Targeted Therapy in the Age of Immunotherapy in Head and Neck Cancer

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The impact of targeted therapies in head and neck cancer has been limited, but we can strategize to integrate the development of targeted and immunotherapeutic agents, according to Christine H. Chung, MD, Senior Member and Chair in the Department of Head and Neck-Endocrine Oncology at Moffitt Cancer Center and Research Institute in Tampa, and Professor in the Department of Oncologic Sciences at the University of South Florida.

“Nowadays, you can’t really talk about head and neck cancer management without considering immunotherapy,” admitted Dr. Chung at a symposium hosted by the Winship Cancer Institute and Emory University: Updates in the Management of Head and Neck Cancer,1 where she discussed current research and efforts to integrate the two treatment modalities. “I think it’s pretty clear that if we’re going to continue to develop targeted therapy, we have to do it in the context of immunotherapy.”

Currently, most research in recurrent metastatic head and neck cancer is focused on immunotherapy, and immunotherapy is actively being integrated into the newly diagnosed and neoadjuvant setting, said Dr. Chung. This should be considered in the development of targeted agents.

A phase III trial comparing gefitinib (Iressa) with methotrexate in recurrent metastatic head and neck cancer showed no difference in survival.2 “It was a completely negative study. We’re not quite getting a handle on who would benefit from targeted agents,” she said. The EXTREME regimen (cetuximab [Erbitux] and cisplatin plus fluorouracil) is currently the first-line standard of care for recurrent/metastatic head and neck cancer, “until we get our randomized phase III results comparing the EXTREME regimen and immune checkpoint inhibitors,” noted Dr. Chung. “But we’re excited about checkpoint inhibitors resulting in a -longer-term survival in the recurrent/metastatic patients, although the number of patients with such a benefit is still relatively small.”

Promise of Combination Therapy

Some patients respond to chemotherapy and targeted agents (cetuximab shifts the survival curve by about 3 months given with chemotherapy), but eventually, every patient will have disease progression in the recurrent/metastatic setting. Median survival with immune checkpoint inhibitors is similar to that with chemotherapy, but survival curves are more promising. “Still, only a small percentage of patients have this durable response, so the goal is to combine these agents and maintain patients in this long-term survival curve.”

“Some of my patients are still alive after starting the checkpoint inhibitors almost 4 years ago, when they had widely metastatic disease,” she noted. “We simply have not seen that before with chemotherapy.”

Nowadays, you can’t really talk about head and neck cancer management without considering immunotherapy.
— Christine H. Chung, MD

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According to Dr. Chung, current combination trials evaluate “programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor plus agent X, whatever you can get your hands on,” she acknowledged. “But I think we have to be smarter about combining agents. We simply don’t have enough patient populations or resources to go through the hundreds of potential combinations you can put together.”

Dr. Chung said the combination therapy may be evaluated using the following three approaches: increasing immune cell infiltration in the tumor by modulating the tumor microenvironment, activating immune cells by inhibiting the immunosuppressive effects in the tumor and the tumor microenvironment, and pursuing cytoreduction with targeted agents—followed by immunotherapy at a state of low disease burden—to prevent the emergence of resistant cells. Immunotherapy seems to work better when a patient’s tumor volume is relatively low, and targeted agents, when they work, can shrink cancer very quickly, she continued. “It may be better to front-load with immunotherapy to make targeted therapy work better.”

Modulating the Microenvironment

Research into modulating the immune microenvironment has shown that when SCC25—a cetuximab-sensitive cell line—was exposed to cetuximab over a 6-month period, resistance began to emerge. “So clearly, exposure of epithelial cells to cetuximab changes the phenotype of the cells,” she said.

Belgian investigators gave patients 2 to 3 doses of cetuximab 2 to 3 weeks prior to their surgery.3 The post-cetuximab tumors were obtained at the time of surgery, and the gene-expression profile was compared before and after the use of cetuximab. About 75% of basal cell–type tumors (driven by the epidermal growth factor receptor pathway) changed their gene expression, and 83% of those changed to the mesenchymal type.

Genetics of Head and Neck Cancer

  • KRAS mutation is found in up to 20% of newly diagnosed patients with head and neck cancer.
  • In patients with recurrent/metastatic head and neck cancer, KRAS mutation is found in 32% of patients
  • The immunosuppressive effects of transforming growth factor beta require further evaluation.

“This is quite consistent with what I’ve seen in my research when using in vitro/in vivo data,” revealed Dr. Chung. Only two patients did not change to the mesenchymal type and stayed basal. “Our current hypothesis is whole characteristics of tumor phenotype as well as tumor microenvironment may change under a selection pressure of targeted agents, which may increase immune cell infiltration to the tumor as seen in mesenchymal subtype,” she explained.

Based on these data, a regimen of concurrent cetuximab and nivolumab (Opdivo) in recurrent/metastatic head and neck cancer will be evaluated at Moffitt Cancer Center, Emory University, and Ohio State University as a multi-institutional phase I/II clinical trial. A loading dose of cetuximab will be used to prime the microenvironment, which potentially can make immunotherapy more effective. Biopsies will be taken after single-agent cetuximab is given, to look for changes in the immune microenvironment. Subsequently, patients will be treated with cetuximab and nivolumab until disease progression. 

“I think this will be a very informative study, and one of the first combining targeted therapy and immunotherapy in head and neck cancer,” she said.

It may be better to front-load with immunotherapy to make targeted therapy work better.
— Christine H. Chung, MD

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Correlative studies will also be conducted to determine molecular subtypes, analyze T-cell repertoire diversity, detect circulating tumor DNA in plasma and its association with PD-L1 expression and PD-L1 inhibitor response, and evaluate flow cytometry of peripheral blood cells to monitor for peripheral lymphocyte changes.

A randomized phase II trial with cetuximab alone and a combination of cetuximab and sorafenib (Nexavar) arms in recurrent/metastatic head and neck cancer showed no difference in survival outcome.4 However, when plasma transforming growth factor beta (TGF-β1) levels were evaluated, the investigators noticed that patients with high TGF-β1 levels had poorer survival. “When we published these data in 2015, we didn’t make the connection that the patients with high TGF-β1 levels were potentially in an immunosuppressive state. We are further evaluating the role of TGF-β signaling in the tumor and microenvironment in head and neck cancer.”

Cytoreduction With Targeted Agents

KRAS mutation has been associated with poor outcomes in oral cancer. This polymorphism is found in 16% to 20% of newly diagnosed and in 32% of recurrent/metastatic head and neck cancer patients. 

In KRAS wild-type patients, adding cetuximab to cisplatin and radiotherapy did not improve outcomes, but KRAS-variant patients given cetuximab did better than KRAS–non-variant patients who did not get cetuximab.5 “Even more interesting are data on the rate of distant metastases,” Dr. Chung commented. “If patients had the KRAS variant and did not get cetuximab, they had a higher rate of developing distant metastatic disease.” Patients with the KRAS variant also had higher levels of TGF-β1 in their plasma.

The immunosuppressive effects of TGF-β1 require further evaluation, as well as the use of immunotherapy in the adjuvant setting in patients with the KRAS variant. Tapping into existing TGF-β1–targeted agents as combination partners of immunotherapy may potentially expedite the development of novel treatment options, Dr. Chung predicted. ■

DISCLOSURE: Dr. Chung has received honoraria from and served on scientific advisory boards for Bristol-Myers Squibb, AstraZeneca, and Lilly Oncology.


1. Chung CH: 2017 Winship Cancer Institute of Emory University Updates in the Management of Head and Neck Cancer Symposium. Presented April 22, 2017.

2. Stewart JS, et al: J Clin Oncol 27:1864-1871, 2009.

3. Schmitz S, et al: Oncotarget 6:34288-34299, 2015.

4. Gilbert J, et al: Oral Oncol 51:376-382, 2015.

5. Weidhaas JB, et al: JAMA Oncol 3:483-491, 2017.