Chemotherapy
Treatment / Immunotherapy

Immunotherapy

A branch of medicine that uses immune stimulating therapies (e.g. immune checkpoint inhibitors) to help the body’s own immune cells’ ability to recognize and destroy tumor cells.

Purpose of immunotherapy

Immunotherapy Immunotherapy A therapy that improves the function of the cells that recognize and destroy foreign objects in your body, such as a virus, bacteria or cancer. is a branch of medicine that uses therapies to augment the body’s own immune cells’ ability to recognize and destroy tumor cells. Immunotherapy is rapidly becoming a preferred systemic systemic Affecting the entire body. Compare to local. therapy in several cancer cancer A term used to describe diseases in which abnormal cells continually divide without normal regulation. Cancerous cells may invade surrounding tissues and may spread to other regions of the body via blood and the lymphatic system. types, especially because responses to immunotherapy (when they occur) are generally long-lasting. The durability of immunotherapy responses places this approach in stark contrast to chemotherapy chemotherapy Treatment with drugs to kill cancer cells or to render them less active. May be given intravenously or orally depending on the drug and situation. , which was previously considered the standard option for patients with metastatic metastatic Having to do with the spread of cancer from a primary site of origin to distant areas beyond the draining lymph nodes. MCC. One study of patients with metastatic MCC showed that while standard chemotherapy led to initial shrinkage of the tumors in the majority of patients, the shrinkage did not last long. By three months after starting chemotherapy, half of patients had recurrent growth of their tumors, and by ten months after starting chemotherapy, over 90% had tumor progression.1

MCC Immune Checkpoint Inhibitors (ICI)

While there are several therapies that can stimulate the immune system, the most promising emerging option includes a class of drugs called the immune checkpoint inhibitors immune checkpoint inhibitors Immune checkpoint inhibitors (ICIs) are therapies that turns on the immune system by blocking an inhibitor (a 'checkpoint') that normally restrains the immune system. Such agents can sometimes cause the immune system to recognize and destroy a cancer. (ICIs). Tumor cells escape the immune system by pressing “brakes” (like the PD-1 protein) on the surface of the killer immune cells. The ICIs block these brakes from getting pressed and allow immune cells to function better. There are several ICIs currently being investigated in MCC. Side effects for such agents may include problems that arise if the immune system damages other parts of the body.

A recent study looked at a type of ICI called pembrolizumab (brandname Keytruda), which was administered as an intravenous infusion every three weeks in the outpatient clinic to 26 patients with metastatic MCC, who had not received any prior systemic therapy. Of those patients, 56% had impressive shrinkage of their tumors. Patients with both virus-positive and virus-negative tumors responded to the treatment. Importantly, 86% of those who initially responded had long lasting responses, which were strikingly more durable than the chemotherapy responses (Nghiem et al, 2016). Based on this data, pembrolizumab was recently listed as a treatment option for patients with metastatic MCC in the 2017 NCCN NCCN National Comprehensive Cancer Network. The NCCN publishes annual consensus guidelines for the care of cancers, including MCC, based on expert opinion from all major cancer centers in the United States. guidelines. Pembrolizumab is approved by the US FDA for treatment of other cancers and can be prescribed by oncologists even outside of clinical trials, although coverage by insurance companies is not certain.

Avelumab, another ICI that also works by blocking the PD-1 pathway (it binds to a ligand of PD-1 called PD-L1), is an investigational drug that has also shown considerable promise in fighting MCC. This drug was tested in 88 patients with metastatic MCC who had previously been treated with chemotherapy, and whose tumors had then come back. These patients thus had especially difficult-to-treat tumors. Of the 88 patients treated, 28 (32%) responded with significant tumor shrinkage. As with pembrolizumab, the responses appeared to be strikingly more durable than chemotherapy responses, with over 80% of patients who initially responded to avelumab having impressively durable responses continuing beyond a year.2

Other ICIs, including nivolumab (brand name Opdivo) and ipilimumab (brand name YERVOY) are also in clinical trials in advanced MCC. In addition, there are several other immunotherapy approaches being investigated for MCC in clinical trials, including intra-tumoral injection approaches and infusion of immune cells (T-cells or Natural Killer cells). Initial results suggest a promising future for immunotherapies in the treatment of MCC.

Below is a list summarizing the ICIs used for MCC, their pharmaceutical manufacturer, and a description of the agent:

Ipilimumab (Yervoy)

  • Pharmaceutical company: Bristol-Myers Squibb
  • Description: Antibody Antibody A highly specific protein made by our bodies that can recognize and bind to an agent such as a bacteria or virus. against CTLA-4

Nivolumab (Opdivo)

  • Pharmaceutical company: Bristol-Myers Squibb
  • Description: Antibody against PD-1

Pembrolizumab (Keytruda)

  • Pharmaceutical company: Merck
  • Description: Antibody against PD-1

Avelumab

  • Pharmaceutical company: EMD Serono/Pfizer
  • Description: Antibody against PD-L1

The following diagrams provide additional information about immunotherapy and ICIs used for MCC:

the maximum percentage change in tumor size from base-line in response to Pembrolizumab.
The maximum percentage change in tumor size from base-line in response to Pembrolizumab. (Nghiem, et al, NEJM, 2016)
The rate of change in tumor size; rapid and durable shrinking was observed in most patients.
The rate of change in tumor size; rapid and durable shrinking was observed in most patients. (Nghiem, et al, NEJM, 2016)
The 16 patients who had initial response to treatment. Fourteen had confirmed response and 12 of those had a continued response at the end of the trial.
The 16 patients who had initial response to treatment. Fourteen had confirmed response and 12 of those had a continued response at the end of the trial. (Nghiem, et al, NEJM, 2016)
A “Waterfall plot” that depicts the best response of patients who received avelumab after having had traditional chemotherapy. Patients with the largest tumor shrinkages are on the right, patients with tumors that grew are on the left. Generally speaking, the right of the figure is more red, the left half tending to be more blue. This suggests that having had 2 or more prior types of chemotherapy may lower chances of response to an immune stimulator. From Kaufman, et al, Lancet Oncology.
A “Waterfall plot” that depicts the best response of patients who received avelumab after having had traditional chemotherapy. Patients with the largest tumor shrinkages are on the right, patients with tumors that grew are on the left. Generally speaking, the right of the figure is more red, the left half tending to be more blue. This suggests that having had two or more prior types of chemotherapy may lower chances of response to an immune stimulator. From Kaufman, et al, Lancet Oncology, 2016.

Who this works for

Patients with advanced MCC, such as those with distant metastases (stage IV) or MCC that cannot be removed surgically.

Who this doesn’t work for

Patients who have a suppressed immune system, which could be due to another cancer or uncontrolled HIV, or prior organ transplant or serious autoimmune disease that requires immunosuppressive drugs.

Side effects

Common side effects for immune checkpoint inhibitors include, but are not limited to, fatigue, cough, nausea, and itching. The vast majority of patients report good quality-of-life while receiving these drugs, which typically do not cause hair loss, nausea, vomiting, infections, etc., in striking contrast to the older chemotherapy options. However, ICIs can sometimes cause severe, life-threatening side-effects, related to immune attack against normal body organs. These include colitis (diarrhea), hepatitis (liver injury), pneumonitis (lung inflammation), hormone changes, nerve damage, etc. Close follow-up and contact with the treating oncologist is critical to avoid serious injury.

Often used in conjunction with

Radiation, T-cells

What to do next

Please visit the Clinical trials page and the National Institutes of Health’s website to learn more about active MCC clinical trials, their eligibility, and location sites.

FAQs

How could a patient get access to an Immune checkpoint inhibitor for MCC?

Immune checkpoint inhibitors are given through clinical trials, off-label, or compassionate use (where the pharmaceutical companies pay for the therapy).

What immune checkpoint inhibitors are FDA-approved for MCC?

There are currently no immune checkpoint inhibitors that are FDA-approved for treating MCC. However, this will most likely change in 2017. Pembrolizumab was recently listed as a treatment option for patients with metastatic MCC on the NCCN guidelines. This drug is approved by the US FDA for treatment of other cancers and can be prescribed by oncologists outside of clinical trials. Avelumab has received orphan drug and breakthrough drug status for its use in MCC.

Understand the Science

The following clinical publications and scientific research provide additional in-depth information about immunotherapy.

Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.

Cytotoxic chemotherapy is commonly used to treat advanced Merkel cell carcinoma (MCC). However, its efficacy in distant metastatic MCC patients is unclear, in part because most prior reports aggregated these patients with those receiving adjuvant chemotherapy and combined chemoradiation for whom pro...

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Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.

Background: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ul...

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PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is...

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