Immunotherapy for Head and Neck Cancers
Medicines that help the immune system recognize and attack cancer: agents used for each cancer type, common side effects, and typical response rates.
What Is Immunotherapy?
Immunotherapy for cancer most often means a group of medicines called immune checkpoint inhibitors. The immune system normally finds and destroys abnormal cells, but cancer cells can hide by flipping "off switches" (called checkpoints) on immune cells. Checkpoint inhibitors block these off switches so the body's own immune cells (T cells) can recognize and attack the cancer. Unlike chemotherapy, immunotherapy does not attack the cancer directly; it "releases the brakes" on the immune system. Responses can take longer to appear than with chemotherapy, but when they occur they often last a long time.
The checkpoints most often targeted are:
PD-1 and PD-L1: Drugs that block this pathway include pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), retifanlimab (Zynyz), cosibelimab (Unloxcyt), and avelumab (Bavencio). These are the backbone of immunotherapy for most of the cancers described on this page.
CTLA-4: Ipilimumab (Yervoy) blocks this checkpoint. It is often combined with a PD-1 drug to strengthen the immune response, at the cost of more side effects.
LAG-3: Relatlimab blocks this checkpoint and is combined with nivolumab (Opdivo) for melanoma; the two drugs are given together in a single infusion as a combination product (Opdualag).
These drugs are usually given as an intravenous (IV) infusion every few weeks; some now have an under-the-skin (subcutaneous) form. Which drug is used depends on the exact type of cancer, how far it has spread, other health conditions, and the results of special tumor tests.
Common Side Effects
Because immunotherapy activates the immune system, its side effects differ from those of chemotherapy. The most common general side effects are fatigue, rash or itching, and diarrhea, along with joint aches, nausea, and low thyroid function.
The distinctive side effects are called immune-related adverse events. They occur when the activated immune system attacks healthy organs and causes inflammation. They can affect almost any part of the body, including:
Skin (rash, itching)
Bowel (diarrhea, colitis)
Lungs (cough or shortness of breath from pneumonitis)
Liver (hepatitis)
Hormone glands (thyroid, adrenal, and pituitary problems; sometimes new diabetes)
Less commonly, the heart, kidneys, nerves, eyes, and joints
Timing: These reactions can occur at any point. They often appear within the first weeks to months of treatment, but sometimes occur many months later or even after treatment has ended. Some hormone-related effects, such as an underactive thyroid, may be permanent and require lifelong hormone replacement.
Most immune-related side effects can be managed when identified early, often with steroids and by pausing the drug, which is why prompt reporting of any new or unusual symptom to the cancer care team is emphasized during and after immunotherapy. Combining a CTLA-4 drug such as ipilimumab (Yervoy) with a PD-1 drug increases the chance of serious side effects compared with a PD-1 drug alone.
A special consideration: People who have had an organ transplant or who take medicines that suppress the immune system require individualized consideration, because immunotherapy can trigger organ rejection or flare autoimmune conditions.
Cutaneous Squamous Cell Carcinoma (Skin)
Cutaneous squamous cell carcinoma is a common skin cancer that is usually cured with surgery (see skin cancer treatments). Immunotherapy is used when the cancer is advanced, meaning it is too large or deep to remove surgically (locally advanced), has come back, or has spread, and when surgery or radiation cannot cure it.
Agents used: The PD-1 inhibitors cemiplimab (Libtayo) and pembrolizumab (Keytruda) are the main FDA-approved options for locally advanced or metastatic disease that cannot be cured with surgery or radiation. The PD-L1 inhibitor cosibelimab (Unloxcyt) is another approved option, and nivolumab (Opdivo) may also be used.
Situations in which they are used:
Locally advanced, recurrent, or metastatic disease not curable by surgery or radiation: cemiplimab (Libtayo) or pembrolizumab (Keytruda) are the preferred first choices.
After surgery (adjuvant): for certain very-high-risk tumors, cemiplimab (Libtayo) given after surgery and radiation can lower the chance of the cancer returning.
Before surgery (neoadjuvant): giving cemiplimab (Libtayo) first to shrink the tumor is used in selected cases and is being studied in clinical trials.
How well it works: About 45% to 50% of people with advanced disease have their tumors shrink significantly, and many of these responses last a long time. Response rates tend to be higher for tumors of the head and neck. In a large trial of cemiplimab (Libtayo) given after surgery and radiation for very-high-risk tumors, about 87% of patients were free of recurrence at 2 years, compared with about 64% of patients who received a placebo.
Mucosal Squamous Cell Carcinoma of the Head and Neck (Mouth, Throat, Voice Box)
Mucosal squamous cell carcinoma arises in the lining (mucosa) of the mouth, throat, and voice box (see also oral tumors and throat cancers). Treatment of these cancers usually centers on surgery and radiation, with or without chemotherapy (see head and neck tumor treatments). Immunotherapy is mainly used when the cancer has come back or has spread and can no longer be removed by surgery or radiation.
Agents used: The PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo).
Situations in which they are used:
First-line (recurrent or metastatic disease): pembrolizumab (Keytruda) is used either by itself (for tumors that make a protein called PD-L1) or combined with chemotherapy. The choice depends on a tumor test score called the combined positive score (CPS), which measures PD-L1 levels.
Later-line (after platinum chemotherapy stops working): either pembrolizumab (Keytruda) or nivolumab (Opdivo) can be given, regardless of PD-L1 status.
Around the time of curative surgery and radiation: research is now extending immunotherapy into this setting, but this is newer.
How well it works: Only a portion of patients respond, but those who do can have long-lasting benefit. In previously treated patients (CheckMate 141 trial), about 36% of those given nivolumab (Opdivo) were alive at one year, compared with about 17% of those given standard chemotherapy, and tumors shrank in about 13% versus 6%. In first-line treatment (KEYNOTE-048 trial), for tumors with high PD-L1 levels, median survival was about 15 months with pembrolizumab (Keytruda) compared with about 11 months with an older standard regimen. Across all patients in that trial, about 14% to 16% of those given pembrolizumab (Keytruda) (alone or with chemotherapy) were alive at 5 years, compared with about 5% to 7% with the older regimen.
Merkel Cell Carcinoma
Merkel cell carcinoma is a rare but aggressive skin cancer. It is often very sensitive to immunotherapy, which has become the main drug treatment for advanced disease.
Agents used: The PD-L1 inhibitor avelumab (Bavencio) and the PD-1 inhibitors pembrolizumab (Keytruda), nivolumab (Opdivo), and retifanlimab (Zynyz). The combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) is sometimes used.
Situations in which they are used:
Advanced (spread or metastatic) disease: avelumab (Bavencio), pembrolizumab (Keytruda), nivolumab (Opdivo), or retifanlimab (Zynyz) are all preferred single-drug options, used first-line.
Locally advanced or regional disease that cannot be cured by surgery or radiation: the same PD-1/PD-L1 drugs are used.
Before surgery (neoadjuvant): nivolumab (Opdivo) is an option in some cases.
If the cancer resists a PD-1/PD-L1 drug: adding ipilimumab (Yervoy) is sometimes tried.
How well it works: This cancer responds unusually well. Roughly 40% to 60% of people treated first with a PD-1 or PD-L1 drug have their tumors shrink, depending on the drug and study (about 40% with avelumab (Bavencio), about 58% with pembrolizumab (Keytruda), and about 46% to 52% with retifanlimab (Zynyz)), and in some patients the tumor disappears completely. Many responses are durable, with about 65% of patients alive at 2 years in pooled studies, which is a major improvement over older chemotherapy.
Melanoma
Melanoma is one of the most immune-responsive cancers, and immunotherapy is a cornerstone of treatment across many stages (see also melanoma treatments).
Agents used: The PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda); the CTLA-4 inhibitor ipilimumab (Yervoy) (usually combined with nivolumab (Opdivo)); and nivolumab combined with relatlimab (Opdualag), in which relatlimab blocks another checkpoint called LAG-3.
Situations in which they are used:
Advanced (unresectable or metastatic) disease: PD-1 drugs alone, nivolumab (Opdivo) plus ipilimumab (Yervoy), or nivolumab (Opdivo) plus relatlimab (Opdualag) are all first-line options.
After surgery (adjuvant): for melanoma at high risk of returning (certain stage II, III, and IV cases), pembrolizumab (Keytruda) or nivolumab (Opdivo) lower the chance of recurrence.
Before surgery (neoadjuvant): giving immunotherapy (often nivolumab (Opdivo) plus ipilimumab (Yervoy), or pembrolizumab (Keytruda)) before surgery is a newer, highly effective approach for melanoma that has spread to nearby lymph nodes.
How well it works: In advanced melanoma, roughly 40% to 50% of people respond to a PD-1 drug alone, and combinations can raise this further. In the CheckMate 067 trial of previously untreated advanced melanoma, about 43% of patients given nivolumab (Opdivo) plus ipilimumab (Yervoy) were alive at 10 years, compared with about 37% given nivolumab (Opdivo) alone and about 19% given ipilimumab (Yervoy) alone. In earlier-stage disease, giving immunotherapy before surgery has substantially reduced the chance of the cancer coming back compared with giving it only after surgery.
Thyroid Cancers
The role of immunotherapy depends heavily on the type of thyroid cancer, because these cancers differ greatly in how the immune system "sees" them.
Differentiated thyroid cancer (papillary, follicular, oncocytic): These cancers (see papillary and follicular thyroid carcinoma) are usually treated with surgery, radioactive iodine, and, when advanced, targeted pill medicines such as lenvatinib (Lenvima). Immunotherapy generally works poorly on its own here, because these tumors tend to be "cold" (not easily recognized by the immune system). Pembrolizumab (Keytruda) may be considered only in uncommon cases where special tumor testing shows features, such as high tumor mutation burden or mismatch-repair deficiency, that predict a response. It is also being studied in combination with targeted pills (for example, lenvatinib (Lenvima) plus pembrolizumab (Keytruda)) for cancer that has progressed.
Medullary thyroid cancer: This type is driven mainly by specific gene changes (RET), and the preferred drug treatments are targeted pill medicines rather than immunotherapy. Immunotherapy has shown only limited activity, mostly in rare tumors with a high mutation burden.
Anaplastic thyroid cancer: This is a rare, very aggressive thyroid cancer, but it is the thyroid cancer type most likely to respond to immunotherapy because it tends to be more "immune-visible." Options include pembrolizumab (Keytruda), nivolumab (Opdivo), the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo), and combinations of immunotherapy with targeted therapy. For tumors with a specific gene change (BRAF V600E), targeted pills, dabrafenib (Tafinlar) plus trametinib (Mekinist), are a standard treatment and are sometimes used together with immunotherapy.
How well it works: For differentiated and medullary thyroid cancers, immunotherapy alone helps only a small minority of patients (response rates roughly under 10%), so it is reserved for special situations or combinations. For anaplastic thyroid cancer, small studies show tumors shrinking in roughly 20% to 45% of patients treated with a PD-1 drug, with higher response rates when the tumor makes PD-L1 and about 36% with a lenvatinib (Lenvima) plus pembrolizumab (Keytruda) combination. These responses can be meaningful and sometimes durable, which is notable for a cancer that is otherwise very difficult to treat.
Key Points
Immunotherapy works by helping the immune system attack cancer, not by poisoning cancer cells directly.
It is used most often for advanced, recurrent, or spread cancers, but is increasingly given before or after surgery in melanoma and some skin cancers.
The main side effects come from the immune system attacking healthy organs; these can appear at any time, even after treatment ends.
How well it works varies a lot by cancer type: very effective in Merkel cell carcinoma, melanoma, and advanced skin squamous cell carcinoma; helpful in mucosal head and neck cancers; and limited for thyroid cancers except anaplastic thyroid cancer.
Prompt reporting of any new or unusual symptom to the cancer care team is emphasized during and after treatment.