Guidelines Equip Patients to Understand Immunotherapy Side Effects

Immune checkpoint inhibitors have revolutionized the way some cancers are now treated. However, it should be noted that these treatments don’t come without potential and unique side effects.

To help educate patients and enable health care teams to effectively manage these side effects, the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) issued new guidelines on understanding and managing immunotherapy-related toxicities.

“It is important to have some consistency in practice across oncology and to get everyone on the same page for how to monitor these patients, what to look for, when patients do have symptoms, how to diagnose them, and finally, how to treat them,” Julie Brahmer, M.D., chair of the expert panel that developed the ASCO guideline, said in an interview with CURE.

How It Works

Because these therapies allow the immune system to attack cancer cells, this action may also allow it to attack normal cells in the organs or tissue.

“Most of the side effects actually relate to what we will call an over-stimulation of the immune system,” explained John A. Thompson, M.D., chair of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Panel on Management of Immunotherapy-Related Toxicity as well as co-chair of the expert panel that developed the ASCO guideline.

“The immune checkpoint inhibitor antibody treatments are administered intravenously, and these antibodies then trigger white blood cells in the patient to become more active and hopefully be more successful at killing cancer cells. As a byproduct, sometimes the activated immune system will attack healthy tissue, and that can lead to what we call autoimmune or self-toxicity.”

These side effects can occur at any time and involve multiple organs. Although they are most often mild, reactions that are severe, irreversible or even life-threatening can still occur. Serious side effects typically occur in less than 5 percent of patients, but certain mild side effects can occur in up to 30 to 50 percent of patients, according to the guidelines.

The most common side effects are rash, diarrhea, low thyroid hormone and fatigue, however, they can also include inflammation of the lung, intestines or liver, as well as hormonal abnormalities and kidney, heart or neurologic problems.

“Any symptoms that come and stay, [patients] definitely need to talk with their treatment team in order for the team to try to tease out what is due to their cancer and what is due to the treatment, or what is due to other symptoms,” said Brahmer, who is also the Director of the Thoracic Oncology Program and Associate Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

The currently FDA-approved therapies include Tecentriq (atezolizumab), Bavencio (avelumab), Imfinzi (durvalumab), Yervoy (ipilimumab), Opdivo (nivolumab) and Keytruda (pembrolizumab) for various cancers, including melanoma, Hodgkin lymphoma, and lung, liver, kidney and bladder cancers.

Guidelines for Patients, Physicians

To develop these guidelines, both organizations organized multidisciplinary panels comprised of representatives from medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine and nursing, as well as patient advocacy experts. The panels conducted systemic literature reviews and an informal consensus process.

For health care teams, the key guideline recommendations included the following:

• Checkpoint inhibitors can be continued with close monitoring for mild, or grade 1 toxicities, except for neurologic and some hematologic toxicities;
• For moderate, or grade 2 toxicities, checkpoint inhibitors should be held until symptoms and/or lab values revert to grade 1 levels or lower; and corticosteroids may be offered;
• For severe, or grade 3 toxicities, patients should be treated with high-dose corticosteroids for at least six weeks; and if immunotherapy is restarted at all, physicians should move forward with extreme caution; and
• For very severe, or grade 4 toxicities, patients should no longer receive checkpoint inhibitor therapy.

In addition, patients and physicians may consult the guidelines to learn more about how checkpoint inhibitors may directly affect each organ of the body.

For patients, Thompson — who is also Co-Director of the Seattle Cancer Care Alliance Melanoma Clinic at Fred Hutchinson Cancer Research Center – recommends for patients to be very open with their health care teams regarding these side effects.

“I frequently advise my patients that we would rather hear from them more rather than less in terms of any side effects that the patients are experiencing because sometimes the early side effects that they experience may be a sign of a potentially serious immune toxicity that is brewing,” he said. “The sooner we can diagnose that, the sooner we can talk with the patient and advise the patient, the better off we are in terms of controlling that side effect.”

Patient Perspective

After seeing strange spots on the bottom of his foot, David Dunnington had them biopsied in February of 2012, all to learn that he had stage 3 acral lentiginous melanoma — a rare type of skin cancer.

Following his diagnosis, Dunnington’s treatment journey included multiple surgeries, a variety of systemic therapies and radiation, as well as an isolated limb profusion. All of which induced serious side effects for him.

After receiving high doses of interleukin 2, Dunnington experienced atrial fibrillation and had to once again discontinue his treatment regimen. However, after being sent home, he received a phone call from Dr. Thompson that would forever change his life.

In July 2013, Dunnington entered the phase 3 MK3475 study, sponsored by Merck, where he would either receive a standard of care drug or a high or low dose of MK-3475 — now known as Keytruda.

After receiving treatment, Dunnington said he experienced very few side effects compared to those he experienced with previous treatment. In addition, he saw progress within weeks, as his tumors had reduced by almost half just three to six weeks following his first cycle.

What Dunnington did not realize was how long this effect would actually last for him.

“What I didn’t know at that point was the durability,” he added. “Dr. Thompson said out of 100 patients, 20 will have a response like I did, out of those 20, 1.5 people would have a durable response, and evidently, I am one of those 1.5 because I haven’t had any cancer for four years just about.”

As a patient advocate, Dunnington recommends for patients to ensure their health care teams have multiple plans in place.

“Work with a doctor who can start with one approach, and if it isn’t going to work, already have the second one, in terms of looking for applications for a trial or some other plan so that if the one you’re taking doesn’t work you have a second and third option,” he said.

In addition, he urges patients to keep close communication with their health care teams. “Everyone responds to drugs differently, so it is about being in close communication with your oncologist. If you’re feeling like you are having symptoms that are well beyond what your oncologist said you should be having, you should call him or her immediately and not wait.”

At the end of the day, despite these potential side effects, patients and physicians have a lot to look forward to when it comes to immune checkpoint inhibitors moving forward.

“The good news is that the immune checkpoint inhibitors represent a new category of therapy that is, in some diseases, offering good responses and prolongation of survival in areas where we did not see progress before,” said Thompson. “So, overall this is a big step forward for oncology, but it does pose these side effect risks, so we have to educate our patients about those.”