in a phase I dose escalation trial (N=85) including 37 patients with MTC.11 A confirmed objective response was achieved in 10 patients among 35 evaluable patients (29%), and 17 patients (49%) had tumor shrinkage of 30% or greater; SD of at least 6 months or a confirmed PR was seen in 25 patients (68%). Overall, the results showed this agent to have activity along with an acceptable toxicity profile in this population of MTC patients that was inclusive of those with somatic RET mutations.¹¹

The recently reported results of the landmark DECISION trial should also be mentioned, as they have provided, for the first time, a therapeutic option for patients with RAI-refractory, advanced DTC. In this phase III trial, the multikinase inhibitor sorafenib was shown to significantly prolong PFS (10.8 vs 5.8 months; hazard ratio [HR] = 0.59;P<.0001), and ORR was also significantly improved compared with placebo (12.2% vs 0.5%;P<.0001).¹Whereas OS was not improved (HR = 0.80;P= 0.14), the endpoint was likely confounded by crossover allowance (from placebo to open-label sorafenib) upon progression. Benefits of sorafenib in this important population were attained at the expense of a largely manageable AE profile that was consistent with prior studies of this agent.¹

References

1. Brose MS, Nutting CM, Jarzab B, et al, on behalf of the DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.Lancet. 2014;384(9940):319-328.
2. Markovic A, Chung CH. Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma.Expert Rev Anticancer Ther. 2012;12(9):1149-1159.
3. Mountzios G, Rampias T, Psyrri A. The mutational spectrum of squamous-cell carcinoma of the head and neck: targetable genetic events and clinical impact [published online ahead of print 2014 April 8].Ann Oncol. pii:mdu143.
4. Cohen EE, Halpern AB, Kasza K, Kocherginsky M, Williams R, Vokes EE. Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and metastatic squamous cell carcinoma of the head and neck.Oral Oncol. 2009;45(10):e155-e160.
5. de Souza JA, Davis DW, Zhang Y, et al. A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck.Clin Cancer Res. 2012;18(8):2336-2343.
6. Seiwert T, Sarantopoulos J, Kallender H, McCallum S, Keer HN, Blumenschein G Jr. Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.Invest New Drugs. 2013;31(2):417-424.
7. Schmitz S, Kaminsky-Forrett MC, Henry S, et al. Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: clinical activity and molecular response (GORTEC 2008-02).Ann Oncol. 2012;23(8):2153-2161.
8. Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck.Clin Cancer Res. 2012;18(5):1435-1446.
9. Abdul Razak AR, Souli&egrave;res D, Laurie SA, et al. A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck.Ann Oncol. 2013;24(3):761-769.
10. Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.J Clin Oncol. 2010;28(5):767-772.
11. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer.J Clin Oncol. 2011;29(19):2660-2666.